Assessment of the effects of sex, age, and rearing condition on ultrasonic vocalizations elicited by pups during the maternal potentiation paradigm in C57BL/6J mice.

Isolation-induced ultrasonic vocalizations (USVs) are important to elicit parental retrieval. This behavior is critical for the animal's survival and can be altered in models of developmental disorders. The potentiation of vocalizations in response to reunion with the dam, also called maternal potentiation, has been extensively studied in rats. However, the assessment of this paradigm in mice is scarce. In rats, the potentiation of vocalizations is dependent on rearing conditions. Since mice are the main species used for genetic models of diseases, we aimed to investigate how different factors such as age, sex, and rearing conditions can affect the potentiation of vocalizations in the maternal potentiation paradigm in mice. We carried out experiments using biparental (dam and sire) or uniparental rearing (dam). Pups were tested on postnatal days (PD) 9 or 12. Pups showed increased potentiation in both sexes at PD9 with uniparental rearing. Both rearing conditions and ages changed the repertoire from the first to the second isolation. Spectral parameters were affected by sex, rearing condition and reunion at PD9. At PD12, only duration was altered by reunion. We conclude that the performance of the pups in the maternal potentiation paradigm is dependent on age, sex, and rearing condition.

NS-Pten knockout mice exhibit sex and hippocampal subregion-specific increases in microglia/macrophage density.

Seizures induce hippocampal subregion dependent enhancements in microglia/macrophage phagocytosis and cytokine release that may contribute to the development of epilepsy. As a model of hyperactive mTOR induced epilepsy, neuronal subset specific phosphatase and tensin homolog (NS-Pten) knockout (KO) mice exhibit hyperactive mTOR signaling in the hippocampus, seizures that progress with age, and enhanced hippocampal microglia/macrophage activation. However, it is unknown where microglia/macrophages are most active within the hippocampus of NS-Pten KO mice. We quantified the density of IBA1 positive microglia/macrophages in the CA1, CA2/3, and dentate gyrus of NS-Pten KO and wildtype (WT) male and female mice at 4, 10, and 15 weeks of age. NS-Pten KO mice exhibited an overall increase in the number of IBA1 positive microglia/macrophages in each subregion and in the entire hippocampus. After accounting for differences in size, the whole hippocampus of NS-Pten KO mice still exhibited an increased density of IBA1 positive microglia/macrophages. Subregion analyses showed that this increase was restricted to the dentate gyrus of both male and female NS-Pten KO mice and to the CA1 of male NS-Pten KO mice. These data suggest enhanced microglia/macrophage activity may occur in the NS-Pten KO mice in a hippocampal subregion and sex-dependent manner. Future work should seek to determine whether these region-specific increases in microgliosis play a role in the progression of epilepsy in this model.

PKMYT1 is a Marker of Treatment Response and a Therapeutic Target for CDK4/6 Inhibitor-Resistance in ER+ Breast Cancer.

Endocrine therapies (ET) with CDK4/6 inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of 22 ER+ breast cancer patient-derived xenografts (PDXs) demonstrated that PKMYT1, a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.