Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations.

Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether and biaryl as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CL compounds while maintaining a WT selectivity margin.

Oncolytic viruses expressing MATEs facilitate target-independent T-cell activation in tumors.

Oncolytic viruses (OV) expressing bispecific T-cell engagers (BiTEs) are promising tools for tumor immunotherapy but the range of target tumors is limited. To facilitate effective T-cell stimulation with broad-range applicability, we established membrane-associated T-cell engagers (MATEs) harboring the protein transduction domain of the HIV-Tat protein to achieve non-selective binding to target cells. In vitro, MATEs effectively activated murine T cells and improved killing of MC38 colon carcinoma cells.

Central statistical monitoring in clinical trial management: A scoping review.

Background: Clinical trials handle a huge amount of data which can be used during the trial to improve the ongoing study conduct. It is suggested by regulators to implement the remote approach to evaluate clinical trials by analysing collected data. Central statistical monitoring helps to achieve that by employing quantitative methods, the results of which are a basis for decision-making on quality issues.

Preoperative quadriceps malalignment is associated with poor outcomes after knee replacement which are avoided by external rotation of the femoral component.

Purpose: Lateralisation of the proximal apex of the quadriceps tendon relative to the mechanical axis or external rotation relative to the femoral shaft can be accurately measured and is strongly associated with patella maltracking. The aim of this study was to first assess the association between preoperative quadriceps tendon alignment (QTA) and the patient-reported outcomes (PROMs) of total knee replacement, and second, determine the influence of component position on outcomes in patients with preoperative quadriceps tendon malalignment (QTM).

Methods: A retrospective analysis of prospectively collected data was performed.

Guidance for creating morally healthy organizations that remediate the experience of moral injury in healthcare: Findings from an international e-Delphi study.

Objective: To date, research and policy directives have focused on identifying individual risk factors for moral injury, with less attention to solutions for establishing non-morally injurious cultures and practices.

Methods: Experts with academic or clinical knowledge of moral injury were recruited to a three-round e-Delphi survey exploring descriptors and characteristics of non-morally injurious organisations.

Results: Forty-nine, forty-one and thirty-nine experts responded at each round.