Noncanonical NF-KB Signaling Drives Glioma Invasion by Promoting MT1-MMP Activation, Pseudopodia Formation, and ITGA11 Expression

A hallmark of high grade glioma is highly aggressive, diffuse invasion into normal brain tissue, contributing to a 100% recurrence rate and resistance to current therapies. Recent efforts to determine molecular differences in high grade glioma and define tumor subtypes have revealed that the noncanonical NF-KB transcription factor RelB is upregulated in the highly aggressive mesenchymal subtype, as well as in recurrent tumors. The studies presented here seek to better understand how noncanonical NF-KB signaling drives glioma cell invasion in a three-dimensional (3D) environment. Stabilization of NF- KB-inducing kinase (NIK), a critical driver of noncanonical NF-KB signaling, promoted glioma cell adhesion, spreading, and pseudopodia formation on collagen, which is expressed at low levels in normal brain tissue but highly upregulated within the stroma and surrounding tissue of glioma. As NIK expression appeared to regulate glioma cell behavior on collagen, we investigated whether NIK controls the expression of integrins known to bind collagen. We found NIK expression upregulated the integrin alpha 11 subunit (ITGA11), while it did not significantly affect the expression of ITGA1, ITGA2, or ITGA10. Analysis of human tumor samples revealed that ITGA11 expression was increased in glioma tissue compared to normal brain tissue. Furthermore, when testing multiple glioma lines, ITGA11 expression positively correlated with invasiveness into 3D collagen matrices. Investigation of a key transmembrane metalloproteinase revealed that NIK expression enhanced the localization of active, phosphorylated membrane-type 1 matrix metalloproteinase (MT1-MMP) to pseudopodial structures. In a heterologous system, ITGA11 and MT1-MMP formed a complex, suggesting these transmembrane proteins could interact in glioma cells to facilitate coordinated recognition and degradation of collagen during invasion. Finally, silencing of ITGA11 in an invasive glioma line attenuated invasion into 3D collagen matrices. Collectively, these data reveal an ability of NIK to promote directed glioma cell invasion, pseudopodia formation, ITGA11 expression, and activated MT1-MMP localization to pseudopodia. These data suggest ITGA11 could serve as a novel marker for more invasive glioma and a potential therapeutic target in glioma

Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress

The intermediate filament (IF) cytoskeleton has been proposed to regulate morphogenic processes by integrating the cell fate signaling machinery with mechanical cues. Signaling between endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) through the Notch pathway regulates arterial remodeling in response to changes in blood flow. Here we show that the IF-protein vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic forces. Vimentin is important for Notch transactivation by ECs and vimentin knockout mice (VimKO) display disrupted VSMC differentiation and adverse remodeling in aortic explants and in vivo. Shear stress increases Jagged1 levels and Notch activation in a vimentin-dependent manner. Shear stress induces phosphorylation of vimentin at serine 38 and phosphorylated vimentin interacts with Jagged1 and increases Notch activation potential. Reduced Jagged1-Notch transactivation strength disrupts lateral signal induction through the arterial wall leading to adverse remodeling. Taken together we demonstrate that vimentin forms a central part of a mechanochemical transduction pathway that regulates multilayer communication and structural homeostasis of the arterial wall

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Search for a Light Charged Higgs Boson Decaying to a W Boson and a CP-Odd Higgs Boson in Final States with eμμ or μμμ in Proton-Proton Collisions at √s=13 TeV

A search for a light charged Higgs boson (H+) decaying to a W boson and a CP-odd Higgs boson (A) in final states with eμμ or μμμ is performed using data from pp collisions at √s=13  TeV, recorded by the CMS detector at the LHC and corresponding to an integrated luminosity of 35.9  fb−1. In this search, it is assumed that the H+ boson is produced in decays of top quarks, and the A boson decays to two oppositely charged muons. The presence of signals for H+ boson masses between 100 and 160 GeV and A boson masses between 15 and 75 GeV is investigated. No evidence for the production of the H+ boson is found. Upper limits at 95% confidence level are obtained on the combined branching fraction for the decay chain, t→bH+→bW+A→bW+μ+μ−, of 1.9×10−6 to 8.6×10−6, depending on the masses of the H+ and A bosons. These are the first limits for these decay modes of the H+ and A bosons.Peer reviewe