Smedley D.,Wellcome Trust Sanger Institute |
Oellrich A.,Wellcome Trust Sanger Institute |
Kohler S.,Universitatsklinikum Charite |
Ruef B.,University of Oregon |
And 4 more authors.
Database | Year: 2013
The ultimate goal of studying model organisms is to translate what is learned into useful knowledge about normal human biology and disease to facilitate treatment and early screening for diseases. Recent advances in genomic technologies allow for rapid generation of models with a range of targeted genotypes as well as their characterization by high-throughput phenotyping. As an abundance of phenotype data become available, only systematic analysis will facilitate valid conclusions to be drawn from these data and transferred to human diseases. Owing to the volume of data, automated methods are preferable, allowing for a reliable analysis of the data and providing evidence about possible gene-disease associations. Here, we propose Phenotype comparisons for DIsease Genes and Models (PhenoDigm), as an automated method to provide evidence about gene-disease associations by analysing phenotype information. PhenoDigm integrates data from a variety of model organisms and, at the same time, uses several intermediate scoring methods to identify only strongly data-supported gene candidates for human genetic diseases. We show results of an automated evaluation as well as selected manually assessed examples that support the validity of PhenoDigm. Furthermore, we provide guidance on how to browse the data with PhenoDigm's web interface and illustrate its usefulness in supporting research. © The Author(s) 2013. Published by Oxford University Press.
Winzer K.-J.,Charité - Medical University of Berlin |
Sauerbrei W.,Albert Ludwigs University of Freiburg |
Liersch T.,Universitatsmedizin Gottingen |
Dunst J.,Universitatsklinikum Halle |
And 2 more authors.
European Journal of Cancer | Year: 2010
To study the role of radiotherapy and tamoxifen after breast-conserving surgery (BCS) in patients with a favourable prognosis, a clinical trial was initiated by the German Breast Cancer Study Group (GBSG-V). Between 1991 and 1998, 361 patients (pT 1pN0M0, aged 45-75 years, receptor positive, grades I and II) were randomised to radiotherapy (yes/no) and tamoxifen for 2 years (yes/no) in a 2 × 2-factorial design; the exclusion of seven centres (14 patients) left 347 patients for the analysis. First results after a median follow-up of 5.9 years were published. Herein we present updated results after a median follow-up of about 10 years. Hundred and eleven events concerning event-free survival (EFS) have been observed. Since a strong interactive effect between radiotherapy and tamoxifen has been established, the results are presented in terms of the treatment effects for all four treatment groups separately. Mainly due to the presence of local recurrences, the event rate was much higher in the group with BCS only than in the other three groups. No significant difference could be established between the four treatment groups for distant disease-free survival rates (DDFS). Updated results give further evidence that even in patients with a favourable prognosis, the avoidance of radiotherapy and tamoxifen after BCS increases the rate of local recurrences substantially. Rates are about three times higher in the BCS only group. For the two outcomes EFS and DDFS, no important difference could be seen between the three groups with an additional treatment. However, because of the limited sample size with corresponding low power the strength of evidence for such a comparison is weak. © 2009 Elsevier Ltd. All rights reserved.
Missense mutations in transcription factors: Assessment and functional characterization of pathogenic transcription factor mutations [Missense-Mutationen in Transkriptionsfaktoren: Einschätzung und funktionelle Charakterisierung pathogener Transkriptionsfaktormutationen]
Ibrahim D.M.,Universitatsklinikum Charite |
Ibrahim D.M.,Max Planck Institute For Molekulare Genetik
Medizinische Genetik | Year: 2015
Transcription factors (TF) are key regulators that control the cell-type-specific gene expression in each individual cell and are crucial for the coordination of embryonic development. Mutations in TFs frequently underlie heritable developmental defects; however, the functional characterization of a variant TF is challenging, since the exact molecular mechanisms by which TFs exert their function are not fully understood. In particular, gain-of-function mutations can lead to novel phenotypes that are difficult to characterize functionally. Recent technological advances, in particular ChIP-seq, have enabled experimental approaches that can distinguish between distinct molecular mechanisms underlying TF-associated diseases. This article reviews the molecular pathomechanisms underlying various TF mutations and proposes approaches to previously unknown TF mutations. © 2015, Springer-Verlag Berlin Heidelberg.
Kvols L.K.,H. Lee Moffitt Cancer Center and Research Institute |
Oberg K.E.,Uppsala University Hospital |
O'Dorisio T.M.,University of Iowa |
Mohideen P.,Novartis |
And 7 more authors.
Endocrine-Related Cancer | Year: 2012
Pasireotide (SOM230) is a novel multireceptor-targeted somatostatin (sst) analog with high binding affinity for sst receptor subtype 1, 2, 3 (sst 1,2,3) and sst5. Because of this binding profile, pasireotide may offer symptom control in patients with neuroendocrine tumors (NETs) and carcinoid syndrome no longer responsive to octreotide LAR. This was a phase II, open-label, multicenter study of pasireotide in patients with advanced NET whose symptoms of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR. Patients received s.c. pasireotide 150 μg twice daily (bid), escalated to a maximum dose of 1200 μg bid until a clinical response was achieved. Forty-four patients were evaluated for efficacy and 45 for tolerability. Pasireotide 600-900 μg s.c. bid effectively controlled the symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 patients showed 13 with stable disease and ten with progressive disease at study end. The most common drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%) and most were of mild or moderate severity. Pasireotide 600-900 μg s.c. bid was effective and generally well tolerated in controlling the symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy. © 2012 Society for Endocrinology.
Van Biesen W.,Ghent University |
Jorres A.,Universitatsklinikum Charite
Kidney International | Year: 2014
McCafferty and colleagues report on a retrospective analysis in peritoneal dialysis patients in whom fluid status was assessed by multifrequency bioimpedance. During 12 months of follow-up, overhydration, as identified by an increased ratio of extracellular over total body water, was not associated with better preservation of residual renal function (RRF). These findings suggest that running patients 'wet' might not contribute to better preservation of RRF in peritoneal dialysis © 2013 International Society of Nephrology.
Janke M.,Deutsches Rheumaforschungszentrum Berlin |
Peine M.,Deutsches Rheumaforschungszentrum Berlin |
Nass A.,Charité - Medical University of Berlin |
Morawietz L.,Universitatsklinikum Charite |
And 3 more authors.
European Journal of Immunology | Year: 2010
Recently, IL-17 produced by Th17 cells was described as pro-inflammatory cytokine with an eminent role in autoimmune diseases, e.g. rheumatoid arthritis. A lack of IL-17 leads to amelioration of collagen-induced arthritis. IL-17 induction in naïve CD4+ T cells depends on IL-6 and TGF-β and is enhanced by IL-23. The in vivo inflammatory potential of in vitro-primed Th17 cells however, remains unclear. Here, we show that, although IL-17 neutralisation results in amelioration of murine OVA-induced arthritis, in vitro-primed Th17 cells cannot exacerbate arthritic symptoms after adoptive transfer. Furthermore, Th17 cells cannot induce an inflammatory delayed type hypersensitivity reaction because they fail to migrate into inflamed sites, possibly due to the lack of CXCR3 expression. Also, re-isolated Th17 cells acquired IFN-γ expression, indicating instability of the Th17 phenotype. Taken together, the data show that IL-6, TGF-β and IL-23 might not provide sufficient signals to induce "fully qualified" Th17 cells. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.
Catar R.,Universitatsklinikum Charite |
Witowski J.,Universitatsklinikum Charite |
Witowski J.,Poznan University of Medical Sciences |
Wagner P.,Universitatsklinikum Charite |
And 6 more authors.
Kidney International | Year: 2013
Vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) are key mediators of adverse peritoneal membrane remodeling in peritoneal dialysis eventually leading to ultrafiltration failure. Both are pleiotropic growth factors with cell type-dependent regulation of expression and biological effects. Here we studied regulation of TGF-β1-induced VEGF expression in human peritoneal mesothelial cells in the absence or presence of proinflammatory stimuli, tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). Quiescent human peritoneal mesothelial cells secreted only trace amounts of VEGF. Stimulation with TGF-β1 resulted in time- and dose-dependent increases in VEGF mRNA expression and protein release. TNF-α and IL-1β alone had minimal effects but acted in synergy with TGF-β1. Combined stimulation led to induction of transcription factor c-Fos and activation of the VEGF promoter region with high-affinity binding sites for c-Fos. Inhibition of c-Fos by small interfering RNA interference or by pharmacological blockade with SR-11302 decreased VEGF promoter activity and downregulated its expression and release. Exposure of human peritoneal mesothelial cells to dialysate effluent containing increased levels of TGF-β1, TNF-α, and IL-1β obtained during peritonitis resulted in a dose-dependent VEGF induction that was significantly attenuated by SR-11302. Thus, dialysate TGF-β1, IL-1β, and TNF-α act through c-Fos to synergistically upregulate VEGF production in peritoneal mesothelium and may represent an important regulatory link between inflammation and angiogenesis in the peritoneal membrane.© 2013 International Society of Nephrology.
Van Der Heijden J.,University of Amsterdam |
Geissler J.,University of Amsterdam |
Geissler J.,Emma Childrens Hospital |
Van Mirre E.,University of Amsterdam |
And 7 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013
Background: Our index case was a patient with common variable immunodeficiency (CVID). She had anaphylactoid reactions on administration of intravenous immunoglobulin (IVIg) associated with the presence of IgG antibodies against IgA. Objective: We sought to determine the role of Fcγ receptor (FcγR) IIa in IVIg-induced anaphylactoid reactions. Methods: Neutrophils and PBMCs were isolated from healthy subjects and IVIg-treated patients. FcγRIIa mRNA and DNA were analyzed by using real-time PCR and sequencing. IgG-mediated elastase release and intracellular Ca2+ mobilization were determined in neutrophils and transfected cell lines, respectively. Results: A novel splice variant of FcγRIIa containing an expressed cryptic exon 6* (FcγRIIaexon6) was identified in our index patient. This exon is normally spliced out of all FcγRII isoforms, except the inhibitory FcγRIIb1. Compared with healthy control subjects, the heterozygous FCGR2Ac.742+871A>G mutation was more frequent in patients with CVID (n = 53, P < .013). Expression in patients with CVID was associated with anaphylaxis on IVIg infusion (P =.002). On screening of additional IVIg-treated patient cohorts, we identified 6 FCGR2A c.742+871A>G allele-positive patients with Kawasaki disease (n = 208) and 1 patient with idiopathic thrombocytopenia (n = 93). None had adverse reactions to IVIg. Moreover, FcγRIIaexon6 was also demonstrated in asymptomatic family members. Functional studies in primary cells and transfected murine cells demonstrated enhanced cellular activation by FcγRIIaexon6 compared with its native form, as shown by increased elastase release and intracellular calcium mobilization. Conclusion: A novel splice variant, FcγRIIaexon6, was characterized as a low-frequency allele, coding for a gain-of-function receptor for IgG. In the presence of immune complexes, FcγRIIaexon6 can contribute to anaphylaxis in patients with CVID. © 2012 American Academy of Allergy, Asthma & Immunology.
Krawitz P.,Universitatsklinikum Charite
Medizinische Genetik | Year: 2010
Recent advances in sequencing technology have reduced the costs and time required to decode a single genome to the extent that complete sequencing of personal genomes becomes affordable for both private individuals and the health care system. The broad availability of individual genomes will drive medicine further towards an information-based science and the importance of IT solutions in medicine will increase. © 2010 Springer-Verlag.
Anticoagulation and perioperative bridging: From the perspective of a proctoligst in medical practice [Antikoagulation und perioperatives “bridging“: Aus der Sicht eines praktisch tätigen Proktologen]
Loch H.,Proktologisches Zentrum Berlin |
Koscielny J.,Universitatsklinikum Charite
Coloproctology | Year: 2016
Before performing proctological surgery on patients receiving long-term anticoagulation therapy, the risk of bleeding and thromboembolism have to be considered. Based on these risks the treatment with vitamin K antagonists should either be continued or switched to low molecular weight heparin for the time around the surgery (bridging). Patients receiving direct oral anticoagulants do not need a bridging due to the short half-life and the rapid resumption of pharmaceutical effects but need to stop taking the medication perioperatively. Those patients treated with antiplatelet drugs as monotherapy should continue taking them perioperatively if deemed medically necessary. In the case of dual antiplatelet treatment after stent implantation, elective surgery should be postponed until the patient can be treated with antiplatelet monotherapy. © 2015, Springer-Verlag Berlin Heidelberg.