Multiplex engineering using microRNA-mediated gene silencing in CAR T cells.

Background: Multiplex gene-edited chimeric antigen receptor (CAR) T-cell therapies face significant challenges, including potential oncogenic risks associated with double-strand DNA breaks. Targeted microRNAs (miRNAs) may provide a safer, functional, and tunable alternative for gene silencing without the need for DNA editing.

Methods: As a proof of concept for multiplex gene silencing, we employed an optimized miRNA backbone and gene architecture to silence T-cell receptor (TCR) and major histocompatibility complex class I (MHC-I) in mesothelin-directed CAR (M5CAR) T cells.

Transforming Drug Therapy with Deep Learning: The Future of Personalized Medicine.

Personalized medicine represents a paradigm shift in healthcare, aiming to tailor treatment strategies to the unique genetic, environmental, and lifestyle characteristics of individual patients. This approach holds immense potential for improving therapeutic efficacy and minimizing adverse drug reactions. With the rapid advancement of artificial intelligence, deep learning has emerged as a transformative tool in pharmacology, enabling precise modeling of complex biological data and uncovering hidden patterns in patient-specific information.

Energetics of Tetrel, Pnicogen, and Hydrogen Bonds in Microhydrated Clusters of CO and NO.

In this study, the noncovalent interactions present in microhydrated clusters of the isoelectronic molecules viz. CO and NO were investigated by evaluating the energy of individual noncovalent interactions and cooperative contributions using the molecular tailoring approach-based (MTA-based) method. The molecular electrostatic potential (MESP) analysis revealed that CO acts as a better electron acceptor due to a more pronounced electron-deficient region on its C-atom, compared to the central N-atom of NO.

Evaluation of Gross Tumour Volume in Head and Neck Cancers on Contrast-Enhanced Computed Tomography vs Magnetic Resonance Imaging and its Implications on Dice Similarity Coefficients and Dose-Volume Parameters.

Aims: Radiotherapy treatment planning for head and neck cancers (HNCs) is usually based on contrast-enhanced computed tomography (CECT). However, soft-tissue contrast is better evident in magnetic resonance imaging (MRI). The study evaluates the gross tumour volumes (GTVs) delineated on CECT vs MRI along with their Dice similarity coefficients (DSCs) and resultant impact on the dose-volume histogram (DVH) parameters, conformity index (CI), and homogeneity index (HI) during intensity-modulated radiotherapy (IMRT) planning in HNCs.

Engineering a Juxtamembrane-Targeting CAR T-Cell Against Mesothelin: A Novel Binder Resilient to Shed Antigen in Ovarian and Pancreatic Cancer.

Mesothelin is an attractive target for CAR-T therapy on a number of cancer types; however, the efficacy of this therapy is diminished because the bulk of the cell surface-expressed mesothelin is shed through naturally occurring proteolysis leaving behind a short juxtamembrane peptide 'stump'. The two problems this creates are (1) the bulk of the target protein is no longer on the tumor cell and (2), the free soluble shed mesothelin remains in the tumor microenvironment and becomes present in blood/other body fluids binding to the mesothelin-targeted CAR-T and interfering with their ability to target the mesothelin that remains on the surface of the tumor. These issues have likely contributed at least in part to the lack of desired efficacy of CAR-T cells that target membrane distal regions of mesothelin (i.