Abstract Background The long-term prognosis of patients with variant angina presenting with aborted sudden cardiac death (ASCD) is unknown. Objectives The purpose of this study was to evaluate the ...long-term mortality and ventricular tachyarrhythmic events of variant angina with and without ASCD. Methods Between March 1996 and September 2014, 188 patients with variant angina with ASCD and 1,844 patients with variant angina without ASCD were retrospectively enrolled from 13 heart centers in South Korea. The primary endpoint was cardiac death. Results Predictors of ASCD manifestation included age (odd ratio OR: 0.980 by 1 year increase; 95% confidence interval CI: 0.96 to 1.00; p = 0.013), hypertension (OR: 0.51; 95% CI: 0.37 to 0.70; p < 0.001), hyperlipidemia (OR: 0.38; 95% CI: 0.25 to 0.58; p < 0.001), family history of sudden cardiac death (OR: 3.67; 95% CI: 1.27 to 10.6; p = 0.016), multivessel spasm (OR: 2.06; 95% CI: 1.33 to 3.19; p = 0.001), and left anterior descending artery spasm (OR: 1.40; 95% CI: 1.02 to 1.92; p = 0.04). Over a median follow-up of 7.5 years, the incidence of cardiac death was significantly higher in ASCD patients (24.1 per 1,000 patient-years vs. 2.7 per 1,000 patient-years; adjusted hazard ratio HR: 7.26; 95% CI: 4.21 to 12.5; p < 0.001). Death from any cause also occurred more frequently in ASCD patients (27.5 per 1,000 patient-years vs. 9.6 per 1,000 patient-years; adjusted HR: 3.00; 95% CI: 1.92 to 4.67; p < 0.001). The incidence rate of recurrent ventricular tachyarrhythmia in ASCD patients was 32.4 per 1,000 patient-years, and the composite of cardiac death and ventricular tachyarrhythmia was 44.9 per 1,000 patient-years. A total of 24 ASCD patients received implantable cardioverter-defibrillators (ICDs). There was a nonsignificant trend of a lower rate of cardiac death in patients with ICDs than those without ICDs (p = 0.15). Conclusions The prognosis of patients with variant angina with ASCD was worse than other patients with variant angina. In addition, our findings supported ICDs in these high-risk patients as a secondary prevention because current multiple vasodilator therapy appeared to be less optimal.
Background Conflicting data on sex-based differences in outcomes after percutaneous coronary intervention (PCI) among Western population exist. Little is known about the nature of sex-specific PCI ...outcomes in an Asian population. Methods We performed a pooled analysis using 23,604 patients from 11 prospective PCI clinical studies performed in Korea. The primary outcome was a major cardiovascular event , defined as composite of cardiovascular death, myocardial infarction, stent thrombosis, or stroke. Secondary outcomes were all-cause mortality and target vessel revascularization. Results Thirty-day and 2-year rates of major cardiovascular events were more frequent in women than in men, mainly because of a higher incidence of periprocedural myocardial infarction in women (30-day: 9.2% vs 7.1%; 2-year: 11.2% vs 8.9%). After multivariable adjustment, women had significantly higher risks of 30-day (hazard ratio HR 1.27, 95% CI 1.19-1.36) and 2-year major cardiovascular events (HR 1.21, 95% CI 1.13-1.30). Unadjusted 30-day and 2-year all-cause mortality was similar between women and men (30-day: 0.5% vs 0.4%; 2-year: 2.8% vs 2.8%). However, after multivariable adjustment, women had a lower adjusted risk of 2-year death (HR 0.82, 95% CI 0.77-0.87). No sex-based difference was observed for target vessel revascularization (HR 1.07, 95% CI 0.91-1.25). Overall, sex-specific findings for outcomes were consistent across multiple patient subgroups. Conclusion Among Korean population undergoing contemporary PCI, women have a significantly higher risk of short- and long-term major cardiovascular events than do men but have better long-term survival.
An assay for protein kinase C delta (PKCδ) activity based on the quantification of a synthetic substrate using capillary electrophoresis with laser‐induced fluorescence detection was developed. The ...peptides labeled with fluorescein isothiocyanate F‐ERK (where ERK is extracellular signal‐regulated kinase) and the phosphorylated form, P‐F‐ERK, were utilized for the method development and validation. The migration time of F‐ERK and P‐F‐ERK were 6.3 ± 0.1 and 8.7 ± 0.2 min, respectively. LOD and LOQ values of F‐ERK were 2 and 6 ng/mL and those of P‐F‐ERK were 4 and 12 ng/mL. The correlation coefficients obtained from two standard curves were approximately 0.99. The reproducibility and accuracy of the method for F‐ERK ranged 1.5–4.7 and 86–109%, respectively, and those for P‐F‐ERK were 1.6–6.1 and 93–109%, respectively. The activity of PKCδ was studied in vitro using the human gastric cancer cell line MKN‐1. The use of PKCδ inhibitor candidates, including Gӧ6983, bisindolylmaleimide II, staurosporine, and rottlerin in the assay resulted in IC50 values of 50 nM, 15 nM, 795 nM, and 4 μM, respectively. Comparison of our assay with a commercial PKC kit revealed that our assay is more adaptable to differing enzyme isoforms. This method has potential for high throughput screening for kinase inhibitors as part of a drug discovery program.
Progesterone-induced calcium ion (Ca2+) signals in the neck region of sperm play a pivotal role in promoting sperm motility. Here, we show that a long-lasting Ca2+ signal required for sperm motility ...in response to progesterone depends on their pH-dependent fusion with prostasomes, which are small vesicles secreted by the prostate. We found that prostasome fusion led to the transfer of progesterone receptors, cyclic adenosine diphosphoribose (cADPR)-synthesizing enzymes, ryanodine receptors (RyRs), and other Ca2+ signaling tools from prostasomes to the sperm neck. Progesterone-induced sperm motility relied on cADPR-mediated Ca2+ mobilization through RyR located on acidic Ca2+ stores, followed by Ca2+ entry through store-operated channels. Treatment of prostasome-fused sperm with a cADPR antagonist or fusion with prostasomes in which type 2 RyR was depleted resulted in low fertilization rates, reduced sperm motility, or both. Thus, we conclude that sperm motility depends on the acquisition of Ca2+ signaling tools from prostasomes.
Leucyl-tRNA synthetase 1 (LARS1) mediates activation of leucine-dependent mechanistic target of rapamycin complex 1 (mTORC1) as well as ligation of leucine to its cognate tRNAs, yet its mechanism of ...leucine sensing is poorly understood. Here we describe leucine binding-induced conformational changes of LARS1. We determine different crystal structures of LARS1 complexed with leucine, ATP, and a reaction intermediate analog, leucyl-sulfamoyl-adenylate (Leu-AMS), and find two distinct functional states of LARS1 for mTORC1 activation. Upon leucine binding to the synthetic site, H251 and R517 in the connective polypeptide and 50FPYPY54 in the catalytic domain change the hydrogen bond network, leading to conformational change in the C-terminal domain, correlating with RagD association. Leucine binding to LARS1 is increased in the presence of ATP, further augmenting leucine-dependent interaction of LARS1 and RagD. Thus, this work unveils the structural basis for leucine-dependent long-range communication between the catalytic and RagD-binding domains of LARS1 for mTORC1 activation.
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•Leucine binding induces conformational change of LARS1 for RagD binding•ATP increases leucine binding to LARS1 for enhanced RagD binding•Leucine-controlled R-lever triggers long-range conformational change of LARS1•LARS1 cycles between “sensing on (leucine+)” and “sensing off (leucine−)” states.
Kim et al. report leucine-induced conformational changes in LARS1 to control the mTORC1 pathway. The results mechanistically validate LARS1 as an amino acid sensor and provide insight into how amino acid and ATP levels are sensed together via LARS1.
Epitaxial growth using graphene (GR), weakly bonded by van der Waals force, is a subject of interest for fabricating technologically important semiconductor membranes. Such membranes can potentially ...offer effective cooling and dimensional scale-down for high voltage power devices and deep ultraviolet optoelectronics at a fraction of the bulk-device cost. Here, we report on a large-area β-Ga2O3 nanomembrane spontaneous-exfoliation (1 cm × 1 cm) from layers of compressive-strained epitaxial graphene (EG) grown on SiC, and demonstrated high-responsivity flexible solar-blind photodetectors. The EG was favorably influenced by lattice arrangement of SiC, and thus enabled β-Ga2O3 direct-epitaxy on the EG. The β-Ga2O3 layer was spontaneously exfoliated at the interface of GR owing to its low interfacial toughness by controlling the energy release rate through electroplated Ni layers. The use of GR templates contributes to the seamless exfoliation of the nanomembranes, and the technique is relevant to eventual nanomembrane-based integrated device technology.
•A sensitive photosensor was developed using CdS nanowires with a high surface density.•CdS nanowires were in situ synthesized directly on interdigitated electrode (IDE).•Properties of the ...photosensor was compared with a conventional thin-film photosensor.•Photosensitivity was further enhanced through the coating of parylene film on nanowires.
In this work, CdS nanowires were synthesized in situ on the finger electrodes of interdigitated Au-electrodes via pulsed-laser deposition (PLD, KrF excimer laser excited at 248nm) using a sintered CdS target at the center of a quartz tube in a hot-wall furnace. The photo-response characteristics of the in situ synthesized CdS nanowires such as sensitivity, reproducibility, and response according to the wavelength of the incident light were analyzed and compared to those of a CdS thin-film electrode. Photosensitivity enhancement was investigated following the deposition of a parylene film with anti-reflecting properties on the CdS nanowires.
Background
The survival paradox between stage IIB/C (T4N0) and stage IIIA (T1-2N1) colon cancer remains in the 7th edition of the American Joint Committee on Cancer staging system. This multicenter ...study aimed to compare the oncologic outcomes of T4N0 and T1-2N1 colon cancers and to investigate the presumptive prognostic factors that might influence the survival paradox.
Methods
Patients who underwent curative surgery for pT4N0 (
n
= 224) and pT1-2N1 (
n
= 135) primary colon cancer between January 1999 and December 2010 at five tertiary referral cancer centers were included for analysis. The clinicopathologic, treatment-related factors, and oncologic outcomes in terms of the 5-year overall survival (5-OS) and 5-year disease-free survival (5-DFS) were compared.
Results
The T4N0 group had significantly worse 5-OS and 5-DFS rates than the T1-2N1 group (5-OS: 84.0 vs. 92.3 %,
p
= 0.012; 5-DFS: 73.6 vs. 88.0 %,
p
= 0.001). T4N0 cancers more frequently showed elevated preoperative carcinoembryonic antigen, lower grade of differentiation, larger tumor size, and higher proportions of perineural invasion, microsatellite instability, obstruction, and perforation than T1-2N1 cancers. Peritoneal seeding and liver metastasis were the predominant recurrence pattern in the T4N0 and T1-2N1 groups, respectively (
p
= 0.042). The T4N0 group showed inferior survival to the T1-2N1 group in postoperative adjuvant chemotherapy (5-OS: 87.1 vs. 93.2 %,
p
= 0.045; 5-DFS: 76.1 vs. 89.0 %,
p
= 0.001).
Conclusions
T4N0 colon cancer had significantly worse oncologic outcomes than T1-2N1 cancer regardless of adjuvant chemotherapy. The survival paradox may result from the biologic aggressiveness of T4N0 colon carcinomas.
Thyroid hormones are involved in wide range of glucose metabolism functions. Overt thyroid dysfunctions are related to altered glucose homeostasis. However, it is not conclusive as to whether subtle ...changes in thyroid hormones within normal ranges can induce alterations in glucose homeostasis. The aim of this study was to evaluate the association between thyroid hormone and glucose homeostasis parameters in subjects without overt thyroid dysfunction based on nationwide population data.
In the Sixth Korea National Health and Nutrition Examination Survey 2015 (n = 7,380), data were collected from subjects with insulin and thyroid function measurements who were older than 19-years-old. After the exclusion of 5,837 subjects, a total of 1,543 patients were included in the analysis. Subjects were categorized into the quartiles of the free thyroxine (FT4). Fasting glucose, insulin, homeostatic model assessment of insulin resistance and hemoglobin A1c (HbA1c) levels were considered to be glucose homeostasis parameters.
Subjects with the highest FT4 quartile showed significantly lower fasting insulin and HbA1c levels. A significant inverse correlation FT4 and HbA1c levels was observed (β = -0.261, p = 0.025). In the logistic regression analysis, the highest quartile of FT4 was demonstrated to lower the risk of HbA1c to a greater degree than the median by approximately 40%, after adjusting for confounders, compared to the lowest quartile (p = 0.028).
We demonstrated subjects with a lower FT4 quartile exhibited high risk of HbA1c levels above the median value in a representative Korean population. Subjects with the lowest FT4 quartile should be cautiously managed in terms of altered glucose homeostasis.
The autoimmune diseases systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) are diagnosed by detection of autoantibodies against Ro and La protein autoantigens, respectively. In this work, ...the diagnosis of autoimmune diseases SLE and SS was demonstrated using thermophoresis of Escherichia coli with the autodisplayed autoantigens. Ro and La protein autoantigens were autodisplayed by constitutive expression together with a fluorescent protein called tdTomato in the cytosol. The binding affinity of the autodisplayed autoantigens was tested against positive and control sera by using FACS as a reference method. The factors influencing interactions between E. coli with autodisplayed autoantigens and autoantibodies in sera during thermophoresis were analyzed by measurement of cell surface charge and size before and after interaction. Finally, the thermophoretic diagnosis of autoimmune diseases SLE and SS was demonstrated using sera from patients afflicted with the respective diseases by estimating sensitivity and selectivity from ROC plots.
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•Thermophoresis was used for diagnosis of autoimmune diseases (SLE and SS).•Autoantigens of SLE and SS were autodisplayed on the outer membrane of E. coli.•Interaction of autoantigens and autoantibodies resulted in the changes in size and charge.•Thermophoretic diagnosis of autoimmune diseases were demonstrated with patient sera.
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