Single nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of combined CDK4/6 and mTOR inhibition in a phase 0/1 trial of recurrent high-grade glioma.

Outcomes for adult patients with a high-grade glioma continue to be dismal and new treatment paradigms are urgently needed. To optimize the opportunity for discovery, we performed a phase 0/1 dose-escalation clinical trial that investigated tumor pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics following combined ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) treatment in recurrent high-grade glioma. Patients with a recurrent high-grade glioma (n = 24) harboring 1) CDKN2A / B deletion or CDK4 / 6 amplification, 2) PTEN loss or PIK3CA mutations, and 3) wild-type retinoblastoma protein (Rb) were enrolled. Patients received neoadjuvant ribociclib and everolimus treatment and no dose-limiting toxicities were observed. The median unbound ribociclib concentrations in Gadolinium non-enhancing tumor regions were 170 nM (range, 65 - 1770 nM) and 634 nM (range, 68 - 2345 nM) in patients receiving 5 days treatment at the daily dose of 400 and 600 mg, respectively. Unbound everolimus concentrations were below the limit of detection (< 0.1 nM) in both enhancing and non-enhancing tumor regions at all dose levels. We identified a significant decrease in MIB1 positive cells suggesting ribociclib-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) based comparisons of 17 IDH-wild-type on-trial recurrences to 31 IDH-wild-type standard of care treated recurrences data demonstrated a significantly lower fraction of cycling and neural progenitor-like (NPC-like) malignant cell populations. We validated the CDK4/6 inhibitor-directed malignant cell state shifts using three patient-derived cell lines. The presented clinical trial highlights the value of integrating pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics to assess treatment effects in phase 0/1 surgical tissues, including malignant cell state shifts. ClinicalTrials.gov identifier: NCT03834740 .

Impact of enriched environment during adolescence on adult social behavior, hippocampal synaptic density and dopamine D2 receptor expression in rats.

Environmental enrichment (EE) is one experimental manipulation that induces changes in the brain. However, it is important to distinguish between physical and social components of enrichment. To this end we established four groups of rats reared in different enriched environments during the adolescent period. Our results indicate heightened social memory and increased spine density in dentate gyrus specifically in socially enriched animals. Physical enrichment increased spine density in CA1. Dopamine D2 receptor expression in hippocampus was decreased across all enrichment conditions. Altogether, our results demonstrate differing effects of physical and social enrichment, supporting an important role for environment in synaptogenesis, behavior, and dopaminergic signaling.

Dysregulated Marginal Zone B Cell Compartment in a Mouse Model of Sjögren's Syndrome with Ocular Inflammation.

The risk of developing lymphoma in patients with Sjögren's syndrome (SS) is 44 times higher than in the normal population with the most common lymphomas derived from marginal zone B (MZB) cells. Current understanding of the role of MZB cells in SS is primarily based on salivary gland pathology, while their contextual association with lacrimal glands and ocular manifestations largely remains unknown. We examined this possibility using a SS mouse model (thrombospondin-1 deficient (TSP1-/-)) with well-characterized ocular disease. We determined the frequency, localization, and cytokine profiles of MZB cells and their association with an antibody response in TSP1-/- mice treated with a TSP-derived peptide. A significantly increased frequency of MZB cells was detected in the spleens and lacrimal glands of TSP1-/- mice in comparison to wild-type tissues as detected by immunostaining. An altered cytokine profile of TSP1-/- MZB cells was supportive of T helper 17 (Th17)-related pathogenesis. A significantly reduced antibody response and the splenic MZB compartment against an eye-derived antigen were noted in TSP-derived peptide-treated mice. These changes correspond with the previously reported ability of the peptide to ameliorate SS-related ocular manifestations. Collectively, our results demonstrate dysregulation of MZB cells in TSP1-/- mice and highlight their role in the context of SS-related chronic ocular surface disease.

Competition injuries in taekwondo: a literature review and suggestions for prevention and surveillance.

OBJECTIVE: To review competition injuries in taekwondo and use this information to develop recommendations to reduce the number and severity of injuries in taekwondo competition. METHODS: The available literature was searched for prospective studies on taekwondo injuries in adult athletes. An injury was defined as any circumstance for which the athlete sought the assistance of the on-site medical personnel. Injury rates were expressed per athlete-exposures (A-E) and 95% CIs calculated. RESULTS: Total injury rates for elite men varied from 20.6/1000 A-E (95% CI 11.8 to 29.3) to 139.5/1000 A-E (95% CI 94.0 to 185.1). For elite women, the rates varied from 25.3/1000 A-E (95% CI 3.1 to 47.4) to 105.5/1000 A-E (95% CI 89.8 to 121.1). About one-third of all injuries (29.6%) in the men were to the head and neck region, while almost half of the injuries (44.5%) were to the lower extremities. In women, 15.2% of injuries were to the head and neck and 53.1% to the lower extremities. The vast majority of all injuries were contusions (42.7% in the men and 62.7% in the women). Point estimates of rates of head injuries and concussions were found to be higher in taekwondo than in other contact sports such as football (soccer) and American gridiron football. Time-loss injury rates in the men varied from 6.9/1000 A-E (95% CI 1.8 to 11.9) to 33.6/1000 A-E (95% CI 18.9 to 48.3). In the women, they varied from 2.4/1000 A-E (95% CI 2.3 to 7.2) to 23.0/1000 A-E (95% CI 15.7 to 30.4). The turning kick was most often involved in causing injury: 56.9% of all injuries in the men and 49.8% in the women. Lack of blocking skills was identified as one of the main injury mechanisms. CONCLUSIONS: Rule changes should be considered and it is recommended that governing bodies employ qualified medical personnel. Establishing an ongoing injury surveillance system in taekwondo should be the first priority.