To my entire family: for your loving support and tireless encouragement, I dedicate this work to you.iii Acknowledgements: Abstract:The precise mechanism regulating focal adhesion disassembly has yet to be elucidated. Recently

Invasion can be stimulated in vitro using the soluble ligand transforming growth factor-β (TGFβ) to induce a process called epithelial-to-mesenchymal transition (EMT) characterized by cell-cell junction breakdown and an invasive phenotype. We have previously demonstrated a role for Ste20-like kinase SLK cell migration and invasion. Here we show that SLK depletion in NMuMG mammary epithelial cells significantly impairs their TGFβ-induced migration and invasion. Immunofluorescence studies show that a fraction of SLK localizes to E-cadherin-positive adherens junction and that SLK impairs the breakdown of cell-cell contacts. We find that SLK-depleted cultures express significantly lower levels of vimentin protein as well as Snai1 and E-cadherin mRNA levels following TGF-β treatment. Surprisingly, our data show that SLK depletion does not affect the activation and nuclear translocation of Smad3. Furthermore, we show that expression of a dominant negative kinase does not impair tight junction breakdown and rescues Snai1 mRNA expression levels. Together these data suggest that SLK plays a novel role in TGFβ-induced EMT, independent of Smads, in a kinase activity-independent manner.

The Ste20-like kinase SLK plays a pivotal role in cell migration and focal adhesion turnover and is regulated by the LIM domain-binding proteins Ldb1 and Ldb2. These adapter proteins have been demonstrated to interact with LMO4 in the organization of transcriptional complexes. Therefore, we have assessed the ability of LMO4 to also interact and regulate SLK activity. Our data show that LMO4 can directly bind to SLK and activate its kinase activity in vitro and in vivo. LMO4 can be co-precipitated with SLK following the induction of cell migration by scratch wounding and Cre-mediated deletion of LMO4 in conditional LMO4(fl/fl) fibroblasts inhibits cell migration and SLK activation. Deletion of LMO4 impairs Ldb1 and SLK recruitment to the leading edge of migrating cells. Supporting this, Src/Yes/Fyn-deficient cells (SYF) expressing very low levels of LMO4 do not recruit SLK to the leading edge. Re-expression of wildtype Myc-LMO4 in SYF cells, but not a mutant version, restores SLK localization and kinase activity. Overall, our data suggest that activation of SLK by haptotactic signals requires its recruitment to the leading edge by LMO4 in a Src-dependent manner. Furthermore, this establishes a novel cytosolic role for the transcriptional co-activator LMO4.

Objectives Previous research reports numerous factors of post-operative mortality in patients undergoing isolated coronary artery bypass graft surgery. However, this evidence has not been mapped to the conceptual framework of care improvement. Without such mapping, interventions designed to improve care quality remain unfounded. Methods We identified reported factors of in-hospital mortality post isolated coronary artery bypass graft surgery in adults over the age of 19, published in English between January 1, 2000 and December 31, 2019, indexed in PubMed, CINAHL, and EMBASE. We grouped factors and their underlying mechanism for association with in-hospital mortality according to the augmented Donabedian framework for quality of care. Results We selected 52 factors reported in 83 articles and mapped them by case-mix, structure, process, and intermediary outcomes. The most reported factors were related to case-mix (characteristics of patients, their disease, and their preoperative health status) (37 articles, 27 factors). Factors related to care processes (27 articles, 12 factors) and structures (11 articles, 6 factors) were reported less frequently; most proposed mechanisms for their mortality effects. Conclusions Few papers reported on factors of in-hospital mortality related to structures and processes of care, where intervention for care quality improvement is possible. Therefore, there is limited evidence to support quality improvement efforts that will reduce variation in mortality after coronary artery bypass graft surgery.

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