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public 01:34:46

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 ( 31 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 01:02:38

Robert Bryant : A Weierstrass representation for affine Bonnet surfaces

  -   Geometry and Topology ( 64 Views )

Ossian Bonnet (1819–1892) classified the surfaces in Euclidean 3-space that can be isometrically deformed without changing the mean curvature function H, showing that there are two types: the surfaces of constant mean curvature and a 4-dimensional ‘exceptional family’ (with variable mean curvature) that are now known as Bonnet surfaces. The corresponding problem in affine 3-space is much more difficult, and the full classification is still unknown. More than 10 years ago, I classified the affine surfaces that can isometrically deformed (with respect to the induced Blaschke metric) while preserving their affine mean curvature in a 3-dimensional family (the maximum dimension possible), showing that they depend on 2 functions of 1 variable in Cartan’s sense. When I gave a talk* in this seminar about these results on September 10, 2013, I only knew that these surfaces corresponded to pseudoholomorphic curves in a certain almost-complex surface. However, I have recently shown that the structure equations for these mysterious surfaces can be interpreted as describing holomorphic Legendrian curves in CP^3 subject to a natural positivity condition, and the integration corresponds to a flat sp(2,R) connection, i.e., they can be interpreted as a Lax pair, but of a very special kind, for which the integration can be effected explicitly. I’ll explain these results and use them to show how the classical problem of determining the affine surfaces with constant affine mean curvature and constant Gauss curvature of the Blaschke metric can be explicitly integrated, which, heretofore, was unknown. * https://www4.math.duke.edu/media/watch_video.php?v=6948e657e69cadbaa1a6915335e9ea87