Using quantitative systems pharmacology modeling to optimize combination therapy of anti-PD-L1 checkpoint inhibitor and T cell engager

Although immune checkpoint blockade therapies have shown evidence of clinical effectiveness in many types of cancer, the outcome of clinical trials shows that very few patients with colorectal cancer benefit from treatments with checkpoint inhibitors. Bispecific T cell engagers (TCEs) are gaining popularity because they can improve patients’ immunological responses by promoting T cell activation. The possibility of combining TCEs with checkpoint inhibitors to increase tumor response and patient survival has been highlighted by preclinical and clinical outcomes. However, identifying predictive biomarkers and optimal dose regimens for individual patients to benefit from combination therapy remains one of the main challenges. In this article, we describe a modular quantitative systems pharmacology (QSP) platform for immuno-oncology that includes specific processes of immune-cancer cell interactions and was created based on published data on colorectal cancer. We generated a virtual patient cohort with the model to conduct in silico virtual clinical trials for combination therapy of a PD-L1 checkpoint inhibitor (atezolizumab) and a bispecific T cell engager (cibisatamab). Using the model calibrated against the clinical trials, we conducted several virtual clinical trials to compare various doses and schedules of administration for two drugs with the goal of therapy optimization. Moreover, we quantified the score of drug synergy for these two drugs to further study the role of the combination therapy

Spatially resolved simulations of the non-equilibrium cavitation bubble dynamics including vapor and air transport

Der Hauptzweck dieser Studie ist es, ein profundes Wissen über die Wechselwirkung zwischen Kavitation und Luftfreisetzung zu erlangen, indem das komplexe Feld der Blasendynamik und die damit verbundenen Dampf- und Luftflüsse unter Nichtgleichgewichtsbedingungen untersucht werden. Um dieses Ziel zu erreichen, werden die maßgeblichen Differentialgleichungen numerisch gelöst, einschließlich der Erhaltung von Masse, Impuls und Energie innerhalb und außerhalb der Blase. Die gesamte Thermodynamik wurde auf der Grundlage validierter experimenteller Datensätze in das Modell implementiert, sodass das Modell für verschiedene Flüssigkeiten und Flüssigkeitsgemische verwendet werden kann. Dieses Modell mit detaillierter Erklärung der Transportprozesse und der hohen Genauigkeit kann auf die CFD-Codes angewendet und als geeignetes Kavitationsmodell verwendet werden.The main purpose of this study is to gain a profound knowledge of the interaction between cavitation and air release by investigating the complex field of bubble dynamics and its associated vapor and air fluxes under non-equilibrium conditions. For achieving this goal, the governing differential equations are solved numerically, including conservation of mass, momentum, and energy both within and outside the bubble. In contrast to existing models, the whole complete thermodynamics has been implemented into the model based on validated experimental data sets, allowing to utilize the model for different liquids and liquid mixtures. This model, with detailed explanation of transport processes, with the least simplifying assumptions, and the high level of accuracy can be applied into the CFD codes and can be utilized as a proper cavitation model

Colored petri net modeling of small interfering RNA-mediated messenger RNA degradation

Background: Mathematical modeling of biological systems is an attractive way for studying complex biological systems and their behaviors. Petri Nets, due to their ability to model systems with various levels of qualitative information, have been wildly used in modeling biological systems in which enough qualitative data may not be at disposal. These nets have been used to answer questions regarding the dynamics of different cell behaviors including the translation process. In one stage of the translation process, the RNA sequence may be degraded. In the process of degradation of RNA sequence, small-noncoding RNA molecules known as small interfering RNA (siRNA) match the target RNA sequence. As a result of this matching, the target RNA sequence is destroyed. Materials and Methods: In this context, the process of matching and destruction is modeled using Colored Petri Nets (CPNs). The model is constructed using CPNs which allow tokens to have a value or type on them. Thus, CPN is a suitable tool to model string structures in which each element of the string has a different type. Using CPNs, long RNA, and siRNA strings are modeled with a finite set of colors. The model is simulated via CPN Tools. Results: A CPN model of the matching between RNA and siRNA strings is constructed in CPN Tools environment. Conclusion: In previous studies, a network of stoichiometric equations was modeled. However, in this particular study, we modeled the mechanism behind the silencing process. Modeling this kind of mechanisms provides us with a tool to examine the effects of different factors such as mutation or drugs on the process

A comparative study of mixed least-squares FEMs for the incompressible Navier-Stokes equations

In the present contribution we compare different mixed least-squares finite element formula-tions (LSFEMs) with respect to computational costs and accuracy. In detail, we consider an approach for Newtonian fluid flow, which is described by the incompressible Navier-Stokes equa-tions. Starting from the residual forms of the equilibrium equation and the continuity condition, various first-order systems are derived. From these systems least-squares functionals are con-structed by means of L2-norms, which are the basis for the associated minimization problems. The first formulation under consideration is a div-grad first-order system resulting in a three-field formulation with stresses, velocities, and pressure as unknowns. This S-V-P formulation is approximated in H(div) × H1 × L2 on triangles and for comparison also in H1 ×H1 × L2 on quadrilaterals. The second formulation is the well-known div-curl-grad first-order velocity-vorticity-pressure (V-V-P) formulation. Here all unknowns are approximated in H1 on quadri-laterals. Besides some numerical advantages, as e.g. an inherent symmetric structure of the system of equations and a directly available error estimator, it is known that least-squares methods have also a drawback concerning mass conservation, especially when lower-order ele

A free-boundary model of a motile cell explains turning behavior - Fig 8

<p>Steady-state cell shapes, myosin distributions (pseudo-colors), actin velocities (arrows), and motility types from solutions of the ZS (<i>a</i>) and ZV (<i>b</i>) models obtained for specified parameter values (<i>v</i>₀, μ_tot). Gridlines are spaced uniformly with <i>h</i> = 1.</p

Mechanical states of ZV and ZS models for varying sets (<i>v</i>₀, μ_tot) and α = 0.5 and 1.

<p>Mechanical states of ZV and ZS models for varying sets (<i>v</i>₀, μ_tot) and α = 0.5 and 1.</p

Onset of steady rotations in ZV model, (<i>v</i>₀, μ_tot, α) = (12.5, 2π, 1).

<p>(<i>a</i>) Entire cell trajectory and cell centroid track (red dashed curve). (<i>b</i>) Snapshots of transient myosin distributions with individual color scales during a transient, and with white arrows representing actin velocities (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005862#pcbi.1005862.s004" target="_blank">S3 Movie</a>).</p