Global stability and parameter analysis reinforce therapeutic targets of PD-L1-PD-1 and MDSCs for glioblastoma.

Glioblastoma (GBM) is an aggressive primary brain cancer that currently has minimally effective treatments. Like other cancers, immunosuppression by the PD-L1-PD-1 immune checkpoint complex is a prominent axis by which glioma cells evade the immune system. Myeloid-derived suppressor cells (MDSCs), which are recruited to the glioma microenviroment, also contribute to the immunosuppressed GBM microenvironment by suppressing T cell functions. In this paper, we propose a GBM-specific tumor-immune ordinary differential equations model of glioma cells, T cells, and MDSCs to provide theoretical insights into the interactions between these cells. Equilibrium and stability analysis indicates that there are unique tumorous and tumor-free equilibria which are locally stable under certain conditions. Further, the tumor-free equilibrium is globally stable when T cell activation and the tumor kill rate by T cells overcome tumor growth, T cell inhibition by PD-L1-PD-1 and MDSCs, and the T cell death rate. Bifurcation analysis suggests that a treatment plan that includes surgical resection and therapeutics targeting immune suppression caused by the PD-L1-PD1 complex and MDSCs results in the system tending to the tumor-free equilibrium. Using a set of preclinical experimental data, we implement the approximate Bayesian computation (ABC) rejection method to construct probability density distributions that estimate model parameters. These distributions inform an appropriate search curve for global sensitivity analysis using the extended fourier amplitude sensitivity test. Sensitivity results combined with the ABC method suggest that parameter interaction is occurring between the drivers of tumor burden, which are the tumor growth rate and carrying capacity as well as the tumor kill rate by T cells, and the two modeled forms of immunosuppression, PD-L1-PD-1 immune checkpoint and MDSC suppression of T cells. Thus, treatment with an immune checkpoint inhibitor in combination with a therapeutic targeting the inhibitory mechanisms of MDSCs should be explored.

Global stability and parameter analysis reinforce therapeutic targets of PD-L1-PD-1 and MDSCs for glioblastoma.

Glioblastoma (GBM) is an aggressive primary brain cancer that currently has minimally effective treatments. Like other cancers, immunosuppression by the PD-L1-PD-1 immune checkpoint complex is a prominent axis by which glioma cells evade the immune system. Myeloid-derived suppressor cells (MDSCs), which are recruited to the glioma microenviroment, also contribute to the immunosuppressed GBM microenvironment by suppressing T cell functions. In this paper, we propose a GBM-specific tumor-immune ordinary differential equations model of glioma cells, T cells, and MDSCs to provide theoretical insights into the interactions between these cells. Equilibrium and stability analysis indicates that there are unique tumorous and tumor-free equilibria which are locally stable under certain conditions. Further, the tumor-free equilibrium is globally stable when T cell activation and the tumor kill rate by T cells overcome tumor growth, T cell inhibition by PD-L1-PD-1 and MDSCs, and the T cell death rate. Bifurcation analysis suggests that a treatment plan that includes surgical resection and therapeutics targeting immune suppression caused by the PD-L1-PD1 complex and MDSCs results in the system tending to the tumor-free equilibrium. Using a set of preclinical experimental data, we implement the Approximate Bayesian Computation (ABC) rejection method to construct probability density distributions that estimate model parameters. These distributions inform an appropriate search curve for global sensitivity analysis using the extended Fourier Amplitude Sensitivity Test (eFAST). Sensitivity results combined with the ABC method suggest that parameter interaction is occurring between the drivers of tumor burden, which are the tumor growth rate and carrying capacity as well as the tumor kill rate by T cells, and the two modeled forms of immunosuppression, PD-L1-PD-1 immune checkpoint and MDSC suppression of T cells. Thus, treatment with an immune checkpoint inhibitor in combination with a therapeutic targeting the inhibitory mechanisms of MDSCs should be explored.

Reaction-Diffusion Modeling of E. coli Colony Growth Based on Nutrient Distribution and Agar Dehydration.

The bacterial colony is a powerful experimental platform for broad biological research, and reaction-diffusion models are widely used to study the mechanisms of its formation process. However, there are still some crucial factors that drastically affect the colony growth but are not considered in the current models, such as the non-homogeneously distributed nutrient within the colony and the substantially decreasing expansion rate caused by agar dehydration. In our study, we propose two plausible reaction-diffusion models (the VN and MVN models) based on the above two factors and validate them against experimental data. Both models provide a plausible description of the non-homogeneously distributed nutrient within the colony and outperform the classical Fisher-Kolmogorov equation and its variation in better describing experimental data. Moreover, by accounting for agar dehydration, the MVN model captures how a colony's expansion slows down and the change of a colony's height profile over time. Furthermore, we demonstrate the existence of a traveling wave solution for the VN model.

Tracking glioblastoma progression after initial resection with minimal reaction-diffusion models.

We describe a preliminary effort to model the growth and progression of glioblastoma multiforme, an aggressive form of primary brain cancer, in patients undergoing treatment for recurrence of tumor following initial surgery and chemoradiation. Two reaction-diffusion models are used: the Fisher-Kolmogorov equation and a 2-population model, developed by the authors, that divides the tumor into actively proliferating and quiescent (or necrotic) cells. The models are simulated on 3-dimensional brain geometries derived from magnetic resonance imaging (MRI) scans provided by the Barrow Neurological Institute. The study consists of 17 clinical time intervals across 10 patients that have been followed in detail, each of whom shows significant progression of tumor over a period of 1 to 3 months on sequential follow up scans. A Taguchi sampling design is implemented to estimate the variability of the predicted tumors to using 144 different choices of model parameters. In 9 cases, model parameters can be identified such that the simulated tumor, using both models, contains at least 40 percent of the volume of the observed tumor. We discuss some potential improvements that can be made to the parameterizations of the models and their initialization.