Demographics, practice patterns and long-term outcomes of patients with non–ST-segment elevation acute coronary syndrome in the past two decades: the CREDO-Kyoto Cohort-2 and Cohort-3

OBJECTIVES: To evaluate patient characteristics and long-term outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) in the past two decades. DESIGN: Multicenter retrospective study. SETTING: The Coronary REvascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) percutaneous coronary intervention (PCI)/coronary artery bypass grafting (CABG) Registry Cohort-2 (2005-2007) and Cohort-3 (2011-2013). PARTICIPANTS: 3254 patients with NSTEACS who underwent first coronary revascularisation. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was all-cause death. The secondary outcomes were cardiovascular death, cardiac death, sudden cardiac death, non-cardiovascular death, non-cardiac death, myocardial infarction, definite stent thrombosis, stroke, hospitalisation for heart failure, major bleeding, any coronary revascularisation and target vessel revascularisation. RESULTS: Patients in Cohort-3 were older and more often had heart failure at admission than those in Cohort-2. The prevalence of PCI, emergency procedure and guideline-directed medical therapy was higher in Cohort-3 than in Cohort-2. In patients who received PCI, the prevalence of transradial approach, drug-eluting stent use and intravascular ultrasound use was higher in Cohort-3 than in Cohort-2. There was no change in 3-year adjusted mortality risk from Cohort-2 to Cohort-3 (HR 1.00, 95% CI 0.83 to 1.22, p=0.97). Patients in Cohort-3 compared with those in Cohort-2 were associated with lower adjusted risks for stroke (HR 0.65, 95% CI 0.46 to 0.92, p=0.02) and any coronary revascularisation (HR 0.76, 95%CI 0.66 to 0.87, p<0.001), but with higher risk for major bleeding (HR 1.25, 95% CI 1.06 to 1.47, p=0.008). The unadjusted risk for definite stent thrombosis was lower in Cohort-3 than in Cohort 2 (HR 0.29, 95% CI 0.11 to 0.67, p=0.003). CONCLUSIONS: In the past two decades, we did not find improvement for mortality in patients with NSTEACS. We observed a reduction in the risks for definite stent thrombosis, stroke and any coronary revascularisation, but an increase in the risk for major bleeding

Necessity of p53-binding to the CDH1 locus for its expression defines two epithelial cell types differing in their integrity

TP53 mutation (i.e., loss of normal-p53) may evoke epithelial-mesenchymal transition (EMT), which was previously attributed to loss of certain miRNAs. However, not all epithelial cells undergo EMT upon TP53 mutation, and the p53-miRNA axis may not fully explain p53 function in epithelial integrity. We here show two modes of epithelial integrity: one involves p53-binding to a nucleotide region and the other does not. In the former, p53 binds to the CDH1 (encoding E-cadherin) locus to antagonize EZH2-mediated H3K27 trimethylation (H3K27me3) to maintain high levels of acetylation of H3K27 (H3K27ac). In the latter, the same locus is not highly acetylated at H3K27, and does not allow p53-binding, nor needs to antagonize EZH2. We moreover demonstrated that although the CDH1 locus in the p53-independent cells, but not in fibroblasts, becomes high-H3K27ac by butyrate and allows p53-biniding, their CDH1 expression does not become dependent on p53. Our results identified novel modes of the epithelial integrity, in which the same epithelial-specific gene locus exhibits different requirement for p53 with different histone modifications among different epithelial cells to warrant its expression

ARF1 recruits RAC1 to leading edge in neutrophil chemotaxis

Abstract Background The small GTPase ARF1 mediates membrane trafficking mostly from the Golgi, and is essential for the G protein-coupled receptor (GPCR)-mediated chemotaxis of neutrophils. In this process, ARF1 is activated by the guanine nucleotide exchanger GBF1, and is inactivated by the GTPase-activating protein GIT2. Neutrophils generate the Gβγ-PAK1-αPIX-GIT2 linear complex during GPCR-induced chemotaxis, in which αPIX activates RAC1/CDC42, which then employs PAK1. However, it has remained unclear as to why GIT2 is included in this complex. Results We investigated the association between ARF1 and RAC1/CDC42 during the fMLP-stimulated chemotaxis of HL60 cells. We found that the silencing of GBF1 significantly impaired the recruitment of RAC1 to the leading edges, but not PAK1, αPIX, RAC2, or CDC42. A significant population of RAC1 colocalized with ARF1 at the leading edges in stimulated cells, whereas fMLP activated both ARF1 and ARF5. Consistently, the silencing of ARF1, but not ARF5, impaired the recruitment of RAC1, whereas the silencing of RAC1 did not affect the recruitment of ARF1 to the leading edges. Conclusions Our results indicated that the activation of ARF1 triggers the plasma membrane recruitment of RAC1 in GPCR-mediated chemotaxis, which is essential for cortical actin remodeling. Thus, membrane remodeling at the leading edges appears to precede actin remodeling in chemotaxis. Together with the fact that GIT2, which inactivates ARF1, is an integral component of the machinery activating RAC1, we proposed a model in which the ARF1-RAC1 linkage enables the regulation of ARF1 by repetitive on/off cycles during GPCR-mediated neutrophil chemotaxis

Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer

Acquisition of mesenchymal properties by cancer cells is critical for their malignant behaviour, but regulators of the mesenchymal molecular machinery and how it is activated remain elusive. Here we show that clear cell renal cell carcinomas (ccRCCs) frequently utilize the Arf6-based mesenchymal pathway to promote invasion and metastasis, similar to breast cancers. In breast cancer cells, ligand-activated receptor tyrosine kinases employ GEP100 to activate Arf6, which then recruits AMAP1; and AMAP1 then binds to the mesenchymal-specific protein EPB41L5, which promotes epithelial-mesenchymal transition and focal adhesion dynamics. In renal cancer cells, lysophosphatidic acid (LPA) activates Arf6 via its G-protein-coupled receptors, in which GTP-G alpha 12 binds to EFA6. The Arf6-based pathway may also contribute to drug resistance. Our results identify a specific mesenchymal molecular machinery of primary ccRCCs, which is triggered by a product of autotaxin and it is associated with poor outcome of patients