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Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. How Parkin recognizes damaged mitochondria, however, is unknown. Here, we show that expression of PINK1 on individual mitochondria is regulated by voltage-dependent proteolysis to maintain low levels of PINK1 on healthy, polarized mitochondria, while facilitating the rapid accumulation of PINK1 on mitochondria that sustain damage. PINK1 accumulation on mitochondria is both necessary and sufficient for Parkin recruitment to mitochondria, and disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps. These findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in Drosophila melanogaster. In addition, they support a novel model for the negative selection of damaged mitochondria, in which PINK1 signals mitochondrial dysfunction to Parkin, and Parkin promotes their elimination.

Phosphorus has recently received extensive attention as a promising anode for lithium ion batteries （LIBs） due to its high theoretical capacity of 2,596 mAh·g^-1. To develop high-performance phosphorus anodes for LIBs, carbon materials have been hybridized with phosphorus （P-C） to improve dispersion and con- ductivity. However, the specific capacity, rate capability, and cycling stability of P-C anodes are still less than satisfactory for practical applications. Furthermore, the exact effects of the carbon support on the electrochemical performance of the P-C anodes are not fully understood. Herein, a series of xP-yC anode materials for LIBs were prepared by a simple and efficient ball-milling method. 6P-4C and 3P-7C were found to be optimum mass ratios of x/y, and delivered initial discharge capacities of 1,803.5 and 1,585.3-mAh·g^-1, respectively, at 0.1 C in the voltage range 0.02-2 V, with an initial capacity retention of 68.3% over 200 cycles （more than 4 months cycling life） and 40.8% over 450 cycles. The excellent electrochemical performance of the 6P-4C and 3P-7C samples was attributed to a synergistic effect from both the adsorbed P and carbon.

Loss-of-function mutations in PINK1 and Parkin cause parkinsonism in humans and mitochondrial dysfunction in model organisms. Parkin is selectively recruited from the cytosol to damaged mitochondria to trigger their autophagy. How Parkin recognizes damaged mitochondria, however, is unknown. Here, we show that expression of PINK1 on individual mitochondria is regulated by voltage-dependent proteolysis to maintain low levels of PINK1 on healthy, polarized mitochondria, while facilitating the rapid accumulation of PINK1 on mitochondria that sustain damage. PINK1 accumulation on mitochondria is both necessary and sufficient for Parkin recruitment to mitochondria, and disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps. These findings provide a biochemical explanation for the genetic epistasis between PINK1 and Parkin in Drosophila melanogaster. In addition, they support a novel model for the negative selection of damaged mitochondria, in which PINK1 signals mitochondrial dysfunction to Parkin, and Parkin promotes their elimination.

The role of Fat Mass and Obesity-associated protein （FTO） and its substrate N6-methyladenosine （m6A） in mRNA processing and adipogenesis remains largely unknown. We show that FTO expression and m6A levels are inversely correlated during adipogenesis. FTO depletion blocks differentiation and only catalytically active FTO restores adi- pogenesis. Transcriptome analyses in combination with m6A-seq revealed that gene expression and mRNA splicing of grouped genes are regulated by FTO. M6A is enriched in exonic regions flanking 5＇- and 3＇-splice sites, spatially over- lapping with mRNA splicing regulatory serine/arginine-rich （SR） protein exonic splicing enhancer binding regions. Enhanced levels of m6A in response to FTO depletion promotes the RNA binding ability of SRSF2 protein, leading to increased inclusion of target exons. FTO controls exonic splicing of adipogenie regulatory factor RUNX1T1 by regulating m6A levels around splice sites and thereby modulates differentiation. These findings provide compelling evidence that FTO-dependent m6A demethylation functions as a novel regulatory mechanism of RNA processing and plays a critical role in the regulation of adipogenesis.

Background Controlled‐release oxycodone/naloxone (OXN‐CR) maintains the effect of opioid‐induced analgesia through oxycodone while reducing the occurrence rate of opioid‐induced constipation through naloxone. The present study was designed to assess the non‐inferiority of OXN‐CR to controlled‐release oxycodone (OX‐CR) for the control of cancer‐related pain in Korean patients. Methods In this randomized, open‐labeled, parallel‐group, phase IV study, we enrolled patients aged 20 years or older with moderate to severe cancer‐related pain [numeric rating scale (NRS) pain score ≥4] from seven Korean oncology/hematology centers. Patients in the intention‐to‐treat (ITT) population were randomized (1:1) to OXN‐CR or OX‐CR groups. OXN‐CR was administered starting at 20 mg/10 mg per day and up‐titrated to a maximum of 80 mg/40 mg per day for 4 weeks, and OX‐CR was administered starting at 20 mg/day and up‐titrated to a maximum of 80 mg/day for 4 weeks. The primary efficacy endpoint was the change in NRS pain score from baseline to week 4, with non‐inferiority margin of −1.5. Secondary endpoints included analgesic rescue medication intake, patient‐reported change in bowel habits, laxative intake, quality of life (QoL), and safety assessments. Results Of the ITT population comprising 128 patients, 7 with missing primary efficacy data and 4 who violated the eligibility criteria were excluded from the efficacy analysis. At week 4, the mean change in NRS pain scores was not significantly different between the OXN‐CR group (n = 58) and the OX‐CR group (n = 59) (−1.586 vs. −1.559, P = 0.948). The lower limit of the one‐sided 95% confidence interval (−0.776 to 0.830) for the difference exceeded the non‐inferiority margin (P < 0.001). The OXN‐CR and OX‐CR groups did not differ significantly in terms of analgesic rescue medication intake, change in bowel habits, laxative intake, QoL, and safety assessments. Conclusions OXN‐CR was non‐inferior to OX‐CR in terms of pain reduction after 4 weeks of treatment and had a similar safety profile. Studies in larger populations of Korean patients with cancer‐related pain are needed to further investigate the effectiveness of OXN‐CR for long‐term pain control and constipation alleviation. Trial registration ClinicalTrials.gov NCT01313780, registered March 8, 2011

We report a simple one-step approach for the synthesis of -4 nm uniform and fully L10-ordered face-centered tetragonal （fct） FePt nanoparticles （NPs） embedded in -60 nm MCM-41 （fct-FePt NPs@MCM-41）. We controlled the Pt-shell thickness of the fct-FePt NPs by treating the fct-FePt NPs@MCM-41 with acetic acid （HOAc） or hydrochloric acid （HC1） under sonicafion, thereby etching the surface Fe atoms of the NPs. The fct-FePt NPs deposited onto the carbon support （fct-FePt NP/C） were prepared by mixing the fct-FePt NPs@MCM-41 with carbon and subsequently removing the MCM-41 using NaOH. We also developed a facile method to synthesize acid-treated fct-FePt NP/C by using a HF solution for simultaneous surface-Fe etching and MCM-41 removal. We studied the effects of both surface-Fe etching and Pt-shell thickness on the electrocatalytic properties of fct-FePt NPs for the methanol oxidation reaction （MOR）. Compared with the non-treated fct-FePt NP/C catalyst, the HOAc-treated and HCl-treated catalysts exhibit up to 34% larger electrochemically active surface areas （ECASAs）; in addition, the HCl-treated fct-FePt NP （with -1.0 nm Pt shell）/C catalyst exhibits the highest specific activity. The HF-treated fct-FePt NP/C exhibits an ECASA almost 2 times larger than those of the other acid-treated fct-FePt NP/C catalysts and shows the highest mass activity （1,435 mA·mgPt^-1, 2.3 times higher than that of the commercial Pt/C catalyst） and stability among the catalysts tested. Our findings demonstrate that the surface-Fe etching for the generation of the Pt shell on fct-FePt NPs and the Pt-shell thickness can be factors for optimizing the electrocatalysis of the MOR.

This study aimed to develop and validate deep-learning-based artificial intelligence algorithm for predicting mortality of AHF (DAHF). 12,654 dataset from 2165 patients with AHF in two hospitals were used as train data for DAHF development, and 4759 dataset from 4759 patients with AHF in 10 hospitals enrolled to the Korean AHF registry were used as performance test data. The endpoints were in-hospital, 12-month, and 36-month mortality. We compared the DAHF performance with the Get with the Guidelines-Heart Failure (GWTG-HF) score, Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score, and other machine-learning models by using the test data. Area under the receiver operating characteristic curve of the DAHF were 0.880 (95% confidence interval, 0.876-0.884) for predicting in-hospital mortality; these results significantly outperformed those of the GWTG-HF (0.728 [0.720-0.737]) and other machine-learning models. For predicting 12- and 36-month endpoints, DAHF (0.782 and 0.813) significantly outperformed MAGGIC score (0.718 and 0.729). During the 36-month follow-up, the high-risk group, defined by the DAHF, had a significantly higher mortality rate than the low-risk group(p<0.001). DAHF predicted the in-hospital and long-term mortality of patients with AHF more accurately than the existing risk scores and other machine-learning models.

BackgroundWith improved short-term surgical outcomes, laparoscopic distal gastrectomy has rapidly gained popularity. However, the safety and feasibility of laparoscopic total gastrectomy (LTG) has not yet been proven due to the difficulty of the technique. This single-arm prospective multi-center study was conducted to evaluate the use of LTG for clinical stage I gastric cancer.MethodsBetween October 2012 and January 2014, 170 patients with pathologically proven, clinical stage I gastric adenocarcinoma located at the proximal stomach were enrolled. Twenty-two experienced surgeons from 19 institutions participated in this clinical trial. The primary end point was the incidence of postoperative morbidity and mortality at postoperative 30 days. The severity of postoperative complications was categorized according to Clavien–Dindo classification, and the incidence of postoperative morbidity and mortality was compared with that in a historical control.ResultsOf the enrolled patients, 160 met criteria for inclusion in the full analysis set. Postoperative morbidity and mortality rates reached 20.6% (33/160) and 0.6% (1/160), respectively. Fifteen patients (9.4%) had grade III or higher complications, and three reoperations (1.9%) were performed. The incidence of morbidity after LTG in this trial did not significantly differ from that reported in a previous study for open total gastrectomy (18%).ConclusionsLTG performed by experienced surgeons showed acceptable postoperative morbidity and mortality for patients with clinical stage I gastric cancer.

Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) given EGFR tyrosine kinase inhibitors (TKIs) inevitably become resistant to first-generation or second-generation drugs. We assessed the safety, tolerability, pharmacokinetics, and activity of lazertinib—an irreversible, third-generation, mutant-selective, EGFR TKI—in patients with advanced NSCLC progressing after EGFR TKI therapy. This first-in-human, open-label, multicentre, phase 1–2 study had three parts: dose escalation, dose expansion, and dose extension; here, we report results on dose escalation and dose expansion. The study was done in 14 hospitals in Korea. Eligible patients were aged 20 years or older and had advanced NSCLC harbouring an activating EGFR mutation and progressing after first-generation or second-generation EGFR TKI treatment, a defined tumour T790M mutation status, an Eastern Cooperative Oncology Group performance status of 0–1, at least one measurable extracranial lesion, defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and adequate organ function. Patients were enrolled to seven dose-escalation cohorts according to a rolling six design; five cohorts were expanded. Patients were given oral lazertinib 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 240 mg, or 320 mg once daily continuously in 21-day cycles. Primary endpoints were safety and tolerability and secondary endpoints included objective response in evaluable patients. This study is registered with ClinicalTrials.gov, NCT03046992, and the phase 2 extension study is ongoing. Between Feb 15, 2017, and May 28, 2018, 127 patients were enrolled into the dose escalation group (n=38) and dose expansion group (n=89). No dose-limiting toxicities occurred. There was no dose-dependent increase in adverse events. The most commonly reported adverse events were grade 1–2 rash or acne (in 38 [30%] of 127 patients) and pruritus (in 34 [27%]). Grade 3 or grade 4 adverse events occurred in 20 (16%) patients, with the most common being grade 3 pneumonia (four [3%]). Treatment-related grade 3 or 4 adverse events occurred in four (3%) patients; treatment-related serious adverse events were reported in six patients (5%). There were no adverse events with an outcome of death and no treatment-related deaths. The proportion of patients achieving an objective response by independent central review assessment was 69 (54%; 95% CI 46–63) of 127. Lazertinib had a tolerable safety profile and showed promosing clinical activity in patients with NSCLC progressing on or after EGFR TKI therapy. Our findings provide a rationale for further clinical investigations. Yuhan Corporation.

Background High glycemic variability (GV) is a poor prognostic marker in cardiovascular diseases. We aimed to investigate the association of GV with all-cause mortality in patients with acute heart failure (HF). Methods The Korean Acute Heart Failure registry enrolled patients hospitalized for acute HF from 2011 to 2014. Blood glucose levels were measured at the time of admission, during hospitalization, and at discharge. We included those who had 3 or more blood glucose measurements in this study. Patients were divided into two groups based on the coefficient of variation (CoV) as an indicator of GV. Among survivors of the index hospitalization, we investigated all-cause mortality at 1 year after discharge. Results The study analyzed 2,617 patients (median age, 72 years; median left-ventricular ejection fraction, 36%; 53% male). During the median follow-up period of 11 months, 583 patients died. Kaplan–Meier curve analysis revealed that high GV (CoV > 21%) was associated with lower cumulative survival (log-rank P < 0.001). Multivariate Cox proportional analysis showed that high GV was associated with an increased risk of 1-year (HR 1.56, 95% CI 1.26–1.92) mortality. High GV significantly increased the risk of 1-year mortality in non-diabetic patients (HR 1.93, 95% CI 1.47–2.54) but not in diabetic patients (HR 1.19, 95% CI 0.86–1.65, P for interaction = 0.021). Conclusions High in-hospital GV before discharge was associated with all-cause mortality within 1 year, especially in non-diabetic patients with acute HF.