Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival.

An Orally Efficacious Thyrotropin Receptor Ligand Inhibits Growth and Metastatic Activity of Thyroid Cancers.

Context: Thyroid-stimulating hormone (or thyrotropin) receptor (TSHR) could be a selective target for small molecule ligands to treat thyroid cancer (TC).

Objective: We report a novel, orally efficacious ligand for TSHR that exhibits proliferation inhibitory activity against human TC in vitro and in vivo, and inhibition of metastasis in vivo.

Methods: A35 (NCATS-SM4420; NCGC00241808) was selected from a sublibrary of >200 TSHR ligands.

A patient safety knowledge graph supporting vaccine product development.

Background: Knowledge graphs are well-suited for modeling complex, unstructured, and multi-source data and facilitating their analysis. During the COVID-19 pandemic, adverse event data were integrated into a knowledge graph to support vaccine safety surveillance and nimbly respond to urgent health authority questions. Here, we provide details of this post-marketing safety system using public data sources.

Validation of a Natural Language Machine Learning Model for Safety Literature Surveillance.

Introduction: As part of routine safety surveillance, thousands of articles of potential interest are manually triaged for review by safety surveillance teams. This manual triage task is an interesting candidate for automation based on the abundance of process data available for training, the performance of natural language processing algorithms for this type of cognitive task, and the small number of safety signals that originate from literature review, resulting in its lower risk profile. However, deep learning algorithms introduce unique risks and the validation of such models for use in Good Pharmacovigilance Practice remains an open question.

Discovery of small molecule agonists of the Relaxin Family Peptide Receptor 2.

The relaxin/insulin-like family peptide receptor 2 (RXFP2) belongs to the family of class A G-protein coupled receptors (GPCRs) and it is the only known target for the insulin-like factor 3 peptide (INSL3). The importance of this ligand-receptor pair in the development of the gubernacular ligament during the transabdominal phase of testicular descent is well established. More recently, RXFP2 has been implicated in maintaining healthy bone formation.