public 53:20

Dean Bottino : Evaluating Strategies for Overcoming Rituximab (R) Resistance Using a Quantitative Systems Pharmacology (QSP) model of Antibody-Dependent Cell-mediated Cytotoxicity & Phagocytosis (ADCC & ADCP): An Academic/Industrial Collaboration

  -   Mathematical Biology ( 72 Views )

Despite the impressive performance of rituximab (R) containing regimens like R-CHOP in CD20+ Non-Hodgkin’s Lymphoma (NHL), 30-60% of R-naïve NHL patients are estimated to be resistant, and approximately 60% of those patients will not respond to subsequent single agent R treatment. Given that antibody dependent cell mediated cytotoxicity (ADCC) and phagocytosis (ADCP) are thought to be the major mechanisms of action of Rituximab, increasing the activation levels of natural killer (NK) and macrophage (MP) cells may be one strategy for overcoming R resistance.

During (and after) the Fields Institute Industrial Problem Solving Workshop in August 2019, academic participants and industry mentors developed and calibrated to literature data a quantitative systems pharmacology (QSP) model of ADCC/ADCP to interrogate which mechanisms of R resistance could be overcome by increased NK or MP activation, and how much effector cell activation would be required to overcome a given degree and mechanism of R resistance.

This work was motivated by a real-world pharmaceutical drug development question, and the academic-industry interactions during and after the workshop resulted in sharknado plots as well as a published QSP model (presented at American Association of Cancer Research Annual Meeting, 2021) that was able to address some of the key questions around overcoming R resistance. The published model was then incorporated into an in-house QSP model supporting the development of a Takeda investigational drug which is being developed to restore R sensitivity in an R-resistant patient population.

public 01:06:01

Vakhtang Poutkaradze : Lie-Poisson Neural Networks (LPNets): Data-Based Computing of Hamiltonian Systems with Symmetries

  -   Applied Math and Analysis ( 55 Views )

Physics-Informed Neural Networks (PINNs) have received much attention recently due to their potential for high-performance computations for complex physical systems, including data-based computing, systems with unknown parameters, and others. The idea of PINNs is to approximate the equations and boundary and initial conditions through a loss function for a neural network. PINNs combine the efficiency of data-based prediction with the accuracy and insights provided by the physical models. However, applications of these methods to predict the long-term evolution of systems with little friction, such as many systems encountered in space exploration, oceanography/climate, and many other fields, need extra care as the errors tend to accumulate, and the results may quickly become unreliable. We provide a solution to the problem of data-based computation of Hamiltonian systems utilizing symmetry methods. Many Hamiltonian systems with symmetry can be written as a Lie-Poisson system, where the underlying symmetry defines the Poisson bracket. For data-based computing of such systems, we design the Lie-Poisson neural networks (LPNets). We consider the Poisson bracket structure primary and require it to be satisfied exactly, whereas the Hamiltonian, only known from physics, can be satisfied approximately. By design, the method preserves all special integrals of the bracket (Casimirs) to machine precision. LPNets yield an efficient and promising computational method for many particular cases, such as rigid body or satellite motion (the case of SO(3) group), Kirchhoff's equations for an underwater vehicle (SE(3) group), and others. Joint work with Chris Eldred (Sandia National Lab), Francois Gay-Balmaz (CNRS and ENS, France), and Sophia Huraka (U Alberta). The work was partially supported by an NSERC Discovery grant.