Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7(Δpan) mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7(Δpan) mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7(Δpan) mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.

Infection with herpes simplex virus-1 (HSV-1) brings numerous changes in cellular gene expression. Levels of most host mRNAs are reduced, limiting synthesis of host proteins, especially those involved in antiviral defenses. The impact of HSV-1 on host microRNAs (miRNAs), an extensive network of short non-coding RNAs that regulate mRNA stability/translation, remains largely unexplored. Here we show that transcription of the miR-183 cluster (miR-183, miR-96, and miR-182) is selectively induced by HSV-1 during productive infection of primary fibroblasts and neurons. ICP0, a viral E3 ubiquitin ligase expressed as an immediate-early protein, is both necessary and sufficient for this induction. Nuclear exclusion of ICP0 or removal of the RING (really interesting new gene) finger domain that is required for E3 ligase activity prevents induction. ICP0 promotes the degradation of numerous host proteins and for the most part, the downstream consequences are unknown. Induction of the miR-183 cluster can be mimicked by depletion of host transcriptional repressors zinc finger E-box binding homeobox 1 (ZEB1)/-crystallin enhancer binding factor 1 (δEF1) and zinc finger E-box binding homeobox 2 (ZEB2)/Smad-interacting protein 1 (SIP1), which we establish as new substrates for ICP0-mediated degradation. Thus, HSV-1 selectively stimulates expression of the miR-183 cluster by ICP0-mediated degradation of ZEB transcriptional repressors.

Insulin-dependent translocation of glucose transporter 4 (Glut4) to the plasma membrane of fat and skeletal muscle cells plays the key role in postprandial clearance of blood glucose. Glut4 represents the major cell-specific component of the insulin-responsive vesicles (IRVs). It is not clear, however, whether the presence of Glut4 in the IRVs is essential for their ability to respond to insulin stimulation. We prepared two lines of 3T3-L1 cells with low and high expression of myc7-Glut4 and studied its translocation to the plasma membrane upon insulin stimulation, using fluorescence-assisted cell sorting and cell surface biotinylation. In undifferentiated 3T3-L1 preadipocytes, translocation of myc7-Glut4 was low regardless of its expression levels. Coexpression of sortilin increased targeting of myc7-Glut4 to the IRVs, and its insulin responsiveness rose to the maximal levels observed in fully differentiated adipocytes. Sortilin ectopically expressed in undifferentiated cells was translocated to the plasma membrane regardless of the presence or absence of myc7-Glut4. AS160/TBC1D4 is expressed at low levels in preadipocytes but is induced in differentiation and provides an additional mechanism for the intracellular retention and insulin-stimulated release of Glut4.

Background Data are still limited regarding whether there are differential long-term outcomes after percutaneous coronary intervention versus coronary artery bypass grafting (CABG) for left main coronary artery disease with or without diabetes mellitus (DM). Methods and Results Using the 10-year data from the MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty Versus Surgical Revascularization) registry, we sought to examine the effect of DM on comparative outcomes after percutaneous coronary intervention or CABG in patients with unprotected left main coronary artery disease. The outcomes of interest were all-cause mortality; a composite of death, Q-wave myocardial infarction, or stroke; and target-vessel revascularization. The primary adjusted analyses were performed with the use of propensity scores and inverse-probability weighting. Of 2240 patients with left main coronary artery revascularization, 722 (32%) had DM. In the overall population, the adjusted 10-year risks of death and composite outcome were similar between percutaneous coronary intervention and CABG, irrespective of DM status (Pinteraction: 0.41, mortality; 0.40, composite outcome). However, in the cohort of bare-metal stents and concurrent CABG, we observed differential outcomes after stenting and CABG by DM status (Pinteraction: 0.09, mortality; 0.04, composite outcome), favoring CABG in patients with DM. In the cohort of drug-eluting stents and concurrent CABG, the better effect of CABG over stenting was narrowed in patients with DM without a significant interaction (Pinteraction: 0.63, mortality; 0.47, composite outcome). Conclusions In this cohort of patients with longest follow-up who underwent left main coronary artery revascularization, the clinical impact of DM favoring CABG over percutaneous coronary intervention has diminished over time from the bare-metal stent to the drug-eluting stent era. Registration URL: http://www.clini​caltr​ials.gov. Unique identifier: NCT02791412.

The need for transvenous lead extraction (TLE) is increasing worldwide including in Asia-Pacific regions. However, supporting evidence for TightRail, a relatively new rotating mechanical dilator sheath, is still lacking in Asian patients. The efficacy and safety of TLE using TightRail performed between March 2018 and June 2021 were evaluated in 86 consecutive patients with 131 leads. The mean lead age was 11.7 ± 7.3 (range, 1.0-41.4) years. Clinical and complete procedural success using TightRail were achieved in 93.0% and 89.5% of 86 patients, respectively, with 6 min of median fluoroscopic time and 9.3% of major complication rate: death (1.2%), cardiac tamponade (3.5%), severe tricuspid regurgitation (3.5%), and stroke (1.2%). However, in 46 patients with longest lead age ≤ 10 years, clinical/complete success and major cardiac complication rates turned out better as 97.8%, 95.7%, and 2.2%, respectively. Additionally, when patients were divided into 3 groups: the first 28, second 29, and the last 29 patients, there was a clear trend toward better efficacy and safety outcomes with more experience with TightRail (Ptrend < 0.05). Longest lead age > 10 years was closely associated with TLE-related major cardiac complication (P = 0.046) with 85.7% sensitivity, 57.0% specificity, 15.0% positive predictive value, and 97.8% negative predictive values. In conclusion, TLE using TightRail may be effectively and safely performed by experienced operators for Asian patients with the longest lead age ≤ 10 years. However, as TightRail is a potentially aggressive tool, special attention should be paid to patients with longer lead dwelling times (e.g., > 10 years).

Caspase-2 (Casp2) is a promising therapeutic target in several human diseases, including nonalcoholic steatohepatitis (NASH) and Alzheimer's disease (AD). However, the design of an active-site-directed inhibitor selective to individual caspase family members is challenging because caspases have extremely similar active sites. Here we present new peptidomimetics derived from the VDVAD pentapeptide structure, harboring non-natural modifications at the P2 position and an irreversible warhead. Enzyme kinetics show that these new compounds, such as LJ2 or its specific isomers LJ2a, and LJ3a, strongly and irreversibly inhibit Casp2 with genuine selectivity. In agreement with the established role of Casp2 in cellular stress responses, LJ2 inhibits cell death induced by microtubule destabilization or hydroxamic acid-based deacetylase inhibition. The most potent peptidomimetic, LJ2a, inhibits human Casp2 with a remarkably high inactivation rate (k3/Ki ~5,500,000 M-1 s-1), and the most selective inhibitor, LJ3a, has close to a 1000 times higher inactivation rate on Casp2 as compared to Casp3. Structural analysis of LJ3a shows that the spatial configuration of Cα at the P2 position determines inhibitor efficacy. In transfected human cell lines overexpressing site-1 protease (S1P), sterol regulatory element-binding protein 2 (SREBP2) and Casp2, LJ2a and LJ3a fully inhibit Casp2-mediated S1P cleavage and thus SREBP2 activation, suggesting a potential to prevent NASH development. Furthermore, in primary hippocampal neurons treated with β-amyloid oligomers, submicromolar concentrations of LJ2a and of LJ3a prevent synapse loss, indicating a potential for further investigations in AD treatment.

Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA.

Cavotricuspid isthmus (CTI) block is easily achieved, and prophylactic ablation can be performed during atrial fibrillation (AF) ablation. However, the previous study was too small and short-term to clarify the efficacy of this block.

Cryoballoon ablation was established as an effective and safe modality to achieve pulmonary vein isolation (PVI) in paroxysmal atrial fibrillation (PAF). However, its role in persistent atrial fibrillation (PersAF) remains unclear.

Glucose transporter isoform 4 (GLUT4), is the sole glucose transporter responsible for the effect of insulin on postprandial blood glucose clearance. However, the nature of the insulin sensitivity of GLUT4 remains unknown. In this study, we replaced the first luminal loop of cellugyrin, a 4-transmembrane protein that does not respond to insulin, with that of GLUT4. The chimera protein is targeted to the intracellular insulin-responsive vesicles and is translocated to the plasma membrane upon insulin stimulation. The faithful targeting of the chimera depends on the expression of the sorting receptor sortilin, which interacts with the unique amino acid residues in the first luminal loop of GLUT4. Thus the first luminal loop may confer insulin responsiveness to the GLUT4 molecule.

The relative efficacy of antiarrhythmic drugs (AADs) after electrical cardioversion are not well established. This study aimed to investigate the efficacies of different AADs for maintaining sinus rhythm (SR) after electrical cardioversion for atrial fibrillation (AF). We selected patients from a retrospective registry including patients admitted for cardioversion between January 2012 and June 2016. The primary outcome was time to AF recurrence during the first year after cardioversion. The secondary outcomes included AF recurrence within 1 month, and first readmission due to heart failure, stroke, or additional non-pharmacological rhythm control. A total of 265 patients were divided into the 4 groups according to AAD type: flecainide (n = 33), propafenone (n = 64), amiodarone (n = 128), and dronedarone (n = 40). During the first year after cardioversion, the AF recurrence-free survival was similar between all AAD groups (69.7% vs. 67.2% vs. 71.9% vs. 80.0%, p = 0.439). About half of all recurrences occurred during the first month. There was no difference in any of the secondary outcomes, although the amiodarone group showed a trend toward more non-pharmacological rhythm control. AAD type was not associated with recurrence in multivariate analysis. In this study, half of all patients received amiodarone after electrical cardioversion. Flecainide, propafenone, amiodarone, and dronedarone showed similar efficacies for maintaining SR after electrical cardioversion. Thus, it might be reasonable to reconsider amiodarone use after cardioversion, since it did not show superior efficacy to the other drugs considered and is associated with potential side effects.

How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to escape p53-induced death and senescence and respond to proliferative signals that promote fixation of mutations and their transmission to daughter cells that go on to become HCC progenitors.

In idiopathic outflow tract ventricular arrhythmias (OT-VAs), identifying the site with the earliest activation time (EAT) using activation mapping is critical to eliminating the arrhythmogenic focus. However, the optimal EAT for predicting successful radiofrequency catheter ablation (RFCA) has not been established.

Invasive fractional flow reserve (FFR) is a standard tool for identifying ischemia-producing coronary stenosis. However, in clinical practice, over 70% of treatment decisions still rely on visual estimation of angiographic stenosis, which has limited accuracy (about 60%-65%) for the prediction of FFR < 0.80. One of the reasons for the visual-functional mismatch is that myocardial ischemia can be affected by the supplied myocardial size, which is not always evident by coronary angiography. The aims of this study were to develop an angiography-based machine learning (ML) algorithm for predicting the supplied myocardial volume for a stenosis, as measured using coronary computed tomography angiography (CCTA), and then to build an angiography-based classifier for the lesions with an FFR < 0.80 versus ≥ 0.80.

 Prolonged dual anti-platelet therapy (DAPT) is intended to reduce ischaemic events, at the cost of an increased bleeding risk in patients undergoing percutaneous coronary intervention (PCI). In this study, we evaluated whether race influences the ischaemia/bleeding risk trade-off.

It is not clear whether screening by coronary computed tomographic angiography (CCTA) and/or exercise electrocardiogram (ECG) can improve clinical outcomes and reduce costs in individuals without known cardiovascular disease (CVD). In total, 71,811 consecutive individuals without known CVD who underwent general health examinations were enrolled. Using propensity-score matching according to screening tests, 1-year clinical outcomes and 6-month total and coronary artery disease-related medical costs were analyzed in separate groups: group 1 (CCTA [n = 2578] vs no screening [n = 5146]), group 2 (exercise ECG [n = 2898] vs no screening [n = 5796]), and group 3 (CCTA and exercise ECG [n = 2003] vs no screening [n = 4006]). There were no significant differences in the composite outcome of death, myocardial infarction, and stroke in each matched group: group 1 (0.35% vs 0.45%, P = 0.501), group 2 (0.14% vs 0.28%, P = 0.157), and group 3 (0.25% vs 0.27%, P = 0.858). However, revascularization was more frequent in the CCTA screening groups: group 1 (2.02% vs 0.45%, P < 0.001) and group 3 (1.40% vs 0.45%, P < 0.001). Matched screening groups had higher 6-month total and coronary artery disease-related medical costs: group 1 ($777 vs $603, P < 0.001 and $177 vs $39, P < 0.001), group 2 ($544 vs $492, P = 0.045 and $12 vs $15, P = 0.611), and group 3 ($705 vs $627, P = 0.090 and $135 vs $35, P < 0.001). In individuals without known CVD, CCTA screening with or without exercise ECG led to more frequent revascularization at the expense of higher medical costs, but did not decrease the 1-year risk of death, myocardial infarction, and stroke.

Atrial fibrillation (AF) is associated with the autonomic nervous system (ANS), and fluctuation of autonomic tone is more prominent in patients with AF. As autonomic tone affects the heart rate (HR), and there is an inverse relationship between HR and PR interval, PR interval variation could be greater in patients with AF than in those without AF. The purpose of this study was to investigate the correlation between PR interval variation and new-onset AF in patients with frequent PACs.We retrospectively enrolled 207 patients with frequent PACs who underwent electrocardiographs at least 4 times during the follow-up period. The PR variation was calculated by subtracting the minimum PR interval from the maximum PR interval. The outcomes were new occurrence of AF and all-cause mortality during the follow-up period.During a median follow-up of 8.3 years, 24 patients (11.6%) developed new-onset AF. Univariate analysis showed that prolonged PR interval (PR interval > 200 ms, P = 0.021), long PR variation (PR variation > 36.5 ms, P = 0.018), and PR variation (P = 0.004) as a continuous variable were associated with an increased risk of AF. Cox regression analysis showed that prolonged PR interval (hazard ratio = 3.321, 95% CI 1.064-10.362, P = 0.039) and PR variation (hazard ratio = 1.013, 95% CI 1.002-1.024, P = 0.022) were independent predictors for new-onset AF. However, PR variation and prolonged PR interval were not associated with all-cause mortality (P = 0.465 and 0.774, respectively).PR interval variation and prolonged PR interval are independent risk factors for new-onset AF in patients with frequent PACs. However we were unable to determine a cut-off value of PR interval variation for new-onset AF.

Current guidelines recommend that coronary artery calcium (CAC) screening should only be used for intermediate risk groups (Framingham risk score [FRS] of 10%-20%). The CAC distributions and coronary artery disease (CAD) prevalence in various FRS strata were determined. The benefit to lower risk populations of CAC score-based screening was also assessed. In total, 1,854 participants (aged 40-79 years) without history of CAD, stroke, or diabetes were enrolled. CAC scores of > 0, ≥ 100, and ≥ 300 were present in 33.8%, 8.2%, and 2.9% of the participants, respectively. The CAC scores rose significantly as the FRS grew more severe (P < 0.01). The total CAD prevalence was 6.1%. The occult CAD prevalence in the FRS ≤ 5%, 6%-10%, 11%-20%, and > 20% strata were 3.4%, 6.7%, 9.0%, and 11.6% (P < 0.001). In multivariate logistic regression analysis adjusting, not only the intermediate and high risk groups but also the low risk (FRS 6%-10%) group had significantly increased odds ratio for occult CAD compared to the very low-risk (FRS ≤ 5%) group (1.89 [95% confidence interval, CI, 1.09-3.29] in FRS 6%-10%; 2.48 [95% CI, 1.47-4.20] in FRS 11%-20%; and 3.10 [95% CI, 1.75-5.47] in FRS > 20%; P < 0.05). In conclusion, the yield of screening for significant CAC and occult CAD is low in the very low risk population but it rises in low and intermediate risk populations.

The overexpression of X-linked inhibitor of apoptosis protein (XIAP), a member of IAP family protein, is intuitively expected to be associated with unfavorable clinical features in malignancies; however, there have been only a very limited number of studies reporting the clinical relevance of XIAP expression. This study was performed to investigate the prognostic relevance of XIAP expression in childhood acute myeloid leukemia (AML). In 53 children with de novo AML, the level of XIAP expression was determined by using quantitative reverse transcriptase-polymerase chain reaction and was analyzed with respect to the clinical characteristics at diagnosis and treatment outcomes. As a result, the XIAP expression was found to be higher in patients with extramedullary disease than in those without (P=0.014). In addition, XIAP overexpression (>or=median expression) was associated with an unfavorable day 7 response to induction chemotherapy and also associated with a worse 3-yr relapsefree survival rate (52.7+/-20.9% vs. 85.9+/-14.8%, P=0.014). Multivariate analyses revealed that XIAP overexpression was an independent unfavorable prognostic factor for relapse-free survival (hazard ratio, 6.16; 95% confidence interval, 1.48-25.74; P=0.013). Collectively, XIAP overexpression may be used as an unfavorable prognostic marker in childhood AML.

Background Various ECG criteria for left ventricular hypertrophy (LVH) have been proposed, but their association with clinical outcomes in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement is unknown. We investigated the prevalence of ECG LVH according to different criteria and its prognostic impact on clinical outcomes after transcatheter aortic valve replacement. Methods and Results In this prospective observational cohort, we evaluated 700 patients who underwent transcatheter aortic valve replacement between March 2010 and December 2019. Baseline preprocedural LVH was defined by 3 ECG criteria-Sokolow-Lyon, Romhilt-Estes, and Cornell voltage criteria. The primary outcome was major adverse cardiac or cerebrovascular event (MACCE; composite of death, myocardial infarction, stroke, or rehospitalization from cardiovascular cause); the key secondary outcome was all-cause and cardiovascular mortality. Among 596 eligible patients, the prevalence of LVH was determined as 56.3% by Sokolow-Lyon, 31.1% by Romhilt-Estes, and 48.1% by Cornell criteria. Regardless of the criteria, patients with ECG LVH had more severe aortic stenosis hemodynamics and higher left ventricular mass index. After multivariate adjustment, the presence of LVH by the Cornell criteria was significantly associated with lower risks of MACCE (adjusted hazard ratio [HR], 0.68; 95% CI, 0.51-0.91; P=0.009), all-cause mortality (adjusted HR, 0.55; 95% CI, 0.34-0.90 [P=0.017]), and cardiovascular mortality (adjusted HR, 0.40; 95% CI, 0.20-0.79 [P=0.008]). However, this association was absent with the Sokolow-Lyon and Romhilt-Estes criteria. Conclusions ECG LVH by Cornell criteria only was significantly associated with lower risks of MACCE and all-cause or cardiovascular mortality. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03298178.