Background:Interactions of many key proteins or genes in signalling pathway have been studied qualitatively in the literature, but only little quantitative information is available.Objective: Although much has been done to clarify the biochemistry of transcriptional dynamics in signalling pathway, it remains difficult to find out and predict quantitative responses. The aim of this study is to construct a computational model of epidermal growth factor receptor (EGFR) signalling pathway as one of hallmarks of cancer so as to predict quantitative responses.Methods: Interaction of Arsenic trioxide (ATO) with EGFR signalling pathway factors has been elicited by systematic search in data bases, as ATO is one of the mysterious chemotherapy agents that control EGFR expression in cancer. ATO has dichotomous manner in vivo, dependent on its concentration. According to fuzzy rules based upon qualitative knowledge and Petri Net, we can construct a quantitative model to describe ATO mechanism in EGFR signalling pathway.Results: By Fuzzy Logic models that have the potential to trade with the loss of quantitative information on how different species interact, along with Petri net quantitatively describe the dynamics of EGFR signalling pathway. By this model the dynamic of different factors in EGFR signalling pathway is achieved.Conclusion: The use of Fuzzy Logic and PNs in biological network modelling causes a deeper understanding and comprehensive analysis of the biological networks.
Background
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with rising incidence and with 5-years overall survival of less than 8%. PDAC creates an immune-suppressive tumor microenvironment to escape immune-mediated eradication. Regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSC) are critical components of the immune-suppressive tumor microenvironment. Shifting from tumor escape or tolerance to elimination is the major challenge in the treatment of PDAC.
Results
In a mathematical model, we combine distinct treatment modalities for PDAC, including 5-FU chemotherapy and anti- CD25 immunotherapy to improve clinical outcome and therapeutic efficacy. To address and optimize 5-FU and anti- CD25 treatment (to suppress MDSCs and Tregs, respectively) schedule in-silico and simultaneously unravel the processes driving therapeutic responses, we designed an in vivo calibrated mathematical model of tumor-immune system (TIS) interactions. We designed a user-friendly graphical user interface (GUI) unit which is configurable for treatment timings to implement an in-silico clinical trial to test different timings of both 5-FU and anti- CD25 therapies. By optimizing combination regimens, we improved treatment efficacy. In-silico assessment of 5-FU and anti- CD25 combination therapy for PDAC significantly showed better treatment outcomes when compared to 5-FU and anti- CD25 therapies separately. Due to imprecise, missing, or incomplete experimental data, the kinetic parameters of the TIS model are uncertain that this can be captured by the fuzzy theorem. We have predicted the uncertainty band of cell/cytokines dynamics based on the parametric uncertainty, and we have shown the effect of the treatments on the displacement of the uncertainty band of the cells/cytokines. We performed global sensitivity analysis methods to identify the most influential kinetic parameters and simulate the effect of the perturbation on kinetic parameters on the dynamics of cells/cytokines.
Conclusion
Our findings outline a rational approach to therapy optimization with meaningful consequences for how we effectively design treatment schedules (timing) to maximize their success, and how we treat PDAC with combined 5-FU and anti- CD25 therapies. Our data revealed that a synergistic combinatorial regimen targeting the Tregs and MDSCs in both crisp and fuzzy settings of model parameters can lead to tumor eradication.
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