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  • 1
    Abstract: New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients.
    Type of Publication: Journal article published
    PubMed ID: 29497170
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    ISSN: 1365-2230
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Journal of Theoretical Biology 164 (1993), S. 85-102 
    ISSN: 0022-5193
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background : There is debate about the optimal colorectal cancer screening test, partly because of concerns about colonoscopy demand.Aim : To quantify the demand for colonoscopy with different screening tests, and to estimate the ability of the United States health care system to meet demand.Methods : We used a previously published Markov model and the United States census data to estimate colonoscopy demand. We then used an endoscopic database to compare current rates of screening-related colonoscopy with those projected by the model, and to estimate the number of endoscopists needed to meet colonoscopy demand.Results : Annual demand for colonoscopy ranges from 2.21 to 7.96 million. Based on current practice patterns, demand exceeds current supply regardless of screening strategy. We estimate that an increase of at least 1360 gastroenterologists would be necessary to meet demand for colonoscopic screening undergone once at age 65, while colonoscopy every 10 years could require 32 700 more gastroenterologists. A system using dedicated endoscopists could meet demand with fewer endoscopists.Conclusions : Colorectal cancer screening leads to demand for colonoscopy that outstrips supply. Systems to train dedicated screening endoscopists may be necessary in order to provide population-wide screening. The costs and feasibility of establishing this infrastructure should be studied further.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Aim : To assess the effectiveness and safety of budesonide in comparison to corticosteroids, 5-aminosalicylic acid (5-ASA), or placebo for inducing remission of active Crohn's disease and for maintaining remission.Study selection criteria : Randomized controlled trials comparing budesonide to corticosteroids, 5-ASA products or placebo were included. Trials had to report on the effectiveness of treatment (defined as decreasing or maintaining Crohn's Disease Activity Index, CDAI, scores ≤ 150) or adverse events.Data analysis : After assessing the validity of study design and independent, duplicate data extraction from selected trials, summary relative risks (RR) were calculated for each outcome. A test of heterogeneity was also calculated for each outcome using a random effects model.Results : Budesonide was more likely to induce remission than placebo (RR=1.82, 95% CI: 1.15–2.88) or 5-ASA (RR=1.73, 95% CI: 1.26–2.39), although only one trial compared budesonide to 5-ASA products. Although budesonide induced remission less frequently than conventional corticosteroids (RR=0.87, 95% CI: 0.76–0.995), there was no significant difference between conventional corticosteroids and budesonide for inducing remission among patients with a low disease activity (initial CDAI=200–300). Budesonide was significantly less likely to cause corticosteroid-associated adverse events than conventional corticosteroids (RR=0.65, 95% CI: 0.53–0.80). No significant difference in total adverse events or corticosteroid-associated adverse events was demonstrated between budesonide and 5-ASA or placebo.Conclusion : Budesonide is significantly more effective than placebo or 5-ASA for inducing remission of active Crohn's disease. Although budesonide is 13% less effective for the induction of remission in active Crohn's disease than conventional corticosteroids, it is less likely to cause corticosteroid-related adverse effects. Budesonide is ineffective in maintaining remission.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Chemical Physics Letters 224 (1994), S. 411-416 
    ISSN: 0009-2614
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology , Physics
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2013-03-16
    Description: A core feature of protective T cell responses to infection is the robust expansion and diversification of naive antigen-specific T cell populations into short-lived effector and long-lived memory subsets. By means of in vivo fate mapping, we found a striking variability of immune responses derived from individual CD8(+) T cells and show that robust acute and recall immunity requires the initial recruitment of multiple precursors. Unbiased mathematical modeling identifies the random integration of multiple differentiation and division events as the driving force behind this variability. Within this probabilistic framework, cell fate is specified along a linear developmental path that progresses from slowly proliferating long-lived to rapidly expanding short-lived subsets. These data provide insights into how complex biological systems implement stochastic processes to guarantee robust outcomes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buchholz, Veit R -- Flossdorf, Michael -- Hensel, Inge -- Kretschmer, Lorenz -- Weissbrich, Bianca -- Graf, Patricia -- Verschoor, Admar -- Schiemann, Matthias -- Hofer, Thomas -- Busch, Dirk H -- New York, N.Y. -- Science. 2013 May 3;340(6132):630-5. doi: 10.1126/science.1235454. Epub 2013 Mar 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitat Munchen, Munich 81675, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23493420" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; CD8-Positive T-Lymphocytes/*immunology ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Clonal Selection, Antigen-Mediated ; Computer Simulation ; *Immunity, Cellular ; *Immunologic Memory ; Immunophenotyping ; Interferon-gamma/biosynthesis ; Interleukin-2/biosynthesis ; Listeria monocytogenes ; Listeriosis/*immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Models, Immunological ; Single-Cell Analysis ; Stochastic Processes ; T-Cell Antigen Receptor Specificity ; T-Lymphocyte Subsets/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2015-10-16
    Description: Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peifer, Martin -- Hertwig, Falk -- Roels, Frederik -- Dreidax, Daniel -- Gartlgruber, Moritz -- Menon, Roopika -- Kramer, Andrea -- Roncaioli, Justin L -- Sand, Frederik -- Heuckmann, Johannes M -- Ikram, Fakhera -- Schmidt, Rene -- Ackermann, Sandra -- Engesser, Anne -- Kahlert, Yvonne -- Vogel, Wenzel -- Altmuller, Janine -- Nurnberg, Peter -- Thierry-Mieg, Jean -- Thierry-Mieg, Danielle -- Mariappan, Aruljothi -- Heynck, Stefanie -- Mariotti, Erika -- Henrich, Kai-Oliver -- Gloeckner, Christian -- Bosco, Graziella -- Leuschner, Ivo -- Schweiger, Michal R -- Savelyeva, Larissa -- Watkins, Simon C -- Shao, Chunxuan -- Bell, Emma -- Hofer, Thomas -- Achter, Viktor -- Lang, Ulrich -- Theissen, Jessica -- Volland, Ruth -- Saadati, Maral -- Eggert, Angelika -- de Wilde, Bram -- Berthold, Frank -- Peng, Zhiyu -- Zhao, Chen -- Shi, Leming -- Ortmann, Monika -- Buttner, Reinhard -- Perner, Sven -- Hero, Barbara -- Schramm, Alexander -- Schulte, Johannes H -- Herrmann, Carl -- O'Sullivan, Roderick J -- Westermann, Frank -- Thomas, Roman K -- Fischer, Matthias -- England -- Nature. 2015 Oct 29;526(7575):700-4. doi: 10.1038/nature14980. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. ; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. ; Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, 50937 Cologne, Germany. ; Division Neuroblastoma Genomics (B087), German Cancer Research Center, 69120 Heidelberg, Germany. ; Department of Prostate Cancer Research, Institute of Pathology, Center for Integrated Oncology Cologne-Bonn, University Hospital of Bonn, 53127 Bonn, Germany. ; NEO New Oncology AG, 51105 Cologne, Germany. ; Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute (UPCI), Hillman Cancer Center, Pittsburgh, Pennsylvania 15213, USA. ; Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany. ; Institute of Biostatistics and Clinical Research, University of Munster, 48149 Munster, Germany. ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. ; National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA. ; Department of Pathology, University of Kiel, 24118 Kiel, Germany. ; Functional Epigenomics, University of Cologne, 50931 Cologne, Germany. ; Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. ; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Computing Center, University of Cologne, 50931 Cologne, Germany. ; Department of Informatics, University of Cologne, 50931 Cologne, Germany. ; Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Pediatric Oncology and Hematology, Charite University Medical Center Berlin, 10117 Berlin, Germany. ; Center for Medical Genetics, Ghent University, 9000 Ghent, Belgium. ; BGI-Shenzhen, Bei Shan Industrial Zone, Yantian District, Shenzhen, Guangdong, 518083 China. ; Center for Pharmacogenomics and Fudan-Zhangjiang Center for Clinical Genomics, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology School of Pharmacy and School of Life Sciences, Fudan University, Shanghai 201203, China. ; Department of Pathology, University of Cologne, 50937 Cologne, Germany. ; Department of Pediatric Oncology and Hematology, University Children's Hospital, 45147 Essen, Germany. ; German Cancer Consortium (DKTK), 10117 Berlin, Germany. ; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany. ; Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466568" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2015-02-18
    Description: Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation. Chromosomal marking, viral integration and barcoding of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2(+) HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or approximately 5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Busch, Katrin -- Klapproth, Kay -- Barile, Melania -- Flossdorf, Michael -- Holland-Letz, Tim -- Schlenner, Susan M -- Reth, Michael -- Hofer, Thomas -- Rodewald, Hans-Reimer -- England -- Nature. 2015 Feb 26;518(7540):542-6. doi: 10.1038/nature14242. Epub 2015 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cellular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; 1] Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium [2] Autoimmune Genetics Laboratory, VIB, B-3000 Leuven, Belgium. ; 1] BIOSS, Centre For Biological Signaling Studies, University of Freiburg, Schanzlestrasse 18, D-79104 Freiburg, Germany [2] Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg, and Max-Planck Institute of Immunobiology and Epigenetics, Stubeweg 51, D-79108 Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686605" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Animals, Newborn ; Bone Marrow Transplantation ; Cell Lineage/*physiology ; Cell Proliferation ; Cell Tracking ; Female ; Fetus/cytology/embryology ; Fluorouracil ; *Hematopoiesis ; Hematopoietic Stem Cells/*cytology/metabolism ; Male ; Mice ; Receptor, TIE-2/metabolism ; Stem Cells/*cytology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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