Housing experience affects adult neurogenesis in turtles (Chrysemys picta).

Adult neurogenesis increases in mammals when they are exposed to an enriched environment or given the opportunity to exercise. In this experiment, we investigated whether turtles would show differences in the number of new neurons in the telencephalon when they were exposed to deep water, conspecifics, and plants and logs (EE group), compared to a group of animals housed in individual cages with shallow water (IN group). A control group (EX) was given deep water and conspecifics but no plants and logs. We gave nine injections of BrdU over a 3-week period, starting when the turtles were introduced to the housing. The results showed that both the EE and the EX groups had more new cells in the dorsal ventricular ridge (DVR), a sensory area of the telencephalon. The two groups did not differ from one another. The group-housed animals also had a higher percentage of new neurons in the DVR that were double labeled for NeuN, a marker of neurons, compared to the IN group. There were no significant differences between groups in the number of new cells in the medial cortex, the homolog of the hippocampus. These findings demonstrate that the housing experience influences the number of new cells that survive in the brains of turtles. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.

Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920.