Comparative assessment of the transduction efficiency and safety associated with the delivery of AAV9-GFP vector via lumbar puncture to cynomolgus macaques with and without anti-AAV9 pre-existing antibodies.

Administration of AAV-based gene therapies into the intra-cerebrospinal fluid (CSF) compartments via routes such as lumbar puncture (LP) has been implemented as an alternative to intravenous dosing to target the CNS regions. This route enables lower doses, decreases systemic toxicity, and circumvents intravascular pre-existing anti-AAV antibodies. In this study, AAV9-GFP vectors were administered via LP to juvenile cynomolgus macaques with and without pre-existing serum anti-AAV9 antibodies at a 5.

Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-]pyrimidine RET Inhibitors.

The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-]pyrimidine scaffold. The optimization of this pyrrolo[2,3-]pyrimidine core resulted in compound , which demonstrated potent RET kinase inhibition and robust efficacy in RET-driven tumor xenografts upon multiday dosing in mice.

Unsupervised Body Hair Detection by Positive-Unlabeled Learning in Photoacoustic Image.

Photoacoustic (PA) imaging is a new imaging technology that can non-invasively visualize blood vessels and body hair in 3D. It is useful in cosmetic surgery for detecting body hair and computing metrics such as the number and thicknesses of hairs. Previous supervised body hair detection methods often do not work if the imaging conditions change from training data.

Efficacy and Tolerability of Pyrazolo[1,5-]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma.

RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse studies, compound demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd).

A Case of Drug-induced Cutaneous Toxicity Observed in Cynomolgus Monkeys.

The purpose of this article is to describe a case of drug-induced cutaneous toxicity observed in cynomolgus monkeys and to introduce approaches attempted in order to elucidate mechanisms. The test article was a small molecule with a ubiquitously distributed target, especially in rapidly dividing cells, and which modulated cell cycle regulation. After 7 consecutive days of oral dosing, animals developed multifocal skin lesions.