Current Non-Viral-Based Strategies to Manufacture CAR-T Cells.

The successful application of CAR-T cells in the treatment of hematologic malignancies has fundamentally changed cancer therapy. With increasing numbers of registered CAR-T cell clinical trials, efforts are being made to streamline and reduce the costs of CAR-T cell manufacturing while improving their safety. To date, all approved CAR-T cell products have relied on viral-based gene delivery and genomic integration methods.

TCR/CD3-based synthetic antigen receptors (TCC) convey superior antigen sensitivity combined with high fidelity of activation.

Low antigen sensitivity and a gradual loss of effector functions limit the clinical applicability of chimeric antigen receptor (CAR)-modified T cells and call for alternative antigen receptor designs for effective T cell-based cancer immunotherapy. Here, we applied advanced microscopy to demonstrate that TCR/CD3-based synthetic constructs (TCC) outperform second-generation CAR formats with regard to conveyed antigen sensitivities by up to a thousandfold. TCC-based antigen recognition occurred without adverse nonspecific signaling, which is typically observed in CAR-T cells, and did not depend-unlike sensitized peptide/MHC detection by conventional T cells-on CD4 or CD8 coreceptor engagement.

Supersymmetric Five-Point Gluon Amplitudes in AdS Space.

We present the tree-level five-point amplitude of the lowest Kaluza-Klein mode of super-Yang-Mills theory on AdS_{5}×S^{3}, dual to the correlator of the flavor current multiplet in the dual 4d N=2 superconformal field theory. Its color and kinematical structure is particularly simple and resembles that of the flat-space gluon amplitude.

Light-Cone Bootstrap of Higher Point Functions and Wilson Loop Duality.

We initiate an exploration of the conformal bootstrap for n>4 point correlation functions. Here we bootstrap correlation functions of the lightest scalar gauge invariant operators in planar non-Abelian conformal gauge theories as their locations approach the cusps of a null polygon. For that we consider consistency of the OPE in the so-called snowflake channel with respect to cyclicity transformations which leave the null configuration invariant.

Inefficient CAR-proximal signaling blunts antigen sensitivity.

Rational design of chimeric antigen receptors (CARs) with optimized anticancer performance mandates detailed knowledge of how CARs engage tumor antigens and how antigen engagement triggers activation. We analyzed CAR-mediated antigen recognition via quantitative, single-molecule, live-cell imaging and found the sensitivity of CAR T cells toward antigen approximately 1,000-times reduced as compared to T cell antigen-receptor-mediated recognition of nominal peptide-major histocompatibility complexes. While CARs outperformed T cell antigen receptors with regard to antigen binding within the immunological synapse, proximal signaling was significantly attenuated due to inefficient recruitment of the tyrosine-protein kinase ZAP-70 to ligated CARs and its reduced concomitant activation and subsequent release.

Uncertain Risk Assessment and Management: Case Studies of the Application of the Precautionary Principle in Portugal.

This study intends to clarify how the precautionary principle (PP) has been interpreted and applied by the courts in Portugal in the analysis of conflicts associated with uncertain and serious potential risks to human health and the environment. It also aims to contribute to the debate of when and how to apply precautionary measures. To this end, recent court cases in the areas of waste incineration, high-voltage power lines, as well as dam and wind farm construction were considered.