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High-grade diffuse glioma (HGG) is the leading cause of brain tumour death. While the genetic drivers of HGG have been well described, targeting these has thus far had little impact on survival suggesting other mechanisms are at play. Here we interrogate the alternative splicing landscape of pediatric and adult HGG through multi-omic analyses, uncovering an increased splicing burden compared with normal brain. The rate of recurrent alternative splicing in cancer drivers exceeds their mutation rate, a pattern that is recapitulated in pan-cancer analyses, and is associated with worse prognosis in HGG. We investigate potential oncogenicity by interrogating cancer pathways affected by alternative splicing in HGG; spliced cancer drivers include members of the RAS/MAPK pathway. RAS suppressor neurofibromin 1 is differentially spliced to a less active isoform in >80% of HGG downstream from REST upregulation, activating the RAS/MAPK pathway and reducing glioblastoma patient survival. Overall, our results identify non-mutagenic mechanisms by which cancers activate oncogenic pathways which need to accounted for in personalized medicine approaches., Targeting genetic drivers of high grade diffuse glioma (HGG) has not improved patient survival, suggesting the involvement of other mechanisms. Here, across cancer types, the authors identify increased alternative splicing burden in cancer drivers compared to mutation rate as an alternative mechanism for activation of oncogenic pathways such as RAS/MAPK.

Enodvascular coils treat intracranial aneurysms (IAs) by causing them to occlude by thrombosis. Ideally, coiled IAs eventually occlude in the long-term. However, 20.8% are found incompletely occluded at treatment follow-up. Computer simulations of coiling and its effect on aneurysmal flow could help clinicians predict treatment outcomes a priori, but it requires accurate modeling of coils and their deployment procedure. In addition to being accurate, coiling simulations must be efficient to be used as a bedside tool. To date, several virtual coiling techniques have been developed, but they lack either accuracy or efficiency. For example, finite-element-based virtual coiling methods model the mechanics of coiling and are highly accurate, at the expense of high computational cost (and thus low efficiency). Geometric-rule-based coiling techniques ignore the mechanics and therefore are computationally efficient, but may produce unrealistic coil deployments. In order to develop a virtual coiling method that combines accuracy and efficiency, we propose a novel virtual coiling algorithm that models coil deployment with nonlinear mechanics and nonlinear contact. Our approach is potentially more accurate than existing "simple" techniques because we model coil mechanics. It is also potentially faster than finite-element techniques because it models the most time-consuming part of these algorithms-namely contact resolution-with a novel formulation that resolves contact faster with exponential functions. Moreover, we model the coil's pre-shape as well as coil packaging into the catheter, both of which are important to model but are lacking from most existing techniques.

Background: Alcoholic hepatitis (AH) is a severe form of alcoholic liver disease (ALD) associated with significant short-term mortality. Existing treatment therapies are not completely effective, highlighting the need to identify molecular drivers in AH. NGAL has recently been identified as one of the most overexpressed genes in patients with AH. Aims: To investigate the role of NGAL as a potential target for therapy in AH using a translational approach including human samples and animal models. Methods: NGAL expression was analyzed in patients with AH, animal models of liver inflammation and fibrogenesis, and cell lines of human hepatocytes. Fibrosis- and inflammation-marker genes were analyzed for expression in hepatic stellate cell (HSC) cell lines treated with NGAL. RNA was extracted from all samples and gene expression of cDNA was measured using real-time qPCR analysis. Results: Gene expression of NGAL in patients with AH had a 44-fold increase in comparison to several other liver diseases. Animal models of liver inflammation and fibrosis had increased NGAL expression. Although cell lines of human hepatocytes exhibited greater NGAL expression than HSC cell lines, there was no noticeable increase in NGAL expression with subsequent pro-inflammatory induction of hepatocyte cell lines. HSC cell lines showed increased expression of several markers of fibrosis and inflammation with NGAL treatment. Conclusion: NGAL is overexpressed in patients with AH and in animal models of liver inflammation and fibrosis and it exerts fibrogenic and inflammatory effects in hepatic stellate cells. Results suggest that NGAL may be a potential target for therapy in AH. Further studies should be done to more fully explore the nature of NGAL overexpression in AH.