Advancing tumor microenvironment and lymphoid tissue research through 3D bioprinting and biofabrication.

Cancer progression is significantly influenced by the complex interactions within the tumor microenvironment (TME). Immune cells, in particular, play a critical role by infiltrating tumors from the circulation and surrounding lymphoid tissues in an attempt to control their spread. However, they often fail in this task.

Non-Conditional and Conditional Metastasis of Uveal Melanoma Per Millimeter-By-Millimeter in Thickness in 8034 Patients.

Purpose: To determine the impact of uveal melanoma thickness on patient survival from the date of presentation and at specific time intervals following metastasis-free survival.

Methods: In this retrospective cohort study, we evaluated data from 8034 consecutive uveal melanoma patients diagnosed at a tertiary care ocular oncology center between May 1972 and August 2007. The patients were categorized on the basis of tumor thickness (per each 1-mm increment) and evaluated for non-conditional survival (from date of presentation) and conditional survival (with 3-years, 5-years, and 10-years of metastasis-free survival) on the cumulative incidence of melanoma-related metastasis at 5-, 10-, 15-, 20-, 25- and 30-years.

Discovery of (2,4)-4-(()-2-Amino-3-methylbutanamido)-2-(4-boronobutyl)pyrrolidine-2-carboxylic Acid (AZD0011), an Actively Transported Prodrug of a Potent Arginase Inhibitor to Treat Cancer.

Arginase is a promising immuno-oncology target that can restore the innate immune response. However, it's highly polar active site often requires potent inhibitors to mimic amino acids, leading to poor passive permeability and low oral exposure. Using structure-based drug design, we discovered a novel proline-based arginase inhibitor () that was potent but had low oral bioavailability in rat.

Peptide Aldehydes Incorporating Thiazol-4-yl Alanine Are Potent In Vitro Inhibitors of SARS-CoV-2 Main Protease.

The main protease of SARS-CoV-2 is an essential enzyme required for polyprotein cleavage during viral replication and thus is an excellent target for development of direct-acting antiviral compounds. Continued research efforts have elucidated several peptidic small molecules like GC376, boceprevir, and nirmatrelvir with potent anticoronaviral activity bearing optimized amino acid side chain residues. To reduce synthetic complexity and cost, we used simple chemical surrogates that were commercially readily available to develop new inhibitors that mimic the potency of these drug compounds.

Design and Synthesis of Acyclic Boronic Acid Arginase Inhibitors.

Arginase has long been a target of interest in immuno-oncology, but discovering an orally bioavailable inhibitor is severely constrained by the requisite boronic acid pharmacophore. We began our drug discovery campaign by building off the β-position of the literature inhibitor ABH (). A divergent synthesis with an Ireland-Claisen rearrangement as the key step allowed access to numerous compounds, some of which we crystallized in the active site of arginase 2.