References of "NPJ Systems Biology and Applications"
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See detailSystemic network analysis identifies XIAP and IkappaBalpha as potential drug targets in TRAIL resistant BRAF mutated melanoma.
Del Mistro, Greta; Lucarelli, Philippe UL; Muller, Ines et al

in NPJ systems biology and applications (2018), 4

Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent ... [more ▼]

Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent TRAIL receptor-targeted agonist IZI1551 to induce pronounced apoptotic cell death in mutBRAF melanoma cells. Aiming to identify molecular changes that may confer IZI1551 resistance we combined Dynamic Bayesian Network modelling with a sophisticated regularization strategy resulting in sparse and context-sensitive networks and show the performance of this strategy in the detection of cell line-specific deregulations of a signalling network. Comparing IZI1551-sensitive to IZI1551-resistant melanoma cells the model accurately and correctly predicted activation of NFkappaB in concert with upregulation of the anti-apoptotic protein XIAP as the key mediator of IZI1551 resistance. Thus, the incorporation of multiple regularization functions in logical network optimization may provide a promising avenue to assess the effects of drug combinations and to identify responders to selected combination therapies. [less ▲]

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See detailSystems medicine disease maps: community-driven comprehensive representation of disease mechanisms.
Mazein, Alexander; Ostaszewski, Marek UL; Kuperstein, Inna et al

in NPJ systems biology and applications (2018), 4

The development of computational approaches in systems biology has reached a state of maturity that allows their transition to systems medicine. Despite this progress, intuitive visualisation and context ... [more ▼]

The development of computational approaches in systems biology has reached a state of maturity that allows their transition to systems medicine. Despite this progress, intuitive visualisation and context-dependent knowledge representation still present a major bottleneck. In this paper, we describe the Disease Maps Project, an effort towards a community-driven computationally readable comprehensive representation of disease mechanisms. We outline the key principles and the framework required for the success of this initiative, including use of best practices, standards and protocols. We apply a modular approach to ensure efficient sharing and reuse of resources for projects dedicated to specific diseases. Community-wide use of disease maps will accelerate the conduct of biomedical research and lead to new disease ontologies defined from mechanism-based disease endotypes rather than phenotypes. [less ▲]

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See detailA roadmap towards personalized immunology.
Delhalle, Sylvie; Bode, Sebastian F. N.; Balling, Rudi UL et al

in NPJ systems biology and applications (2018), 4

Big data generation and computational processing will enable medicine to evolve from a "one-size-fits-all" approach to precise patient stratification and treatment. Significant achievements using "Omics ... [more ▼]

Big data generation and computational processing will enable medicine to evolve from a "one-size-fits-all" approach to precise patient stratification and treatment. Significant achievements using "Omics" data have been made especially in personalized oncology. However, immune cells relative to tumor cells show a much higher degree of complexity in heterogeneity, dynamics, memory-capability, plasticity and "social" interactions. There is still a long way ahead on translating our capability to identify potentially targetable personalized biomarkers into effective personalized therapy in immune-centralized diseases. Here, we discuss the recent advances and successful applications in "Omics" data utilization and network analysis on patients' samples of clinical trials and studies, as well as the major challenges and strategies towards personalized stratification and treatment for infectious or non-communicable inflammatory diseases such as autoimmune diseases or allergies. We provide a roadmap and highlight experimental, clinical, computational analysis, data management, ethical and regulatory issues to accelerate the implementation of personalized immunology. [less ▲]

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See detailMINERVA—a platform for visualization and curation of molecular interaction networks
Gawron, Piotr; Ostaszewski, Marek UL; Satagopam, Venkata UL et al

in NPJ Systems Biology and Applications (2016)

Our growing knowledge about various molecular mechanisms is becoming increasingly more structured and accessible. Different repositories of molecular interactions and available literature enable ... [more ▼]

Our growing knowledge about various molecular mechanisms is becoming increasingly more structured and accessible. Different repositories of molecular interactions and available literature enable construction of focused and high-quality molecular interaction networks. Novel tools for curation and exploration of such networks are needed, in order to foster the development of a systems biology environment. In particular, solutions for visualization, annotation and data cross-linking will facilitate usage of network-encoded knowledge in biomedical research. To this end we developed the MINERVA (Molecular Interaction NEtwoRks VisuAlization) platform, a standalone webservice supporting curation, annotation and visualization of molecular interaction networks in Systems Biology Graphical Notation (SBGN)-compliant format. MINERVA provides automated content annotation and verification for improved quality control. The end users can explore and interact with hosted networks, and provide direct feedback to content curators. MINERVA enables mapping drug targets or overlaying experimental data on the visualized networks. Extensive export functions enable downloading areas of the visualized networks as SBGN-compliant models for efficient reuse of hosted networks. The software is available under Affero GPL 3.0 as a Virtual Machine snapshot, Debian package and Docker instance at http://r3lab.uni.lu/web/minerva-website/. We believe that MINERVA is an important contribution to systems biology community, as its architecture enables set-up of locally or globally accessible SBGN-oriented repositories of molecular interaction networks. Its functionalities allow overlay of multiple information layers, facilitating exploration of content and interpretation of data. Moreover, annotation and verification workflows of MINERVA improve the efficiency of curation of networks, allowing life-science researchers to better engage in development and use of biomedical knowledge repositories. [less ▲]

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See detailModel-based dietary optimization for late-stage, levodopa-treated, Parkinson’s disease patients
Ben Guebila, Marouen UL; Thiele, Ines UL

in NPJ Systems Biology and Applications (2016), 2

Levodopa has been the gold standard for Parkinson’s disease treatment for more than 40 years. Its bioavailability is hindered by dietary amino acids, leading to fluctuations in the motor response ... [more ▼]

Levodopa has been the gold standard for Parkinson’s disease treatment for more than 40 years. Its bioavailability is hindered by dietary amino acids, leading to fluctuations in the motor response particularly in late-stage (stage 3 and 4 on Hoehn and Yahr scale) patients. The routine dietary intervention consists of low-protein (<0.8 g/kg) diets or the redistribution of daily protein allowance to the last meal. Computational modeling was used to examine the fluctuation of gastrointestinal levodopa absorption under consideration of the diet by (i) identifying the group of patients that could benefit from dietary interventions, (ii) comparing existing diet recommendations for their impact on levodopa bioavailability, and (iii) suggesting a mechanism-based dietary intervention. We developed a multiscale computational model consisting of an ordinary differential equations-based advanced compartmentalized absorption and transit (ACAT) gut model and metabolic genome-scale small intestine epithelial cell model. We used this model to investigate complex spatiotemporal relationship between dietary amino acids and levodopa absorption. Our model predicted an improvement in bioavailability, as reflected by blood concentrations of levodopa with protein redistribution diet by 34% compared with a low-protein diet and by 11% compared with the ante cibum (a.c.) administration. These results are consistent with the reported better outcome in late-stage patients. A systematic analysis of the effect of different amino acids in the diet suggested that a serine-rich diet could improve the bioavailability by 22% compared with the a.c. administration. In addition, the slower gastric emptying rate in PD patients exacerbates the loss of levodopa due to competition. Optimizing dietary recommendations in quantity, composition, and intake time holds the promise to improve levodopa efficiency and patient’s quality of life based on highly detailed, mechanistic models of gut physiology endowed with improved extrapolative properties, thus paving the way for precision medical treatment. [less ▲]

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