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Malignancy grading, pattern of invasion, and juxtatumoral stromal response (desmoplastic change) in squamous cell carcinoma of the uterine cervix.
ProstataCA

Abstract

Not specified

Authors: L. C. Horn, B. Hentschel, U. D. Braumann

Date Published: 30th Aug 2008

Publication Type: Not specified

Human Diseases: cervical cancer

Management of ARDS: From ventilation strategies to intelligent technical support – Connecting the dots
SMITH - Smart Medical Information Technology for Healthcare

Abstract

Not specified

Authors: Julian Kunze, Sebastian Fritsch, Arne Peine, Oliver Maaßen, Gernot Marx, Johannes Bickenbach

Date Published: 1st May 2020

Publication Type: Journal article

Management von Informationssystemen: Analyse, Bewertung, Auswahl, Bereitstellung und Einführung von Informationssystemkomponenten am Beispiel von Krankenhausinformationssystemen
Management of health information systems

Abstract

Not specified

Authors: Reinhold Haux, A. Lagemann, Petra Knaup-Gregori, P. Schmücker, Alfred Winter

Date Published: 1998

Publication Type: Book

Manifest: Kundeninduzierte Orchestrierung komplexer Dienstleistungen - Gestaltung eines Paradigmenwechsels
Management of health information systems

Abstract

Not specified

Authors: Alfred Winter, Rainer Alt, Jan Ehmke, Reinhold Haux, Wolfram Ludwig, Dirk Mattfeld, Andreas Oberweis, Barbara Paech

Date Published: 1st Dec 2012

Publication Type: Journal article

Manifest: Strategische Bedeutung des Software Engineering für die Medizin
Management of health information systems

Abstract

Not specified

Authors: Sabine Glesner, Stefan Jähnichen, Barbara Paech, Bernhard Rumpe, Thomas Wetter, Alfred Winter

Date Published: 2008

Publication Type: Journal article

Mapping heterogeneity in patient-derived melanoma cultures by single-cell RNA-seq.
Leipzig Melanoma Studies

Abstract (Expand)

Recent technological advances in single-cell genomics make it possible to analyze cellular heterogeneity of tumor samples. Here, we applied single-cell RNA-seq to measure the transcriptomes of 307 … single cells cultured from three biopsies of three different patients with a BRAF/NRAS wild type, BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant melanoma metastasis, respectively. Analysis based on self-organizing maps identified sub-populations defined by multiple gene expression modules involved in proliferation, oxidative phosphorylation, pigmentation and cellular stroma. Gene expression modules had prognostic relevance when compared with gene expression data from published melanoma samples and patient survival data. We surveyed kinome expression patterns across sub-populations of the BRAF/NRAS wild type sample and found that CDK4 and CDK2 were consistently highly expressed in the majority of cells, suggesting that these kinases might be involved in melanoma progression. Treatment of cells with the CDK4 inhibitor palbociclib restricted cell proliferation to a similar, and in some cases greater, extent than MAPK inhibitors. Finally, we identified a low abundant sub-population in this sample that highly expressed a module containing ABC transporter ABCB5, surface markers CD271 and CD133, and multiple aldehyde dehydrogenases (ALDHs). Patient-derived cultures of the BRAF mutant/NRAS wild type and BRAF wild type/NRAS mutant metastases showed more homogeneous single-cell gene expression patterns with gene expression modules for proliferation and ABC transporters. Taken together, our results describe an intertumor and intratumor heterogeneity in melanoma short-term cultures which might be relevant for patient survival, and suggest promising targets for new treatment approaches in melanoma therapy.

Authors: T. Gerber, E. Willscher, H. Loeffler-Wirth, L. Hopp, D. Schadendorf, M. Schartl, U. Anderegg, G. Camp, B. Treutlein, H. Binder, M. Kunz

Date Published: 3rd Jan 2017

Publication Type: Not specified

Human Diseases: melanoma

Markov State Modelling of Disease Courses and Mortality Risks of Patients with Community-Acquired Pneumonia
Genetical Statistics and Systems Biology

Abstract (Expand)

Community-acquired pneumonia (CAP) is one of the most frequent infectious diseases worldwide, with high lethality. Risk evaluation is well established at hospital admission, and re-evaluation is advised … for patients at higher risk. However, severe disease courses may develop from all levels of severity. We propose a stochastic continuous-time Markov model describing daily development of time courses of CAP severity. Disease states were defined based on the Sequential Organ Failure Assessment (SOFA) score. Model calibration was based on longitudinal data from 2838 patients with a primary diagnosis of CAP from four clinical studies (PROGRESS, MAXSEP, SISPCT, VISEP). We categorized CAP severity into five disease states and estimated transition probabilities for CAP progression between these states and corresponding sojourn times. Good agreement between model predictions and clinical data was observed. Time courses of mortality were correctly predicted for up to 28 days, including validation with patient data not used for model calibration. We conclude that CAP disease course follows a Markov process, suggesting the necessity of daily monitoring and re-evaluation of patient’s risk. Our model can be used for regular updates of risk assessments of patients and could improve the design of clinical trials by estimating transition rates for different risk groups.

Authors: Jens Przybilla, Peter Ahnert, Holger Bogatsch, Frank Bloos, Frank M. Brunkhorst, Critical Care Trials Group SepNet, Study Group Progress, Michael Bauer, Markus Loeffler, Martin Witzenrath, Norbert Suttorp, Markus Scholz

Date Published: 1st Feb 2020

Publication Type: Journal article

Massive transcriptional perturbation in subgroups of diffuse large B-cell lymphomas.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

Based on the assumption that molecular mechanisms involved in cancerogenesis are characterized by groups of coordinately expressed genes, we developed and validated a novel method for analyzing … transcriptional data called Correlated Gene Set Analysis (CGSA). Using 50 extracted gene sets we identified three different profiles of tumors in a cohort of 364 Diffuse large B-cell (DLBCL) and related mature aggressive B-cell lymphomas other than Burkitt lymphoma. The first profile had high level of expression of genes related to proliferation whereas the second profile exhibited a stromal and immune response phenotype. These two profiles were characterized by a large scale gene activation affecting genes which were recently shown to be epigenetically regulated, and which were enriched in oxidative phosphorylation, energy metabolism and nucleoside biosynthesis. The third and novel profile showed only low global gene activation similar to that found in normal B cells but not cell lines. Our study indicates novel levels of complexity of DLBCL with low or high large scale gene activation related to metabolism and biosynthesis and, within the group of highly activated DLBCLs, differential behavior leading to either a proliferative or a stromal and immune response phenotype.

Authors: M. Rosolowski, J. Lauter, D. Abramov, H. G. Drexler, M. Hummel, W. Klapper, R. A. Macleod, S. Pellissery, F. Horn, R. Siebert, M. Loeffler

Date Published: 14th Nov 2013

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls
Genetical Statistics and Systems Biology

Abstract (Expand)

Many genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. … Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes.

Authors: Esther Walton, Jingyu Liu, Johanna Hass, Tonya White, Markus Scholz, Veit Roessner, Randy Gollub, Vince D. Calhoun, Stefan Ehrlich

Date Published: 6th May 2014

Publication Type: Journal article

Measurement of cerebral biomarkers proving traumatic brain injuries in post-mortem body fluids
Genetical Statistics and Systems Biology

Abstract (Expand)

Until now, it is impossible to identify a fatal traumatic brain injury (TBI) before post-mortem radiological investigations or an autopsy take place. It would be preferable to have an additional … diagnostic tool like post-mortem biochemistry to get greater insight into the pathological pathways and survival times after sustaining TBI. Cerebrospinal fluid (CSF) and serum samples of 84 autopsy cases were collected from forensic autopsies with post-mortem intervals (PMI) of up to 148 h. The cases were categorized into a fatal TBI case group (n=42) and non-TBI controls (n=42). The values of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and neutrophil gelatinase-associated lipocalin (NGAL) were analyzed by means of quantitative chemiluminescent multiplex immunoassays. The main results indicate that the usage of liquid samples with good macroscopic quality is more relevant for meaningful biomarker analyses than the length of the PMI. All three proteins were shown to differentiate TBI fatalities from the controls in CSF. In serum, only GFAP could be shown to be able to identify TBI cases. This study is the first approach to measure the three proteins together in CSF and serum in autopsy cases. Determined threshold values may differentiate between fatal TBI and control cases. The presented results emphasize the possible use of post-mortem biochemistry as a supplemental tool in everyday forensic routine.

Authors: Benjamin Ondruschka, Monique Sieber, Holger Kirsten, Heike Franke, Jan Dressler

Date Published: 1st Sep 2018

Publication Type: Journal article

Medical informatics education needs information system practicums in health care settings–experiences and lessons learned from 32 practicums at four universities in two countries
Management of health information systems

Abstract (Expand)

OBJECTIVES: To report about the themes and about experiences with practicums in the management of information systems in health care settings (health information management) for medical informatics … students. METHODS: We first summarize the topics of the health information management practicums/projects that the authors organized between 1990 and 2003 for the medical informatics programs at Heidelberg/Heilbronn, Germany, UMIT, Austria, as well as for the informatics program at the University of Leipzig, Germany. Experiences and lessons learned, obtained from the faculty that organized the practicums in the past 14 years, are reported. RESULTS: Thirty (of 32) health information management practicums focused on the analysis of health information systems. These took place inside university medical centers. Although the practicums were time-intensive and required intensively tutoring students with regard to health information management and project management, feedback from the students and graduates was mainly positive. DISCUSSION: It is clearly recommended that students specializing in medical informatics need to be confronted with real-world problems of health information systems during their studies.

Authors: Reinhold Haux, Elske Ammenwerth, A. Haber, Gudrun Hübner-Bloder, Petra Knaup-Gregori, G. Lechleitner, F. Leiner, R. Weber, Alfred Winter, A. C. Wolff

Date Published: 2006

Publication Type: Journal article

Medical Information Extraction in the age of Deep Learning
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

OBJECTIVES: We survey recent developments in medical Information Extraction (IE) as reported in the literature from the past three years. Our focus is on the fundamental methodological paradigm shift … from standard Machine Learning (ML) techniques to Deep Neural Networks (DNNs). We describe applications of this new paradigm concentrating on two basic IE tasks, named entity recognition and relation extraction, for two selected semantic classes-diseases and drugs (or medications)-and relations between them. METHODS: For the time period from 2017 to early 2020, we searched for relevant publications from three major scientific communities: medicine and medical informatics, natural language processing, as well as neural networks and artificial intelligence. RESULTS: In the past decade, the field of Natural Language Processing (NLP) has undergone a profound methodological shift from symbolic to distributed representations based on the paradigm of Deep Learning (DL). Meanwhile, this trend is, although with some delay, also reflected in the medical NLP community. In the reporting period, overwhelming experimental evidence has been gathered, as illustrated in this survey for medical IE, that DL-based approaches outperform non-DL ones by often large margins. Still, small-sized and access-limited corpora create intrinsic problems for data-greedy DL as do special linguistic phenomena of medical sublanguages that have to be overcome by adaptive learning strategies. CONCLUSIONS: The paradigm shift from (feature-engineered) ML to DNNs changes the fundamental methodological rules of the game for medical NLP. This change is by no means restricted to medical IE but should also deeply influence other areas of medical informatics, either NLP- or non-NLP-based.

Authors: Udo Hahn, Michel Oleynik

Date Published: 1st Aug 2020

Publication Type: Journal article

Medical Information Extraction in the Age of Deep Learning
SMITH - Smart Medical Information Technology for Healthcare

Abstract

Not specified

Authors: Udo Hahn, Michel Oleynik

Date Published: 21st Aug 2020

Publication Type: Journal article

Medical multivariate time series imputation and forecasting based on a recurrent conditional Wasserstein GAN and attention
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

OBJECTIVE: In the fields of medical care and research as well as hospital management, time series are an important part of the overall data basis. To ensure high quality standards and enable suitable … decisions, tools for precise and generic imputations and forecasts that integrate the temporal dynamics are of great importance. Since forecasting and imputation tasks involve an inherent uncertainty, the focus of our work lay on a probabilistic multivariate generative approach that samples infillings or forecasts from an analysable distribution rather than producing deterministic results. MATERIALS AND METHODS: For this task, we developed a system based on generative adversarial networks that consist of recurrent encoders and decoders with attention mechanisms and can learn the distribution of intervals from multivariate time series conditioned on the periods before and, if available, periods after the values that are to be predicted. For training, validation and testing, a data set of jointly measured blood pressure series (ABP) and electrocardiograms (ECG) (length: 1,250=ˆ10s) was generated. For the imputation tasks, one interval of fixed length was masked randomly and independently in both channels of every sample. For the forecasting task, all masks were positioned at the end. RESULTS: The models were trained on around 65,000 bivariate samples and tested against 14,000 series of different persons. For the evaluation, 50 samples were produced for every masked interval to estimate the range of the generated infillings or forecasts. The element-wise arithmetic average of these samples served as an estimator for the mean of the learned conditional distribution. The approach showed better results than a state-of-the-art probabilistic multivariate forecasting mechanism based on Gaussian copula transformation and recurrent neural networks. On the imputation task, the proposed method reached a mean squared error (MSE) of 0.057 on the ECG channel and an MSE of 28.30 on the ABP channel, while the baseline approach reached MSEs of 0.095 (ECG) and 229.1 (ABP). Moreover, on the forecasting task, the presented system achieved MSEs of 0.069 (ECG) and 33.73 (ABP), outperforming the recurrent copula approach, which reached MSEs of 0.082 (ECG) and 196.53 (ABP). CONCLUSION: The presented generative probabilistic system for the imputation and forecasting of (medical) time series features the flexibility to handle masks of different sizes and positions, the ability to quantify uncertainty due to its probabilistic predictions, and an adjustable trade-off between the goals of minimising errors in individual predictions and minimising the distance between the learned and the real conditional distribution of the infillings or forecasts.

Authors: Sven Festag, Cord Spreckelsen

Date Published: 1st Feb 2023

Publication Type: Journal article

Medical students’ attitudes and wishes towards extending an educational general practice app to be suitable for practice: A cross-sectional survey from Leipzig, Germany
Management of health information systems

Abstract

Not specified

Authors: Maximilian Sandholzer, Tobias Deutsch, Thomas Frese, Alfred Winter

Date Published: 2nd Apr 2016

Publication Type: Journal article

Medizinische Informatik im Krankenhaus
Management of health information systems

Abstract

Not specified

Authors: Reinhold Haux, Alfred Winter

Date Published: 1993

Publication Type: Journal article

Medizinische Informatik – Perspektiven einer wissenschaftlichen Disziplin
Management of health information systems

Abstract

Not specified

Authors: Alfred Winter, Michael Marschollek

Date Published: 2013

Publication Type: Journal article

MEK inhibitor cobimetinib rescues a dRaf mutant lethal phenotype in Drosophila melanogaster
Genetical Statistics and Systems Biology

Abstract (Expand)

Since Drosophila melanogaster has proven to be a useful model system to study phenotypes of oncogenic mutations and to identify new anti-cancer drugs, we generated human BRAFV600E homologous dRaf mutant … (dRaf A572E ) Drosophila melanogaster strains to use these for characterization of mutant phenotypes and exploit these phenotypes for drug testing. For mutant gene expression, the GAL4/UAS expression system was used. dRaf A572E was expressed tissue-specific in the eye, epidermis, heart, wings, secretory glands and in the whole animal. Expression of dRaf A572E under the control of an eye-specific driver led to semi-lethality and a rough eye phenotype. tumor, genetics, molecular biology, BRAF, small molecule inhibitors The vast majority of other tissue-specific and ubiquitous drivers led to a lethal phenotype only. The rough eye phenotype was used to test BRAF inhibitor vemurafenib and MEK1/2 inhibitor cobimetinib. There was no phenotype rescue by this treatment. However, a significant rescue of the lethal phenotype was observed under a gut-specific driver. Here, MEK1/2 inhibitor cobimetinib rescued Drosophila larvae to reach pupal stage in 37% of cases as compared to 1% in control experiments. Taken together, the BRAFV600E homolog dRaf A572E exerts mostly lethal effects in Drosophila. Gut-specific dRaf A572E expression might in future be developed further for drug testing. This article is protected by copyright. All rights reserved.

Authors: Isabelle Pfeifle, Jens Bohnekamp, Anna Volkhardt, Holger Kirsten, Astrid Rohwedder, Andreas Thum, Thomas M. Magin, Manfred Kunz

Date Published: 1st Aug 2019

Publication Type: Journal article

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. …. METHODS We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction \textless 0.05). CONCLUSION Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

Authors: Frank Qian, Matti A. Rookus, Goska Leslie, Harvey A. Risch, Mark H. Greene, Cora M. Aalfs, Muriel A. Adank, Julian Adlard, Bjarni A. Agnarsson, Munaza Ahmed, Kristiina Aittomäki, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Margreet G. E. M. Ausems, Jacopo Azzollini, Daniel Barrowdale, Julian Barwell, Javier Benitez, Katarzyna Białkowska, Valérie Bonadona, Julika Borde, Ake Borg, Angela R. Bradbury, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Jonathan Carter, Jocelyne Chiquette, Wendy K. Chung, Kathleen B. M. Claes, J. Margriet Collée, Marie-Agnès Collonge-Rame, Fergus J. Couch, Mary B. Daly, Capucine Delnatte, Orland Diez, Susan M. Domchek, Cecilia M. Dorfling, Jacqueline Eason, Douglas F. Easton, Ros Eeles, Christoph Engel, D. Gareth Evans, Laurence Faivre, Lidia Feliubadaló, Lenka Foretova, Eitan Friedman, Debra Frost, Patricia A. Ganz, Judy Garber, Vanesa Garcia-Barberan, Andrea Gehrig, Gord Glendon, Andrew K. Godwin, Encarna B. Gómez Garcia, Ute Hamann, Jan Hauke, John L. Hopper, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Anna Jakubowska, Ramunas Janavicius, Esther M. John, Beth Y. Karlan, Carolien M. Kets, Yael Laitman, Conxi Lázaro, Dominique Leroux, Jenny Lester, Fabienne Lesueur, Jennifer T. Loud, Jan Lubiński, Alicja Łukomska, Lesley McGuffog, Noura Mebirouk, Hanne E. J. Meijers-Heijboer, Alfons Meindl, Austin Miller, Marco Montagna, Thea M. Mooij, Emmanuelle Mouret-Fourme, Katherine L. Nathanson, Bita Nehoray, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Kenneth Offit, Edith Olah, Kai-Ren Ong, Jan C. Oosterwijk, Laura Ottini, Michael T. Parsons, Paolo Peterlongo, Georg Pfeiler, Nisha Pradhan, Paolo Radice, Susan J. Ramus, Johanna Rantala, Gad Rennert, Mark Robson, Gustavo C. Rodriguez, Ritu Salani, Maren T. Scheuner, Rita K. Schmutzler, Payal D. Shah, Lucy E. Side, Jacques Simard, Christian F. Singer, Doris Steinemann, Dominique Stoppa-Lyonnet, Yen Yen Tan, Manuel R. Teixeira, Mary Beth Terry, Mads Thomassen, Marc Tischkowitz, Silvia Tognazzo, Amanda E. Toland, Nadine Tung, Christi J. van Asperen, Klaartje van Engelen, Elizabeth J. van Rensburg, Laurence Venat-Bouvet, Jeroen Vierstraete, Gabriel Wagner, Lisa Walker, Jeffrey N. Weitzel, Drakoulis Yannoukakos, Antonis C. Antoniou, David E. Goldgar, Olufunmilayo I. Olopade, Georgia Chenevix-Trench, Timothy R. Rebbeck, Dezheng Huo

Date Published: 1st Jul 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood.
Genetical Statistics and Systems Biology

Abstract (Expand)

Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we … evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genome-wide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (\textgreekb = - 0.76, 95% CI - 2.45 to 1.08 mmHg), 0.06 mmHg lower diastolic blood pressure (\textgreekb = - 0.06, 95% CI - 0.93 to 0.87 mmHg), or pulse pressure (\textgreekb = - 0.65, 95% CI - 1.38 to 0.69 mmHg, all p \textgreater 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.

Authors: Yan Zheng, Tao Huang, Tiange Wang, Zhendong Mei, Zhonghan Sun, Tao Zhang, Christina Ellervik, Jin-Fang Chai, Xueling Sim, Rob M. van Dam, E-Shyong Tai, Woon-Puay Koh, Rajkumar Dorajoo, Seang-Mei Saw, Charumathi Sabanayagam, Tien Yin Wong, Preeti Gupta, Peter Rossing, Tarunveer S. Ahluwalia, Rebecca K. Vinding, Hans Bisgaard, Klaus Bønnelykke, Yujie Wang, Mariaelisa Graff, Trudy Voortman, Frank J. A. van Rooij, Albert Hofman, Diana van Heemst, Raymond Noordam, Angela C. Estampador, Tibor V. Varga, Cornelia Enzenbach, Markus Scholz, Joachim Thiery, Ralph Burkhardt, Marju Orho-Melander, Christina-Alexandra Schulz, Ulrika Ericson, Emily Sonestedt, Michiaki Kubo, Masato Akiyama, Ang Zhou, Tuomas O. Kilpeläinen, Torben Hansen, Marcus E. Kleber, Graciela Delgado, Mark McCarthy, Rozenn N. Lemaitre, Janine F. Felix, Vincent W. V. Jaddoe, Ying Wu, Karen L. Mohlke, Terho Lehtimäki, Carol A. Wang, Craig E. Pennell, Heribert Schunkert, Thorsten Kessler, Lingyao Zeng, Christina Willenborg, Annette Peters, Wolfgang Lieb, Veit Grote, Peter Rzehak, Berthold Koletzko, Jeanette Erdmann, Matthias Munz, Tangchun Wu, Meian He, Caizheng Yu, Cécile Lecoeur, Philippe Froguel, Dolores Corella, Luis A. Moreno, Chao-Qiang Lai, Niina Pitkänen, Colin A. Boreham, Paul M. Ridker, Frits R. Rosendaal, Renée de Mutsert, Chris Power, Lavinia Paternoster, Thorkild I. A. Sørensen, Anne Tjønneland, Kim Overvad, Luc Djousse, Fernando Rivadeneira, Nanette R. Lee, Olli T. Raitakari, Mika Kähönen, Jorma Viikari, Jean-Paul Langhendries, Joaquin Escribano, Elvira Verduci, George Dedoussis, Inke König, Beverley Balkau, Oscar Coltell, Jean Dallongeville, Aline Meirhaeghe, Philippe Amouyel, Frédéric Gottrand, Katja Pahkala, Harri Niinikoski, Elina Hyppönen, Winfried März, David A. Mackey, Dariusz Gruszfeld, Katherine L. Tucker, Frédéric Fumeron, Ramon Estruch, Jose M. Ordovas, Donna K. Arnett, Dennis O. Mook-Kanamori, Dariush Mozaffarian, Bruce M. Psaty, Kari E. North, Daniel I. Chasman, Lu Qi

Date Published: 7th May 2020

Publication Type: Journal article

Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnHematopoiesis is a complex process involving different cell types and feedback mechanisms mediated by cytokines. This complexity stimulated various models with different … scopes and applications. A combination of complementary models promises to provide their mutual confirmation and to explain a broader range of scenarios. Here we propose a combination of an ordinary differential equation (ODE) model of human granulopoiesis and an agent-based model (ABM) of hematopoietic stem cell (HSC) organization. The first describes the dynamics of bone marrow cell stages and circulating cells under various perturbations such as G-CSF treatment or chemotherapy. In contrast to the ODE model describing cell numbers, our ABM focuses on the organization of individual cells in the stem population.\backslashr\backslashnRESULTS\backslashr\backslashnWe combined the two models by replacing the HSC compartment of the ODE model by a difference equation formulation of the ABM. In this hybrid model, regulatory mechanisms and parameters of the original models were kept unchanged except for a few specific improvements: (i) Effect of chemotherapy was restricted to proliferating HSC and (ii) HSC regulation in the ODE model was replaced by the intrinsic regulation of the ABM. Model simulations of bleeding, chronic irradiation and stem cell transplantation revealed that the dynamics of hybrid and ODE model differ markedly in scenarios with stem cell damage. Despite these differences in response to stem cell damage, both models explain clinical data of leukocyte dynamics under four chemotherapy regimens.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnABM and ODE model proved to be compatible and were combined without altering the structure of both models. The new hybrid model introduces model improvements by considering the proliferative state of stem cells and enabling a cell cycle-dependent effect of chemotherapy. We demonstrated that it is able to explain and predict granulopoietic dynamics for a large variety of scenarios such as irradiation, bone marrow transplantation, chemotherapy and growth factor applications. Therefore, it promises to serve as a valuable tool for studies in a broader range of clinical applications, in particular where stem cell activation and proliferation are involved.

Authors: Axel Krinner, Ingo Roeder, Markus Loeffler, Markus Scholz

Date Published: 2013

Publication Type: Journal article

Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline.
LIFE Adult, Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for … rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

Authors: M. Gorski, B. Jung, Y. Li, P. R. Matias-Garcia, M. Wuttke, S. Coassin, C. H. L. Thio, M. E. Kleber, T. W. Winkler, V. Wanner, J. F. Chai, A. Y. Chu, M. Cocca, M. F. Feitosa, S. Ghasemi, A. Hoppmann, K. Horn, M. Li, T. Nutile, M. Scholz, K. B. Sieber, A. Teumer, A. Tin, J. Wang, B. O. Tayo, T. S. Ahluwalia, P. Almgren, S. J. L. Bakker, B. Banas, N. Bansal, M. L. Biggs, E. Boerwinkle, E. P. Bottinger, H. Brenner, R. J. Carroll, J. Chalmers, M. L. Chee, M. L. Chee, C. Y. Cheng, J. Coresh, M. H. de Borst, F. Degenhardt, K. U. Eckardt, K. Endlich, A. Franke, S. Freitag-Wolf, P. Gampawar, R. T. Gansevoort, M. Ghanbari, C. Gieger, P. Hamet, K. Ho, E. Hofer, B. Holleczek, V. H. Xian Foo, N. Hutri-Kahonen, S. J. Hwang, M. A. Ikram, N. S. Josyula, M. Kahonen, C. C. Khor, W. Koenig, H. Kramer, B. K. Kramer, B. Kuhnel, L. A. Lange, T. Lehtimaki, W. Lieb, R. J. F. Loos, M. A. Lukas, L. P. Lyytikainen, C. Meisinger, T. Meitinger, O. Melander, Y. Milaneschi, P. P. Mishra, N. Mononen, J. C. Mychaleckyj, G. N. Nadkarni, M. Nauck, K. Nikus, B. Ning, I. M. Nolte, M. L. O'Donoghue, M. Orho-Melander, S. A. Pendergrass, B. W. J. H. Penninx, M. H. Preuss, B. M. Psaty, L. M. Raffield, O. T. Raitakari, R. Rettig, M. Rheinberger, K. M. Rice, A. R. Rosenkranz, P. Rossing, J. I. Rotter, C. Sabanayagam, H. Schmidt, R. Schmidt, B. Schottker, C. A. Schulz, S. Sedaghat, C. M. Shaffer, K. Strauch, S. Szymczak, K. D. Taylor, J. Tremblay, L. Chaker, P. van der Harst, P. J. van der Most, N. Verweij, U. Volker, M. Waldenberger, L. Wallentin, D. M. Waterworth, H. D. White, J. G. Wilson, T. Y. Wong, M. Woodward, Q. Yang, M. Yasuda, L. M. Yerges-Armstrong, Y. Zhang, H. Snieder, C. Wanner, C. A. Boger, A. Kottgen, F. Kronenberg, C. Pattaro, I. M. Heid

Date Published: 30th Oct 2020

Publication Type: Journal article

Metabolite-Investigator: an integrated user-friendly workflow for metabolomics multi-study analysis
Genetical Statistics and Systems Biology

Abstract (Expand)

Motivation Many diseases have a metabolic background, which is increasingly investigated due to improved measurement techniques allowing high-throughput assessment of metabolic features in several body … fluids. Integrating data from multiple cohorts is of high importance to obtain robust and reproducible results. However, considerable variability across studies due to differences in sampling, measurement techniques and study populations needs to be accounted for. Results We present Metabolite-Investigator, a scalable analysis workflow for quantitative metabolomics data from multiple studies. Our tool supports all aspects of data pre-processing including data integration, cleaning, transformation, batch analysis as well as multiple analysis methods including uni- and multivariable factor-metabolite associations, network analysis and factor prioritization in one or more cohorts. Moreover, it allows identifying critical interactions between cohorts and factors affecting metabolite levels and inferring a common covariate model, all via a graphical user interface. Availability and implementation We constructed Metabolite-Investigator as a free and open web-tool and stand-alone Shiny-app. It is hosted at https://apps.health-atlas.de/metabolite-investigator/, the source code is freely available at https://github.com/cfbeuchel/Metabolite-Investigator. Supplementary information Supplementary data are available at Bioinformatics online.

Authors: Carl Beuchel, Holger Kirsten, Uta Ceglarek, Markus Scholz

Date Published: 16th Nov 2020

Publication Type: Journal article

Metadata Management for Data Integration in Medical Sciences - Experiences from the LIFE Study -
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Clinical and epidemiological studies are commonly used in medical sciences. They typically collect data by using different input forms and information systems. Metadata describing input forms, database … schemas and input systems are used for data integration but are typically distributed over different software tools; each uses portions of metadata, such as for loading (ETL), data presentation and analysis. In this paper, we describe an approach managing metadata centrally and consistently in a dedicated Metadata Repository (MDR). Metadata can be provided to different tools. Moreover, the MDR includes a matching component creating schema mappings as a prerequisite to integrate captured medical data. We describe the approach, the MDR infrastructure and provide algorithms for creating schema mappings. Finally, we show selected evaluation results. The MDR is fully operational and used to integrate data from a multitude of input forms and systems in the epidemiological study LIFE.

Authors: Toralf Kirsten, A. Kiel, M. Rühle, J.Wagner

Date Published: 2nd Mar 2017

Publication Type: Not specified

Method and Tool to support the Management of Heterogenous Hospital Information Systems
Management of health information systems

Abstract

Not specified

Authors: Anke Buchauer, Elske Ammenwerth, Alfred Winter, Reinhold Haux

Date Published: 1997

Publication Type: InCollection

Methodenpluralismus in der Wirtschaftsinformatik?
Management of health information systems

Abstract

Not specified

Authors: Peter Loos, Tobias Mettler, Robert Winter, Matthias Goeken, Ulrich Frank, Alfred Winter

Date Published: 1st Dec 2013

Publication Type: Journal article

Methodische Erweiterungen und Anwendung des graphenbasierten Drei-Ebenen-Modells
Management of health information systems

Abstract

Not specified

Authors: Anke Buchauer, Alfred Winter, Reinhold Haux

Date Published: 16

Publication Type: Misc

Methodological Pluralism in Business and Information Systems Engineering?
Management of health information systems

Abstract

Not specified

Authors: Peter Loos, Tobias Mettler, Robert Winter, Matthias Goeken, Ulrich Frank, Alfred Winter

Date Published: 1st Dec 2013

Publication Type: Journal article

Methylation associated pathway activity deregulation in lung adenocarcinoma
CapSys - Systems Medicine of Community Acquired Pneumonia

Abstract (Expand)

Methylation impairments are tightly associated with gene expression and molecular pathway deregulation in cancer development. However, other regulatory mechanisms exist, making it important to distinguish … those from methylation driven changes. Here we specifically assessed molecular pathway states associated with gene methylation in lung adenocarcinoma. Paired gene expression and methylation data (id:GSE32867) were obtained from Gene Expression Omnibus. Self organizing maps (Wirth, H. et al.BMC Bioinformatics 2011;12:306 ) and in-house pathway signal flow algorithms were applied to describe expression (PSF) and methylation (mPSF) states in KEGG pathways. 35 and 24 KEGG pathways had at least one branch deregulated at significance levels p<0.05 and 0.05<p < 0.1, respectively. Because many pathways are multibranch, our analysis totalled in 54 up- (PSF>1) and 73 down-regulated (PSF<1) branches. From these branches, 19 were positively (mPSF<0) or negatively (mPSF>0) correlated with methylation states (see table).

Authors: L. Nersisyan, Henry Löffler-Wirth, A. Gevorgyan, Hans Binder, A. Arakelyan

Date Published: 2014

Publication Type: Not specified

Human Diseases: lung disease

Mice overexpressing CD97 in intestinal epithelial cells provide a unique model for mammalian postnatal intestinal cylindrical growth
Genetical Statistics and Systems Biology

Abstract (Expand)

Postnatal enlargement of the mammalian intestine comprises cylindrical and luminal growth, associated with crypt fission and crypt/villus hyperplasia, respectively, which subsequently predominate before … and after weaning. The bipartite adhesion G protein-coupled receptor CD97 shows an expression gradient along the crypt-villus axis in the normal human intestine. We here report that transgenic mice overexpressing CD97 in intestinal epithelial cells develop an upper megaintestine. Intestinal enlargement involves an increase in length and diameter but does not affect microscopic morphology, as typical for cylindrical growth. The megaintestine is acquired after birth and before weaning, independent of the genotype of the mother, excluding altered availability of milk constituents as driving factor. CD97 overexpression does not regulate intestinal growth factors, stem cell markers, and Wnt signaling, which contribute to epithelial differentiation and renewal, nor does it affect suckling-to-weaning transition. Consistent with augmented cylindrical growth, suckling but not adult transgenic mice show enlarged crypts and thus more crypt fissions caused by a transient increase of the crypt transit-amplifying zone. Intestinal enlargement by CD97 requires its seven-span transmembrane/cytoplasmic C-terminal fragment but not the N-terminal fragment binding partner CD55. In summary, ectopic expression of CD97 in intestinal epithelial cells provides a unique model for intestinal cylindrical growth occurring in breast-fed infants.

Authors: Gabriela Aust, Christiane Kerner, Susann Gonsior, Doreen Sittig, Hartmut Schneider, Peter Buske, Markus Scholz, Norman Dietrich, Sindy Oldenburg, Olga N. Karpus, Jörg Galle, Salah Amasheh, Jörg Hamann

Date Published: 15th Jul 2013

Publication Type: Journal article

MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas.
GLA - German Lymphoma Alliance

Abstract (Expand)

MicroRNAs (miRNA, miR) are negative regulators of gene expression that play an important role in diverse biological processes such as development, cell growth, apoptosis and haematopoiesis, suggesting … their association with cancer. Here we analysed the expression signatures of 157 miRNAs in 58 diffuse large B-cell lymphoma (DLBCL), 46 follicular lymphoma (FL) and seven non-neoplastic lymph nodes (LN). Comparison of the possible combinations of DLBCL-, FL- and LN resulted in specific DLBCL- and FL-signatures, which include miRNAs with previously published function in haematopoiesis (MIRN150 and MIRN155) or tumour development (MIRN210, MIRN10A, MIRN17-5P and MIRN145). As compared to LN, some miRNAs are differentially regulated in both lymphoma types (MIRN155, MIRN210, MIRN106A, MIRN149 and MIRN139). Conversely, some miRNAs show lymphoma-specific aberrant expression, such as MIRN9/9*, MIRN301, MIRN338 and MIRN213 in FL and MIRN150, MIRN17-5P, MIRN145, MIRN328 and others in DLBCL. A classification tree was computed using four miRNAs (MIRN330, MIRN17-5P, MIRN106a and MIRN210) to correctly identify 98% of all 111 cases that were analysed in this study. Finally, eight miRNAs were found to correlate with event-free and overall survival in DLBCL including known tumour suppressors (MIRN21, MIRN127 and MIRN34a) and oncogenes (MIRN195 and MIRNLET7G).

Authors: A. Roehle, K. P. Hoefig, D. Repsilber, C. Thorns, M. Ziepert, K. O. Wesche, M. Thiere, M. Loeffler, W. Klapper, M. Pfreundschuh, A. Matolcsy, H. W. Bernd, L. Reiniger, H. Merz, A. C. Feller

Date Published: 10th Jun 2008

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

MI-Lab - A Laboratory Environment for Medical Informatics Students
Management of health information systems

Abstract

Not specified

Authors: Karsten Brandt, Matthias Löbe, Michael Schaaf, Franziska Jahn, Alfred Winter, Sebastian Stäubert

Date Published: 2016

Publication Type: InProceedings

Mining common pathway deregulation profiles in lung diseases
CapSys - Systems Medicine of Community Acquired Pneumonia

Abstract (Expand)

This study is aimed at investigating lung diseases described by common pathomechanisms based on evaluation of gene expression profiles in molecular pathways. 16 datasets containing 428 samples for 22 … health conditions were taken from Gene Expression Omnibus. Self organizing maps (Wirth, H. et al.BMC Bioinformatics 2011;12:306) and cluster analysis with dynamic tree cut were used for gene expression based disease clustering. In-house pathway signal flow algorithm and phylogenetic analysis were applied to find common pathway deregulation patterns in clusters. Analysis resulted in grouping the 22 conditions into 5 clusters (fig.1). PSF and phylogenetic analysis identified unique pathway deregulation patterns for each cluster (fig.2).

Authors: A. Arakelyan, L. Nersisyan, Henry Löffler-Wirth, Hans Binder

Date Published: 2014

Publication Type: Not specified

Human Diseases: lung disease

Mobile Informationswerkzeuge im Krankenhaus: Revolution statt Evolution?
Management of health information systems

Abstract (Expand)

Die Mobilität ärztlichen und pflegerischen Handelns in Krankenhäusern führt zu dem Bedarf einer ebenfalls mobilen Informationsunterstützung. Die Möglichkeit überall Informationen zu verarbeiten, z.B. … durch die Verfügbarkeit neuartiger ’mobiler Informationswerkzeuge’, kann nach Meinung der Autoren die Grundbedürfnisse der Anwender befriedigen (z.B. durch Kommunikationsfunktionen) und diese rechtzeitig am jeweiligen Arbeitsplatz bei patientenbezogenen Verfahren unterstützen (z.B. durch aktuelle Laborbefunde). Bei der Einführung von mobilen Informationswerkzeugen als integraler Bestandteil eines Krankenhausinformationssystems können sicherlich viele Vorarbeiten der herkömmlichen papier- und rechnerbasierten Informationsverarbeitung wiederverwendet werden. Trotzdem sollte die Einführung dieser neuartigen mobilen Informationswerkzeuge nach Meinung der Autoren nicht als logische evolutionäre Weiterentwicklung angesehen werden. Es sollte die Chance ergriffen werden, durch Berücksichtung weiterer Anforderungen des mobilen Arbeitens die Qualität der Informationsverarbeitung in Krankenhäusern insgesamt zu steigern. In diesem Übersichtsreferat werden mögliche Potentiale der Verwendung mobiler Informationswerkzeuge im Krankenhaus aufgezeigt und Anforderungen für deren Integration in ein Krankenhausinformationssystem aufgestellt. Am Beispiel des Heidelberger Forschungsprojektes \textquotedblKooperatives Problemlösen\textquotedbl wird ein Modell für die Einführung mobiler Informationswerkzeuge vorgestellt.

Authors: R. Werner, Reinhold Haux, F. Leiner, Alfred Winter

Date Published: 1995

Publication Type: InCollection

Model-Based Assessment of Data Availability in Health Information Systems
Management of health information systems

Abstract

Not specified

Authors: Alfred Winter, Alexander Strübing

Date Published: 2008

Publication Type: Journal article

Model-based design of chemotherapeutic regimens that account for heterogeneity in leucopoenia
Genetical Statistics and Systems Biology

Abstract (Expand)

Patients treated with multicycle chemotherapy can exhibit large interindividual heterogeneity of haematotoxicity. We describe how a biomathematical model of human granulopoiesis can be used to design … risk-adapted dose-dense chemotherapies, leading to more similar leucopoenias in the population. Calculations were performed on a large data set for cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP)-like chemotherapies for aggressive non-Hodgkin lymphoma. Age, gender, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase and the degree of leucopoenia within the first therapy cycle were used to stratify patients into groups with different expected severity of leucopoenia. We estimated risk-specific bone marrow toxicities depending on the drug doses administered. These toxicities were used to derive risk-adapted therapy schedules. We determined different doses of cyclophosphamide and additional etoposide for patients treated with CHOP-14. Alternatively, the model predicted that further reductions of cycle duration were feasible in groups with low toxicity. We also used the model to identify appropriate granulocyte colony-stimulating factor (G-CSF) schedules. In conclusion, we present a method to estimate the potential of risk-specific dose adaptation of different cytotoxic drugs in order to design chemotherapy protocols that result in decreased diversity of leucopoenia between patients, to develop dose-escalation strategies in cases of low leucopoenic reaction and to determine optimal G-CSF support.

Authors: Markus Scholz, Christoph Engel, Markus Loeffler

Date Published: 1st Mar 2006

Publication Type: Journal article

Model-Based Design of Trustworthy Health Information Systems
Management of health information systems

Abstract

Not specified

Authors: Ruth Breu, John C. Mitchell, Janos Sztipanovits, Alfred Winter

Date Published: 2008

Publication Type: Misc

Model-based individual managing of thrombocytopenia during multi-cyclic chemotherapy
HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles

Abstract (Expand)

Background: Thrombocytopenia is a major side-effect of cytotoxic cancer therapies. The aim of precision medicine is to develop therapy modifications accounting for the individual’s risk. Methodology/Principle … Findings: To solve this task, we develop an individualized bio-mechanistic model of the dynamics of bone marrow thrombopoiesis, circulating platelets and therapy effects thereon. Comprehensive biological knowledge regarding cell differentiation, amplification, apoptosis rates, transition times and corresponding regulations are translated into ordinary differential equations. A model of osteoblast/osteoclast interactions was incorporated to mechanistically describe bone marrow support of quiescent cell stages. Thrombopoietin (TPO) as a major regulator is explicitly modelled including pharmacokinetics and –dynamics of TPO injections. Effects of cytotoxic drugs are modelled by transient depletions of proliferating cells. To calibrate the model, we used population data from the literature and close-meshed individual data of N=135 high-grade non-Hodgkin’s lymphoma patients treated with CHOP-like chemotherapies. To limit the number of free parameters, several parsimony assumptions were derived from biological data and tested via Likelihood methods. Heterogeneity of patients was explained by a few model parameters. The over-fitting issue of individual parameter estimation was successfully dealt with a virtual participation of each patient in population-based experiments. The model qualitatively and quantitatively explains a number of biological observations such as the role of osteoblasts in explaining long-term toxic effects, megakaryocyte-mediated feedback on stem cells, bi-phasic stimulation of thrombopoiesis by TPO, dynamics of megakaryocyte ploidies and non-exponential platelet degradation. Almost all individual time series could be described with high precision. We demonstrated how the model can be used to provide predictions regarding individual therapy adaptations. Conclusions: We propose a mechanistic thrombopoiesis model of unprecedented comprehensiveness in both, biological mechanisms considered and experimental data sets explained. Our innovative method of parameter estimation allows robust determinations of individual parameter settings facilitating the development of individual treatment adaptations during chemotherapy.

Authors: Y. Kheifetz, Markus Scholz, Markus Löffler

Date Published: 9th Jun 2017

Publication Type: Not specified

Human Diseases: thrombocytopenia

Model-based optimization of G-CSF treatment during cytotoxic chemotherapy.
Genetical Statistics and Systems Biology

Abstract (Expand)

PURPOSE: Although G-CSF is widely used to prevent or ameliorate leukopenia during cytotoxic chemotherapies, its optimal use is still under debate and depends on many therapy parameters such as dosing … and timing of cytotoxic drugs and G-CSF, G-CSF pharmaceuticals used and individual risk factors of patients. METHODS: We integrate available biological knowledge and clinical data regarding cell kinetics of bone marrow granulopoiesis, the cytotoxic effects of chemotherapy and pharmacokinetics and pharmacodynamics of G-CSF applications (filgrastim or pegfilgrastim) into a comprehensive model. The model explains leukocyte time courses of more than 70 therapy scenarios comprising 10 different cytotoxic drugs. It is applied to develop optimized G-CSF schedules for a variety of clinical scenarios. RESULTS: Clinical trial results showed validity of model predictions regarding alternative G-CSF schedules. We propose modifications of G-CSF treatment for the chemotherapies 'BEACOPP escalated' (Hodgkin's disease), 'ETC' (breast cancer), and risk-adapted schedules for 'CHOP-14' (aggressive non-Hodgkin's lymphoma in elderly patients). CONCLUSIONS: We conclude that we established a model of human granulopoiesis under chemotherapy which allows predictions of yet untested G-CSF schedules, comparisons between them, and optimization of filgrastim and pegfilgrastim treatment. As a general rule of thumb, G-CSF treatment should not be started too early and patients could profit from filgrastim treatment continued until the end of the chemotherapy cycle.

Authors: S. Schirm, C. Engel, S. Loibl, M. Loeffler, M. Scholz

Date Published: 6th Nov 2017

Publication Type: Journal article

Modeling a graph data model for FHIR resources
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

Introduction: (Fast Healthcare Interoperability Resources) is a modern standard for communication and representation of clinical data, where each dataset is defined by a single resource, linked to other … resources [ref:1]. But FHIR\textregistered does explicitely not define how to persist these resources[for full text, please go to the a.m. URL]

Authors: Henner M Kruse, Alexander Helhorn, Lo An Phan-Vogtmann, Eric Thomas, Andrew J Heidel, Kutaiba Saleh, André Scherag, Danny Ammon

Date Published: 2019

Publication Type: Misc

Modeling a Graph Data Model for FHIR Resources
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

Introduction: (Fast Healthcare Interoperability Resources) is a modern standard for communication and representation of clinical data, where each dataset is defined by a single resource, linked to other … resources [ref:1]. But FHIR\circledR does explicitely not define how to persist these resources[for full text, please go to the a.m. URL]

Authors: Henner M. Kruse, Alexander Helhorn, Lo Phan-Vogtmann an , Eric Thomas, Andrew J. Heidel, Kutaiba Saleh, André Scherag, Danny Ammon

Date Published: 6th Sep 2019

Publication Type: InProceedings

Modeling combined chemo- and immunotherapy of high-grade non-Hodgkin lymphoma.
LIFE - Leipzig Research Center for Civilization Diseases, Genetical Statistics and Systems Biology

Abstract (Expand)

Moderate, but not massive intensification of CHOP-21 improves outcome in aggressive non-Hodgkin lymphoma. Adding immunotherapy with Rituximab was a break-through, but levels differences in chemotherapy. … Ongoing trials attempt to optimize R-CHOP type regimens. We present a mathematical model of chemo-immunotherapy to explain published and aiming at predicting future trials comparing R-CHOP variants. We hypothesize that, for cure, the immune system must dominate residual tumor cells at the end of treatment. Chemotherapy reduces both tumor and immune cells. Rituximab immunotherapy boosts the immune response. We translate this reasoning into a differential equations model. Model parameters are estimated using data of randomized clinical trials in elderly patients. The model explains observed hazard ratios between treatments. It explains why too intense chemotherapy could be detrimental. The model is validated predicting six published independent studies. As an application, we varied treatment schedules and predict that current R-CHOP variants have only limited optimization potential.

Authors: K. Rosch, M. Scholz, D. Hasenclever

Date Published: 16th Dec 2015

Publication Type: Not specified

Human Diseases: lymphoma

Modeling Economic Aspects of Hospital Information Systems to Give Decision Support for Strategic Information Management
Management of health information systems

Abstract

Not specified

Authors: Ansgar Kutscha, Birgit Brigl, Alfred Winter

Date Published: 2006

Publication Type: Journal article

Modeling Hospital Information Systems (Part 1): The Revised Three-Layer Graph-Based Meta Model 3LGM2
Management of health information systems

Abstract

Not specified

Authors: Alfred Winter, B. Brigl, T. Wendt

Date Published: 2003

Publication Type: Journal article

Modeling Hospital Information Systems (Part 2): Using the 3LGM2 Tool for Modeling Patient Record Management
Management of health information systems

Abstract

Not specified

Authors: T. Wendt, A. Häber, B. Brigl, Alfred Winter

Date Published: 2004

Publication Type: Journal article

Modeling individual time courses of thrombopoiesis during multi-cyclic chemotherapy.
Genetical Statistics and Systems Biology, HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles

Abstract (Expand)

BACKGROUND: Thrombocytopenia is a major side-effect of cytotoxic cancer therapies. The aim of precision medicine is to develop therapy modifications accounting for the individual's risk. … METHODOLOGY/PRINCIPLE FINDINGS: To solve this task, we develop an individualized bio-mechanistic model of the dynamics of bone marrow thrombopoiesis, circulating platelets and therapy effects thereon. Comprehensive biological knowledge regarding cell differentiation, amplification, apoptosis rates, transition times and corresponding regulations are translated into ordinary differential equations. A model of osteoblast/osteoclast interactions was incorporated to mechanistically describe bone marrow support of quiescent cell stages. Thrombopoietin (TPO) as a major regulator is explicitly modelled including pharmacokinetics and-dynamics of TPO injections. Effects of cytotoxic drugs are modelled by transient depletions of proliferating cells. To calibrate the model, we used population data from the literature and close-meshed individual data of N = 135 high-grade non-Hodgkin's lymphoma patients treated with CHOP-like chemotherapies. To limit the number of free parameters, several parsimony assumptions were derived from biological data and tested via Likelihood methods. Heterogeneity of patients was explained by a few model parameters. The over-fitting issue of individual parameter estimation was successfully dealt with a virtual participation of each patient in population-based experiments. The model qualitatively and quantitatively explains a number of biological observations such as the role of osteoblasts in explaining long-term toxic effects, megakaryocyte-mediated feedback on stem cells, bi-phasic stimulation of thrombopoiesis by TPO, dynamics of megakaryocyte ploidies and non-exponential platelet degradation. Almost all individual time series could be described with high precision. We demonstrated how the model can be used to provide predictions regarding individual therapy adaptations. CONCLUSIONS: We propose a mechanistic thrombopoiesis model of unprecedented comprehensiveness in both, biological mechanisms considered and experimental data sets explained. Our innovative method of parameter estimation allows robust determinations of individual parameter settings facilitating the development of individual treatment adaptations during chemotherapy.

Authors: Y. Kheifetz, M. Scholz

Date Published: 7th Mar 2019

Publication Type: Not specified

Human Diseases: blood platelet disease

Modeling interdependencies between business and communication processes in hospitals
Management of health information systems

Abstract

Not specified

Authors: B. Brigl, T. Wendt, Alfred Winter

Date Published: 2003

Publication Type: InCollection

Modeling Interdependencies between Information Processes and Communication Paths in Hospitals
Management of health information systems

Abstract (Expand)

Objectives: For planning hospital information systems it is important to recognize the interrelation between business processes and the communication needs between supporting application systems. We … therefore present an approach to model, visualize and analyze those interdependencies. Methods: The approach is based on the concepts defined in 3LGM(2), a meta-model to describe health information systems (HIS). An information process is defined as a sequence of functions using or updating information; a communication path as a sequence of communication links between interfaces belonging to application systems. The search for communication paths belonging to an information process is interpreted as an all-pairs shortest-paths problem. To solve this problem the Floyd-Warshall algorithm is applied. Results: The resulting algorithm has been implemented as function of the 3LGM(2) tool, a tool to create 3LGM(2) compliant models. With it, it is possible to interactively define information processes at the domain layer and to analyze step by step whether the infrastructure at the logical tool layer is sufficient to communicate necessary data between application systems. Conclusions: The presented approach enables the representation and analysis of dependencies between information processes and communication paths. With it, the HIS architecture is directly associated with the business needs. This is an important condition for the systematic planning of hospital information systems.

Authors: B. Brigl, A. Strubing, T. Wendt, Alfred Winter

Date Published: 2006

Publication Type: Journal article

Modeling Interoperable Information Systems with 3LGM^2 and IHE
Management of health information systems

Abstract

Not specified

Authors: Sebastian Stäubert, Michael Schaaf, Franziska Jahn, Ralf Brandner, Alfred Winter

Date Published: 22nd Jan 2018

Publication Type: Journal article

Modeling Requirements for Cohort and Register IT
Management of health information systems

Abstract

Not specified

Authors: Sebastian Stäubert, Ulrike Weber, C. Michalik, J. Dress, Sylvie M. N. Ngouongo, Jürgen Stausberg, Alfred Winter

Date Published: 2016

Publication Type: InProceedings

Modeling Requirements for Cohort and Register IT with 3LGM
Management of health information systems

Abstract

Not specified

Authors: Sebastian Stäubert, U. Weber, C. Michalik, J. Dress, S. Ngouongo, Jürgen Stausberg, A. Strubing, Alfred Winter

Date Published: 2014

Publication Type: Journal article

Modellieren von Krankenhausinformationssystemen am Beispiel des 3LGM^2-Baukastens
Management of health information systems

Abstract

Not specified

Authors: Alfred Winter, Birgit Brigl, Thomas Wendt

Date Published: 2005

Publication Type: InCollection

Modellierung eines Anwendungssystems zur Unterstützung der Pflegedokumentation unter Berücksichtigung der Integration in ein klinisches Arbeitsplatzsystem
Management of health information systems

Abstract

Not specified

Authors: A. Lagemann, Reinhold Haux, Alfred Winter

Date Published: No date defined

Publication Type: Misc

Modellierung eines Anwendungssystems zur Unterstützung der Pflegedokumentation unter Berücksichtigung der Integration in ein Klinisches Arbeitsplatzsystem
Management of health information systems

Abstract

Not specified

Authors: A. Lagemann, Reinhold Haux, Alfred Winter

Date Published: 1996

Publication Type: Journal article

Modellierung interoperabler Informationssysteme mit 3LGM^2 und IHE
Management of health information systems

Abstract

Not specified

Authors: Michael Schaaf, Sebastian Stäubert, R. Brandner, Alfred Winter

Date Published: 2014

Publication Type: Misc

Modellierung von Architekturstilen mit dem 3LGM^2
Management of health information systems

Abstract

Not specified

Authors: Thomas Wendt, Birgit Brigl, Alfred Winter

Date Published: 2003

Publication Type: Misc

Modellierung von Informations- und Kommunikationsprozessen zur Unterstützung des Informationsmanagements im Krankenhaus
Management of health information systems

Abstract

Not specified

Authors: B. Brigl, A. Strübing, Alfred Winter

Date Published: 2004

Publication Type: InCollection

Modellierung von Integrationstypen (Abstract)
Management of health information systems

Abstract

Not specified

Authors: T. Wendt, B. Brigl, Alfred Winter

Date Published: 2001

Publication Type: Journal article

Modelling and comparing hospitals’ information systems in Japan and Germany
Management of health information systems

Abstract

Not specified

Authors: Alfred Winter, Franziska Jahn, Lutz Ißler, Katsuhiko Takabayashi

Date Published: 2008

Publication Type: Journal article

Modelling chemotherapy effects on granulopoiesis.
GLA - German Lymphoma Alliance, Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: Although the growth-factor G-CSF is widely used to prevent granulotoxic side effects of cytotoxic chemotherapies, its optimal use is still unknown since treatment outcome depends on many … parameters such as dosing and timing of chemotherapies, pharmaceutical derivative of G-CSF used and individual risk factors. We showed in the past that a pharmacokinetic and -dynamic model of G-CSF and human granulopoiesis can be used to predict the performance of yet untested G-CSF schedules. However, only a single chemotherapy was considered so far. RESULTS: Model assumptions proved to be feasible in explaining granulotoxicity of 10 different chemotherapeutic drugs or drug-combinations applied in 33 different schedules with and without G-CSF. Risk groups of granulotoxicity were traced back to differences in toxicity parameters. CONCLUSION: We established a comprehensive model of combined G-CSF and chemotherapy action in humans which allows us to predict and compare the outcome of alternative G-CSF schedules. We aim to apply the model in different clinical contexts to optimize and individualize G-CSF treatment.

Authors: S. Schirm, C. Engel, M. Loeffler, M. Scholz

Date Published: 24th Dec 2014

Publication Type: Not specified

Human Diseases: leukopenia

Modelling lymphoma therapy and outcome
Genetical Statistics and Systems Biology

Abstract (Expand)

Dose and time intensifications of chemotherapy improved the outcome of lymphoma therapy. However, recent study results show that too intense therapies can result in inferior tumour control. We hypothesise … that the immune system plays a key role in controlling residual tumour cells after treatment. More intense therapies result in a stronger depletion of immune cells allowing an early re-growth of the tumour.We propose a differential equations model of the dynamics and interactions of tumour and immune cells under chemotherapy. Major model features are an exponential tumour growth, a modulation of the production of effector cells by the presence of the tumour (immunogenicity), and mutual destruction of tumour and immune cells. Chemotherapy causes damage to both, immune and tumour cells. Growth rate, chemosensitivity, immunogenicity, and initial size of the tumour are assumed to be patient-specific, resulting in heterogeneity regarding therapy outcome. Maximum-entropy distributions of these parameters were estimated on the basis of clinical survival data. The resulting model can explain the outcome of five different chemotherapeutic regimens and corresponding hazard-ratios.We conclude that our model explains observed paradox effects in lymphoma therapy by the simple assumption of a relevant anti-tumour effect of the immune system. Heterogeneity of therapy outcomes can be explained by distributions of model parameters, which can be estimated on the basis of clinical survival data. We demonstrate how the model can be used to make predictions regarding yet untested therapy options.

Authors: Katja Roesch, Dirk Hasenclever, Markus Scholz

Date Published: 1st Feb 2014

Publication Type: Journal article

Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

Treatment of relapse and primary progression in aggressive lymphoma remains unsatisfactory; outcome is still poor. Better treatment strategies are much needed for this patient population. The R1 study … is a prospective multi-center phase I/II study evaluating a dose finding approach with a triple transplant regimen in four BEAM dose levels in patients with relapsed aggressive non-Hodgkin lymphoma. The aim of the study was to determine feasibility, toxicity, and remission rate. In a total of 39 patients (pts.) enrolled in the study, 24 pts. were evaluated in the following analysis. Twenty pts. had aggressive B cell lymphoma, and two pts. had T cell lymphoma. All evaluated patients responded to DexaBEAM with a sufficient stem cell harvest. The phase I/II study was started with BEAM dose level II. Four patients were treated at dose level II, and 20 pts. were treated at dose level III. Due to the early termination of the study, dose levels I and IV were never administered. Sixteen pts. completed therapy according to protocol, and eight pts. (33.3 %) stopped treatment early. Infections (27 %) and stomatitis (13 %) were the most frequent grade III/IV non-hematologic toxicities. Thirteen percent of patients presented with severe grade III/IV lung toxicity during modified BEAM (m-BEAM). Fourteen pts. achieved a complete response (CR), one pt. achieved no change (NC), six pts. had progressive disease (PD), and two pts. died; for one pt., outcome is not known. One-year and 3-year event-free survival (EFS) was 38 and 33 %, respectively. Overall survival (OS) after 1 and 3 years was 50 and 38 %. In conclusion, dose escalation of standard BEAM is not feasible due to toxicity.

Authors: K. Hohloch, S. Zeynalova, B. Chapuy, M. Pfreundschuh, M. Loeffler, M. Ziepert, A. C. Feller, L. Trumper, D. Hasenclever, G. Wulf, N. Schmitz

Date Published: 12th May 2016

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma

Molecular analyses of glioblastoma stem-like cells and glioblastoma tissue.
Genetical Statistics and Systems Biology

Abstract (Expand)

Glioblastoma is a common, malignant brain tumor whose disease incidence increases with age. Glioblastoma stem-like cells (GSCs) are thought to contribute to cancer therapy resistance and to be responsible … for tumor initiation, maintenance, and recurrence. This study utilizes both SNP array and gene expression profiling to better understand GSCs and their relation to malignant disease. Peripheral blood and primary glioblastoma tumor tissue were obtained from patients, the latter of which was used to generate GSCs as well as a CD133pos./CD15pos. subpopulation. The stem cell features of GSCs were confirmed via the immunofluorescent expression of Nestin, SOX2, and CD133. Both tumor tissue and the isolated primary cells shared unique abnormal genomic characteristics, including a gain of chromosome 7 as well as either a partial or complete loss of chromosome 10. Individual genomic differences were also observed, including the loss of chromosome 4 and segmental uniparental disomy of 9p24.3-->p21.3 in GSCs. Gene expression profiling revealed 418 genes upregulated in tumor tissue vs. CD133pos./CD15pos. cells and 44 genes upregulated in CD133pos./CD15pos. cells vs. tumor tissue. Pathway analyses demonstrated that upregulated genes in CD133pos./CD15pos. cells are relevant to cell cycle processes and cancerogenesis. In summary, we detected previously undescribed genomic and gene expression differences when comparing tumor tissue and isolated stem-like subpopulations.

Authors: M. Wallenborn, L. X. Xu, H. Kirsten, L. Rohani, D. Rudolf, P. Ahnert, C. Schmidt, R. M. Schulz, M. Richter, W. Krupp, W. Mueller, A. A. Johnson, J. Meixensberger, H. Holland

Date Published: 8th Jul 2020

Publication Type: Journal article

Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling.
GGN - German Glioma Network

Abstract (Expand)

The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. To elucidate the … molecular aberrations in glioblastomas of long-term survivors, we performed genome- and/or transcriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-term survivors with >36 months overall survival (OS), 20 short-term survivors with <12 months OS and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O(6) -methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups of IDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomas in our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients.

Authors: G. Reifenberger, R. G. Weber, V. Riehmer, K. Kaulich, E. Willscher, H. Wirth, J. Gietzelt, B. Hentschel, M. Westphal, M. Simon, G. Schackert, J. Schramm, J. Matschke, M. C. Sabel, D. Gramatzki, J. Felsberg, C. Hartmann, J. P. Steinbach, U. Schlegel, W. Wick, B. Radlwimmer, T. Pietsch, J. C. Tonn, A. von Deimling, H. Binder, M. Weller, M. Loeffler

Date Published: 15th Oct 2014

Publication Type: Not specified

Human Diseases: brain glioma

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups.
GGN - German Glioma Network

Abstract (Expand)

Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale … genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.

Authors: M. Weller, R. G. Weber, E. Willscher, V. Riehmer, B. Hentschel, M. Kreuz, J. Felsberg, U. Beyer, H. Loffler-Wirth, K. Kaulich, J. P. Steinbach, C. Hartmann, D. Gramatzki, J. Schramm, M. Westphal, G. Schackert, M. Simon, T. Martens, J. Bostrom, C. Hagel, M. Sabel, D. Krex, J. C. Tonn, W. Wick, S. Noell, U. Schlegel, B. Radlwimmer, T. Pietsch, M. Loeffler, A. von Deimling, H. Binder, G. Reifenberger

Date Published: 19th Mar 2015

Publication Type: Not specified

Human Diseases: brain glioma

Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network.
GGN - German Glioma Network

Abstract (Expand)

PURPOSE: The prognostic value of genetic alterations characteristic of glioblastoma in patients treated according to present standards of care is unclear. PATIENTS AND METHODS: Three hundred one patients … with glioblastoma were prospectively recruited between October 2004 and December 2006 at the clinical centers of the German Glioma Network. Two hundred fifty-eight patients had radiotherapy, 199 patients had temozolomide, 189 had both, and seven had another chemotherapy as the initial treatment. The tumors were investigated for TP53 mutation, p53 immunoreactivity, epidermal growth factor receptor, cyclin-dependent kinase CDK 4 or murine double minute 2 amplification, CDKN2A homozygous deletion, allelic losses on chromosome arms 1p, 9p, 10q, and 19q, O(6)-methylguanine methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutations. RESULTS: Median progression-free (PFS) and overall survival (OS) were 6.8 and 12.5 months. Multivariate analysis revealed younger age, higher performance score, MGMT promoter methylation, and temozolomide radiochemotherapy as independent factors associated with longer OS. MGMT promoter methylation was associated with longer PFS (relative risk [RR], 0.5; 95% CI, 0.38 to 0.68; P < .001) and OS (RR, 0.39; 95% CI, 0.28 to 0.54; P < .001) in patients receiving temozolomide. IDH1 mutations were associated with prolonged PFS (RR, 0.42; 95% CI, 0.19 to 0.91; P = .028) and a trend for prolonged OS (RR, 0.43; 95% CI, 0.15 to 1.19; P = .10). No other molecular factor was associated with outcome. CONCLUSION: Molecular changes associated with gliomagenesis do not predict response to therapy in glioblastoma patients managed according to current standards of care. MGMT promoter methylation and IDH1 mutational status allow for stratification into prognostically distinct subgroups.

Authors: M. Weller, J. Felsberg, C. Hartmann, H. Berger, J. P. Steinbach, J. Schramm, M. Westphal, G. Schackert, M. Simon, J. C. Tonn, O. Heese, D. Krex, G. Nikkhah, T. Pietsch, O. Wiestler, G. Reifenberger, A. von Deimling, M. Loeffler

Date Published: 1st Dec 2009

Publication Type: Not specified

Human Diseases: brain glioma, glioblastoma multiforme

Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.
GLA - German Lymphoma Alliance

Abstract (Expand)

Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined … activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification.

Authors: B. Chapuy, C. Stewart, A. J. Dunford, J. Kim, A. Kamburov, R. A. Redd, M. S. Lawrence, M. G. M. Roemer, A. J. Li, M. Ziepert, A. M. Staiger, J. A. Wala, M. D. Ducar, I. Leshchiner, E. Rheinbay, A. Taylor-Weiner, C. A. Coughlin, J. M. Hess, C. S. Pedamallu, D. Livitz, D. Rosebrock, M. Rosenberg, A. A. Tracy, H. Horn, P. van Hummelen, A. L. Feldman, B. K. Link, A. J. Novak, J. R. Cerhan, T. M. Habermann, R. Siebert, A. Rosenwald, A. R. Thorner, M. L. Meyerson, T. R. Golub, R. Beroukhim, G. G. Wulf, G. Ott, S. J. Rodig, S. Monti, D. S. Neuberg, M. Loeffler, M. Pfreundschuh, L. Trumper, G. Getz, M. A. Shipp

Date Published: 2nd May 2018

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Monitoring Disease Progression and Therapeutic Response in a Disseminated Tumor Model for Non-Hodgkin Lymphoma by Bioluminescence Imaging
Genetical Statistics and Systems Biology

Abstract (Expand)

Xenograft tumor models are widely studied in cancer research. Our aim was to establish and apply a model for aggressive CD20-positive B-cell non-Hodgkin lymphomas, enabling us to monitor tumor growth … and shrinkage in a noninvasive manner. By stably transfecting a luciferase expression vector, we created two bioluminescent human non-Hodgkin lymphoma cell lines, Jeko1(luci) and OCI-Ly3(luci), that are CD20 positive, a prerequisite to studying rituximab, a chimeric anti-CD20 antibody. To investigate the therapy response in vivo, we established a disseminated xenograft tumor model injecting these cell lines in NOD/SCID mice. We observed a close correlation of bioluminescence intensity and tumor burden, allowing us to monitor therapy response in the living animal. Cyclophosphamide reduced tumor burden in mice injected with either cell line in a dose-dependent manner. Rituximab alone was effective in OCI-Ly3(luci)-injected mice and acted additively in combination with cyclophosphamide. In contrast, it improved the therapeutic outcome of Jeko1(luci)-injected mice only in combination with cyclophosphamide. We conclude that well-established bioluminescence imaging is a valuable tool in disseminated xenograft tumor models. Our model can be translated to other cell lines and used to examine new therapeutic agents and schedules.

Authors: Margarethe Köberle, Kristin Müller, Manja Kamprad, Friedemann Horn, Markus Scholz

Date Published: 2015

Publication Type: Journal article

Monitoring Motor Skills of Children and Adolescents in LIFE Child
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Life Child is an epidemiological study running at the LIFE Research Center for Civilization Diseas-es (University of Leipzig) since 2011. It aims at monitoring the development in children and adolescents … by examining thousands of children in and around Leipzig. Of particular interest in this study are motor skills and physical activities of children between 6 and 18 years. There are multiple examinations including interviews, self-completed questionnaires and physical examinations (e.g., sport tests) to generate data describing the determined child as well her lifestyle and environment. The goal is to find causes for low to non physical activity and unincisive motor skills and capabilities since they are commonly attended with diseases, such as obesity and diabetes. As a first step in this direction, we analyzed data of specific sport tests, such as pushups, side steps and long jumps, according to the body mass index (BMI) of participants. We found that participants with high BMI achieve a similar number of pushups in early years like the normal BMI group, while in later years the pushup number of participants with normal BMI exceeds the pushup number of high BMI group. Surprisingly, the number of side steps is indifferent over age categories (6-18, yearly) between both groups. Conversely, the normal BMI group achieve higher distances through-out all age categories than the high BMI group. In future, we will associate these results with socio-economic and lifestyle indicators, e.g., interest in sport and physical activities of child and parents.

Authors: J. Lang, C. Warnatsch, M. Vogel, Toralf Kirsten, W. Kiess

Date Published: 17th Dec 2014

Publication Type: Not specified

Monitoring of WT1 expression in PB and CD34(+) donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning
Genetical Statistics and Systems Biology

Abstract (Expand)

Relapse of malignant disease remains the major complication in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) with … reduced-intensity conditioning (RIC). In this study, we investigated the predictive value of disease-specific markers (DSMs), donor chimerism (DC) analysis of unsorted (UDC) or CD34(+) sorted cells and Wilms’ tumor gene 1 (WT1) expression. Eighty-eight patients with AML or MDS were monitored after allogenic HCT following 2 Gy total-body irradiation with (n=84) or without (n=4) fludarabine 3 \times 30 mg/m(2), followed by cyclosporin A and mycophenolate mofetil. DSMs were determined by fluorescence in situ hybridization (FISH) and WT1 expression by real-time polymerase chain reaction. Chimerism analysis was performed on unsorted or CD34(+) sorted cells, by FISH or short tandem repeat polymerase chain reaction. Twenty-one (24%) patients relapsed within 4 months after HCT. UDC, CD34(+) DC and WT1 expression were each significant predictors of relapse with sensitivities ranging from 53 to 79% and specificities of 82-91%. Relapse within 28 days was excluded almost entirely on the basis of WT1 expression combined with CD34(+) DC kinetics. Monitoring of WT1 expression and CD34(+) DC predict relapse of AML and MDS after RIC-HCT.

Authors: T. Lange, M. Hubmann, Ralph Burkhardt, G-N Franke, M. Cross, Markus Scholz, S. Leiblein, H. K. Al-Ali, J. Edelmann, Joachim Thiery, D. Niederwieser

Date Published: 1st Mar 2011

Publication Type: Journal article

More than Four Decades of Medical Informatics Education for Medical Students in Germany - New Recommendations Published
Management of health information systems

Abstract

Not specified

Authors: Alfred Winter, R. -D Hilgers, R. Hofestädt, Petra Knaup-Gregori, C. Ose, A. Timmer

Date Published: 2013

Publication Type: Journal article

Mortality in incident dementia - results from the German Study on Aging, Cognition, and Dementia in Primary Care Patients.
LIFE Adult

Abstract (Expand)

OBJECTIVE: Dementia is known to increase mortality, but the relative loss of life years and contributing factors are not well established. Thus, we aimed to investigate mortality in incident dementia … from disease onset. METHOD: Data were derived from the prospective longitudinal German AgeCoDe study. We used proportional hazards models to assess the impact of sociodemographic and health characteristics on mortality after dementia onset, Kaplan-Meier method for median survival times. RESULTS: Of 3214 subjects at risk, 523 (16.3%) developed incident dementia during a 9-year follow-up period. Median survival time after onset was 3.2 years (95% CI = 2.8-3.7) at a mean age of 85.0 (SD = 4.0) years (>/=2.6 life years lost compared with the general German population). Survival was shorter in older age, males other dementias than Alzheimer's, and in the absence of subjective memory complaints (SMC). CONCLUSION: Our findings emphasize that dementia substantially shortens life expectancy. Future studies should further investigate the potential impact of SMC on mortality in dementia.

Authors: S. Roehr, T. Luck, H. Bickel, C. Brettschneider, A. Ernst, A. Fuchs, K. Heser, H. H. Konig, F. Jessen, C. Lange, E. Mosch, M. Pentzek, S. Steinmann, S. Weyerer, J. Werle, B. Wiese, M. Scherer, W. Maier, S. G. Riedel-Heller

Date Published: 9th Jun 2015

Publication Type: Not specified

Human Diseases: cognitive disorder, dementia

Mortality in Individuals with Subjective Cognitive Decline: Results of the Leipzig Longitudinal Study of the Aged (LEILA75+).
LIFE Adult

Abstract (Expand)

BACKGROUND: Studies have shown that dementia and cognitive impairment can increase mortality, but less is known about the association between subjectively perceived cognitive deficits (subjective … cognitive decline, SCD) and mortality risk. OBJECTIVE: In this study, we analyzed mortality in non-demented individuals with SCD in a general population sample aged 75+ years. METHOD: Data were derived from the Leipzig Longitudinal Study of the Aged (LEILA75+). We used the Kaplan-Meier survival method to estimate survival times of individuals with and without SCD and multivariable Cox proportional hazards regression to assess the association between SCD and mortality risk, controlled for covariates. RESULTS: Out of 953 non-demented individuals at baseline, 117 (12.3% ) expressed SCD. Participants with SCD showed a significantly higher case-fatality rate per 1,000 person-years (114.8, 95% CI = 90.5-145.7 versus 71.7, 95% CI = 64.6-79.5) and a significantly shorter mean survival time than those without (5.4 versus 6.9 years, p < 0.001). The association between SCD and mortality remained significant in the Cox analysis; SCD increased mortality risk by about 50% (adjusted Hazard Ratio = 1.51) during the study period. Besides SCD, older age, male gender, diabetes mellitus, stroke, and lower global cognitive functioning were also significantly associated with increased mortality. CONCLUSION: Our findings suggest an increased mortality risk in non-demented older individuals with SCD. Even though further studies are required to analyze potential underlying mechanisms, subjective reports on cognitive deficits may be taken seriously in clinical practice not only for an increased risk of developing dementia and AD but also for a broader range of possible adverse health outcomes.

Authors: T. Luck, S. Roehr, F. Jessen, A. Villringer, M. C. Angermeyer, S. G. Riedel-Heller

Date Published: 24th Sep 2015

Publication Type: Not specified

Human Diseases: dementia

Multi-institutional breast cancer detection using a secure on-boarding service for Distributed Analytics
SMITH - Smart Medical Information Technology for Healthcare

Abstract (Expand)

The constant upward movement of data-driven medicine as a valuable option to enhance daily clinical practice has brought new challenges for data analysts to get access to valuable but sensitive data … due to privacy considerations. One solution for most of these challenges are Distributed Analytics (DA) infrastructures, which are technologies fostering collaborations between healthcare institutions by establishing a privacy-preserving network for data sharing. However, in order to participate in such a network, a lot of technical and administrative prerequisites have to be made, which could pose bottlenecks and new obstacles for non-technical personnel during their deployment. We have identified three major problems in the current state-of-the-art. Namely, the missing compliance with FAIR data principles, the automation of processes, and the installation. In this work, we present a seamless on-boarding workflow based on a DA reference architecture for data sharing institutions to address these problems. The on-boarding service manages all technical configurations and necessities to reduce the deployment time. Our aim is to use well-established and conventional technologies to gain acceptance through enhanced ease of use. We evaluate our development with six institutions across Germany by conducting a DA study with open-source breast cancer data, which represents the second contribution of this work. We find that our on-boarding solution lowers technical barriers and efficiently deploys all necessary components and is, therefore, indeed an enabler for collaborative data sharing.

Authors: Sascha Welten, Lars Hempel, Masoud Abedi, Yongli Mou, Mehrshad Jaberansary, Laurenz Neumann, Sven Weber, Kais Tahar, Yeliz Ucer Yediel, Matthias Löbe, Stefan Decker, Oya Beyan, Toralf Kirsten

Date Published: 1st Apr 2022

Publication Type: Journal article

Multilineage communication regulates human liver bud development from pluripotency.
Leipzig Melanoma Studies

Abstract (Expand)

Conventional two-dimensional differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. Three-dimensional organoids generate complex organ-like tissues; … however, it is unclear how heterotypic interactions affect lineage identity. Here we use single-cell RNA sequencing to reconstruct hepatocyte-like lineage progression from pluripotency in two-dimensional culture. We then derive three-dimensional liver bud organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during liver bud development. We find that liver bud hepatoblasts diverge from the two-dimensional lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark three-dimensional liver buds against fetal and adult human liver single-cell RNA sequencing data, and find a striking correspondence between the three-dimensional liver bud and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signalling in liver buds, and show that vascular endothelial growth factor (VEGF) crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.

Authors: J. G. Camp, K. Sekine, T. Gerber, H. Loeffler-Wirth, H. Binder, M. Gac, S. Kanton, J. Kageyama, G. Damm, D. Seehofer, L. Belicova, M. Bickle, R. Barsacchi, R. Okuda, E. Yoshizawa, M. Kimura, H. Ayabe, H. Taniguchi, T. Takebe, B. Treutlein

Date Published: 22nd Jun 2017

Publication Type: Not specified

Human Diseases: liver disease

Multi-omics cartography of glioma heterogeneity
GGN - German Glioma Network

Abstract (Expand)

Molecular mechanisms of lower grade (II- III) diffuse gliomas (LGG) are still poorly understood, mainly because of their heterogeneity. They split into astrocytoma- (IDH-A) and oligodendro-glioma-like … (IDH-O) tumors both carrying mutations(s) at the Isocitrate dehydrogenase (IDH) gene and into IDH wild type (IDH-wt) gliomas of glioblastoma-resemblance. We generated de-tailed maps of the transcriptomes and DNA-methylomes revealing that cell functions divide into three major archeotypic hallmarks: (i) increased proliferation in IDH-wt and, to a less degree, IDH-O, (ii) increased inflammation in IDH-A and IDH-wt, and (iii) the loss of synaptic transmis-sion in all subtypes. Immunogenic properties of IDH-A are diverse partly resembling signatures observed in grade IV mesenchymal glioblastomas or in grade I pilocytic astrocytomas. We ana-lyzed details of coregulation between gene expression and DNA-methylation and of the immu-nogenic micro-environment presumably driving tumor development and treatment resistance. Our transcriptome and methylome maps support personalized, case-by-case views to decipher the heterogeneity of glioma states in terms of data portraits. Thereby molecular cartography provides a graphical coordinate system, which links gene-level information with glioma sub-types, their phenotypes and clinical context.

Authors: Hans Binder, Maria Schmidt, Lydia Hopp, Arsen Arakelyan, Henry Löffler-Wirth

Date Published: No date defined

Publication Type: Journal article

Human Diseases: brain glioma

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed \sim480 SNPs at the TERT locus … in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 \times 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 \times 10(-8)) and BRCA1 mutation carrier (P = 1.1 \times 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 \times 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 \times 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 \times 10(-12)) and BRCA1 mutation carrier (P = 1.6 \times 10(-14)) breast and invasive ovarian (P = 1.3 \times 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Authors: Stig E. Bojesen, Karen A. Pooley, Sharon E. Johnatty, Jonathan Beesley, Kyriaki Michailidou, Jonathan P. Tyrer, Stacey L. Edwards, Hilda A. Pickett, Howard C. Shen, Chanel E. Smart, Kristine M. Hillman, Phuong L. Mai, Kate Lawrenson, Michael D. Stutz, Yi Lu, Rod Karevan, Nicholas Woods, Rebecca L. Johnston, Juliet D. French, Xiaoqing Chen, Maren Weischer, Sune F. Nielsen, Melanie J. Maranian, Maya Ghoussaini, Shahana Ahmed, Caroline Baynes, Manjeet K. Bolla, Qin Wang, Joe Dennis, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Sue Healey, Michael Lush, Daniel C. Tessier, Daniel Vincent, Françis Bacot, Ignace Vergote, Sandrina Lambrechts, Evelyn Despierre, Harvey A. Risch, Anna González-Neira, Mary Anne Rossing, Guillermo Pita, Jennifer A. Doherty, Nuria Alvarez, Melissa C. Larson, Brooke L. Fridley, Nils Schoof, Jenny Chang-Claude, Mine S. Cicek, Julian Peto, Kimberly R. Kalli, Annegien Broeks, Sebastian M. Armasu, Marjanka K. Schmidt, Linde M. Braaf, Boris Winterhoff, Heli Nevanlinna, Gottfried E. Konecny, Diether Lambrechts, Lisa Rogmann, Pascal Guénel, Attila Teoman, Roger L. Milne, Joaquin J. Garcia, Angela Cox, Vijayalakshmi Shridhar, Barbara Burwinkel, Frederik Marme, Rebecca Hein, Elinor J. Sawyer, Christopher A. Haiman, Shan Wang-Gohrke, Irene L. Andrulis, Kirsten B. Moysich, John L. Hopper, Kunle Odunsi, Annika Lindblom, Graham G. Giles, Hermann Brenner, Jacques Simard, Galina Lurie, Peter A. Fasching, Michael E. Carney, Paolo Radice, Lynne R. Wilkens, Anthony Swerdlow, Marc T. Goodman, Hiltrud Brauch, Montserrat Garcia-Closas, Peter Hillemanns, Robert Winqvist, Matthias Dürst, Peter Devilee, Ingo Runnebaum, Anna Jakubowska, Jan Lubinski, Arto Mannermaa, Ralf Butzow, Natalia V. Bogdanova, Thilo Dörk, Liisa M. Pelttari, Wei Zheng, Arto Leminen, Hoda Anton-Culver, Clareann H. Bunker, Vessela Kristensen, Roberta B. Ness, Kenneth Muir, Robert Edwards, Alfons Meindl, Florian Heitz, Keitaro Matsuo, Andreas Du Bois, Anna H. Wu, Philipp Harter, Soo-Hwang Teo, Ira Schwaab, Xiao-Ou Shu, William Blot, Satoyo Hosono, Daehee Kang, Toru Nakanishi, Mikael Hartman, Yasushi Yatabe, Ute Hamann, Beth Y. Karlan, Suleeporn Sangrajrang, Susanne Krüger Kjaer, Valerie Gaborieau, Allan Jensen, Diana Eccles, Estrid Høgdall, Chen-Yang Shen, Judith Brown, Yin Ling Woo, Mitul Shah, Mat Adenan Noor Azmi, Robert Luben, Siti Zawiah Omar, Kamila Czene, Robert A. Vierkant, Børge G. Nordestgaard, Henrik Flyger, Celine Vachon, Janet E. Olson, Xianshu Wang, Douglas A. Levine, Anja Rudolph, Rachel Palmieri Weber, Dieter Flesch-Janys, Edwin Iversen, Stefan Nickels, Joellen M. Schildkraut, Isabel Dos Santos Silva, Daniel W. Cramer, Lorna Gibson, Kathryn L. Terry, Olivia Fletcher, Allison F. Vitonis, C. Ellen van der Schoot, Elizabeth M. Poole, Frans B. L. Hogervorst, Shelley S. Tworoger, Jianjun Liu, Elisa V. Bandera, Jingmei Li, Sara H. Olson, Keith Humphreys, Irene Orlow, Carl Blomqvist, Lorna Rodriguez-Rodriguez, Kristiina Aittomäki, Helga B. Salvesen, Taru A. Muranen, Elisabeth Wik, Barbara Brouwers, Camilla Krakstad, Els Wauters, Mari K. Halle, Hans Wildiers, Lambertus A. Kiemeney, Claire Mulot, Katja K. Aben, Pierre Laurent-Puig, Anne Mvan Altena, Thérèse Truong, Leon F. A. G. Massuger, Javier Benitez, Tanja Pejovic, Jose Ignacio Arias Perez, Maureen Hoatlin, M. Pilar Zamora, Linda S. Cook, Sabapathy P. Balasubramanian, Linda E. Kelemen, Andreas Schneeweiss, Nhu D. Le, Christof Sohn, Angela Brooks-Wilson, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Cezary Cybulski, Brian E. Henderson, Janusz Menkiszak, Fredrick Schumacher, Nicolas Wentzensen, Loic Le Marchand, Hannah P. Yang, Anna Marie Mulligan, Gord Glendon, Svend Aage Engelholm, Julia A. Knight, Claus K. Høgdall, Carmel Apicella, Martin Gore, Helen Tsimiklis, Honglin Song, Melissa C. Southey, Agnes Jager, Ans M. Wvan den Ouweland, Robert Brown, John W. M. Martens, James M. Flanagan, Mieke Kriege, James Paul, Sara Margolin, Nadeem Siddiqui, Gianluca Severi, Alice S. Whittemore, Laura Baglietto, Valerie McGuire, Christa Stegmaier, Weiva Sieh, Heiko Müller, Volker Arndt, France Labrèche, Yu-Tang Gao, Mark S. Goldberg, Gong Yang, Martine Dumont, John R. McLaughlin, Arndt Hartmann, Arif B. Ekici, Matthias W. Beckmann, Catherine M. Phelan, Michael P. Lux, Jenny Permuth-Wey, Bernard Peissel, Thomas A. Sellers, Filomena Ficarazzi, Monica Barile, Argyrios Ziogas, Alan Ashworth, Aleksandra Gentry-Maharaj, Michael Jones, Susan J. Ramus, Nick Orr, Usha Menon, Celeste L. Pearce, Thomas Brüning, Malcolm C. Pike, Yon-Dschun Ko, Jolanta Lissowska, Jonine Figueroa, Jolanta Kupryjanczyk, Stephen J. Chanock, Agnieszka Dansonka-Mieszkowska, Arja Jukkola-Vuorinen, Iwona K. Rzepecka, Katri Pylkäs, Mariusz Bidzinski, Saila Kauppila, Antoinette Hollestelle, Caroline Seynaeve, Rob A. E. M. Tollenaar, Katarzyna Durda, Katarzyna Jaworska, Jaana M. Hartikainen, Veli-Matti Kosma, Vesa Kataja, Natalia N. Antonenkova, Jirong Long, Martha Shrubsole, Sandra Deming-Halverson, Artitaya Lophatananon, Pornthep Siriwanarangsan, Sarah Stewart-Brown, Nina Ditsch, Peter Lichtner, Rita K. Schmutzler, Hidemi Ito, Hiroji Iwata, Kazuo Tajima, Chiu-Chen Tseng, Daniel O. Stram, David van den Berg, Cheng Har Yip, M. Kamran Ikram, Yew-Ching Teh, Hui Cai, Wei Lu, Lisa B. Signorello, Qiuyin Cai, Dong-Young Noh, Keun-Young Yoo, Hui Miao, Philip Tsau-Choong Iau, Yik Ying Teo, James McKay, Charles Shapiro, Foluso Ademuyiwa, George Fountzilas, Chia-Ni Hsiung, Jyh-Cherng Yu, Ming-Feng Hou, Catherine S. Healey, Craig Luccarini, Susan Peock, Dominique Stoppa-Lyonnet, Paolo Peterlongo, Timothy R. Rebbeck, Marion Piedmonte, Christian F. Singer, Eitan Friedman, Mads Thomassen, Kenneth Offit, Thomas v. O. Hansen, Susan L. Neuhausen, Csilla I. Szabo, Ignacio Blanco, Judy Garber, Steven A. Narod, Jeffrey N. Weitzel, Marco Montagna, Edith Olah, Andrew K. Godwin, Drakoulis Yannoukakos, David E. Goldgar, Trinidad Caldes, Evgeny N. Imyanitov, Laima Tihomirova, Banu K. Arun, Ian Campbell, Arjen R. Mensenkamp, Christi J. van Asperen, Kees E. P. van Roozendaal, Hanne Meijers-Heijboer, J. Margriet Collée, Jan C. Oosterwijk, Maartje J. Hooning, Matti A. Rookus, Rob B. van der Luijt, Theo A. Mvan Os, D. Gareth Evans, Debra Frost, Elena Fineberg, Julian Barwell, Lisa Walker, M. John Kennedy, Radka Platte, Rosemarie Davidson, Steve D. Ellis, Trevor Cole, Brigitte Bressac-de Paillerets, Bruno Buecher, Francesca Damiola, Laurence Faivre, Marc Frenay, Olga M. Sinilnikova, Olivier Caron, Sophie Giraud, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux-Moncoutier, Aleksandra Toloczko-Grabarek, Jacek Gronwald, Tomasz Byrski, Amanda B. Spurdle, Bernardo Bonanni, Daniela Zaffaroni, Giuseppe Giannini, Loris Bernard, Riccardo Dolcetti, Siranoush Manoukian, Norbert Arnold, Christoph Engel, Helmut Deissler, Kerstin Rhiem, Dieter Niederacher, Hansjoerg Plendl, Christian Sutter, Barbara Wappenschmidt, Ake Borg, Beatrice Melin, Johanna Rantala, Maria Soller, Katherine L. Nathanson, Susan M. Domchek, Gustavo C. Rodriguez, Ritu Salani, Daphne Gschwantler Kaulich, Muy-Kheng Tea, Shani Shimon Paluch, Yael Laitman, Anne-Bine Skytte, Torben A. Kruse, Uffe Birk Jensen, Mark Robson, Anne-Marie Gerdes, Bent Ejlertsen, Lenka Foretova, Sharon A. Savage, Jenny Lester, Penny Soucy, Karoline B. Kuchenbaecker, Curtis Olswold, Julie M. Cunningham, Susan Slager, Vernon S. Pankratz, Ed Dicks, Sunil R. Lakhani, Fergus J. Couch, Per Hall, Alvaro N. A. Monteiro, Simon A. Gayther, Paul D. P. Pharoah, Roger R. Reddel, Ellen L. Goode, Mark H. Greene, Douglas F. Easton, Andrew Berchuck, Antonis C. Antoniou, Georgia Chenevix-Trench, Alison M. Dunning

Date Published: 1st Apr 2013

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Multiple meningioma with different grades of malignancy: case report with genetic analysis applying single-nucleotide polymorphism array and classical cytogenetics
Genetical Statistics and Systems Biology

Abstract (Expand)

Multiple meningiomas with synchronous tumor lesions represent only 1-9% of all meningiomas and usually show a uniform histology. The simultaneous occurrence of different grades of malignancy in these … nodules is observed in only one third of multiple meningiomas. We report a case of a sporadic multiple meningioma presenting with different histopathological grades (WHO I and II). The tumor genome of both nodules was analyzed by GTG-banding, spectral karyotyping (SKY), locus-specific FISH, and single nucleotide polymorphism array (SNP-A) karyotyping. GTG-banding and SKY revealed 25 structural and 33 numerical aberrations with a slightly increased aberration frequency in the WHO grade II nodule. We could confirm terminal deletions on chromosomes 1p [ish del(1)(p36)(p58-,pter-) 16.5% WHO grade I and 20.9% WHO grade II], partial deletions on 22q, and/or monosomy 22 (monosomy 22 14% WHO grade I and 34% WHO grade II) as the most frequent aberrations in both meningioma nodules. In the meningioma WHO grade II, in addition, a de novo paracentric inversion within chromosomal band 1p36 was detectable. Furthermore, for meningiomas de novo, dicentric chromosomes 4 could be identified in both tumor nodules. We also detected previously published segmental uniparental disomy regions 1p31.1, 6q14.1, 10q21.1, and 14q23.3 in normal control DNA of the patient and in both tumor nodules. Taken together, we describe a very rare case of multiple meningioma with overlapping but also distinct genetic aberration patterns in two nodules of different WHO grades of malignancy.

Authors: Kristin Mocker, Heidrun Holland, Peter Ahnert, Ralf Schober, Manfred Bauer, Holger Kirsten, Ronald Koschny, Jürgen Meixensberger, Wolfgang Krupp

Date Published: 2011

Publication Type: Journal article

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium … of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Authors: Timothy R. Rebbeck, Tara M. Friebel, Eitan Friedman, Ute Hamann, Dezheng Huo, Ava Kwong, Edith Olah, Olufunmilayo I. Olopade, Angela R. Solano, Soo-Hwang Teo, Mads Thomassen, Jeffrey N. Weitzel, T. L. Chan, Fergus J. Couch, David E. Goldgar, Torben A. Kruse, Edenir Inêz Palmero, Sue Kyung Park, Diana Torres, Elizabeth J. van Rensburg, Lesley McGuffog, Michael T. Parsons, Goska Leslie, Cora M. Aalfs, Julio Abugattas, Julian Adlard, Simona Agata, Kristiina Aittomäki, Lesley Andrews, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Ella Asseryanis, Leo Auerbach, Jacopo Azzollini, Judith Balmaña, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Andreas Berger, Raanan Berger, Amie M. Blanco, Kathleen R. Blazer, Marinus J. Blok, Valérie Bonadona, Bernardo Bonanni, Angela R. Bradbury, Carole Brewer, Bruno Buecher, Saundra S. Buys, Trinidad Caldes, Almuth Caliebe, Maria A. Caligo, Ian Campbell, Sandrine M. Caputo, Jocelyne Chiquette, Wendy K. Chung, Kathleen B. M. Claes, J. Margriet Collée, Jackie Cook, Rosemarie Davidson, Miguel de La Hoya, Kim de Leeneer, Antoine de Pauw, Capucine Delnatte, Orland Diez, Yuan Chun Ding, Nina Ditsch, Susan M. Domchek, Cecilia M. Dorfling, Carolina Velazquez, Bernd Dworniczak, Jacqueline Eason, Douglas F. Easton, Ros Eeles, Hans Ehrencrona, Bent Ejlertsen, Christoph Engel, Stefanie Engert, D. Gareth Evans, Laurence Faivre, Lidia Feliubadaló, Sandra Fert Ferrer, Lenka Foretova, Jeffrey Fowler, Debra Frost, Henrique C. R. Galvão, Patricia A. Ganz, Judy Garber, Marion Gauthier-Villars, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Giuseppe Giannini, Sophie Giraud, Gord Glendon, Andrew K. Godwin, Mark H. Greene, Jacek Gronwald, Angelica Gutierrez-Barrera, Eric Hahnen, Jan Hauke, Alex Henderson, Julia Hentschel, Frans B. L. Hogervorst, Ellen Honisch, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Angel Izquierdo, Anna Jakubowska, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Joseph Vijai, Katarzyna Kaczmarek, Beth Y. Karlan, Karin Kast, Kconfab Investigators, Sung-Won Kim, Irene Konstantopoulou, Jacob Korach, Yael Laitman, Adriana Lasa, Christine Lasset, Conxi Lázaro, Annette Lee, Min Hyuk Lee, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Noralane M. Lindor, Michel Longy, Jennifer T. Loud, Karen H. Lu, Jan Lubinski, Eva Machackova, Siranoush Manoukian, Véronique Mari, Cristina Martínez-Bouzas, Zoltan Matrai, Noura Mebirouk, Hanne E. J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Ugnius Mickys, Austin Miller, Marco Montagna, Kirsten B. Moysich, Anna Marie Mulligan, Jacob Musinsky, Susan L. Neuhausen, Heli Nevanlinna, Joanne Ngeow, Huu Phuc Nguyen, Dieter Niederacher, Henriette Roed Nielsen, Finn Cilius Nielsen, Robert L. Nussbaum, Kenneth Offit, Anna Öfverholm, Kai-Ren Ong, Ana Osorio, Laura Papi, Janos Papp, Barbara Pasini, Inge Sokilde Pedersen, Ana Peixoto, Nina Peruga, Paolo Peterlongo, Esther Pohl, Nisha Pradhan, Karolina Prajzendanc, Fabienne Prieur, Pascal Pujol, Paolo Radice, Susan J. Ramus, Johanna Rantala, Muhammad Usman Rashid, Kerstin Rhiem, Mark Robson, Gustavo C. Rodriguez, Mark T. Rogers, Vilius Rudaitis, Ane Y. Schmidt, Rita Katharina Schmutzler, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Jacques Simard, Christian F. Singer, Anne-Bine Skytte, Thomas P. Slavin, Katie Snape, Hagay Sobol, Melissa Southey, Linda Steele, Doris Steinemann, Grzegorz Sukiennicki, Christian Sutter, Csilla I. Szabo, Yen Y. Tan, Manuel R. Teixeira, Mary Beth Terry, Alex Teulé, Abigail Thomas, Darcy L. Thull, Marc Tischkowitz, Silvia Tognazzo, Amanda Ewart Toland, Sabine Topka, Alison H. Trainer, Nadine Tung, Christi J. van Asperen, Annemieke H. van der Hout, Lizet E. van der Kolk, Rob B. van der Luijt, Mattias van Heetvelde, Liliana Varesco, Raymonda Varon-Mateeva, Ana Vega, Cynthia Villarreal-Garza, Anna von Wachenfeldt, Lisa Walker, Shan Wang-Gohrke, Barbara Wappenschmidt, Bernhard H. F. Weber, Drakoulis Yannoukakos, Sook-Yee Yoon, Cristina Zanzottera, Jamal Zidan, Kristin K. Zorn, Christina G. Hutten Selkirk, Peter J. Hulick, Georgia Chenevix-Trench, Amanda B. Spurdle, Antonis C. Antoniou, Katherine L. Nathanson

Date Published: 1st May 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma.
GLA - German Lymphoma Alliance

Abstract (Expand)

MYC rearrangements occur in 5% to 10% of diffuse large B-cell lymphomas (DLBCL) and confer an increased risk to cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and rituximab … (R)-CHOP treated patients. We investigated the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression in a prospective randomized trial. Paraffin-embedded tumor samples from 442 de novo DLBCL treated within the RICOVER study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH) to detect protein expression and breaks of MYC, BCL2, and BCL6. Rearrangements of MYC, BCL2, and BCL6 were detected in 8.8%, 13.5%, and 28.7%, respectively. Protein overexpression of MYC (>40%) was encountered in 31.8% of tumors; 79.6% and 82.8% of tumors expressed BCL2 and BCL6, respectively. MYC translocations, MYChigh, BCL2high, and BCL6low protein expressions were associated with inferior survival. In multivariate Cox regression modeling, protein expression patterns of MYC, BCL2 and BCL6, and MYC rearrangements were predictive of outcome and provided prognostic information independent of the International Prognostic Index (IPI) for overall survival and event-free survival. A combined immunohistochemical or FISH/immunohistochemical score predicts outcome in DLBCL patients independent of the IPI and identifies a subset of 15% of patients with dismal prognosis in the high-risk IPI group following treatment with R-CHOP. Registered at http://www.cancer.gov/clinicaltrials: RICOVER trial of the DSHNHL is NCT 00052936.

Authors: H. Horn, M. Ziepert, C. Becher, T. F. Barth, H. W. Bernd, A. C. Feller, W. Klapper, M. Hummel, H. Stein, M. L. Hansmann, C. Schmelter, P. Moller, S. Cogliatti, M. Pfreundschuh, N. Schmitz, L. Trumper, R. Siebert, M. Loeffler, A. Rosenwald, G. Ott

Date Published: 21st Mar 2013

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Myocardial Infarction-Associated Circular RNA Predicting Left Ventricular Dysfunction.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract

Not specified

Authors: M. Vausort, A. Salgado-Somoza, L. Zhang, P. Leszek, M. Scholz, A. Teren, R. Burkhardt, J. Thiery, D. R. Wagner, Y. Devaux

Date Published: 13th Sep 2016

Publication Type: Journal article

Human Diseases: left ventricular noncompaction, myocardial infarction

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