Diffusion of MMPs on the Surface of Collagen Fibrils: The Mobile Cell Surface – Collagen Substratum Interface

Remodeling of the extracellular matrix catalyzed by MMPs is central to morphogenetic phenomena during development and wound healing as well as in numerous pathologic conditions such as fibrosis and cancer. We have previously demonstrated that secreted MMP-2 is tethered to the cell surface and activated by MT1-MMP/TIMP-2-dependent mechanism. The resulting cell-surface collagenolytic complex (MT1-MMP)2/TIMP-2/MMP-2 can initiate (MT1-MMP) and complete (MMP-2) degradation of an underlying collagen fibril. The following question remained: What is the mechanism of substrate recognition involving the two structures of relatively restricted mobility, the cell surface enzymatic complex and a collagen fibril embedded in the ECM? Here we demonstrate that all the components of the complex are capable of processive movement on a surface of the collagen fibril. The mechanism of MT1-MMP movement is a biased diffusion with the bias component dependent on the proteolysis of its substrate, not adenosine triphosphate (ATP) hydrolysis. It is similar to that of the MMP-1 Brownian ratchet we described earlier. In addition, both MMP-2 and MMP-9 as well as their respective complexes with TIMP-1 and -2 are capable of Brownian diffusion on the surface of native collagen fibrils without noticeable dissociation while the dimerization of MMP-9 renders the enzyme immobile. Most instructive is the finding that the inactivation of the enzymatic activity of MT1-MMP has a detectable negative effect on the cell force developed in miniaturized 3D tissue constructs. We propose that the collagenolytic complex (MT1-MMP)2/TIMP-2/MMP-2 represents a Mobile Cell Surface – Collagen Substratum Interface. The biological implications of MT1-MMP acting as a molecular ratchet tethered to the cell surface in complex with MMP-2 suggest a new mechanism for the role of spatially regulated peri-cellular proteolysis in cell-matrix interactions

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

Immunotherapy biomarkers 2016: overcoming the barriers

This report summarizes the symposium, ‘Immunotherapy Biomarkers 2016: Overcoming the Barriers’, which was held on April 1, 2016 at the National Institutes of Health in Bethesda, Maryland. The symposium, cosponsored by the Society for Immunotherapy of Cancer (SITC) and the National Cancer Institute (NCI), focused on emerging immunotherapy biomarkers, new technologies, current hurdles to further progress, and recommendations for advancing the field of biomarker development

Comprehending complexity:data-rate constraints in large-scale networks

\u3cp\u3eThis paper is concerned with the rate at which a discrete-time, deterministic, and possibly large network of nonlinear systems generates information, and so with the minimum rate of data transfer under which the addressee can maintain the level of awareness about the current state of the network. While being aimed at development of tractable techniques for estimation of this rate, this paper advocates benefits from directly treating the dynamical system as a set of interacting subsystems. To this end, a novel estimation method is elaborated that is alike in flavor to the small gain theorem on input-to-output stability. The utility of this approach is demonstrated by rigorously justifying an experimentally discovered phenomenon. The topological entropy of nonlinear time-delay systems stays bounded as the delay grows without limits. This is extended on the studied observability rates and appended by constructive upper bounds independent of the delay. It is shown that these bounds are asymptotically tight for a time-delay analog of the bouncing ball dynamics.\u3c/p\u3

A small-gain-theorem-like approach to nonlinear observability via finite capacity channels\u3csup\u3e*\u3c/sup\u3e

\u3cp\u3eThe paper is concerned with observation of discrete-time, nonlinear, deterministic, and maybe chaotic systems via communication channels with finite data rates, with a focus on minimum data-rates needed for various types of observability. With the objective of developing tractable techniques to estimate these rates, the paper discloses benefits from regard to the operational structure of the system in the case where the system is representable as a feedback interconnection of two subsystems with inputs and outputs. To this end, a novel estimation method is elaborated, which is alike in flavor to the celebrated small gain theorem on input-to-output stability. The utility of this approach is demonstrated for general nonlinear time-delay systems by rigorously justifying an experimentally discovered phenomenon: Their topological entropy stays bounded as the delay grows without limits. This is extended on the studied observability rates and appended by constructive finite upper bounds independent of the delay. It is shown that these bounds are asymptotically tight for a time-delay analog of the bouncing ball dynamics.\u3c/p\u3