Exploratory Biomarker Analysis In The Ph 3 Echelon‐1 Study: Worse Outcome With Abvd In Patients With Elevated Baseline Levels Of Scd30 And Tarc

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149507/1/hon99_2630.pd

Modeling Robustness Tradeoffs in Yeast Cell Polarization Induced by Spatial Gradients

Cells localize (polarize) internal components to specific locations in response to external signals such as spatial gradients. For example, yeast cells form a mating projection toward the source of mating pheromone. There are specific challenges associated with cell polarization including amplification of shallow external gradients of ligand to produce steep internal gradients of protein components (e.g. localized distribution), response over a broad range of ligand concentrations, and tracking of moving signal sources. In this work, we investigated the tradeoffs among these performance objectives using a generic model that captures the basic spatial dynamics of polarization in yeast cells, which are small. We varied the positive feedback, cooperativity, and diffusion coefficients in the model to explore the nature of this tradeoff. Increasing the positive feedback gain resulted in better amplification, but also produced multiple steady-states and hysteresis that prevented the tracking of directional changes of the gradient. Feedforward/feedback coincidence detection in the positive feedback loop and multi-stage amplification both improved tracking with only a modest loss of amplification. Surprisingly, we found that introducing lateral surface diffusion increased the robustness of polarization and collapsed the multiple steady-states to a single steady-state at the cost of a reduction in polarization. Finally, in a more mechanistic model of yeast cell polarization, a surface diffusion coefficient between 0.01 and 0.001 µm2/s produced the best polarization performance, and this range is close to the measured value. The model also showed good gradient-sensitivity and dynamic range. This research is significant because it provides an in-depth analysis of the performance tradeoffs that confront biological systems that sense and respond to chemical spatial gradients, proposes strategies for balancing this tradeoff, highlights the critical role of lateral diffusion of proteins in the membrane on the robustness of polarization, and furnishes a framework for future spatial models of yeast cell polarization

Autocatalytic Loop, Amplification and Diffusion: A Mathematical and Computational Model of Cell Polarization in Neural Chemotaxis

The chemotactic response of cells to graded fields of chemical cues is a complex process that requires the coordination of several intracellular activities. Fundamental steps to obtain a front vs. back differentiation in the cell are the localized distribution of internal molecules and the amplification of the external signal. The goal of this work is to develop a mathematical and computational model for the quantitative study of such phenomena in the context of axon chemotactic pathfinding in neural development. In order to perform turning decisions, axons develop front-back polarization in their distal structure, the growth cone. Starting from the recent experimental findings of the biased redistribution of receptors on the growth cone membrane, driven by the interaction with the cytoskeleton, we propose a model to investigate the significance of this process. Our main contribution is to quantitatively demonstrate that the autocatalytic loop involving receptors, cytoplasmic species and cytoskeleton is adequate to give rise to the chemotactic behavior of neural cells. We assess the fact that spatial bias in receptors is a precursory key event for chemotactic response, establishing the necessity of a tight link between upstream gradient sensing and downstream cytoskeleton dynamics. We analyze further crosslinked effects and, among others, the contribution to polarization of internal enzymatic reactions, which entail the production of molecules with a one-to-more factor. The model shows that the enzymatic efficiency of such reactions must overcome a threshold in order to give rise to a sufficient amplification, another fundamental precursory step for obtaining polarization. Eventually, we address the characteristic behavior of the attraction/repulsion of axons subjected to the same cue, providing a quantitative indicator of the parameters which more critically determine this nontrivial chemotactic response

A Comparison of Mathematical Models for Polarization of Single Eukaryotic Cells in Response to Guided Cues

Polarization, a primary step in the response of an individual eukaryotic cell to a spatial stimulus, has attracted numerous theoretical treatments complementing experimental studies in a variety of cell types. While the phenomenon itself is universal, details differ across cell types, and across classes of models that have been proposed. Most models address how symmetry breaking leads to polarization, some in abstract settings, others based on specific biochemistry. Here, we compare polarization in response to a stimulus (e.g., a chemoattractant) in cells typically used in experiments (yeast, amoebae, leukocytes, keratocytes, fibroblasts, and neurons), and, in parallel, responses of several prototypical models to typical stimulation protocols. We find that the diversity of cell behaviors is reflected by a diversity of models, and that some, but not all models, can account for amplification of stimulus, maintenance of polarity, adaptation, sensitivity to new signals, and robustness

Mathematical models for immunology:current state of the art and future research directions

The advances in genetics and biochemistry that have taken place over the last 10 years led to significant advances in experimental and clinical immunology. In turn, this has led to the development of new mathematical models to investigate qualitatively and quantitatively various open questions in immunology. In this study we present a review of some research areas in mathematical immunology that evolved over the last 10 years. To this end, we take a step-by-step approach in discussing a range of models derived to study the dynamics of both the innate and immune responses at the molecular, cellular and tissue scales. To emphasise the use of mathematics in modelling in this area, we also review some of the mathematical tools used to investigate these models. Finally, we discuss some future trends in both experimental immunology and mathematical immunology for the upcoming years

Numerical computation of diffusion on a surface

We present a numerical method for computing diffusive transport on a surface derived from image data. Our underlying discretization method uses a Cartesian grid embedded boundary method for computing the volume transport in a region consisting of all points a small distance from the surface. We obtain a representation of this region from image data by using a front propagation computation based on level set methods for solving the Hamilton–Jacobi and eikonal equations. We demonstrate that the method is second-order accurate in space and time and is capable of computing solutions on complex surface geometries obtained from image data of cells

Response to brentuximab vedotin versus physician's choice by CD30 expression and large cell transformation status in patients with mycosis fungoides: An ALCANZA sub-analysis

INTRODUCTION: Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study. METHODS: Baseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30min < 10% (≥1 biopsy with <10% CD30 expression), or CD30min ≥ 10% (all biopsies with ≥10% CD30 expression) and baseline LCT present or absent. Efficacy analyses were the proportion of patients with objective response lasting ≥4 months (ORR4) and progression-free survival (PFS). RESULTS: Clinical activity with brentuximab vedotin was observed across all CD30 expression levels in patients with ≥1 biopsy showing ≥10% CD30 expression. Superior ORR4 was observed with brentuximab vedotin versus physician's choice in patients: with CD30min < 10% (40.9% versus 9.5%), with CD30min ≥ 10% (57.1% versus 10.3%), with LCT (64.7% versus 17.6%) and without LCT (38.7% versus 6.5%). Brentuximab vedotin improved median PFS versus physician's choice in patients: with CD30min < 10% (16.7 versus 2.3 months), with CD30min ≥ 10% (15.5 versus 3.9 months), with LCT (15.5 versus 2.8 months) and without LCT (16.1 versus 3.5 months). Safety profiles were generally comparable across subgroups. CONCLUSION: These exploratory analyses demonstrated that brentuximab vedotin improved rates of ORR4 and PFS versus physician's choice in patients with CD30-positive MF and ≥1 biopsy showing ≥10% CD30 expression, regardless of LCT status. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT01578499