Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia.

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments.

The power of public-private partnership in medical technology innovation: Lessons from the development of FDA-cleared medical devices for assessment of concussion.

Given the convergence of the long and challenging development path for medical devices with the need for diagnostic capabilities for mild traumatic brain injury (mTBI/concussion), the effective role of public-private partnership (PPP) can be demonstrated to yield Food and Drug Administration (FDA) clearances and innovative product introductions. An overview of the mTBI problem and landscape was performed. A detailed situation analysis of an example of a PPP yielding an innovative product was further demonstrated. The example of PPP has led to multiple FDA clearances and product introductions in the TBI diagnostic product category where there was an urgent military and public need. Important lessons included defining the primary public and military health objective for new product introduction, the importance of the government-academia-industry PPP triad with a "collaboration towards solutions" Quality-by-Design (QbD) mindset to assure clinical validity with regulatory compliance, the development of device comparators and integration of measurements into a robust, evidence-based statistical and FDA pathway, and the utility of top-down, flexible, practical action while operating within governmental guidelines and patient safety.

The type 2 diabetes 'modern preventable pandemic' and replicable lessons from the COVID-19 crisis.

To frame the substantial prevalence of type 2 diabetes (T2D) as a 'Modern Preventable Pandemic' (MPP) and present certain replicable policy lessons from the COVID-19 crisis to address it. A literature and policy review was performed to analyze data about the COVID-19 and T2D pandemics to establish their multi-factorial health, social, and economic impacts. With the global prevalence of T2D tripling in the last two decades, T2D has become an MPP largely due to modifiable human behaviors. Certain successful elements of the response to the COVID-19 pandemic provide important lessons that can be adapted for the growing T2D MPP. With proper education and access to resources, it is possible to mitigate the T2D MPP through focused government policies as illustrated by many of the lessons of the COVID-19 pandemic response. Without such government intervention, the T2D MPP will continue to grow at an unsustainable pace with enormous health, social and economic implications. Immediate action is necessary. The scale of the T2D pandemic warrants a robust response in health policy as outlined through eight coordinated efforts; the lessons of the COVID-19 crisis should be studied and applied to the T2D MPP.