Discovery of SMD-3236: A Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers.

SMARCA2 is an attractive synthetic lethal target in human cancers with mutated, inactivated SMARCA4. We report herein the discovery of highly potent and selective SMARCA2 PROTAC degraders, as exemplified by SMD-3236, which was designed using a new, high-affinity SMARCA ligand and a potent VHL-1 ligand. SMD-3236 achieves DC < 1 nM and > 95% against SMARCA2 and >2000-fold degradation selectivity over SMARCA4.

Discovery of Potent, Highly Selective, and Efficacious SMARCA2 Degraders.

We describe the identification of selective SMARCA2, VHL-based heterobifunctional degraders. Structurally novel indolo[1,2-]quinazolin-5(7)-one SMARCA bromodomain binders were optimized and then converted to SMARCA2 degraders by linking them to well-defined VHL ligands. Our exploration led to the discovery of potent and selective degraders of SMARCA2 over the SMARCA4 paralog, leading to potent and selective growth inhibition of SMARCA4 mutant versus wild type cell lines.

Obstetric outcomes among rural parturients across US urban and rural hospitals.

Introduction: The objective of this study is to evaluate severe maternal morbidity (SMM) of rural parturients delivering at rural compared to urban hospitals in the US.

Methods: We identified patients aged 18-40 years in a multi-institutional claims database who lived in a rural ZIP code and delivered at a rural or urban hospital between October-December of 2015 and October-December of 2022. The primary outcome was SMM, and the secondary outcome was SMM exclusive of blood transfusions.

Nitinol Staple Use in Primary Arthrodesis of Lisfranc Fracture-Dislocations.

Background: Primary arthrodesis of Lisfranc fracture-dislocations is a reliable treatment option, yet concerns remain about nonunion. Nitinol staple use has recently proliferated in midfoot arthrodesis. The purpose of this study is to examine the union rate of primary arthrodesis of acute Lisfranc fracture-dislocations treated with nitinol staples compared with traditional plate-and-screw fixation.

DRL-GAN: A Hybrid Approach for Binary and Multiclass Network Intrusion Detection.

Our increasingly connected world continues to face an ever-growing number of network-based attacks. An Intrusion Detection System (IDS) is an essential security technology used for detecting these attacks. Although numerous Machine Learning-based IDSs have been proposed for the detection of malicious network traffic, the majority have difficulty properly detecting and classifying the more uncommon attack types.