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

AS-826-17 Resolution to Establish Exit Interview Protocol, and a Request for Outside Review

Request that administration develops a protocol for all permanent employee

Hic-5 mediates the initiation of endothelial sprouting by regulating a key surface metalloproteinase

During angiogenesis, endothelial cells must coordinate matrix proteolysis with migration. Here, we tested whether the focal adhesion scaffold protein Hic-5 (also known as TGFB1I1) regulated endothelial sprouting in three dimensions. Hic-5 silencing reduced endothelial sprouting and lumen formation, and sprouting defects were rescued by the return of Hic-5 expression. Pro-angiogenic factors enhanced colocalization and complex formation between membrane type-1 matrix metalloproteinase (MT1-MMP, also known as MMP14) and Hic-5, but not between paxillin and MT1-MMP. The LIM2 and LIM3 domains of Hic-5 were necessary and sufficient for Hic-5 to form a complex with MT1-MMP. The degree of interaction between MT1-MMP and Hic-5 and the localization of the complex within detergent-resistant membrane fractions were enhanced during endothelial sprouting, and Hic-5 depletion lowered the surface levels of MT1-MMP. In addition, we observed that loss of Hic-5 partially reduced complex formation between MT1-MMP and focal adhesion kinase (FAK, also known as PTK2), suggesting that Hic-5 bridges MT1-MMP and FAK. Finally, Hic-5 LIM2–LIM3 deletion mutants reduced sprout initiation. Hic-5, MT1-MMP and FAK colocalized in angiogenic vessels during porcine pregnancy, supporting that this complex assembles during angiogenesis in vivo. Collectively, Hic-5 appears to enhance complex formation between MT1-MMP and FAK in activated endothelial cells, which likely coordinates matrix proteolysis and cell motility

Integrative taxonomy reveals first record of Loxosceles rufescens (Dufour, 1820) (Araneae, Sicariidae) in the Philippines

The spider family Sicariidae Keyserling, 1880 represented by the synanthropic Mediterranean recluse spider, Loxosceles rufescens (Dufour, 1820), is reported in the Philippines for the first time, based on morphological and molecular data. The introduced spider was observed in a small cave (Kamantigue Cave) in Lobo, Batangas Province. Considering the medical importance of this spider, the proximity of its habitat to human habitation and tourist sites poses a potential public health concern.This study reports on the first record of the family Sicariidae in the Philippines and the fourth recorded occurrence of L. rufescens in Southeast Asia

Canonical and Atypical E2Fs Regulate the Mammalian Endocycle

SUMMARY The endocycle is a variant cell cycle consisting of successive DNA synthesis and Gap phases that yield highly polyploid cells. Although essential for metazoan development, relatively little is known about its control or physiologic role in mammals. Using novel lineage-specific cre mice we identified two opposing arms of the E2F program, one driven by canonical transcription activation (E2F1, E2F2 and E2F3) and the other by atypical repression (E2F7 and E2F8), that converge on the regulation of endocycles in vivo. Ablation of canonical activators in the two endocycling tissues of mammals, trophoblast giant cells in the placenta and hepatocytes in the liver, augmented genome ploidy, whereas ablation of atypical repressors diminished ploidy. These two antagonistic arms coordinate the expression of a unique G2/M transcriptional program that is critical for mitosis, karyokinesis and cytokinesis. These results provide in vivo evidence for a direct role of E2F family members in regulating non-traditional cell cycles in mammals

Systematic Analysis of Cell Cycle Effects of Common Drugs Leads to the Discovery of a Suppressive Interaction between Gemfibrozil and Fluoxetine

Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show that the antilipemic gemfibrozil delays initiation of DNA replication, while cells treated with the antidepressant fluoxetine severely delay progression through mitosis. Based on their effects on cell cycle progression, we also examined cell proliferation in the presence of both compounds. We discovered a strong suppressive interaction between gemfibrozil and fluoxetine. Combinations of interest among diverse pharmaceuticals are difficult to identify, due to the daunting number of possible combinations that must be evaluated. The novel interaction between gemfibrozil and fluoxetine suggests that identifying and combining drugs that show cell cycle effects might streamline identification of drug combinations with a pronounced impact on cell proliferation

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

Association between T2-related co-morbidities and effectiveness of biologics in severe asthma

Acknowledgments The authors thank Mr. Joash Tan (BSc, Hons), of the Observational and Pragmatic Research Institute (OPRI), and Ms Andrea Lim (BSc, Hons) of the Observational Pragmatic Research Institute (OPRI) for their editorial and formatting assistance that supported the development of this publication. Funding statement: This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was partially funded by Optimum Patient Care Global and AstraZeneca Ltd. AstraZeneca UK LimitedPeer reviewe

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

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