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1.  The COPD Knowledge Base: enabling data analysis and computational simulation in translational COPD research 
Journal of Translational Medicine  2014;12(Suppl 2):S6.
Previously we generated a chronic obstructive pulmonary disease (COPD) specific knowledge base ( from clinical and experimental data, text-mining results and public databases. This knowledge base allowed the retrieval of specific molecular networks together with integrated clinical and experimental data.
The COPDKB has now been extended to integrate over 40 public data sources on functional interaction (e.g. signal transduction, transcriptional regulation, protein-protein interaction, gene-disease association). In addition we integrated COPD-specific expression and co-morbidity networks connecting over 6 000 genes/proteins with physiological parameters and disease states. Three mathematical models describing different aspects of systemic effects of COPD were connected to clinical and experimental data. We have completely redesigned the technical architecture of the user interface and now provide html and web browser-based access and form-based searches. A network search enables the use of interconnecting information and the generation of disease-specific sub-networks from general knowledge. Integration with the Synergy-COPD Simulation Environment enables multi-scale integrated simulation of individual computational models while integration with a Clinical Decision Support System allows delivery into clinical practice.
The COPD Knowledge Base is the only publicly available knowledge resource dedicated to COPD and combining genetic information with molecular, physiological and clinical data as well as mathematical modelling. Its integrated analysis functions provide overviews about clinical trends and connections while its semantically mapped content enables complex analysis approaches. We plan to further extend the COPDKB by offering it as a repository to publish and semantically integrate data from relevant clinical trials. The COPDKB is freely available after registration at
PMCID: PMC4255911  PMID: 25471253
2.  Metabolic alterations to the mucosal microbiota in inflammatory bowel disease 
Inflammatory bowel diseases  2014;20(4):723-731.
Inflammation during inflammatory bowel disease (IBD) may alter nutrient availability to adherent mucosal bacteria and impact their metabolic function. Microbial metabolites may regulate intestinal CD4+ T cell homeostasis. We investigated the relationship between inflammation and microbial function by inferred metagenomics of the mucosal microbiota from colonic pinch biopsies of IBD patients.
Paired pinch biopsy samples of known inflammation states were analyzed from UC (23), CD (21) and controls (24) by 16S ribosomal sequencing, histopathology and flow cytometry. PICRUSt was used to generate metagenomic data, and derive relative Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway abundance information. Leukocytes were isolated from paired biopsy samples and analyzed by multi-color flow cytometry. Active inflammation was defined by neutrophil infiltration into the epithelium
Carriage of metabolic pathways in the mucosal microbiota was relatively stable among IBD patients despite large variations in individual bacterial community structures. However, microbial function was significantly altered in inflamed tissue of UC patients, with a reduction in carbohydrate and nucleotide metabolism in favor of increased lipid and amino acid metabolism. These differences were not observed in samples from CD patients. In CD, microbial lipid, carbohydrate, and amino acid metabolism was tightly correlated with frequency of CD4+Foxp3+ Tregs, whereas in UC these pathways were correlated with frequency of CD4+IL-22+ (TH22) cells.
Metabolic pathways of the mucosal microbiota in CD do not vary as much as UC with inflammation state, indicating a more systemic perturbation of host-bacteria interactions in CD compared to more localized dysfunction in UC.
PMCID: PMC4158619  PMID: 24583479
3.  Helminthic therapy: improving mucosal barrier function 
Trends in parasitology  2012;28(5):187-194.
The epidemiology of autoimmune diseases and helminth infections led to suggestions that helminths could improve inflammatory conditions, which was then tested using animal models. This has translated to clinical investigations aimed at the safe and controlled reintroduction of helminthic exposure to patients suffering from autoimmune diseases (so-called “helminthic therapy”) in an effort to mitigate the inflammatory response. In this review, we will summarize the results of recent clinical trials of helminthic therapy, with particular attention to mechanisms of action. Whereas previous reviews have emphasized immune regulatory mechanisms activated by helminths, we propose that enhancement of mucosal barrier function may have an equally important role in improving conditions of inflammatory bowel diseases.
PMCID: PMC4015520  PMID: 22464690
4.  Preferential HIV Infection of CCR6+ Th17 Cells Is Associated with Higher Levels of Virus Receptor Expression and Lack of CCR5 Ligands 
Journal of Virology  2013;87(19):10843-10854.
Th17 cells are enriched in the gut mucosa and play a critical role in maintenance of the mucosal barrier and host defense against extracellular bacteria and fungal infections. During chronic human immunodeficiency virus (HIV) infection, Th17 cells were more depleted compared to Th1 cells, even when the patients had low or undetectable viremia. To investigate the differential effects of HIV infection on Th17 and Th1 cells, a culture system was used in which CCR6+ CD4+ T cells were sorted from healthy human peripheral blood and activated in the presence of interleukin 1β (IL-1β) and IL-23 to drive expansion of Th17 cells while maintaining Th1 cells. HIV infection of these cultures had minimal effects on Th1 cells but caused depletion of Th17 cells. Th17 loss correlated with greater levels of virus-infected cells and cell death. In identifying cellular factors contributing to higher susceptibility of Th17 cells to HIV, we compared Th17-enriched CCR6+ and Th17-depleted CCR6− CD4 T cell cultures and noted that Th17-enriched CCR6+ cells expressed higher levels of α4β7 and bound HIV envelope in an α4β7-dependent manner. The cells also had greater expression of CD4 and CXCR4, but not CCR5, than CCR6− cells. Moreover, unlike Th1 cells, Th17 cells produced little CCR5 ligand, and transfection with one of the CCR5 ligands, MIP-1β (CCL4), increased their resistance against HIV. These results indicate that features unique to Th17 cells, including higher expression of HIV receptors and lack of autocrine CCR5 ligands, are associated with enhanced permissiveness of these cells to HIV.
PMCID: PMC3807416  PMID: 23903844
5.  Clash of the microbes: let’s bring back the good guys 
A 38-year-old man with a history of HIV infection virologically suppressed on antiretroviral therapy presents to his gastroenterologist for evaluation of iron deficiency anemia and weight loss. A diagnostic colonoscopy demonstrates a two-centimeter ulcerated mass in the cecum. Biopsies of the lesion return moderately differentiated adenocarcinoma that is wild type for the KRAS mutation by real-time PCR.
PMCID: PMC3561820  PMID: 23321673
6.  Seeded Fibrillation as Molecular Basis of the Species Barrier in Human Prion Diseases 
PLoS ONE  2013;8(8):e72623.
Prion diseases are transmissible spongiform encephalopathies in humans and animals, including scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in deer, and Creutzfeldt-Jakob disease (CJD) in humans. The hallmark of prion diseases is the conversion of the host-encoded prion protein (PrPC) to its pathological isoform PrPSc, which is accompanied by PrP fibrillation. Transmission is not restricted within one species, but can also occur between species. In some cases a species barrier can be observed that results in limited or unsuccessful transmission. The mechanism behind interspecies transmissibility or species barriers is not completely understood. To analyse this process at a molecular level, we previously established an in vitro fibrillation assay, in which recombinant PrP (recPrP) as substrate can be specifically seeded by PrPSc as seed. Seeding with purified components, with no additional cellular components, is a direct consequence of the “prion-protein-only” hypothesis. We therefore hypothesise, that the species barrier is based on the interaction of PrPC and PrPSc. Whereas in our earlier studies, the interspecies transmission in animal systems was analysed, the focus of this study lies on the transmission from animals to humans. We therefore combined seeds from species cattle, sheep and deer (BSE, scrapie, CWD) with human recPrP. Homologous seeding served as a control. Our results are consistent with epidemiology, other in vitro aggregation studies, and bioassays investigating the transmission between humans, cattle, sheep, and deer. In contrast to CJD and BSE seeds, which show a seeding activity we can demonstrate a species barrier for seeds from scrapie and CWD in vitro. We could show that the seeding activity and therewith the molecular interaction of PrP as substrate and PrPSc as seed is sufficient to explain the phenomenon of species barriers. Therefore our data supports the hypothesis that CWD is not transmissible to humans.
PMCID: PMC3748051  PMID: 23977331
Molecular Cancer Research  2012;10(5):605-614.
Transforming growth factor-beta1 (TGF-β1) and vascular endothelial growth factor (VEGF), both angiogenesis inducers, have opposing effects on vascular endothelial cells. TGF-β1 induces apoptosis; VEGF induces survival. We have previously shown that TGF-β1 induces endothelial cell expression of VEGF, which mediates TGF-β1 induction of apoptosis through activation of p38 mitogen-activated protein kinase (MAPK). Because VEGF activates p38MAPK but protects the cells from apoptosis, this finding suggested that TGF-β1 converts p38MAPK signaling from prosurvival to proapoptotic. Four isoforms of p38MAPK - α, β, γ and δ – have been identified. Therefore, we hypothesized that different p38MAPK isoforms control endothelial cell apoptosis or survival, and that TGF-β1 directs VEGF activation of p38MAPK from a pro-survival to a proapoptotic isoform. Here we report that cultured endothelial cells express p38 α, β and γ. VEGF activates p38 β, whereas TGF-β1 activates p38 α. TGF-β1 treatment rapidly induces p38 α activation and apoptosis. Subsequently, p38 α activation is downregulated, p38 β is activated, and the surviving cells become refractory to TGF-β1 induction of apoptosis and proliferate. Gene silencing of p38 α blocks TGF-β1 induction of apoptosis, whereas downregulation of p38 β or p38 γ expression results in massive apoptosis. Thus, in endothelial cells p38 α mediates apoptotic signaling, whereas p38 β and p38 γ transduce survival signaling. TGF-β1 activation of p38 α is mediated by VEGF, which in the absence of TGF-β1 activates p38 β. Therefore, these results show that TGF-β1 induces endothelial cell apoptosis by shifting VEGF signaling from the prosurvival p38 β to the proapoptotic p38 α.
PMCID: PMC3356490  PMID: 22522454
TGF-β1; VEGF; p38MAPK isoforms; endothelial cells; apoptosis
8.  TH17, TH22 and TReg Cells Are Enriched in the Healthy Human Cecum 
PLoS ONE  2012;7(7):e41373.
There is increasing evidence that dysregulation of CD4+ T cell populations leads to intestinal inflammation, but the regional distribution of these populations throughout the intestinal tract in healthy individuals remains unclear. Here, we show that TH17, TH22 and TReg cells are enriched in the healthy human cecum compared to the terminal ileum and sigmoid colon, whereas TH1 and TH2 cells do not significantly vary by location. Transcriptional profiling analysis of paired pinch biopsies from different regions of the intestine identified significant differences in the metabolic state of the terminal ileum, cecum, and sigmoid colon. An increased proportion of TH17 cells was positively associated with expression of resistin (RETN) and negatively associated with expression of trefoil factor 1 (TFF1). These results suggest that CD4+ T helper cells that are important in maintaining mucosal barrier function may be enriched in the cecum as a result of metabolic differences of the surrounding microenvironment.
PMCID: PMC3400627  PMID: 22829946
9.  Knowledge management for systems biology a general and visually driven framework applied to translational medicine 
BMC Systems Biology  2011;5:38.
To enhance our understanding of complex biological systems like diseases we need to put all of the available data into context and use this to detect relations, pattern and rules which allow predictive hypotheses to be defined. Life science has become a data rich science with information about the behaviour of millions of entities like genes, chemical compounds, diseases, cell types and organs, which are organised in many different databases and/or spread throughout the literature. Existing knowledge such as genotype - phenotype relations or signal transduction pathways must be semantically integrated and dynamically organised into structured networks that are connected with clinical and experimental data. Different approaches to this challenge exist but so far none has proven entirely satisfactory.
To address this challenge we previously developed a generic knowledge management framework, BioXM™, which allows the dynamic, graphic generation of domain specific knowledge representation models based on specific objects and their relations supporting annotations and ontologies. Here we demonstrate the utility of BioXM for knowledge management in systems biology as part of the EU FP6 BioBridge project on translational approaches to chronic diseases. From clinical and experimental data, text-mining results and public databases we generate a chronic obstructive pulmonary disease (COPD) knowledge base and demonstrate its use by mining specific molecular networks together with integrated clinical and experimental data.
We generate the first semantically integrated COPD specific public knowledge base and find that for the integration of clinical and experimental data with pre-existing knowledge the configuration based set-up enabled by BioXM reduced implementation time and effort for the knowledge base compared to similar systems implemented as classical software development projects. The knowledgebase enables the retrieval of sub-networks including protein-protein interaction, pathway, gene - disease and gene - compound data which are used for subsequent data analysis, modelling and simulation. Pre-structured queries and reports enhance usability; establishing their use in everyday clinical settings requires further simplification with a browser based interface which is currently under development.
PMCID: PMC3060864  PMID: 21375767
10.  C-reactive protein is a prognostic indicator in patients with perihilar cholangiocarcinoma 
AIM: To evaluate prognostic indicators for the outcome of patients with perihilar extrahepatic cholangiocarcinoma in an unselected cohort.
METHODS: We retrospectively analyzed 98 patients with perihilar cholangiocarcinoma. Twenty-three patients (23.5%) underwent tumor resection. Patients with non-resectable tumors underwent either transpapillary or percutaneous transhepatic biliary drainage. Additionally, 32 patients (32.7%) received photodynamic therapy (PDT) and 18 patients (18.4%) systemic chemotherapy. Predefined variables at the time of diagnosis and characteristics considering the mode of treatment were entered into a Cox’s proportional hazards model. Included in the analysis were age, tumor stage following the modified Bismuth-Corlette classification, bilirubin, prothrombin time (PT), C-reactive protein (CRP), carbohydrate antigen 19-9 (CA19-9), history of weight loss, surgical resection, chemotherapy and PDT.
RESULTS: The Kaplan-Meier estimate of overall median survival was 10.5 (95%CI: 8.4-12.6) mo. In the univariate analysis, low Bismuth stage, low CRP and surgical resection correlated significantly with better survival. In the multivariate analysis, only CRP (P = 0.005) and surgical resection (P = 0.029) were found to be independently predictive of survival in the cohort. Receiver operating characteristic (ROC) analysis identified a CRP level of 11.75 mg/L as the value associated with the highest sensitivity and specificity predicting a survival > 5 mo. Applying Kaplan-Meier analysis, patients with a CRP < 12 mg/L at the time of diagnosis had a significantly longer median survival than patients with higher values (16.2 vs 7.6 mo; P = 0.009).
CONCLUSION: This retrospective analysis identified CRP level at the time of diagnosis as a novel indicator for the prognosis of patients with perihilar cholangiocarcinoma. It should be evaluated in future prospective trials on this entity.
PMCID: PMC4088232  PMID: 17006987
Perihilar cholangiocarcinoma; Prognostic factors; C-reactive protein; Resection; Outcome

Results 1-10 (10)