Childhood cancer mutagenesis caused by transposase-derived PGBD5.

Genomic rearrangements are a hallmark of most childhood tumors, including medulloblastoma, one of the most common brain tumors in children, but their causes remain largely unknown. Here, we show that PiggyBac transposable element derived 5 (Pgbd5) promotes tumor development in multiple developmentally accurate mouse models of Sonic Hedgehog (SHH) medulloblastoma. Most Pgbd5-deficient mice do not develop tumors, while maintaining normal cerebellar development. Ectopic activation of SHH signaling is sufficient to enforce cerebellar granule cell progenitor-like cell states, which exhibit Pgbd5-dependent expression of distinct DNA repair and neurodevelopmental factors. Mouse medulloblastomas expressing Pgbd5 have increased numbers of somatic structural DNA rearrangements, some of which carry PGBD5-specific sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. This identifies PGBD5 as a medulloblastoma mutator and provides a genetic mechanism for the generation of oncogenic DNA rearrangements in childhood cancer.

P-selectin-targeted nanocarriers induce active crossing of the blood-brain barrier via caveolin-1-dependent transcytosis.

Medulloblastoma is the most common malignant paediatric brain tumour, with ~30% mediated by Sonic hedgehog signalling. Vismodegib-mediated inhibition of the Sonic hedgehog effector Smoothened inhibits tumour growth but causes growth plate fusion at effective doses. Here, we report a nanotherapeutic approach targeting endothelial tumour vasculature to enhance blood-brain barrier crossing. We use fucoidan-based nanocarriers targeting endothelial P-selectin to induce caveolin-1-dependent transcytosis and thus nanocarrier transport into the brain tumour microenvironment in a selective and active manner, the efficiency of which is increased by radiation treatment. In a Sonic hedgehog medulloblastoma animal model, fucoidan-based nanoparticles encapsulating vismodegib exhibit a striking efficacy and marked reduced bone toxicity and drug exposure to healthy brain tissue. Overall, these findings demonstrate a potent strategy for targeted intracranial pharmacodelivery that overcomes the restrictive blood-brain barrier to achieve enhanced tumour-selective penetration and has therapeutic implications for diseases within the central nervous system.

Improving patient and clinician safety during COVID-19 through rapidly adaptive simulation and a randomised controlled trial: a study protocol.

INTRODUCTION: COVID-19 required healthcare systems to iteratively adapt for safe and up-to-date care as knowledge of the disease rapidly evolved. Rates of COVID-19 infections continue to fluctuate and patients without COVID-19 increasingly return to the emergency department (ED) for care. This leads to new challenges and threats to patient and clinician safety as suspected patients with COVID-19 need to be quickly detected and isolated among other patients with non-COVID-19-related illnesses. At the front lines, emergency physicians also face continued personal safety concerns and increased work burden, which heighten stress and anxiety, especially given the prolonged course of the pandemic. Burnout, already a serious concern for emergency physicians due to the cumulative stresses of their daily practice, may present as a longer-term outcome of these acute stressors. METHODS AND ANALYSIS: We will implement a rapidly adaptive simulation-based approach to understand and improve physician preparedness while decreasing physician stress and anxiety. First, we will conduct semi-structured qualitative interviews and human factor observations to determine the challenges and facilitators of COVID-19 preparedness and mitigation of physician stress. Next, we will conduct a randomised controlled trial to test the effectiveness of a simulation preparedness intervention on physician physiological stress as measured by decreased heart rate variability on shift and anxiety as measured by the State-Trait Anxiety Inventory. ETHICS AND DISSEMINATION: The protocol was reviewed and approved by the Agency for Healthcare Research and Quality for funding, and ethics approval was obtained from the Yale University Human Investigation Committee in 2020 (HIC# 2000029370 and 2000029372). To support ongoing efforts to address clinician stress and preparedness, we will strategically disseminate the simulation intervention to areas most impacted by COVID-19. Using a virtual telesimulation and webinar format, the dissemination efforts will provide hands-on learning for ED and hospital administrators as well as simulation educators. TRIAL REGISTRATION NUMBER: NCT04614844.