Interferon α/ß Enhances the Cytotoxic Response of MEK Inhibition in Melanoma.

Drugs that inhibit the MAPK pathway have therapeutic benefit in melanoma, but responses vary between patients, for reasons that are still largely unknown. Here we aim at explaining this variability using pre- and post-MEK inhibition transcriptional profiles in a panel of melanoma cell lines. We found that most targets are context specific, under the influence of the pathway in only a subset of cell lines. We developed a computational method to identify context-specific targets, and found differences in the activity levels of the interferon pathway, driven by a deletion of the interferon locus. We also discovered that IFNα/ß treatment strongly enhances the cytotoxic effect of MEK inhibition, but only in cell lines with low activity of interferon pathway. Taken together, our results suggest that the interferon pathway plays an important role in, and predicts, the response to MAPK inhibition in melanoma. Our analysis demonstrates the value of system-wide perturbation data in predicting drug response.

Identifying Healthcare Professionals With Lower Human Papillomavirus (HPV) Vaccine Recommendation Quality: A Systematic Review.

PURPOSE: Strengthening healthcare professionals' (HCPs) communication is an evidence-based approach to increasing human papillomavirus (HPV) vaccine uptake among adolescents. To better target future interventions, we sought to synthesize evidence on HCP subgroups who most need to improve their HPV vaccine recommendation quality. METHODS: We searched five databases for quantitative studies published from 2012 to 2022 on HPV vaccine recommendation quality, including recommendation consistency and strength, for United States adolescents. Two coders independently abstracted data from each eligible study, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We summarized variation in recommendation quality by clinical and HCP characteristics. RESULTS: The 28 eligible studies indicated that relatively low proportions of HCPs used higher-quality recommendation practices (median: 61% across 30 measures) and that recommendation quality varied across HCP subgroups. The most consistent findings were that more pediatric HCPs used higher-quality recommendations than family medicine HCPs (8 of 11 studies, 2-60 percentage point difference) and that HPV-related knowledge was associated with higher recommendation quality (four of seven studies). Most studies observed no differences in recommendation quality by clinical role (e.g., provider vs. nurse) or HCP demographics (e.g., gender, age, race/ethnicity). DISCUSSION: Studies suggest a substantial need to improve HCPs' recommendation quality, with opportunities for targeting future interventions.

CITED4 induces physiologic hypertrophy and promotes functional recovery after ischemic injury.

The mechanisms by which exercise mediates its multiple cardiac benefits are only partly understood. Prior comprehensive analyses of the cardiac transcriptional components and microRNAs dynamically regulated by exercise suggest that the CBP/p300-interacting protein CITED4 is a downstream effector in both networks. While CITED4 has documented functional consequences in neonatal cardiomyocytes in vitro, nothing is known about its effects in the adult heart. To investigate the impact of cardiac CITED4 expression in adult animals, we generated transgenic mice with regulated, cardiomyocyte-specific CITED4 expression. Cardiac CITED4 expression in adult mice was sufficient to induce an increase in heart weight and cardiomyocyte size with normal systolic function, similar to the effects of endurance exercise training. After ischemia-reperfusion, CITED4 expression did not change initial infarct size but mediated substantial functional recovery while reducing ventricular dilation and fibrosis. Forced cardiac expression of CITED4 also induced robust activation of the mTORC1 pathway after ischemic injury. Moreover, pharmacological inhibition of mTORC1 abrogated CITED4's effects in vitro and in vivo. Together, these data establish CITED4 as a regulator of mTOR signaling that is sufficient to induce physiologic hypertrophy at baseline and mitigate adverse ventricular remodeling after ischemic injury.