Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma.

PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell-mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma (DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies.

Detection of a Broad Range of Low-Level Major Histocompatibility Complex Class II-Restricted, Hepatitis Delta Virus (HDV)-Specific T-Cell Responses Regardless of Clinical Status.

Background: This study aimed to comprehensively define the breadth and specificity of the hepatitis delta virus (HDV)-specific T-cell response in patients at different stages of chronic coinfection with hepatitis B virus (HBV). Methods: Following in vitro stimulation with an overlapping set of 21 HDV-specific 20mer peptides and exogenous interleukin 2, HDV-specific CD4+ and CD8+ T-cell responses of 32 HDV-infected patients were analyzed by enzyme-linked immunospot analysis and intracellular cytokine staining for interferon γ production at the single-peptide level. Additionally, HLA-binding studies were performed both in silico and in vitro. Results: We were able to detect ≥1 T-cell response in >50% our patients. Interestingly, there was no significant difference between the breadth of the response in patients positive and those negative for HDV by PCR. HDV-specific T-cell responses focused on 3 distinct HDV-specific epitopes that were each detected in 12%-21% of patients-2 HLA class II-restricted epitopes (amino acids 11-30 and 41-60) and 1 major histocompatibility complex class I-restricted epitope (amino acids 191-210). In in vitro HLA-binding assays, the 2 CD4+ T-cell specificities (amino acids 11-30 and 41-60) showed promiscuous binding to multiple HLA-DR molecules. Conclusions: This comprehensive characterization of HDV T-cell epitopes provides important information that will facilitate further studies of HDV immunopathogenesis.

Objective and perceptual evaluation of distance-dependent scattered sound effects in a small variable-acoustics hall.

Performance spaces are characterized by a complex sound field, due to the presence of absorptive and diffusive surfaces. In situ evaluations of the acoustic effects that these surfaces have on the objective acoustic parameters and on sound perception have not yet been fully understood. To this aim, acoustic measurements have been performed in a variable-acoustic concert hall, the Espace de Projection, at the Institut de Recherche et Coordination Acoustique/Musique. These measurements have allowed the effects of one single wall to be determined. A diffusive and a reflective condition of one of the long lateral walls of the shoebox-like hall have been considered, while the other surfaces have been fixed in absorptive mode. Measurements have been carried out at different distances from the test wall, using an artificial head and an array of omnidirectional microphones. Objective acoustic parameters, such as early decay time, reverberation time (T30), clarity (C80), definition (D50), and interaural cross correlation, have been compared between both conditions. In addition to the objective indexes, a perceptual evaluation has been performed using listening tests that had the purpose of determining the maximum distance from a diffusive surface at which acoustic scattering effects are still audible.

The Need for Integrative Computational Oncology: An Illustrated Example through MMP-Mediated Tissue Degradation.

PHYSICAL ONCOLOGY IS A GROWING FORCE IN CANCER RESEARCH, AND IT IS ENHANCED BY INTEGRATIVE COMPUTATIONAL ONCOLOGY: the fusion of novel experiments with mathematical and computational modeling. Computational models must be assessed with accurate numerical methods on correctly scaled tissues to avoid numerical artifacts that can cloud analysis. Simulation-driven analyses can only be validated by careful experiments. In this perspectives piece, we evaluate a current, widespread model of matrix metalloproteinase-driven tissue degradation during cancer invasion to illustrate that integrative computational oncology may not realize its fullest potential if either of these critical steps is neglected.

An agent-based model for elasto-plastic mechanical interactions between cells, basement membrane and extracellular matrix.

The basement membrane (BM) and extracellular matrix (ECM) play critical roles in developmental and cancer biology, and are of great interest in biomathematics. We introduce a model of mechanical cell-BM-ECM interactions that extends current (visco)elastic models (e.g. [8,16]), and connects to recent agent-based cell models (e.g. [2,3,20,26]). We model the BM as a linked series of Hookean springs, each with time-varying length, thickness, and spring constant. Each BM spring node exchanges adhesive and repulsive forces with the cell agents using potential functions. We model elastic BM-ECM interactions with analogous ECM springs. We introduce a new model of plastic BM and ECM reorganization in response to prolonged strains, and new constitutive relations that incorporate molecular-scale effects of plasticity into the spring constants. We find that varying the balance of BM and ECM elasticity alters the node spacing along cell boundaries, yielding a nonuniform BM thickness. Uneven node spacing generates stresses that are relieved by plasticity over long times. We find that elasto-viscoplastic cell shape response is critical to relieving uneven stresses in the BM. Our modeling advances and results highlight the importance of rigorously modeling of cell-BM-ECM interactions in clinically important conditions with significant membrane deformations and time-varying membrane properties, such as aneurysms and progression from in situ to invasive carcinoma.