Most trials comparing percutaneous coronary intervention (PCI) with coronary-artery bypass grafting (CABG) have not made use of second-generation drug-eluting stents.
We conducted a randomized ...noninferiority trial at 27 centers in East Asia. We planned to randomly assign 1776 patients with multivessel coronary artery disease to PCI with everolimus-eluting stents or to CABG. The primary end point was a composite of death, myocardial infarction, or target-vessel revascularization at 2 years after randomization. Event rates during longer-term follow-up were also compared between groups.
After the enrollment of 880 patients (438 patients randomly assigned to the PCI group and 442 randomly assigned to the CABG group), the study was terminated early owing to slow enrollment. At 2 years, the primary end point had occurred in 11.0% of the patients in the PCI group and in 7.9% of those in the CABG group (absolute risk difference, 3.1 percentage points; 95% confidence interval CI, -0.8 to 6.9; P=0.32 for noninferiority). At longer-term follow-up (median, 4.6 years), the primary end point had occurred in 15.3% of the patients in the PCI group and in 10.6% of those in the CABG group (hazard ratio, 1.47; 95% CI, 1.01 to 2.13; P=0.04). No significant differences were seen between the two groups in the occurrence of a composite safety end point of death, myocardial infarction, or stroke. However, the rates of any repeat revascularization and spontaneous myocardial infarction were significantly higher after PCI than after CABG.
Among patients with multivessel coronary artery disease, the rate of major adverse cardiovascular events was higher among those who had undergone PCI with the use of everolimus-eluting stents than among those who had undergone CABG. (Funded by CardioVascular Research Foundation and others; BEST ClinicalTrials.gov number, NCT00997828.).
The prevalence of head and neck squamous cell carcinoma (HNSCC) has continued to rise for decades. However, drug resistance to chemotherapeutics and relapse, mediated by cancer stem cells (CSCs), ...remains a significant impediment in clinical oncology to achieve successful treatment. Therefore, we focused on analyzing CSCs in HNSCC and demonstrated the effect of melatonin (Mel) and verteporfin (VP) on SCC‐25 cells. HNSCC CSCs were enriched in the reactive oxygen species‐low state and in sphere‐forming cultures. Combination treatment with Mel and VP decreased HNSCC viability and increased apoptosis without causing significant damage to normal cells. Sphere‐forming ability and stem cell population were reduced by co‐treatment with Mel and VP, while mitochondrial ROS level was increased by the treatment. Furthermore, the expression of mitophagy markers, parkin and PINK1, was significantly decreased in the co‐treated cells. Mel and VP induced mitochondrial depolarization and inhibited mitochondrial function. Parkin/TOM20 was localized near the nucleus and formed clusters of mitochondria in the cells after treatment. Moreover, Mel and VP downregulated the expression of markers involved in epithelial‐mesenchymal transition and metastasis. The migration capacity of cells was significantly decreased by co‐treatment with Mel and VP, accompanied by the down‐regulation of MMP‐2 and MMP‐9 expression. Taken together, these results indicate that co‐treatment with Mel and VP induces mitochondrial dysfunction, resulting in the apoptosis of CSCs. Mel and VP could thus be further investigated as potential therapies for HNSCC through their action on CSCs.
Abstract Objective Although soybeans have been shown to alleviate metabolic syndromes, fermented soybeans may have even greater effects. We investigated the antidiabetic effects of meju , a soy food ...that is fermented up to 2 mo, and the mechanism by which it exerts its effects. Methods Meju was prepared by a traditional fermentation process: soybeans were fermented outdoors for 20 or 60 d. Methanol (M-60) and water (W-60) extracts from meju that had fermented for 60 d contained mostly isoflavonoid aglycones and small peptides, respectively, as opposed to mostly glycosylated isoflavonoids and proteins in the original soybeans. Results Daidzein, M-60, and W-60 had better insulin-sensitizing actions by activating peroxisome proliferator-activated receptor-γ in 3T3-L1 adipocytes than did unfermented soybeans. In addition, Min6 insulinoma cells treated with genistein, M-60, and W-60 had greater glucose-stimulated insulin secretion capacity and greater β-cell viability than those treated with unfermented soybeans. This improvement was associated with insulin/insulin-like growth factor-1 signaling that was activated by the tyrosine phosphorylation of insulin receptor substrate-2 and serine phosphorylation of Akt, and this in turn increased pancreatic and duodenal homeobox-1 expression. Furthermore, genistein, daidzein, and M-60 stimulated glucagon-like peptide-1 secretion in enteroendocrine NCI-H716 cells, which generated insulinotropic actions. Conclusion The compositional changes in isoflavonoids and peptides that occurred during a longer fermentation period, without the use of salt, enhanced the antidiabetic effect of soybeans.
This paper reports highly bright and efficient CsPbBr3 perovskite light‐emitting diodes (PeLEDs) fabricated by simple one‐step spin‐coating of uniform CsPbBr3 polycrystalline layers on a ...self‐organized buffer hole injection layer and stoichiometry‐controlled CsPbBr3 precursor solutions with an optimized concentration. The PeLEDs have maximum current efficiency of 5.39 cd A−1 and maximum luminance of 13752 cd m−2. This paper also investigates the origin of current hysteresis, which can be ascribed to migration of Br− anions. Temperature dependence of the electroluminescence (EL) spectrum is measured and the origins of decreased spectrum area, spectral blue‐shift, and linewidth broadening are analyzed systematically with the activation energies, and are related with Br− anion migration, thermal dissociation of excitons, thermal expansion, and electron–phonon interaction. This work provides simple ways to improve the efficiency and brightness of all‐inorganic polycrystalline PeLEDs and improves understanding of temperature‐dependent ion migration and EL properties in inorganic PeLEDs.
Efficient and bright CsPbBr3 perovskite light‐emitting diodes are achieved using a one‐step fabrication of uniform CsPbBr3 polycrystalline layers on a self‐organized buffer hole injection layer without synthesis of quantum dots. A study of the temperature dependence of current hysteresis and electroluminescence spectrum provides understanding of ion migration, nonradiative pathways, and electron–phonon interaction in the CsPbBr3 perovskite light‐emitting diodes.
Acute coronary syndromes are commonly caused by the rupture of vulnerable plaque, which often appear angiographically not severe. Although pharmacologic management is considered standard therapy for ...stabilizing plaque vulnerability, the potential role of preventive local treatment for vulnerable plaque has not yet been determined. The PREVENT trial was designed to compare preventive percutaneous coronary intervention (PCI) plus optimal medical therapy (OMT) with OMT alone in patients with functionally nonsignificant high-risk vulnerable plaques.
The PREVENT trial is a multinational, multicenter, prospective, open-label, active-treatment-controlled randomized trial. Eligible patients have at least 1 angiographically significant stenosis (diameter stenosis >50% by visual estimation) without functional significance (fractional flow reserve FFR >0.80). Target lesions are assessed by intracoronary imaging and must meet at least 2 imaging criteria for vulnerable plaque; (1) minimal lumen area <4.0 mm2; (2) plaque burden >70%; (3) maximal lipid core burden index in a 4 mm segment >315 by near infrared spectroscopy; and (4) thin cap fibroatheroma as determined by virtual histology or optical coherence tomography. Enrolled patients are randomly assigned in a 1:1 ratio to either preventive PCI with either bioabsorbable vascular scaffolds or metallic everolimus-eluting stents plus OMT or OMT alone. The primary endpoint is target-vessel failure, defined as the composite of death from cardiac causes, target-vessel myocardial infarction, ischemic-driven target-vessel revascularization, or hospitalization for unstable or progressive angina, at 2 years after randomization.
Enrollment of a total of 1,608 patients has been completed. Follow-up of the last enrolled patient will be completed in September 2023 and primary results are expected to be available in early 2024.
The PREVENT trial is the first large-scale, randomized trial to evaluate the effect of preventive PCI on non–flow-limiting vulnerable plaques containing multiple high-risk features that is appropriately powered for clinical outcomes. PREVENT will provide compelling evidence as to whether preventive PCI of vulnerable plaques plus OMT improves patient outcomes compared with OMT alone.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT02316886.
The PREVENT trial is the first, large-scale randomized clinical trial to evaluate the effect of preventive PCI on non-flow-limiting vulnerable plaque with high-risk features. It will provide compelling evidence to determine whether PCI of focal vulnerable plaques on top of OMT improves patient outcomes.
In patients with multivessel disease and proximal left anterior descending artery (LAD) involvement, the best revascularisation strategy is still unclear. We assess outcomes after coronary artery ...bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) with drug-eluting stents in a pooled analysis of individual patient-level data of the SYNTAX and BEST randomised trials.
Proximal LAD involvement was defined by any lesion ≥ 50% diameter stenosis in the arterial segment starting from the left-main bifurcation up to (and including) the origin of the first major septal branch. The primary endpoint was the composite of all-cause death, myocardial infarction (MI) or stroke at 5 years of follow-up.
The present study population comprises 1166 patients of which 577 were randomised to PCI and 589 to CABG. Baseline characteristics were well balanced across study arms. The primary endpoint occurred in 94 (16.3%) patients in the PCI arm and in 68 (11.5%) patients in the CABG arm (HR 1.43; 95%CI 1.05 to 1.95; p=0.026). CABG was also associated with a significantly lower rate of cardiac death (p=0.007), MI (p<0.001), all-cause revascularisation (p<0.001) and major adverse cardiovascular and cerebrovascular events (all-cause death, MI, stroke, revascularisation) (p<0.001). The rates of all-cause mortality (p=0.06) and stroke (p=0.09) were not statistically different between the two groups. The overall study results for the primary outcome were consistent across several subgroups.
In patients with multivessel disease with proximal LAD involvement, CABG is associated with lower rates of the safety composite endpoint of death, MI or stroke as compared with PCI with drug-eluting stents at 5 years of follow-up (number needed to treat=21).
PRECOMBAT clinicaltrials.gov NCT00997828; SYNTAX: clinicaltrials.gov identifier: NCT00114972 NCT00114972.
Myocardial viability test to guide revascularization remains uncertain in patients with ischemic cardiomyopathy. We evaluated the different impacts of revascularization on cardiac mortality according ...to the extent of myocardial scar assessed by cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) in patients with ischemic cardiomyopathy. A total of 404 consecutive patients with significant coronary artery disease and an ejection fraction ≤35% were assessed by LGE-CMR before revascularization. Of them, 306 patients underwent revascularization and 98 patients received medical treatment alone. The primary outcome was cardiac death. During a median follow-up of 6.3 years, cardiac death occurred in 158 patients (39.1%). Revascularization was associated with a significantly lower risk of cardiac death than medical treatment alone in the overall population (adjusted hazard ratio aHR 0.29, 95% confidence interval (CI) 0.19 to 0.45, p <0.001). There was a significant interaction between the number of segments with >75% transmural LGE and revascularization on the risk of cardiac death (p = 0.037 for interaction). In patients with limited myocardial scar (<6 segments with >75% transmural LGE, n = 354), revascularization had a significantly lower risk of cardiac death than medical treatment alone (aHR 0.24, 95% CI 0.15 to 0.37, p <0.001); in patients with extensive myocardial scar (≥6 segments with >75% transmural LGE, n = 50), there was no significant difference between revascularization and medical treatment alone regarding the risk of cardiac death (aHR 1.33, 95% CI 0.46 to 3.80, p = 0.60). In conclusion, the assessment of myocardial scar by LGE-CMR may be helpful in the decision-making process for revascularization in patients with ischemic cardiomyopathy.
Olfactory loss has been considered as the earliest complication for the aging process while underlying mechanisms and therapeutic strategies remain unclear. Given the correlation between microglial ...activation and olfactory dysfunction, here we investigated whether the immunomodulatory action of mesenchymal stem cells (MSCs) can rescue the olfactory impairment in old mice. The intranasal delivery of MSCs limited microglial activation and neuronal apoptosis in the olfactory bulb (OB), leading to improvement in olfaction. MSCs down-regulated the proportion of CD86+ microglia and prevented the maturation of cathepsin S, one of the inflammatory mediators in olfactory impairment, via the suppression of p38 MAPK signaling. Notably, old astrocytes could not prevent excessive microgliosis because the endogenous production of Galectin-1 (Gal1), one of the key microglia regulators secreted by astrocytes, was not sufficiently upregulated in the aged brain despite the presence of reactive astrogliosis. Considering that Gal1 is known as a potent paracrine factor of MSCs, we investigated whether MSC-derived Gal1 could compensate for defective astrocyte function in terms of microglial regulation. MSCs and their culture supernatant (MSC-CM) could regulate the direction of microglial differentiation by impeding the polarization towards the pro-inflammatory M1 type; notably, a selective Gal1 inhibitor OTX008 could hinder this phenomenon, indicating that Gal1 is involved in immunomodulation exerted by MSCs. Also, acute microglial activation within the OB upon LPS infusion was attenuated by MSC-CM in a Gal1-dependent manner. Our study demonstrates the therapeutic benefit of MSCs on age-related olfactory dysfunction and suggests Gal1 as a key mediator of the anti-inflammatory action of MSCs.
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•Excessive microgliosis impairs the olfactory function in the aging context.•The olfactory performance of old mice is significantly improved upon MSC delivery.•MSCs and their secretomes regulate the M1–M2 polarization of microglia.•Galectin-1-dependent microglial regulation of astrocytes is defective in old mice.•Galectin-1 is a key paracrine factor involved in MSC-mediated microglial inhibition.
Despite the well-established benefits of secondary cardiovascular prevention, the importance of concurrent medical therapy in clinical trials of coronary revascularization is often overlooked.
The ...goal of this study was to assess compliance with guideline-directed medical therapy (GDMT) in clinical trials and its potential impact on the comparison between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG).
The Cochrane Central Register of Controlled Trials and MEDLINE were searched from 2005 to August 2017. Clinical trial registries and reference lists of relevant studies were also searched. Randomized controlled trials comparing PCI with drug-eluting stents versus CABG and reporting medical therapy after revascularization were included. The study outcome was compliance with GDMT, defined as the following: 1) any antiplatelet agent plus beta-blocker plus statin (GDMT1); and 2) any antiplatelet agent plus beta-blocker plus statin plus angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (GDMT2). Data collection and analysis were performed according to the methodological recommendations of The Cochrane Collaboration.
From a total of 439 references, 5 trials were included based on our inclusion and exclusion criteria. Overall, compliance with GDMT1 was low and decreased over time from 67% at 1 year to 53% at 5 years. Compliance with GDMT2 was even lower and decreased from 40% at 1 year to 38% at 5 years. Compliance with both GDMT1 and GDMT2 was higher in PCI than in CABG at all time points. Meta-regression suggested an association between lower use of GDMT1 and adverse clinical outcomes in PCI versus CABG at 5 years.
Compliance with GDMT in contemporary clinical trials remains suboptimal and is significantly lower after CABG than after PCI, which may influence the comparison of clinical trial endpoints between those study groups.
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