Citations

Time-restricted feeding improves glucose homeostasis through epigenetic control of pancreatic β cell function.

ABSTRACT Background Uncertainties exist about the use of mycophenolate mofetil (MMF) in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), particularly for remission maintenance. Methods Systematic review and meta-analysis of phase II and III trials assessing the use of MMF in AAV, granulomatosis with polyangiitis and microscopic polyangiitis (MPA). A comprehensive search of several databases (Medline, EMBASE, Cochrane, Web of Science, Scopus) from inception to 5 May 2020 has been conducted. Trial data were extracted to estimate odds ratios (ORs) and estimates (ES) for MMF efficacy (remission-induction and maintenance). Severe adverse effects (SAEs) were collected. Results From 565 articles captured, 10 met the predefined criteria, 5 phase II and 5 III trials; 4 assessed remission-induction, 3 remission maintenance and 3 both. The pooled OR for remission-induction at 6 months was 1.06 (95% confidence interval 0.74, 1.52), with no significant difference by subgroup meta-analysis of trials stratified by different study-level features (i.e. kidney disease, MPA, myeloperoxidase-ANCA positivity, newly diagnosed disease) (P > 0.05). The overall ES for remission maintenance at the end of follow-up ranged between 51% and 91% (I2 = 74.8%). Subgroup meta-analysis identified kidney involvement as a possible source of heterogeneity, yielding a significantly higher rate of sustained remission in trials enrolling only patients with kidney involvement (92%, 76–100%) versus those enrolling patients with and without kidney involvement (56%, 45–66%). Results were similar in multiple sensitivity analyses. During follow-up, the frequency of SAEs in MMF-based treatment arms was 31.8%. Conclusions In AAV, MMF use was significantly associated with higher sustained remission rates in trials enrolling only patients with kidney involvement. These findings might influence clinical practice.

Abstract Rationale Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. Objectives To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. Methods Genotypes of SERPINA1were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. Measurements and Main Results We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV1% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV1was 3.9% lower (95% confidence interval [CI], −6.55% to −1.26%) and emphysema (the percentage of lung attenuation areas <−950 HU) was 4.14% greater (95% CI, 1.44% to 6.84%) in MZ subjects. We found one gene, PGF(placental growth factor), to be differentially expressed in lung tissue from one study between MZ subjects and MM subjects. Conclusions Carriers of the AAT Z allele (those who were MZ heterozygous) with COPD had lower lung function and more emphysema than MM subjects with COPD. Taken with the subtle differences in gene expression between the two groups, our findings suggest that MZ subjects represent an endotype of COPD.

The clock is ticking for senescent cells Senescent cells promote their own recognition and removal through the immune system by generating a bioactive secretome called the senescence-associated secretory phenotype (SASP). Sturmlechner et al . report that the cell cycle regulator p21 directs an early form of the SASP, which they call the p21-activated secretory phenotype (PASP) (see the Perspective by Reen and Gil). As part of the PASP, the chemokine CXCL14 attracts macrophages, which monitor stressed cells expressing elevated p21. If stressed cells recuperate and p21 levels return to normal within 4 days, then macrophages disengage from their targets. Otherwise, macrophages recruit cytotoxic T cells that facilitate target cell removal. Other cell cycle regulators such as p16 can induce many factors overlapping with the PASP, but p21 uniquely drives this CXCL14-mediated “timer” mechanism of senescent cell immunosurveillance. —STS

RNA polymerase II (Pol II)-dependent transcription in stimulus-inducible genes requires topoisomerase IIβ (TOP2B)-mediated DNA strand break and the activation of DNA damage response signalling in humans. Here, we report a novel function of the breast cancer 1 (BRCA1)-BRCA1-associated ring domain 1 (BARD1) complex in this process. We found that BRCA1 is phosphorylated at S1524 by the kinases ataxia-telangiectasia mutated and ATR during gene activation, and that this event is important for productive transcription. Our biochemical and genomic analyses showed that the BRCA1-BARD1 complex interacts with TOP2B in the EGR1 transcription start site and in a large number of protein-coding genes. Intriguingly, the BRCA1-BARD1 complex ubiquitinates TOP2B, which stabilizes TOP2B binding to DNA while BRCA1 phosphorylation at S1524 controls the TOP2B ubiquitination by the complex. Together, these findings suggest the novel function of the BRCA1-BARD1 complex in the regulation of TOP2B and Pol II-mediated gene expression.

The aim of this study was to identify the optimal echocardiographic measurement of aortic regurgitation (AR) in continuous flow left ventricular assist devices (LVAD) and determine risk factors and clinical implications of de novo AR. Echocardiographic images from consecutive patients who underwent LVAD implantation from February 2007 to March 2017 were reviewed. Severity of de novo AR was determined by vena contracta (VC). Preimplant clinical characteristics, LVAD settings at discharge, and outcomes including heart failure hospitalizations, all-cause mortality, and ventricular arrhythmias of patients with greater than or equal to moderate de novo AR were compared with those with mild or no AR. Among 219 patients, greater than or equal to moderate de novo AR occurred in 65 (29.7%). Left ventricular assist devices support duration was longer with greater than or equal to moderate AR than no or mild AR. In multivariable analysis, preimplant trivial AR and persistent aortic valve (AV) closure were independently associated with de novo AR. By time-varying covariate analysis, survival and freedom from cardiovascular events in greater than or equal to moderate AR were significantly worse (hazard ratio [HR] = 3.947, p < 0.001 and HR = 4.666, p < 0.001). In conclusion, de novo greater than or equal to moderate AR measured by VC increases risk of adverse events. Longer LVAD support duration, preimplant trivial AR, and a closed AV are associated with occurrence of greater than or equal to moderate de novo AR.

Background: Acute cellular rejection is a major determinant of mortality and retransplantation after heart transplantation. We sought to evaluate the prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for the risk of acute cellular rejection after heart transplantation. Methods: The present study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure×hyperemic mean transit time. The primary end point was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared by using multivariable Cox proportional hazards regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of C-index, net reclassification index, and integrated discrimination index. Results: The mean age of recipients was 51.2±13.1 years (81.2% male), and the cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 versus 16.8±11.1, P =0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-U increase: adjusted hazard ratio, 1.18 [95% CI, 1.04–1.34], P =0.011) and the optimal cutoff value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% versus 3.8%; adjusted hazard ratio, 15.3 [95% CI 3.6–65.7], P <0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 versus 0.74, P <0.001; net reclassification index 1.05, P <0.001; integrated discrimination index 0.20, P <0.001). Conclusions: Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02798731.

Abstract Background and Aims Chronic HCV infection is a leading etiologic driver of cirrhosis and ultimately HCC. Of the approximately 71 million individuals chronically infected with HCV, 10%‐20% are expected to develop severe liver complications in their lifetime. Epigenetic mechanisms including DNA methylation and histone modifications become profoundly disrupted in disease processes including liver disease. Approach and Results To understand how HCV infection influences the epigenome and whether these events remain as “scars” following cure of chronic HCV infection, we mapped genome‐wide DNA methylation, four key regulatory histone modifications (H3K4me3, H3K4me1, H3K27ac, and H3K27me3), and open chromatin in parental and HCV‐infected immortalized hepatocytes and the Huh7.5 HCC cell line, along with DNA methylation and gene‐expression analyses following elimination of HCV in these models through treatment with interferon‐α (IFN‐α) or a direct‐acting antiviral (DAA). Our data demonstrate that HCV infection profoundly affects the epigenome (particularly enhancers); HCV shares epigenetic targets with interferon‐α targets; and an overwhelming majority of epigenetic changes induced by HCV remain as “scars” on the epigenome following viral cure. Similar findings are observed in primary human patient samples cured of chronic HCV infection. Supplementation of IFN‐α/DAA antiviral regimens with DNA methyltransferase inhibitor 5‐aza‐2’‐deoxycytidine synergizes in reverting aberrant DNA methylation induced by HCV. Finally, both HCV‐infected and cured cells displayed a blunted immune response, demonstrating a functional effect of epigenetic scarring. Conclusions Integration of epigenetic and transcriptional data elucidate key gene deregulation events driven by HCV infection and how this may underpin the long‐term elevated risk for HCC in patients cured of HCV due to epigenome scarring.

Objective: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. Background: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. Methods: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014–2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. Results: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. Conclusion: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.