Blockade of tumor cell-intrinsic PD-L1 signaling enhances AURKA-targeted therapy in triple negative breast cancer.

Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and mainly affects pre-menopausal and minority women. Because of the lack of ER, PR or HER2 expression in TNBC, there are limited options for tailored therapies. While TNBCs respond initially to standard of care chemotherapy, tumor recurrence commonly occurs within 1 to 3 years post-chemotherapy and is associated with early organ metastasis and a high incidence of mortality. One of the major mechanisms responsible for drug resistance and emergence of organ metastasis is activation of epithelial to mesenchymal transition (EMT) reprogramming. EMT-mediated cancer cell plasticity also promotes the enrichment of cancer cells with a CD44high/CD24low and/or ALDHhigh cancer stem-like phenotype [cancer stem cells (CSCs)], characterized by an increased capacity for tumor self-renewal, intrinsic drug resistance, immune evasion and metastasis. In this study we demonstrate for the first time a positive feedback loop between AURKA and intra-tumoral PD-L1 oncogenic pathways in TNBC. Genetic targeting of intra-tumoral PD-L1 expression impairs the enrichment of ALDHhigh CSCs and enhances the therapeutic efficacy of AURKA-targeted therapy. Moreover, dual AURKA and PD-L1 pharmacological blockade resulted in the strongest inhibition of tumor growth and organ metastatic burden. Taken together, our findings provide a compelling preclinical rationale for the development of novel combinatorial therapeutic strategies aimed to inhibit cancer cell plasticity, immune evasion capacity and organ metastasis in patients with advanced TNBC.

Prevalence of sleep disorders and sleep problems in an elite super rugby union team.

The aim of this study was to determine the prevalence of sleep disorders in an elite rugby union team using in-laboratory polysomnography (PSG) and sleep questionnaires. Twenty-five elite rugby union players underwent a night of PSG during the "off-season" of the Super Rugby competition to assess their sleep. Of interest were measurements that detected the presence of obstructive sleep apnea (OSA; apnea-hypopnea index ≥5 events/hr) and the presence of moderate-severe periodic leg movements during sleep (PLMs; ≥15 events/hr). Players completed sleep-related questionnaires to assess daytime sleepiness, perception of insomnia, risk of OSA, and the presence of restless legs syndrome (RLS) and underwent basic anthropometric assessments including body mass index and neck circumference. OSA was present in 24% (n=6) of players and PLMs ≥15 events/hr in 12% (n=3). Questionnaire responses showed that all players had insomnia defined subthreshold insomnia and excessive daytime sleepiness, two players were identified as being at risk for OSA and none were classified as having RLS. In conclusion, sleep disorders and excessive sleepiness are common in elite rugby union players. A process to identify and manage sleep disorders should be considered by teams to optimise their physical recovery, athletic performance and to safeguard their health.