The increasing worldwide prevalence of Hepatocellular carcinoma (HCC), characterized by resistance to conventional chemotherapy, poor prognosis and eventually mortality, place it as a prime target ...for new modes of prevention and treatment. Hepatitis C Virus (HCV) is the predominant risk factor for HCC in the US and Europe. Multiple epidemiological studies showed that sustained virological responses (SVR) following treatment with the powerful direct acting antivirals (DAAs), which have replaced interferon-based regimes, do not eliminate tumor development. We aimed to identify an HCV-specific pathogenic mechanism that persists post SVR following DAAs treatment. We demonstrate that HCV infection induces genome-wide epigenetic changes by performing chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) for histone post-translational modifications that are epigenetic markers for active and repressed chromatin. The changes in histone modifications correlate with reprogramed host gene expression and alter signaling pathways known to be associated with HCV life cycle and HCC. These epigenetic alterations require the presence of HCV RNA or/and expression of the viral proteins in the cells. Importantly, the epigenetic changes induced following infection persist as an "epigenetic signature" after virus eradication by DAAs treatment, as detected using in vitro HCV infection models. These observations led to the identification of an 8 gene signature that is associated with HCC development and demonstrate persistent epigenetic alterations in HCV infected and post SVR liver biopsy samples. The epigenetic signature was reverted in vitro by drugs that inhibit epigenetic modifying enzyme and by the EGFR inhibitor, Erlotinib. This epigenetic "scarring" of the genome, persisting following HCV eradication, suggest a novel mechanism for the persistent pathogenesis of HCV after its eradication by DAAs. Our study offers new avenues for prevention of the persistent oncogenic effects of chronic hepatitis infections using specific drugs to revert the epigenetic changes to the genome.
Background and Aims
Survival data among patients with hepatitis C virus (HCV)‐related hepatocellular carcinoma (HCC) after achieving sustained virologic response (SVR) with interferon‐free ...direct‐acting antivirals (DAAs) in both Asian and western countries are limited. Survival rates were compared between patients with HCV‐related HCC who were untreated for HCV and those who achieved SVR.
Approach and Results
Using data from two U.S. and six Asian centers from 2005 to 2017, we categorized 1,676 patients who were mono‐infected with HCV‐related HCC into patients untreated for HCV (untreated group) and DAA‐treated patients with SVR (SVR group) and matched by propensity score matching (PSM); multivariable Cox regression with HCV treatment status as a time‐varying covariate was used to determine mortality risk and landmark analysis to avoid immortal time bias. There were 1,239 untreated patients and 437 patients with SVR. After PSM, background risks of the 321 pairs of matched patients were balanced (all P > 0.05). After time‐varying adjustment for HCV treatment initiation compared with untreated patients, patients with SVR had significantly higher 5‐year overall survival (87.78% vs. 66.05%, P < 0.001). Multivariable Cox regression showed that SVR was independently associated with a 63% lower risk of 5‐year all‐cause mortality (hazard ratio HR, 0.37; 95% confidence interval CI, 0.16‐0.83; P = 0.016) and 66% lower risk of 5‐year liver‐related mortality (HR, 0.34; 95% CI, 0.13‐0.88; P = 0.026) with similar trends after removing patients with liver transplants. Landmark analysis at 90, 180, and 360 days showed consistent results (HRs ranged 0.22 to 0.44, all P < 0.05).
Conclusion
In this multinational consortium, patients with HCV‐related HCC who obtained SVR achieved a 60%‐70% improvement in 5‐year survival (both all‐cause and liver related) compared with patients untreated for HCV. Patients eligible for HCC therapy should also be considered for DAA therapy.
Lifestyle modification is the standard of care for nonalcoholic fatty liver disease (NAFLD) patients. We aimed to investigate the efficacy of a short‐term lifestyle modification program in the ...disease course of Taiwanese nonalcoholic steatohepatitis (NASH) patients with paired biopsies. All patients received a 6‐month, strict multidisciplinary program of lifestyle modifications led by physicians, dieticians, and nursing staff. The histopathological and clinical features were assessed. The endpoints were normalization of transaminase levels, metabolic parameters, a decrease in the NAFLD activity score (NAS) ≥1, and a decrease in the fibrosis stage ≥1. We also aimed to elucidate the predictors associated with disease progression. A total of 37 patients with biopsy‐proven NASH were enrolled. The normalization of transaminase levels increased from 0% to 13.5%. There were also significantly increased proportions of patients with normal total cholesterol, triglyceride, and hemoglobin A1c levels. Fifteen (40.5%) patients had an increased NAS ≥1, whereas 10 (27.0%) patients had NAS regression. Twelve (32.4%) patients had increased fibrosis ≥1 stage. Only 2 (5.4%) patients experienced fibrosis regression. A high fasting plasma glucose (FPG) level was associated with NAS progression. Older age and higher transaminase and FPG levels were factors associated with fibrosis progression. Seven (18.9%) patients achieved a body weight reduction >3%, and 4 (57.1%) of them experienced NAS regression. No significant effect of weight reduction on the progression of fibrosis was observed. The short‐term lifestyle modification program significantly decreased liver enzymes and metabolic parameters in NASH patients. A more precise or intensive program may be needed for fibrosis improvement.
Background
The efficacy and safety of insulin sensitizer in Asians with non-alcoholic steatohepatitis (NASH) remain elusive.
Aims
The double-blind, randomized, placebo-controlled trial was conducted ...aiming to investigate the efficacy and safety of pioglitazone in NASH patients.
Methods
A total of 90 NASH patients (66 males, age = 44.1 ± 12.7 years) were prospectively randomized into oral pioglitazone 30 mg/day (Arm A) or placebo (Arm B) for 24 weeks. The primary endpoint was the efficacy of pioglitazone in reducing inflammation and liver fat at end-of-treatment (EOT). NASH resolution/improvement without fibrosis worsening was also evaluated.
Results
At EOT, there was a significantly decline of alanine aminotransferase (86.9 ± 34.3 to 45.7 ± 35.8 IU/L,
p
= 0.003) level in Arm A patients. In intention-to-treat analysis among 66 patients who completed paired biopsies, The NAFLD activity score (NAS) of 30 Arm A patients significantly decreased from 4.27 ± 1.14 at baseline to 2.53 ± 1.63 at EOT (
p
< 0.0001), whereas there was no significant change in patients of Arm B (3.94 ± 1.41 vs 3.94 ± 1.51,
p
= 1.0). NASH improvement without worsening of fibrosis was achieved in 46.7% (14/30) patients in Arm A, compared to 11.1% (4/36) patients in Arm B (
p
= 0.002). Liver fat content reduced (20.2 ± 9.0 to 14.3 ± 6.9%,
p
< 0.0001) on MRI–PDFF in Arm A compared to their counterparts. No significant difference of adverse events occurred between groups.
Conclusions
A 24-week pioglitazone treatment was well-tolerated and effective in improving liver histology and reducing liver steatosis in Asian NASH patients. (ClinicalTrials.gov number: NCT01068444)
•Fully automatic extraction and classification for repeating printed fabric patterns.•The similarity was used as a criterion for judging pattern design derivativeness.•The average automatic repeated ...pattern extraction time is 10 s per image.•The similarity has accuracy of 98.0%, sensitivity of 94.4% and specificity of 98.5%
Repeating pattern recognition and extraction are important processes in the production and analysis of printed fabrics. In this study, the repeating patterns on printed fabric were extracted and innovatively analyzed using gray-scale image transform, two-dimensional discrete wavelet transform, fast Fourier transform and adaptive K-means clustering methods. The gray-scale image and two-dimensional discrete wavelet transforms were applied to compress the image. Image spectral characteristics were analyzed with a fast Fourier transform (FFT), the true fundamental frequency was extrapolated from its multiples, and frequency grouping was achieved using adaptive k-means clustering. The groups with the lowest frequencies in the image rows and columns were taken as giving the extraction frequency, and then the extraction frequency was mapped back onto the uncompressed fabric image to obtain the repeating pattern of the printed fabric. The similarity between patterns was used as a criterion for judging pattern design derivativeness. Similarity analysis was divided into two stages to reduce the calculation time and the amount of calculation required. In the first stage, repeating patterns were extracted and compared with existing patterns in an image database. In the second phase similarity analysis was carried out. The experimental results show the feasibility of the application of fast Fourier transforms to establishing a database of repeating patterns of printed fabrics. The average automatic repeated pattern extraction time is 10 s per image. The similarity analysis developed in the study has an accuracy rate of 98.0%, a sensitivity of 94.4% and a specificity of 98.5%. It is suitable for the analysis of all printing patterns, and meets the needs of the industry and printing pattern designers for data sharing and economical, competitive product management, over the total lifecycle of a fabric product from development to delivery, so satisfying market and societal needs.
Background and Aim
The prevalence of metabolic dysfunction‐associated fatty liver disease (MAFLD) and its interplay with hepatitis B virus (HBV) and hepatitis C virus (HCV) in terms of liver disease ...severity is elusive.
Methods
A mass surveillance program was conducted in a viral hepatitis endemic area. The objective was to identify MAFLD/non‐MAFLD subjects with advanced liver disease.
Results
Two thousand two hundred and forty‐two (41.7%) of the 5378 subjects were identified as having MAFLD, and 375 (7.0%) had advanced liver disease. The proportions of anti‐HCV and HBsAg seropositivity were 19.3% and 9.7%, respectively. The proportions of advanced fibrosis in subjects with non‐viral hepatitis (NBNC), HBV and HCV infection were 2.8%, 5.7% and 23.4%, respectively. Subjects with MAFLD had a significantly higher proportion of advanced fibrosis (8.7% vs 5.7%, P < 0.001). Factors associated with advanced fibrosis included age (odds ratio OR/95% confidence interval CI: 4.8/3.7–6.0, P < 0.001), male sex (OR/CI: 1.3/1.0–1.7, P = 0.019), anti‐HCV seropositivity (OR/CI: 5.9/4.6–7.5, P = 0.019), MAFLD‐lean metabolic dysregulation (MS) (OR/CI: 2.6/1.3–5.2, P = 0.005; compared with the non‐MAFLD group) and MAFLD‐diabetes (OR/CI: 1.5/1.1–2.1, P = 0.008; compared with the non‐MAFLD group). MAFLD did not aggravate liver disease severity in patients with viral hepatitis. However, among NBNC subjects, factors associated with advanced liver disease included MAFLD‐lean MS group (OR/CI: 9.1/2.4–34.6, P = 0.001; compared with non‐MAFLD group) and MAFLD‐DM group (OR/CI: 2.0/1.2–3.2, P = 0.004; compared with non‐MAFLD group).
Conclusions
MAFLD patients with diabetes and metabolic dysregulation had a higher risk of advanced liver disease. The effect was more significant in non‐viral hepatitis subjects in a community level.
Background & Aims
Differentiation antagonizing non‐protein coding RNA is associated with various types of neoplasms. Hepatitis C virus‐related hepatocellular carcinoma has a high risk of recurrence. ...Here we determined the role of differentiation antagonizing non‐protein coding RNA in hepatitis C virus‐related hepatocarcinogenesis and identified potential therapeutic targets and non‐invasive prognostic markers for long‐term outcome of hepatitis C virus‐related hepatocellular carcinoma after surgical resection.
Methods
Differentiation antagonizing non‐protein coding RNAs relevant to hepatitis C virus‐related hepatocellular carcinoma were identified through comparative RNA‐sequencing of tumour and adjacent non‐tumour (ANT) tissues in a screening set, and were validated using real‐time polymerase chain reaction. Target long non‐coding RNAs (lncRNAs) in tissues and serum exosomes were used to predict the recurrence of hepatitis C virus‐related hepatocellular carcinoma after curative surgical resection in a large application cohort from 2005 to 2012.
Results
We confirmed that differentiation antagonizing non‐protein coding RNA was upregulated following hepatitis C virus infection and identified as the lncRNA most relevant to hepatitis C virus‐related hepatocellular carcinoma in tumour tissues as compared to that in ANT tissues. In 183 hepatitis C virus‐related hepatocellular carcinoma patients followed for 10 years after curative HCC resection, the expression level of circulating exosomal differentiation antagonizing non‐protein coding RNA was positively associated with HCC recurrence and was the most predictive factor associated with HCC recurrence and mortality (hazard ratio/95% confidence intervals: 7.0/4.3‐11.6 and 2.7/1.5‐5.1 respectively).
Conclusions
Differentiation antagonizing non‐protein coding RNA is highly relevant to disease progression of hepatitis C virus‐related hepatocellular carcinoma. Our finding indicated that circulating exosomal differentiation antagonizing non‐protein coding RNA might serve as a non‐invasive prognostic biomarker for hepatitis C virus‐related hepatocellular carcinoma.
Background/Aims Hepatitis C Virus (HCV) infection is diagnosed by the presence of antibody to HCV and/or HCV RNA. This study aimed to evaluate the accuracy of anti-HCV titer (S/CO ratio) in ...predicting HCV viremia in patients with or without hepatitis B virus (HBV) dual infection. Methods Anti-HCV seropositive patients who were treatment-naïve consecutively enrolled. Anti-HCV antibodies were detected using a commercially chemiluminescent microparticle immunoassay. HCV RNA was detected by real-time PCR method. Results A total of 1321 including1196 mono-infected and 125 HBV dually infected patients were analyzed. The best cut-off value of anti-HCV titer in predicting HCV viremia was 9.95 (AUROC 0.99, P<0.0001). Of the entire cohort, the anti-HCV cut-off value of 10 provided the best accuracy, 96.8%, with the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 96.3%, 98.9%, 99.7% and 87.3% respectively. The best cut-off value of anti-HCV titer in predicting HCV viremia was 9.95 (AUROC 0.99, P<0.0001) and 9.36 (AUROC 1.00, P<0.0001) in patients with HCV mono-infection and HBV dual-infection respectively. Among the HBV dually infected patients, the accuracy of anti-HCV titer in predicting HCV viremia reached up to 100% with the cut-off value of 9. All the patients were HCV-viremic if their anti-HCV titer was greater than 9 (PPV 100%). On the other hand, all the patients were HCV non-viremic if their anti-HCV titer was less than 9 (NPV 100%). Conclusions Anti-HCV titer strongly predicted HCV viremia. This excellent performance could be generalized to either HCV mono-infected or HBV dually infected patients.
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