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Abstract We aimed to investigate the association between air pollution and advanced fibrosis among patients with metabolic associated fatty liver disease (MAFLD) and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. A total of 1376 participants who were seropositive for HBV surface antigen (HBsAg) or antibodies to HCV (anti‐HCV) or had abnormal liver function in a community screening program from 2019 to 2021 were enrolled for the assessment of liver fibrosis using transient elastography. Daily estimates of air pollutants (particulate matter ≤2.5 μm in diameter [PM2.5], nitrogen dioxide [NO2], ozone [O3] and benzene) were aggregated into mean estimates for the previous year based on the date of enrolment. Of the 1376 participants, 767 (52.8%) and 187 (13.6) had MAFLD and advanced fibrosis, respectively. A logistic regression analysis revealed that the factors associated with advanced liver fibrosis were HCV viremia (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.05–4.77; p

Background The effect of glycated hemoglobin (HbA1c) variability on adverse outcomes in patients with heart failure (HF) is unclear. We aim to investigate the predictive value of HbA1c variability on the risks of all‐cause death and HF rehospitalization in patients with HF irrespective of their diabetic status. Methods and Results Using a previously validated territory‐wide clinical data registry, HbA1c variability was assessed by average successive variability (ASV) or SD of all HbA1c measurements after HF diagnosis. Multivariable Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) and its corresponding 95% CI. A total of 65 950 patients with HF were included in the study. Over a median follow‐up of 6.7 (interquartile range, 4.0–10.6) years, 34 508 patients died and 52 446 required HF rehospitalization. Every unit increment of variability in HbA1c was significantly associated with higher HF rehospitalization (HR ASV, 1.20 [95% CI, 1.18–1.23]) and all‐cause death (HR ASV, 1.50 [95% CI, 1.47–1.53]). Diabetes significantly modified the association between HbA1c variability and outcomes (Pinteraction

Abstract Background Sex disparities constitute a significant issue in hepatocellular carcinoma (HCC). However, the mechanism of gender dimorphism in HCC is still not completely understood. Methods 5‐Hydroxymethylcytosine (5hmC)‐Seal technology was utilised to detect the global 5hmC levels from four female and four male HCC samples. Methylation of XIST was detected by Sequenom MassARRAY methylation profiling between HCC tissues (T) and adjacent normal liver tissues (L). The role of Tet methylcytosine dioxygenase 2 (TET2) was investigated using diethylnitrosamine (DEN)‐administered Tet2−/− female mice, which regulated XIST in hepatocarcinogenesis. All statistical analyses were carried out by GraphPad Prism 9.0 and SPSS version 19.0 software. Results The results demonstrated that the numbers of 5hmC reads in the first exon of XIST from female HCC tissues (T) were remarkably lower than that in female adjacent normal liver tissues (L). Correspondingly, DNA methylation level of XIST first exon region was significantly increased in female T than in L. By contrast, no significant change was observed in male HCC patients. Compared to L, the expression of XIST in T was also significantly downregulated. Female patients with higher XIST in HCC had a higher overall survival (OS) and more extended recurrence‐free survival (RFS). Moreover, TET2 can interact with YY1 binding to the promoter region of XIST and maintain the hypomethylation state of XIST. In addition, DEN‐administered Tet2−/− mice developed more tumours than controls in female mice. Conclusions Our study provided that YY1 and TET2 could interact to form protein complexes binding to the promoter region of XIST, regulating the methylation level of XIST and then affecting the expression of XIST. This research will provide a new clue for studying sex disparities in hepatocarcinogenesis. Highlights XIST was significantly downregulated in HCC tissues and had gender disparity. Methylation levels in the XIST first exon were higher in female HCC tissues, but no significant change in male HCC patients. The TET2–YY1 complex regulate XIST expression in female hepatocytes. Other ways regulate XIST expression in male hepatocytes.

Abstract Hepatitis C virus (HCV) eradication through antivirals ameliorates metabolic profiles. The changes in 2‐h plasma glucose (2HPG) levels by oral glucose tolerance test (OGTT), in chronic hepatitis C (CHC) patients who receive directly acting antivirals (DAAs) was elusive. Five hundred and thirty‐three CHC patients who achieved sustained virological response (SVR, undetectable HCV RNA throughout 3 months after the end‐of‐treatment) by DAAs were consecutively enrolled. Pre‐ and posttreatment 2HPG levels and glucose status were compared. The proportion of patients with improved, worsened, and stable 2HPG was 14.4% (n = 77), 18.6% (n = 99), and 67.0% (n = 357), respectively. Compared with patients with worsening 2HPG, those with improved 2HPG had a higher proportion of cirrhosis (45.5% vs. 24.2%, p = 0.004) and higher pretreatment 2HPG levels (175.3 vs. 129.5 mg/dl, p

Abstract This paper is concerned with security problems for cyber‐physical systems (CPSs) under dynamic load altering attacks (DLAA) and false data injection attacks (FDIA). The smart grid, as a typical CPS system, is taken as an example in this paper. Since the communication channel is vulnerable to FDIA and DLAA, the stability of the smart grid may be influenced. For enhancing resilience and stability of smart grids, first of all, the power system model including both DLAA and FDIA is introduced. Second, an adaptive sliding mode controller is proposed. The controller can ensure the reliable operation of the power system in the case of unknown attack information by using the adaptive mechanism online estimating the upper bound of attack signal to automatically eliminate the effect of mixed attacks. Finally, a power system with three generators and six buses is taken as an illustrative example, and simulation and experiment results obtained by using MATLAB and Hardware‐in‐time platform built by Sartsim verify the effectiveness of the proposed resilient defense strategy.

Abstract The phytohormone abscisic acid (ABA) is the best‐known stress signaling molecule in plants. ABA protects sessile land plants from biotic and abiotic stresses. The conserved pyrabactin resistance/pyrabactin resistance‐like/regulatory component of ABA receptors (PYR/PYL/RCAR) perceives ABA and triggers a cascade of signaling events. A thorough knowledge of the sequential steps of ABA signaling will be necessary for the development of chemicals that control plant stress responses. The core components of the ABA signaling pathway have been identified with adequate characterization. The information available concerning ABA biosynthesis, transport, perception, and metabolism has enabled detailed functional studies on how the protective ability of ABA in plants might be modified to increase plant resistance to stress. Some of the significant contributions to chemical manipulation include ABA biosynthesis inhibitors, and ABA receptor agonists and antagonists. Chemical manipulation of key control points in ABA signaling is important for abiotic and biotic stress management in agriculture. However, a comprehensive review of the current knowledge of chemical manipulation of ABA signaling is lacking. Here, a thorough analysis of recent reports on small‐molecule modulation of ABA signaling is provided. The challenges and prospects in the chemical manipulation of ABA signaling for the development of ABA‐based agrochemicals are also discussed.

We previously demonstrated that interleukin‐17A (IL‐17A) is associated with the progression of hepatocellular carcinoma (HCC). However, its role in the invasion–metastasis cascade of HCC and the efficacy of IL‐17A‐targeting therapeutics in HCC remain largely unknown. In this study, we found that IL‐17A promoted intrahepatic and pulmonary metastasesis of HCC cells in an orthotopic implant model. Moreover, our results showed that IL‐17A induced epithelial–mesenchymal transition (EMT) and promoted HCC cell colonization in vitro and in vivo, and the role of IL‐17A in invasion–metastasis was dependent on activation of the AKT pathway. Remarkably, combined therapy using both secukinumab and sorafenib has better inhibition on tumour growth and metastasis compared to sorafenib monotherapy. Additionally, the combination of intratumoral IL‐17A+ cells and E‐cadherin predicted the outcome of patients with HCC at an early stage after hepatectomy based on tissue microarray and immunohistochemistry. In conclusion, our studies reveal that IL‐17A induces early EMT and promotes late colonization of HCC metastasis by activating AKT signalling. Secukinumab is a promising candidate for clinical development in combination with sorafenib for the management of HCC.

Direct-acting antiviral agents (DAAs) have been widely used for chronic hepatitis C (CHC) treatment recently. The characteristics of glucose abnormalities after DAAs therapy however, remain elusive. We aimed to elucidate the mutual impact between treatment response and parameters of glucose abnormalities after DAAs therapy in CHC patients. CHC patients who received DAAs therapy were recruited. The primary outcome measurements were their insulin resistance (IR) and beta-cell function assessed by the homeostasis model assessment (HOMA) method before treatment and at end-of-follow-up (EOF). Sixty-five CHC patients (19 males, mean age = 59.8 ± 10.3 years) were consecutively enrolled. They included 47 (72.3%) patients of genotype-1 infection. The treatment regimens among patients were sofosbuvir in 30 patients, paritaprevir-ritonavir/ombitasvir/dasabuvir in 23 patients, and asunaprevir/daclatasvir in 12 patients respectively. The overall sustained virological response rate was 98.5%. The mean IR at EOF was 2.6 ± 1.8, which was not significantly different from baseline level (2.7 ± 2.9, P = 0.75). There was a significant improvement of beta-cell function at EOF compared to baseline (107.7 ± 86.8 to 86.7 ± 44.5, P = 0.05). The amelioration of beta-cell function at EOF was significantly observed among 23 patients of high baseline IR (166.7 ± 111.3 of baseline vs 105.7 ± 48.2 of EOF, P = 0.04). Six (60%) of the 10 pre-diabetic patients at baseline achieved a normoglycemic state at EOF. Successful eradication of HCV by DAAs might improve glucose abnormalities in CHC patients, particularly among those who had high IR.

Chronic infection by hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC). Despite the clear clinical importance of virus-associated HCC, the underlying molecular mechanisms remain largely unclarified. Oxidative stress, in particular, DNA lesions associated with oxidative damage, plays a major role in carcinogenesis, and is strongly linked to the development of many cancers, including HCC. However, in identifying hepatocytes with HCV viral RNA, estimates of the median proportion of HCV-infected hepatocytes have been found as high as 40% in patients with chronic HCV infection. In order to explore the gene alternation and association between different viral loads of HCV-infected cells, we established a method to dissect high and low viral load cells and examined the expression of DNA damage-related genes using a quantitative polymerase chain reaction array. We found distinct expression patterns of DNA damage-related genes between high and low viral load cells. This study provides a new method for future study on virus-associated gene expression research.

In Taiwan, injecting drug use has been the main route of human immunodeficiency virus (HIV) transmission since 2005, with hepatitis B virus (HBV) and hepatitis D virus (HDV) also having similar transmission routes. This has now become an important public health issue. The aim of this study is to explore the conditions of HDV infections between injecting drug users (IDUs) with and without HIV infection in Southern Taiwan. In this study, 87 IDUs were enrolled, including 27 anti-HDV seronegative IDUs and 60 anti-HDV seropositive IDUs, and the results of their liver function tests, CD4 cell counts, and anti-HIV and HIV RNA levels were analyzed. The prevalence of anti-HDV seropositivity among hepatitis B surface antigen (HBsAg) seropositive IDUs in this study was 68.9% (60/87). The prevalence rate of anti-HDV seropositive IDUs among anti-HIV seronegative and anti-HIV seropositive cases was 40.0% (12/30) and 84.2% (48/57), respectively. Anti-HIV seropositivity was related to anti-HDV seropositivity (odds ratio = 9.34, 95% confidence interval = 2.67–31.59, p

Sonography-based noninvasive liver fibrosis assessment is promising in the prediction of treatment efficacy and prognosis in chronic liver disease (CLD) patients. Acoustic radiation force impulse imaging (ARFI) is a newly-developed transient elastography (TE) method integrated into a conventional ultrasound machine. The study aimed to assess the performance of ARFI imaging in the diagnosis of liver fibrosis in Taiwanese CLD patients. We also aimed to search for the optimal cut-off values in different fibrosis stages. A total of 60 CLD patients (40 males; mean age, 51.8±11 years) were consecutively included. They received standard ARFI measurement within 2 weeks at the time of liver biopsy. There were eight patients with Metavir fibrosis stage 0 (F0), 16 patients with F1, 20 patients with F2, eight patients with F3, and eight patients with F4, respectively. The mean values among patient with F0, F1, F2, F3, and F4 were 1.17±0.13, 1.30±0.17, 1.31±0.24, 2.01±0.45, and 2.69±0.91, respectively (p

In Taiwan, the number of new cases of human immunodeficiency virus (HIV) infection via drug injection has been increasing since 2003. Due to HIV and hepatitis B virus (HBV) having similar transmission routes, HBV and HIV infections among injecting drug users (IDUs) has become an important public health issue. The aim of this study was explore the prevalence of HBV infection among IDUs with and without HIV infection, and examine whether HIV infection is associated with HBV infection among IDUs in Southern Taiwan. We enrolled 566 IDUs, including 87 anti-HBV positive IDUs and 479 anti-HBV negative IDUs, and also analyzed the results of liver function tests, HBV DNA, anti-HIV, HIV RNA, and CD4 cell count. The results showed that the prevalence of HBV infection among IDUs was 15.4%. The prevalence of hepatitis B surface antigen (HBsAg) was higher among individuals born before 1985 (15.9% vs. 4.0%), but this was not significant. Anti-HIV seropositivity was related to HBsAg seropositivity [odds ratio (OR) = 2.47, 95% confidence interval = 1.26–4.82, p = 0.008). Anti-HCV and anti-HIV were risk factors for abnormal alanine aminotransferase (ALT; OR = 2.11, 95% confidence interval = 1.005–4.42, p = 0.048 and OR = 1.47, 95% confidence interval = 1.02–2.10, p = 0.04, respectively), and HBsAg was not a factor related to abnormal ALT. In conclusion, the prevalence of HBV infection was similar in the general population and in IDUs, and due to anti-HIV seropositivity being significantly related to HBsAg seropositivity, HBV infection among IDUs is still important. We suggest that for IDUs, HBsAg should be monitored closely.

Cytokine production capacity varies among individuals and depends on cytokine gene polymorphisms. Transforming growth factor-beta 1 (TGF-β1) plays a significant role in regulating the proliferation and apoptosis of epithelial cells. Interleukin 10 (IL-10) is an immunoregulatory cytokine with biological functions of anti-inflammation, immunosuppression, allergy, and anti-agenesis. The two cytokines are supposed to play an important role in carcinogenesis. The association between cytokine gene polymorphisms with oral cancer (OC) was investigated. We studied the association between the polymorphism in TGF-β1 (G to C polymorphism at codon 25 ) and IL-10 (−1082 G/A, -819 C/T, and −592 C/A) and the risk of OC in patients (n = 162) and healthy controls (n = 118) in Taiwan. All genotyping experiments were performed using the polymerase chain reaction sequence-specific primer (PCR-SSP) method. It was found that the codon 25 GC genotype of TGF-β1 is significantly higher in frequency in patients with OC compared with a healthy control group (p

Oral squamous cell carcinoma can be preceded by some benign oral lesions with malignant potential, including leukoplakia, erythroplakia, oral lichen planus, and oral submucous fibrosis. There are different degrees of inflammatory cells infiltration in histopathology. Inflammatory cytokines may play a pathogenic role in the development of oral precancerous lesions (OPCLs). Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. We hypothesized that the risk of OPCLs might be associated with cytokine gene polymorphisms of interferon (IFN)-γ, transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10. In the present study, 42 OPCL patients and 128 controls were analyzed for eight polymorphisms in five different cytokine genes [IFN-γ (+874 T/A), TGF-β1 (codons 10 T/C and 25 G/C), TNF-α (−308 G/A), IL-6 (−174 G/C), and IL-10 (−1082 A/G, –819 T/C, and −592 A/C)]. Cytokine genotyping was determined by the polymerase chain reaction sequence-specific primer technique using commercial primers. Allele and genotype data were analyzed for significance of differences between cases and controls using the Chi-square (χ2) test. Two-sided p