SummaryCells inversely adjust the plasma membrane levels of integrins and cadherins during cell migration and cell-cell adhesion but the regulatory mechanisms that coordinate these trafficking events remain unknown. Here, we demonstrate that the small GTPase Rab35 maintains cadherins at the cell surface to promote cell-cell adhesion. Simultaneously, Rab35 supresses the activity of the GTPase Arf6 to downregulate an Arf6-dependent recycling pathway for b1-integrin and EGF receptors, resulting in inhibition of cell migration and attenuation of signaling downstream of these receptors. Importantly, the phenotypes of decreased cell adhesion and increased cell migration observed following Rab35 knock down are consistent with the epithelial-mesenchymal transition, a feature of invasive cancer cells, and we show that Rab35 expression is suppressed in a subset of cancers characterized by Arf6 hyperactivity. Our data thus identify a key molecular mechanism that efficiently coordinates the inverse intracellular sorting and cell surface levels of cadherin and integrin receptors for cell migration and differentiation.

Our work, the first study of gene expression profiles in pGBM, provides valuable insight into active pathways and targets in a cancer with minimal survival, and suggests that these tumors cannot be understood exclusively through studies of aGBM.

This model represents a reproducible approach to the preparation of implantable spheroids with invasive potential that compares with those produced using spinner culture. The use of hanging drops broadens the applicability of three-dimensional in vitro assays examining brain tumor invasiveness.

Glioblastoma (GBM) is the most common and deadly malignant brain cancer, with a median survival of less than two years. GBM displays a cellular complexity that includes brain tumour-initiating cells (BTICs), which are considered as potential key targets for GBM therapies. Here we show that the transcription factors FOXG1 and Groucho/TLE are expressed in poorly differentiated astroglial cells in human GBM specimens and in primary cultures of GBM-derived BTICs, where they form a complex. FOXG1 knockdown in BTICs causes downregulation of neural stem/progenitor and proliferation markers, increased replicative senescence, upregulation of astroglial differentiation genes, and decreased BTIC-initiated tumour growth upon intracranial transplantation into host mice. These effects are phenocopied by Groucho/TLE knockdown or dominant-inhibition of the FOXG1:Groucho/TLE complex. These results provide evidence that transcriptional programs regulated by FOXG1 and Groucho/TLE are important for BTIC-initiated brain tumour growth, implicating FOXG1 and Groucho/TLE in GBM tumorigenesis.

No abstract

Simulation-based training is increasingly being used for assessment and training of psychomotor skills involved in medicine. The application of artificial intelligence and machine learning technologies has provided new methodologies to utilize large amounts of data for educational purposes. A significant criticism of the use of artificial intelligence in education has been a lack of transparency in the algorithms' decision-making processes. This study aims to 1) introduce a new framework using explainable artificial intelligence for simulationbased training in surgery, and 2) validate the framework by creating the Virtual Operative Assistant, an automated educational feedback platform. Twenty-eight skilled participants (14 staff neurosurgeons, 4 fellows, 10 PGY 4-6 residents) and 22 novice participants (10 PGY 1-3 residents, 12 medical students) took part in this study. Participants performed a virtual reality subpial brain tumor resection task on the NeuroVR simulator using a simulated ultrasonic aspirator and bipolar. Metrics of performance were developed, and leave-one-out cross validation was employed to train and validate a support vector machine in Matlab. The classifier was combined with a unique educational system to build the Virtual Operative Assistant which provides users with automated feedback on their metric performance with regards to expert proficiency performance benchmarks. The Virtual Operative Assistant successfully classified skilled and novice participants using 4 metrics with an accuracy, specificity and sensitivity of 92, 82 and 100%, respectively. A 2-step feedback system was developed to provide participants with an immediate visual representation of their standing related to expert proficiency performance benchmarks. The educational system outlined establishes a basis for the potential role of integrating artificial intelligence and virtual reality simulation into surgical educational teaching. The potential of linking expertise classification, objective feedback based on proficiency benchmarks, and instructor input creates a novel educational tool by integrating these three components into a formative educational paradigm.

This is the first online database of its kind. These images can be used by image processing scientists as well as clinicians wishing to compare findings from magnetic resonance and ultrasound imaging.

Our pilot study demonstrates that the safety, quality, and efficiency of novice and expert operators can be measured using metrics derived from the NeuroTouch platform, helping to understand how specific operator performance is dependent on both psychomotor ability and cognitive input during multiple virtual reality brain tumor resections.