Publications by authors named "Wei-Lun Tsai"

116 Publications

Sofosbuvir induces gene expression for promoting cell proliferation and migration of hepatocellular carcinoma cells.

Aging (Albany NY) 2022 Jul 12;14(14):5710-5726. Epub 2022 Jul 12.

Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.

Direct-acting antivirals (DAAs) have achieved a sustained virological response (SVR) rate of 95-99% in treating HCV. Several studies suggested that treatment with sofosbuvir (SOF), one type of DAAs, may be associated with increased risk of developing HCC. The aim of this study is to investigate the potential mechanisms of SOF on the development of HCC. OR-6 (harboring full-length genotype 1b HCV) and Huh 7.5.1 cells were used to examine the effects of SOF on cell proliferation and migration of HCC cells. SOF-upregulated genes in OR-6 cells were inspected using next generation sequencing (NGS)and the clinical significance of these candidate genes was analyzed using The Cancer Genome Atlas (TCGA) database. We found that SOF increased cell proliferation and cell migration in OR-6 and Huh 7.5.1 cells. Several SOF-upregulated genes screened from NGS were confirmed by real-time PCR in OR-6 cells. Among these genes, PHOSPHO2, KLHL23, TRIM39, TSNAX-DISC1 and RPP21 expression were significantly elevated in the tumor tissues compared with the non-tumor tissues of HCC according to TCGA database. High expression of PHOSPHO2 and RPP21 was associated with poor overall survival of HCC patients. Moreover, knockdown of PHOSPHO2-KLHL23, TSNAX-DISC1, TRIM39 and RPP21 diminished cell proliferation and migration increased by SOF in OR-6 and Huh 7.5.1 cells. In conclusion, SOF-upregulated genes promoted HCC cell proliferation and migration, which might be associated with the development of HCC.
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http://dx.doi.org/10.18632/aging.204170DOI Listing
July 2022

Factors Associated with Significant Platelet Count Improvement in Thrombocytopenic Chronic Hepatitis C Patients Receiving Direct-Acting Antivirals.

Viruses 2022 02 7;14(2). Epub 2022 Feb 7.

Penghu Hospital, Ministry of Health and Welfare, Penghu 880, Taiwan.

To clarify the predictive factors of significant platelet count improvement in thrombocytopenic chronic hepatitis C (CHC) patients. CHC patients with baseline platelet counts of <150 × 10/μL receiving direct-acting antiviral (DAA) therapy with at least 12-weeks post-treatment follow-up (PTW12) were enrolled. Significant platelet count improvement was defined as a ≥10% increase in platelet counts at PTW12 from baseline. Platelet count evolution at treatment week 4, end-of-treatment, PTW12, and PTW48 was evaluated. This study included 4922 patients. Sustained virologic response after 12 weeks post-treatment was achieved in 98.7% of patients. Platelet counts from baseline, treatment week 4, and end-of-treatment to PTW12 were 108.8 ± 30.2, 121.9 ± 41.1, 123.1 ± 43.0, and 121.1 ± 40.8 × 10/μL, respectively. Overall, 2230 patients (45.3%) showed significant platelet count improvement. Multivariable analysis revealed that age (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.99-1.00, = 0.01), diabetes mellitus (DM) (OR = 1.20, 95% CI: 1.06-1.38, = 0.007), cirrhosis (OR = 0.66, 95% CI: 0.58-0.75, < 0.0001), baseline platelet counts (OR = 0.99, 95% CI: 0.98-0.99, < 0.0001), and baseline total bilirubin level (OR = 0.80, 95% CI: 0.71-0.91, = 0.0003) were independent predictive factors of significant platelet count improvement. Subgroup analyses showed that patients with significant platelet count improvement and sustained virologic responses, regardless of advanced fibrosis, had a significant increase in platelet counts from baseline to treatment week 4, end-of-treatment, PTW12, and PTW48. Young age, presence of DM, absence of cirrhosis, reduced baseline platelet counts, and reduced baseline total bilirubin levels were associated with significant platelet count improvement after DAA therapy in thrombocytopenic CHC patients.
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http://dx.doi.org/10.3390/v14020333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8879038PMC
February 2022

Ledipasvir/sofosbuvir for HCV genotype 1, 2, 4-6 infection: Real-world evidence from a nationwide registry in Taiwan.

J Formos Med Assoc 2022 Aug 3;121(8):1567-1578. Epub 2022 Feb 3.

Penghu Hospital, Ministry of Health and Welfare, Taiwan.

Background/purpose: The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry of chronic hepatitis C patients in Taiwan. This study evaluated antiviral effectiveness of ledipasvir (LDV)/sofosbuvir (SOF) in patients in the TACR.

Methods: Patients enrolled in TACR from 2017-2020 treated with LDV/SOF were eligible. The primary outcome was the proportion of patients with sustained virologic response 12 weeks after end of treatment (SVR12).

Results: 5644 LDV/SOF ± ribavirin-treated patients were included (mean age: 61.4 years; 54.4% female). Dominant viral genotypes were GT1 (50.8%) and GT2 (39.3%). 1529 (27.1%) patients had liver cirrhosis, including 201 (3.6%) with liver decompensation; 686 (12.2%) had chronic kidney disease. SVR12 was achieved in 98.6% of the overall population and in 98.2% and 98.7% of patients with and without cirrhosis, respectively. SVR12 rates in patients with compensated cirrhosis treated with LDV/SOF without RBV were >98%, regardless of prior treatment experience. SVR12 was 98.6%, 98.4%, 100%, 100%, and 98.7% among those with GT1, GT2, GT4, GT5, and GT6 infections, respectively. Although patient numbers were relatively small, SVR12 rates of 100% were reported in patients infected with HCV GT2, GT5, and GT6 with decompensated cirrhosis and 98% in patients with severely compromised renal function. LDV/SOF adherence ≤60% (P < 0.001) was the most important factor associated with treatment failure. Incidence of adverse events was 15.8%, with fatigue being the most common.

Conclusion: LDV/SOF is effective and well tolerated in routine clinical practice in Taiwan. Cure rates were high across patient populations.
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http://dx.doi.org/10.1016/j.jfma.2022.01.012DOI Listing
August 2022

Sofosbuvir/Velpatasvir for Hepatitis C Virus Infection: Real-World Effectiveness and Safety from a Nationwide Registry in Taiwan.

Infect Dis Ther 2022 Feb 28;11(1):485-500. Epub 2021 Dec 28.

Division of Gastroenterology and Hepatology, Far Eastern Memorial Hospital, New Taipei, Taiwan.

Introduction: Pangenotypic direct-acting antivirals are expected to cure hepatitis C virus (HCV) in more than 95% of treated patients. However, data on the effectiveness and safety of sofosbuvir/velpatasvir (SOF/VEL) in Taiwan are limited. This study aims to characterize the patient population in the nationwide Taiwan Association for the Study of the Liver (TASL) HCV Registry and evaluate treatment outcome in Taiwanese patients receiving SOF/VEL.

Methods: This study was a retrospective-prospective, observational, multicenter, real-world analysis. Adults with chronic hepatitis C were treated with SOF/VEL 400/100 mg ± ribavirin for 12 weeks. The primary outcome was sustained virologic response 12 weeks after end of therapy (SVR12). Factors associated with not achieving SVR12 were evaluated using logistic regression and covariate analysis. Safety was also assessed.

Results: In total, 3480 patients were included: 86.8% genotype 1/2, 2.8% genotype 3, 0.1% genotype 4/5, 9.6% genotype 6; unclassified, 0.8%; 12.2% compensated cirrhosis; 3.3% decompensated cirrhosis; and 15.8% chronic kidney disease. Overall SVR12 rate was 99.4% (genotype 1, 99.5%; genotype 2, 99.4%; genotype 3, 96.9%; genotype 4, 100%; genotype 6, 99.7%). SVR12 rates among patients with compensated cirrhosis, decompensated cirrhosis, and chronic kidney disease stages 4-5 were 99.5%, 100%, and 100%, respectively. There were 21 patients (0.6%) who did not achieve SVR12. Factors associated with failure were treatment adherence below 60%, high viral load, and genotype 3 (p < 0.001, p = 0.028, and p = 0.001, respectively). Adverse events occurred in 10% of patients; 0.6% were serious and one was related to treatment. Treatment discontinuation occurred in 0.3% of patients; none were treatment related. The estimated glomerular filtration rate remained stable throughout treatment and follow-up, regardless of baseline values and cirrhosis status.

Conclusion: SOF/VEL was highly effective and well tolerated in Taiwanese patients, irrespective of viral genotype, liver disease severity, and comorbidities.
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http://dx.doi.org/10.1007/s40121-021-00576-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847492PMC
February 2022

Effect of Tempeh on Gut Microbiota and Anti-Stress Activity in Zebrafish.

Int J Mol Sci 2021 Nov 23;22(23). Epub 2021 Nov 23.

Department of Food Science and Nutrition, Meiho University, Pingtung 912009, Taiwan.

is a fungus used to ferment tempeh in Indonesia and is generally recognized as safe (GRAS) for human consumption by the USA FDA. We previously assessed the effect of a tempeh extract on cortisol levels in zebrafish but did not include behavioral studies. Here, we measured the GABA content in three strains of , two isolated by us (MHU 001 and MHU 002) and one purchased. We then investigated the effect of tempeh on cortisol and the gut microbiota in a zebrafish experimental model. GABA concentration was the highest in MHU 002 (9.712 ± 0.404 g kg) followed by our MHU 001 strain and the purchased one. The fish were divided into one control group fed a normal diet and three experimental groups fed soybean tempeh fermented with one of the three strains of . After two weeks, individual fish were subjected to unpredicted chronic stress using the novel tank diving test and the tank light-dark test. Next-generation sequencing was used to analyze gut microbial communities and RT-PCR to analyze the expression of BDNF (brain-derived neurotrophic factor) gene and of other genes involved in serotonin signaling/metabolism in gut and brain. Tempeh-fed zebrafish exhibited increased exploratory behavior (less stress) in both tank tests. They also had significantly reduced gut Proteobacteria (include ) (51.90% vs. 84.97%) and significantly increased gut Actinobacteria (include spp.) (1.80% vs. 0.79%). The content of , a "psychobiotic", increased ten-fold from 0.04% to 0.45%. Tempeh also increases BDNF levels in zebrafish brain. MHU 001 greatly improved the anti-stress effect of tempeh and microbiota composition in zebrafish gut.
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http://dx.doi.org/10.3390/ijms222312660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658004PMC
November 2021

Randomized Controlled Study of Tenofovir versus Lamivudine Followed by Tenofovir in Severe Exacerbation of Hepatitis B.

Antimicrob Agents Chemother 2022 02 22;66(2):e0166421. Epub 2021 Nov 22.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospitalgrid.415011.0, Kaohsiung, Taiwan.

Spontaneous severe acute exacerbation (SAE) is not uncommon in the natural history of chronic hepatitis B (CHB). Lamivudine (LAM) has the advantages of low price, quick onset, good efficacy, and no drug resistance within 24 weeks. This study aimed to compare the short-term efficacy of tenofovir disoproxil fumarate (TDF) and LAM for 24 weeks followed by TDF in the treatment of CHB with severe acute exacerbation. Consecutive patients of CHB with SAE were randomized to receive either TDF (19 patients) or LAM for 24 weeks, followed by TDF (18 patients). The primary endpoint was overall mortality or receipt of liver transplantation by week 24. This study was approved by the Institutional Review Board (IRB) of the Kaohsiung Veterans General Hospital (VGHKS12-CT5-10). The baseline characteristics were comparable between the two groups. By week 24, seven (37%) and five (28%) patients in the TDF and LAM-TDF groups died or received liver transplantation ( = 0.487). Multivariate analysis showed that albumin level, prothrombin time (PT), and hepatic encephalopathy were independent factors associated with mortality or liver transplantation by week 24. Early reductions in HBV DNA of more than or equal to 2 log at 1 and 2 weeks were similar between the two groups. The biochemical and virological responses at 12, 24, and 48 weeks were also similar between the two groups. TDF and LAM for 24 weeks followed by TDF achieved a similar clinical outcome in CHB patients with SAE. (This study has been registered at ClinicalTrials.gov under identifier NCT01848743).
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http://dx.doi.org/10.1128/AAC.01664-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846303PMC
February 2022

A New Light on Potential Therapeutic Targets for Colorectal Cancer Treatment.

Biomedicines 2021 Oct 10;9(10). Epub 2021 Oct 10.

PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.

The development and progression of colorectal cancer (CRC) involve changes in genetic and epigenetic levels of oncogenes and/or tumor suppressors. In spite of advances in understanding of the molecular mechanisms involved in CRC, the overall survival rate of CRC still remains relatively low. Thus, more research is needed to discover and investigate effective biomarkers and targets for diagnosing and treating CRC. The roles of long non-coding RNAs (lncRNAs) participating in various aspects of cell biology have been investigated and potentially contribute to tumor development. Our recent study also showed that CRNDE was among the top 20 upregulated genes in CRC clinical tissues compared to normal colorectal tissues by analyzing a Gene Expression Omnibus (GEO) dataset (GSE21815). Although CRNDE is widely reported to be associated with different types of cancer, most studies of CRNDE were limited to examining regulation of its transcription levels, and in-depth mechanistic research is lacking. In the present study, CRNDE was found to be significantly upregulated in CRC patients at an advanced TNM stage, and its high expression was correlated with poor outcomes of CRC patients. In addition, we found that knocking down CRNDE could reduce lipid accumulation through the miR-29b-3p/ANGPTL4 axis and consequently induce autophagy of CRC cells.
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http://dx.doi.org/10.3390/biomedicines9101438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533612PMC
October 2021

Long-term outcome of liver complications in patients with chronic HBV/HCV co-infection after antiviral therapy: a real-world nationwide study on Taiwanese Chronic Hepatitis C Cohort (T-COACH).

Hepatol Int 2021 Oct 7;15(5):1109-1121. Epub 2021 Aug 7.

Division of Gastroenterology and Hepatology, Department of Medicine, Institute of Clinical Medicine, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan.

Background And Aim: The long-term outcome of hepatitis B virus (HBV) infection among patients dually infected with HBV and hepatitis C virus (HCV) remains unclear. We aimed to investigate the long-term liver outcomes of HBV/HCV-coinfected patients after antiviral therapy.

Methods: A total of 11,359 chronically HCV-infected patients with interferon-based therapy were registered in a nationwide Taiwanese Chronic Hepatitis C Cohort. A propensity score matched (PSM) cohort of HCV mono-infected (n = 7020) and HBV/HCV (n = 702) co-infected patients by age, sex, and fibrosis was recruited for outcome analysis. The primary outcome was liver-related complications, including hepatocellular carcinoma (HCC) and liver decompensation during a mean follow-up period of 4.44 years.

Results: Among HBV/HCV co-infected patients, patients without HCV-SVR had a significantly higher 10-year cumulative incidence of major liver-related complications than those with HCV-SVR. However, among patients with HCV-SVR in the PSM cohort, the risk of major liver-related complications, both HCC and liver decompensation, did not differ between HBV/HCV co-infected and HCV mono-infected patients. Similar results were observed among those without HCV-SVR. A substantial lower risk of major liver-related complications was found in HBV/HCV co-infected patients with HCV SVR and subsequent anti-HBV nucleot(s)ide analogues treatment. Overall, factors associated with major liver-related complications included age ≥ 65 year-old, BMI ≥ 27 kg/m, FIB-4 ≥ 3.25, eGFR < 60 ml/min/1.73 m, and non-HCV SVR, but not HBV co-infection.

Conclusion: Interferon-based therapy reduced the long-term risk of major liver-related complications among HBV/HCV co-infected patients, as among HCV mono-infected patients. Nevertheless, post-HCV-SVR surveillance for major liver-related complications is mandatory among those high-risk groups.
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http://dx.doi.org/10.1007/s12072-021-10220-8DOI Listing
October 2021

Hepatitis B Virus Screening Before Cancer Chemotherapy in Taiwan: A Nationwide Population-Based Study.

Front Med (Lausanne) 2021 15;8:657109. Epub 2021 Jul 15.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Reactivation of the hepatitis B virus (HBV) during cancer chemotherapy is a severe and sometimes fatal complication. In 2009, the National Health Insurance (NHI) in Taiwan recommended and reimbursed screening for HBV infection and prophylactic antiviral therapy before cancer chemotherapy. In this study, we determined the HBV screening rate in patients with cancer undergoing chemotherapy in Taiwan. We retrospectively collected data from the National Health Insurance Research Database on patients who received systemic chemotherapy for solid or hematologic cancers from January 2000 through December 2012. We defined HBV screening based on testing for serum HBsAg within 2 years of the first chemotherapy commencement. We calculated overall and annual HBV screening rates in all patients and subgroups of age, gender, cancer type, hospital level, physician's department, and implementation of NHI reimbursement for HBV screening before cancer chemotherapy. We enrolled 379,639 patients. The overall HBV screening rate was 45.9%. The screening rates were higher in males, those with hematological cancer, those at non-medical centers and medical departments. The HBV screening rates before (2000-2008) and after the implementation of NHI reimbursement (2009-2012) were 38.1 and 57.5%, respectively ( < 0.0001). The most common practice pattern of HBV screening was only HBsAg (64.6%) followed by HBsAg/HBsAb (22.1%), and HBsAg/HBcAb/HBsAb (0.7%) ( < 0.0001). The annual HBV screening rate increased from 31.5 to 66.3% ( < 0.0001). The screening rates of solid and hematological cancers significantly increased by year; however, the trend was greater in solid cancer than in hematological cancer (35.9 and 26.2%, < 0.0001). The HBV screening rate before cancer chemotherapy was fair but increased over time. These figures improved after implementing a government-based strategy; however, a mandatory hospital-based strategy might improve awareness of HBV screening and starting prophylactic antiviral therapy before cancer chemotherapy.
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http://dx.doi.org/10.3389/fmed.2021.657109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319464PMC
July 2021

Impact of Sofosbuvir-Based Direct-Acting Antivirals on Renal Function in Chronic Hepatitis C Patients With Impaired Renal Function: A Large Cohort Study From the Nationwide HCV Registry Program (TACR).

Clin Gastroenterol Hepatol 2022 05 30;20(5):1151-1162.e6. Epub 2021 Jul 30.

Yang Ming Hospital, Taiwan.

Background & Aims: Sofosbuvir is approved for chronic hepatitis C (CHC) patients with severe chronic kidney disease (CKD). The impact of sofosbuvir-based therapy on renal function augmentation on a real-world nationwide basis is elusive.

Methods: The 12,995 CHC patients treated with sofosbuvir-based (n = 6802) or non-sofosbuvir-based (n = 6193) regimens were retrieved from the Taiwan nationwide real-world HCV Registry Program. Serial estimated glomerular filtration rate (eGFR) levels were measured at baseline, end of treatment (EOT), and end of follow-up (EOF) (3 months after EOT).

Results: The eGFR decreased from baseline (91.4 mL/min/1.73 m) to EOT (88.4 mL/min/1.73 m; P < .001) and substantially recovered at EOF (88.8 mL/min/1.73 m) but did not return to pretreatment levels (P < .001). Notably, a significant decrease in eGFR was observed only in patients with baseline eGFR ≥90 mL/min/1.73 m (from 112.9 to 106.4 mL/min/1.73 m; P < .001). In contrast, eGFR increased progressively in patients whose baseline eGFR was <90 mL/min/1.73 m (from 70.0 to 71.5 mL/min/1.73 m; P < .001), and this increase was generalized across different stages of CKD. The trend of eGFR amelioration was consistent irrespective of sofosbuvir usage. Multivariate adjusted analysis demonstrated that baseline eGFR >90 mL/min/1.73 m was the only factor independently associated with significant slope coefficient differences of eGFR (-1.98 mL/min/1.73 m; 95% confidence interval, -2.24 to -1.72; P < .001). The use of sofosbuvir was not an independent factor associated with eGFR change.

Conclusions: Both sofosbuvir and non-sofosbuvir-based regimens restored renal function in CHC patients with CKD, especially in those with significant renal function impairment.
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http://dx.doi.org/10.1016/j.cgh.2021.07.037DOI Listing
May 2022

Types and spatial contexts of neighborhood greenery matter in associations with weight status in women across 28 U.S. communities.

Environ Res 2021 08 19;199:111327. Epub 2021 May 19.

Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.

Excess body weight is a risk factor for many chronic diseases. Studies have identified neighborhood greenery as supportive of healthy weight. However, few have considered plausible effect pathways for ecosystem services (e.g., heat mitigation, landscape aesthetics, and venues for physical activities) or potential variations by climate. This study examined associations between weight status and neighborhood greenery that capture ecosystem services most relevant to weight status across 28 U.S. communities. Weight status was defined by body mass index (BMI) reported for 6591 women from the U.S. Sister Study cohort. Measures of greenery within street and circular areas at 500 m and 2000 m buffer distances from homes were derived for each participant using 1 m land cover data. Street area was defined as a 25 m-wide zone on both sides of street centerlines multiplied by the buffer distances, and circular area was the area of the circle centered on a home within each of the buffer distances. Measures of street greenery characterized the pedestrian environment to capture physically and visually accessible greenery for shade and aesthetics. Circular greenery was generated for comparison. Greenery types of tree and herbaceous cover were quantified separately, and a combined measure of tree and herbaceous cover (i.e., aggregate greenery) was also included. Mixed models accounting for the clustering at the community level were applied to evaluate the associations between neighborhood greenery and the odds of being overweight or obese (BMI > 25) with adjustment for covariates selected using gradient boosted regression trees. Analyses were stratified by climate zone (arid, continental, and temperate). Tree cover was consistently associated with decreased odds of being overweight or obese. For example, the adjusted odds ratio [AOR] was 0.92, 95% Confidence Interval [CI]: 0.88-0.96, given a 10% increase in street tree cover at the 2000 m buffer across the 28 U.S. communities. These associations held across climate zones, with the lowest AOR in the arid climate (AOR: 0.74, 95% CI: 0.54-1.01). In contrast, associations with herbaceous cover varied by climate zone. For the arid climate, a 10% increase in street herbaceous cover at the 2000 m buffer was associated with lower odds of being overweight or obese (AOR: 0.75, 95% CI: 0.55-1.03), whereas the association was reversed for the temperate climate, the odds increased (AOR: 1.19, 95% CI: 1.05-1.35). Associations between greenery and overweight/obesity varied by type and spatial context of greenery, and climate. Our findings add to a growing body of evidence that greenery design in urban planning can support public health. These findings also justify further defining the mechanism that underlies the observed associations.
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http://dx.doi.org/10.1016/j.envres.2021.111327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457404PMC
August 2021

Hepatitis C virus eradication decreases the risks of liver cirrhosis and cirrhosis-related complications (Taiwanese chronic hepatitis C cohort).

J Gastroenterol Hepatol 2021 Oct 21;36(10):2884-2892. Epub 2021 May 21.

Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Background And Aim: It is currently unknown how hepatitis C virus (HCV) eradication with pegylated interferon and ribavirin (PR) therapy affects the incidence of new-onset liver cirrhosis (LC) in patients without cirrhosis and the incidence of decompensated liver disease (DLD) or hepatocellular carcinoma (HCC) in patients with cirrhosis.

Methods: Taiwanese chronic hepatitis C cohort (T-COACH) is a nationwide HCV registry cohort from 23 hospitals in Taiwan recruited between 2003 and 2015. This study enrolled 10 693 patients with chronic hepatitis C (CHC), linked to the Taiwan National Health Insurance Research Database, receiving PR therapy for at least 4 weeks for new-onset LC and liver-related complications (DLD or HCC).

Results: Of the 10 693 patients, 1372 (12.8%) patients had LC, and the mean age was 54.0 ± 11.4 years. The mean follow-up duration was 4.38 ± 2.79 years, with overall 46 798 person-years. The 10-year cumulative incidence rates of new-onset LC were 5.0% (95% confidence interval [CI]: 3.2-7.7) in patients without cirrhosis with a sustained virologic response (SVR) and 21.9% (95% CI: 13.4-32.4) in those without SVR (hazard ratio [HR]: 0.22, P < 0.001). The 10-year cumulative incidence rates of liver-related complications were 21.4% (95% CI: 11.1-37.2) in patients with cirrhosis with SVR and 47.0% (95% CI: 11.1-86.0) in those without SVR after adjustment for age, sex, and competing mortality (HR: 0.52, P < 0.001).

Conclusions: Hepatitis C virus eradication with PR therapy decreased the incidence of new-onset LC in noncirrhotic patients and the incidence of liver-related complications in cirrhotic patients with CHC.
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http://dx.doi.org/10.1111/jgh.15538DOI Listing
October 2021

Clinicopathological Association of Autophagy Related 5 Protein with Prognosis of Colorectal Cancer.

Diagnostics (Basel) 2021 Apr 26;11(5). Epub 2021 Apr 26.

Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

Gene mutation and pathogenesis bacteria are highly associated with colorectal cancer (CRC) development and progression. Autophagy is a self-clearance pathway to degrade abnormal proteins and infected bacteria in cells. Autophagy plays a dual role in cancer development. Among the autophagy-related (ATG) proteins, ATG5 is the key component required for the core machinery of autophagy. However, the role of ATG5 in CRC malignancy remains unclear. Herein, we found that a high ATG5 protein level was correlated with poor overall survival (OS) and disease-free survival (DFS) of 118 patients with CRC. After stratification with demographic and clinicopathologic factors, a high ATG5 protein level was significantly correlated with unfavorable overall survival in female and elder (>60 year) CRC patients and tumor tissues with poor differentiation, late T stages (III + IV), whereas the ATG5 protein level was positively associated with the overall survival in CRC patients without lymph node invasion and radiation therapy. In contrast, a high ATG5 protein level was significantly associated with worse DFS in CRC patients with early stage of AJCC and no radiation therapy. In addition, colorectal cancer cells stably harboring small interfering RNA (siRNA) against ATG5 diminished the tumorsphere formation and sensitized cancer cells to chemotherapeutic agents. Taken together, our results suggest that ATG5 might be a prognostic biomarker for CRC and a potential therapeutic target for CRC patients.
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http://dx.doi.org/10.3390/diagnostics11050782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146491PMC
April 2021

A seroprevalence study of COVID-19 at a campus in southern Taiwan.

J Microbiol Immunol Infect 2021 Oct 8;54(5):1008-1010. Epub 2021 Apr 8.

Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.jmii.2021.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028599PMC
October 2021

Detection of Autophagy-Related Gene Expression by Conjunctival Impression Cytology in Age-Related Macular Degeneration.

Diagnostics (Basel) 2021 Feb 12;11(2). Epub 2021 Feb 12.

Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan.

Purpose: To investigate the association of autophagy-related gene expression with age-related macular degeneration (AMD).

Methods: Patients with AMD were recruited for analysis by conjunctival impression cytology. mRNA was assessed by real-time polymerase chain reaction (RT-PCR) to evaluate whether the expression of 26 autophagy-related genes (ATGs) was correlated with AMD. Further studies on cell viability and autophagic flux in response to oxidative stress by H2O2 were performed in human retinal pigment epithelial (RPE) cell lines based on the results of impression cytology.

Results: Both the neovascular AMD (nAMD) and polypoidal choroidal vasculopathy (PCV) groups had significantly higher mRNA levels of gamma-aminobutyric acid receptor-associated protein-like 1 (GABARAPL1) and microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B) than the control group, but there was no significant difference between these two groups. Age difference existed only in the AMD group. GABARAPL1 and MAP1LC3B mRNA expression increased significantly after acute oxidative stress in adult retinal pigment epithelial (ARPE-19) cells. Cell viability significantly increased and decreased in the cells harboring GABARAPL1 expression vector and silenced with siRNA against GABARAPL1, respectively, during short-term oxidative stress, whereas viability increased in the GABARAPL1-silenced cells after long-term oxidative stress. Silencing GABARAPL1 itself caused a reduction in autophagic flux under both short and long-term oxidative stress.

Conclusion: Our study showed the possibility of assessing autophagy-related gene expression by conjunctival impression cytology. GABARAPL1 was significantly higher in AMD. Although an in vitro study showed an initial protective effect of autophagy, a cell viability study revealed the possibility of a harmful effect after long-term oxidative injury. The underlying mechanism or critical factors require further investigation.
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http://dx.doi.org/10.3390/diagnostics11020296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918710PMC
February 2021

Factors associated with treatment failure of direct-acting antivirals for chronic hepatitis C: A real-world nationwide hepatitis C virus registry programme in Taiwan.

Liver Int 2021 06 12;41(6):1265-1277. Epub 2021 Mar 12.

Division of Gastroenterology, Department of Internal Medicine, Yuan's General Hospital, Kaohsiung, Taiwan.

Background/aims: Direct-acting antivirals (DAAs) are highly effective in treating chronic hepatitis C virus (HCV)-infected patients. The real-world treatment outcome in Taiwanese patients on a nationwide basis is elusive.

Methods: The Taiwan HCV Registry (TACR) programme is a nationwide registry platform including 48 study sites, which is organized and supervised by the Taiwan Association for the Study of the Liver. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA 12 weeks after end-of-treatment).

Results: A total of 13 951 registered patients with SVR12 data available were analysed (mean age, 63.0 years; female, 55.9%; HCV genotype-1 [GT1], 57.9%; cirrhosis, 38.4%; preexisting hepatocellular carcinoma [HCC], 10.6%; and hepatitis B virus coinfection, 7.7%). The overall SVR12 rate was 98.3%, with 98.7%, 98.0%, 98.4% and 97.4% in treatment-naïve noncirrhotic, treatment-naïve cirrhotic, treatment-experienced noncirrhotic and treatment-experienced cirrhotic patients, respectively. The SVR12 rate was > 95% across all subgroups except treatment-experienced cirrhotic patients who received sofosbuvir/ribavirin (88.7%), treatment-naïve noncirrhotic patients (94.8%) and treatment-experienced cirrhotic (94.8%) patients who received daclatasvir/asunaprevir. The most important factor associated with treatment failure was DAA adherence < 60% ( adjusted odds ratio [aOR]/95% confidence interval [CI]: 117.1/52.4-261.3, P < .001), followed by GT3/GT2 (aOR/CI: 5.78/2.25-14.9, P = .0003 and aOR/CI: 1.55/1.05-2.29, P = .03, compared with GT1), active hepatocellular carcinoma (aOR/CI: 4.29/2.57-7.16, P < .001), the use of sofosbuvir/ribavirin (aOR/CI: 2.51/1.67-3.77, P < .001) and daclatasvir/asunaprevir (aOR/CI: 3.29/1.94-5.58, P < .001), decompensated liver cirrhosis (aOR/CI: 2.50/1.20-5.22, P = .02) and high HCV viral loads (aOR/CI: 2.16/1.57-2.97, P < .001).

Conclusions: DAAs are highly effective in treating Taiwanese HCV patients in the real-world setting. Maintaining DAA adherence and selecting highly efficacious regimens are keys to ensure treatment success.
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http://dx.doi.org/10.1111/liv.14849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252422PMC
June 2021

Long-term risk of end-stage renal diseases with maintenance dialysis among chronic hepatitis C patients after antiviral therapy in Taiwan.

J Gastroenterol Hepatol 2021 Aug 30;36(8):2247-2254. Epub 2021 Mar 30.

Division of Gastroenterology, Department of Internal Medicine, Taipei Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, New Taipei City, School of Medicine, Tzu Chi University, Hualien, Taiwan.

Background And Aim: Chronic hepatitis C virus (HCV) infection is associated with impaired renal function. The aim of this study is to explore the risk of and factors associated with end-stage renal diseases (ESRD) under maintenance dialysis among HCV patients after anti-HCV therapy.

Methods: A total of 12 696 HCV-infected patients with interferon-based therapy, including 9679 (76.2%) achieving sustained virological response (SVR), were enrolled from 23 hospitals in Taiwan.

Results: During a mean follow-up period of 5.3 years (67 554 person-years), the annual incidence of 4.1/10 000 person-years, 4.0/10 000 and 4.7/10 000 person-years among SVR patients and non-SVR patients, respectively. History of diabetes and baseline estimated glomerular filtration rate < 60 mL/min/m , instead of SVR, were the significant risk factors for developing ESRD with maintenance dialysis after anti-HCV therapy (adjusted hazard ratio 7.75 and 9.78).

Conclusion: Diabetes and baseline impaired renal function were strongly associated with progression to ESRD with maintenance dialysis among chronic HCV-infected patients after antiviral therapy.
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http://dx.doi.org/10.1111/jgh.15469DOI Listing
August 2021

Successful Antiviral Therapy Reduces Risk of Schizophrenia Among Chronic Hepatitis C Patients: A Nationwide Real-World Taiwanese Cohort (T-COACH).

Open Forum Infect Dis 2020 Oct 31;7(10):ofaa397. Epub 2020 Aug 31.

Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Background: Chronic hepatitis C (CHC) has been associated with major psychoses, and interferon (IFN)-based therapy may cause psychiatric sequelae. We aimed to evaluate the effects of sustained virological response (SVR) on the incidence of major psychoses in a nationwide Taiwanese CHC cohort.

Methods: Fifteen thousand eight hundred thirty-six CHC Taiwanese who received IFN-based therapy were enrolled between 2003 and 2015. Of those, 12 723 patients were linked to the National Health Insurance Research Databases for the incidence of major psychoses. Death before major psychoses was considered a competing risk.

Results: Twenty-four patients developed new-onset major psychoses during 67 554 person-years (3.6 per 10 000 person-years), including 16 affective psychoses, 7 schizophrenia, and 1 organic psychotic condition. The incidence of major psychoses and affective psychoses did not differ between the SVR and non-SVR groups. The 10-year cumulative incidence of schizophrenia were significantly higher in the non-SVR than in SVR patients (0.14% vs 0.04%, .036). Cox subdistribution hazards showed that SVR and older age were associated with a significantly lower risk of schizophrenia (hazard ratio = 0.18 and 0.17). Sustained virological response was associated with decreased incidence of schizophrenia and majorly observed among patients with age <45 (= .02).

Conclusions: Successful IFN-based therapy might reduce the incidence of schizophrenia among CHC patients, especially among younger patients.
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http://dx.doi.org/10.1093/ofid/ofaa397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751132PMC
October 2020

Characteristics of patients with hepatitis C virus infection and antiviral treatment initiation in Taiwan: The MOSAIC study.

Kaohsiung J Med Sci 2021 Mar 22;37(3):245-252. Epub 2020 Oct 22.

Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.

Hepatitis C virus (HCV) infection is the leading cause of chronic liver diseases worldwide. Monitoring its epidemiology, diagnosis, and treatment patterns are important for the management of patients with chronic HCV infection from both individual and public health perspectives. The MOSAIC study was an observational study conducted in 20 countries, including Taiwan; its primary objective was to describe epidemiology and treatment initiation patterns in patients seeking HCV care. Of the 111 chronic HCV patients enrolled from Taiwan, 58 (52.3%) had not previously received treatment. HCV genotype 1 was reported in 58 (52.3%) patients, of whom the majority (n = 47; 81.0%) were identified as having subtype 1b. Sixty-two (55.9%) patients had HCV RNA level > 800 000 IU/mL. Liver cirrhosis was found in 35 (29.3%) patients and was more prevalent in patients who previously received treatment (71.0%). Interferon (IFN)-based treatment was started within 12 weeks from study inclusion in 12 (10.8%) patients, of whom 11 (91.7%) who had not previously received treatment. Anti-HCV treatment was not recommended by physicians in 70 (71.4%) and was refused by 23 (23.5%) patients. The MOSAIC study provides data on the epidemiology of HCV infection and IFN-based treatment decision patterns in Taiwan. Further studies are needed to observe the impact of IFN-free treatment on the treatment selection pattern.
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http://dx.doi.org/10.1002/kjm2.12317DOI Listing
March 2021

Hepatoma-derived growth factor participates in concanavalin A-induced hepatitis.

FASEB J 2020 12 15;34(12):16163-16178. Epub 2020 Oct 15.

Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.

Hepatitis is an important health problem worldwide. Novel molecular targets are in demand for detection and management of hepatitis. Hepatoma-derived growth factor (HDGF) has been delineated to participate in hepatic fibrosis and liver carcinogenesis. However, the relationship between hepatitis and HDGF remains unclear. This study aimed to elucidate the role of HDGF during hepatitis using concanavalin A (ConA)-induced hepatitis model. In cultured hepatocytes, ConA treatment-elicited HDGF upregulation at transcriptional level and promoted HDGF secretion while reducing intracellular HDGF protein level and cellular viability. Similarly, mice receiving ConA administration exhibited reduced hepatic HDGF expression and elevated circulating HDGF level, which was positively correlated with serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. By using HDGF knockout (KO) mice, it was found the ConA-evoked cell death was prominently alleviated in KO compared with control. Besides, it was delineated HDGF ablation conferred protection by suppressing the ConA-induced neutrophils recruitment in livers. Above all, the ConA-mediated activation of tumor necrosis factor-α (TNF-α)/interleukin-1β (IL-1β)/interleukin-6 (IL-6)/cyclooxygenase-2 (COX-2) inflammatory signaling was significantly abrogated in KO mice. Treatment with recombinant HDGF (rHDGF) dose-dependently stimulated the expression of TNF-α/IL-1β/IL-6/COX-2 in hepatocytes, further supporting the pro-inflammatory function of HDGF. Finally, application of HDGF antibody not only attenuated the ConA-mediated inflammatory cascade in hepatocytes, but also ameliorated the ConA-induced hepatic necrosis and AST elevation in mice. In summary, HDGF participates in ConA-induced hepatitis via neutrophils recruitment and may constitute a therapeutic target for acute hepatitis.
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http://dx.doi.org/10.1096/fj.202000511RRDOI Listing
December 2020

Identification of the Effects of Aspirin and Sulindac Sulfide on the Inhibition of HMGA2-Mediated Oncogenic Capacities in Colorectal Cancer.

Molecules 2020 Aug 22;25(17). Epub 2020 Aug 22.

Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.

Distant metastatic colorectal cancer (CRC) is present in approximately 25% of patients at initial diagnosis, and eventually half of CRC patients will develop metastatic disease. The 5-year survival rate for patients with metastatic CRC is a mere 12.5%; thus, there is an urgent need to investigate the molecular mechanisms of cancer progression in CRC. High expression of human high-mobility group A2 (HMGA2) is related to tumor progression, a poor prognosis, and a poor response to therapy for CRC. Therefore, HMGA2 is an attractive target for cancer therapy. In this study, we identified aspirin and sulindac sulfide as novel potential inhibitors of HMGA2 using a genome-wide mRNA signature-based approach. In addition, aspirin and sulindac sulfide induced cytotoxicity of CRC cells stably expressing HMGA2 by inhibiting cell proliferation and migration. Moreover, a gene set enrichment analysis (GSEA) revealed that gene sets related to inflammation were positively correlated with HMGA2 and that the main molecular function of these genes was categorized as a G-protein-coupled receptor (GPCR) activity event. Collectively, this is the first study to report that aspirin and sulindac sulfide are novel potential inhibitors of HMGA2, which can induce cytotoxicity of CRC cells stably expressing HMGA2 by inhibiting cell proliferation and migration through influencing inflammatory-response genes, the majority of which are involved in GPCR signaling.
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http://dx.doi.org/10.3390/molecules25173826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504004PMC
August 2020

Hepatic arterial infusion chemotherapy vs transcatheter arterial embolization for patients with huge unresectable hepatocellular carcinoma.

Medicine (Baltimore) 2020 Aug;99(32):e21489

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung.

For the treatment of huge unresectable hepatocellular carcinoma (HCC), transcatheter arterial chemoembolization (TACE) or transcatheter arterial embolization (TAE) generally had poor effects and high complication rates. Our previous study found that Hepatic arterial infusion chemotherapy (HAIC) is a safe procedure and provides better survival than symptomatic treatment for the patients with huge unresectable HCC. The aim of the study is to compare the effect of HAIC vs TAE in patients with huge unresectable HCC.Since 2000 to 2005, patients with huge (size > 8 cm) unresectable HCC were enrolled. Twenty-six patients received HAIC and 25 patients received TAE. Each patient in the HAIC group received 2.5 + 1.4 (range: 1-6) courses of HAIC and in the TAE group received 1.8 + 1.2 (range: 1-5) courses of TAE. Baseline characteristics and survival were compared between the HAIC and TAE group.The HAIC group and the TAE group were similar in baseline characteristics and tumor stages. The overall survival rates at 1 and 2 years were 42% and 31% in the HAIC group and 28% and 24% in the TAE group. The patients in the HAIC group had higher overall survival than the TAE group (P = .077). Cox-regression multivariate analysis revealed that HAIC is the significant factor associated with overall survival (relative risk: 0.461, 95% confidence interval: 0.218-0.852, P = .027). No patients died of the complications of HAIC but three patients (12%) died of the complications of TAE.In conclusion, HAIC is a safe procedure and provides better survival than TAE for patients with huge unresectable HCCs.
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http://dx.doi.org/10.1097/MD.0000000000021489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593048PMC
August 2020

Omega-3 Fatty Acid-Enriched Fish Oil and Selenium Combination Modulates Endoplasmic Reticulum Stress Response Elements and Reverses Acquired Gefitinib Resistance in HCC827 Lung Adenocarcinoma Cells.

Mar Drugs 2020 Jul 29;18(8). Epub 2020 Jul 29.

Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan.

Non-small cell lung cancer (NSCLC)-carrying specific epidermal growth factor receptor (EGFR) mutations can be effectively treated by a tyrosine kinase inhibitor such as gefitinib. However, the inevitable development of acquired resistance leads to the eventual failure of therapy. In this study, we show the combination effect of omega-3 fatty acid-enriched fish oil (FO) and selenium (Se) on reversing the acquired gefitinib-resistance of HCC827 NSCLC cells. The gefitinib-resistant subline HCC827GR possesses lowered proapoptotic CHOP (CCAAT/enhancer-binding protein homologous protein) and elevated cytoprotective GRP78 (glucose regulated protein of a 78 kDa molecular weight) endoplasmic reticulum (ER) stress response elements, and it has elevated β-catenin and cyclooxygenase-2 (COX-2) levels. Combining FO and Se counteracts the above features of HCC827GR cells, accompanied by the suppression of their raised epithelial-to-mesenchymal transition (EMT) and cancer stem markers, such as vimentin, AXL, N-cadherin, CD133, CD44, and ABCG2. Accordingly, an FO and Se combination augments the gefitinib-mediated growth inhibition and apoptosis of HCC827GR cells, along with the enhanced activation of caspase -3, -9, and ER stress-related caspase-4. Intriguingly, gefitinib further increases the elevated ABCG2 and cancer stem-like side population in HCC827GR cells, which can also be diminished by the FO and Se combination. The results suggest the potential of combining FO and Se in relieving the acquired resistance of NSCLC patients to targeted therapy.
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http://dx.doi.org/10.3390/md18080399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460277PMC
July 2020

How do natural features in the residential environment influence women's self-reported general health? Results from cross-sectional analyses of a U.S. national cohort.

Environ Res 2020 04 30;183:109176. Epub 2020 Jan 30.

Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA. Electronic address:

Background: The relationship between health and human interaction with nature is complex. Here we conduct analyses to provide insights into potential health benefits related to residential proximity to nature.

Objectives: We aimed to examine associations between measures of residential nature and self-reported general health (SRGH), and to explore mediation roles of behavioral, social, and air quality factors, and variations in these relationships by urbanicity and regional climate.

Methods: Using residential addresses for 41,127 women from the Sister Study, a U.S.-based national cohort, we derived two nature exposure metrics, canopy and non-gray cover, using Percent Tree Canopy and Percent Developed Imperviousness from the National Land Cover Database. Residential circular buffers of 250 m and 1250 m were considered. Gradient boosted regression trees were used to model the effects of nature exposure on the odds of reporting better SRGH (Excellent/Very Good versus the referent, Good/Fair/Poor). Analyses stratified by urbanicity and regional climate (arid, continental, temperate) and mediation by physical activity, social support, and air quality were conducted.

Results: A 10% increase in canopy and non-gray cover within 1250 m buffer was associated with 1.02 (95% CI: 1.00-1.03) and 1.03 (95% CI: 1.01-1.04) times the odds of reporting better SRGH, respectively. Stronger associations were observed for the urban group and for continental climate relative to other strata. Social support and physical activity played a more significant mediation role than air quality for the full study population.

Discussion: Findings from this study identified a small but important beneficial association between residential nature and general health. These findings could inform community planning and investments in neighborhood nature for targeted health improvements and potential societal and environmental co-benefits.
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http://dx.doi.org/10.1016/j.envres.2020.109176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255623PMC
April 2020

Severe acute exacerbation of HCV infection in cancer patients who undergo chemotherapy without antiviral prophylaxis.

J Viral Hepat 2020 09 14;27(9):873-879. Epub 2020 May 14.

Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital and National Yang-Ming University, Kaohsiung, Taiwan.

No guidelines have been developed for the management of HCV-infected cancer patients receiving chemotherapy. The current study aimed to investigate the incidence of severe acute exacerbation of HCV infection in cancer patients receiving chemotherapy and to search for risk factors predicting severe acute exacerbation of HCV infection. This retrospective cohort study reviewed the clinical data of the cancer patients receiving chemotherapy in our institute from August 2012 to December 2017. Incidences of severe acute exacerbation of HCV infection in different kinds of cancers were assessed, and risk factors were analysed. Cancer patients with HCV infection (n = 306) had a higher frequency of severe acute liver injury (2.3% vs 0.7%; P = .003) than those without HCV infection (n = 4419). The incidence of severe acute exacerbation in HCV-infected haematological cancer patients was higher than that in those with HCC and non-HCC solid tumours (9.4% vs 1.9% and 1.1%). Rituximab-containing chemotherapy and haematological malignancy were the risk factors related to the acute exacerbation (P < .001 and P = .004, respectively). None of the patients with severe acute HCV flares developed hepatic decompensation or mortality. However, 57.1% of them discontinued chemotherapy due to liver dysfunction. In conclusion, HCV infection increases the risk of acute severe liver injury in cancer patients undergoing chemotherapy. Rituximab-containing chemotherapy and haematological malignancy are the risk factors related to severe acute exacerbation of HCV infection in cancer patients undergoing chemotherapy. Pre-chemotherapy HCV testing is therefore mandatory before rituximab-containing chemotherapy for the treatment of haematological malignancy.
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http://dx.doi.org/10.1111/jvh.13302DOI Listing
September 2020

Extrahepatic Malignancy Among Patients With Chronic Hepatitis C After Antiviral Therapy: A Real-World Nationwide Study on Taiwanese Chronic Hepatitis C Cohort (T-COACH).

Am J Gastroenterol 2020 08;115(8):1226-1235

Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Introduction: Chronic hepatitis C virus (HCV) infection is associated with nonhepatocellular carcinoma malignancies. We aimed to evaluate whether achieving a sustained virological response (SVR, defined as HCV RNA seronegativity throughout posttreatment 24-week follow-up) could reduce the risk of non-hepatocellular carcinoma malignancy in a real-world nationwide Taiwanese Chronic Hepatitis C Cohort (T-COACH).

Methods: A total of 10,714 patients with chronic hepatitis C who had received interferon-based therapy (8,186 SVR and 2,528 non-SVR) enrolled in T-COACH and were linked to the National Cancer Registry database for the development of 12 extrahepatic malignancies, including those with potential associations with HCV and with the top-ranking incidence in Taiwan, over a median follow-up period was 3.79 years (range, 0-16.44 years).

Results: During the 44,354 person-years of follow-up, 324 (3.02%) patients developed extrahepatic malignancies, without a difference between patients with and without SVR (annual incidence: 0.69% vs 0.87%, respectively). Compared with patients with SVR, patients without SVR had a significantly higher risk of gastric cancer (0.10% vs 0.03% per person-year, P = 0.004) and non-Hodgkin lymphoma (NHL) (0.08% vs 0.03% per person-year, respectively, P = 0.03). When considering death as a competing risk, non-SVR was independently associated with gastric cancer (hazard ratio [HR]/95% confidence intervals [CIs]: 3.29/1.37-7.93, P = 0.008). When patients were stratified by age, the effect of SVR in reducing gastric cancer (HR/CI: 0.30/0.11-0.83) and NHL (HR/CI: 0.28/0.09-0.85) was noted only in patients aged <65 years but not those aged >65 years.

Discussion: HCV eradication reduced the risk of gastric cancer and NHL, in particular among younger patients, indicating that patients with chronic hepatitis C should be treated as early as possible.
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http://dx.doi.org/10.14309/ajg.0000000000000606DOI Listing
August 2020

Sustained virological response to hepatitis C therapy does not decrease the incidence of systemic lupus erythematosus or rheumatoid arthritis.

Sci Rep 2020 03 25;10(1):5372. Epub 2020 Mar 25.

Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

In patients with chronic hepatitis C (CHC), the effects of baseline characteristics, virological profiles, and therapeutic outcome to pegylated interferon plus ribavirin (PR) therapy on autoimmune diseases are unknown. Taiwanese Chronic Hepatitis C Cohort is a nationwide hepatitis C virus registry cohort comprising 23 hospitals of Taiwan. A total of 12,770 CHC patients receiving PR therapy for at least 4 weeks between January 2003 and December 2015 were enrolled and their data were linked to the Taiwan National Health Insurance Research Database for studying the development of 10 autoimmune diseases. The mean follow-up duration was 5.3 ± 2.9 years with a total of 67,930 person-years, and the annual incidence of systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) was 0.03%. Other autoimmune diseases were not assessable due to few events. Body mass index ≥24 kg/m was an independent predictor of the low incidence of SLE or RA (hazard ratio 0.40, 95% confidence interval 0.17-0.93, p = 0.034). A sustained virological response (SVR) to PR therapy was not associated with the low incidence of SLE or RA in any subgroup analysis. CHC patients achieving SVR to PR therapy did not exhibit an impact on the incidence of SLE or RA compared with non-SVR patients.
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http://dx.doi.org/10.1038/s41598-020-61991-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096452PMC
March 2020

Sofosbuvir-based regimen for genotype 2 HCV infected patients in Taiwan: A real world experience.

PLoS One 2020 10;15(1):e0227424. Epub 2020 Jan 10.

School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Background: Sofosbuvir (SOF)-based regimens achieve excellent efficacy and safety in the treatment of chronic hepatitis C (CHC) with various genotypes. There are few real-world instances of the use of SOF-based regimens to treat genotype 2 CHC. This study determines the effectiveness and safety of SOF/Ribavirn (RBV), SOF/Daclatasvir (DCV) and SOF/DCV/RBV in the treatment of genotype 2 CHC patients in Taiwan.

Material And Methods: Patients with genotype 2 CHC were treated for 12 weeks with SOF/RBV, SOF/DCV or SOF/DCV/RBV under the National Health Insurance reimbursement program in three hospitals in Taiwan. The sustained virological response at 12 weeks (SVR12) was determined. Adverse events were recorded for a safety analysis.

Results: A total of 467 genotype 2 CHC patients were enrolled from January to October 2018. One hundred and eleven patients (24%) had cirrhosis, including 10 patients (2.1%) with hepatic decompensation. Fifty-five patients (12%) had already experienced interferon-alpha/RBV treatment. Forty-two patients (9%) had a history of hepatocellular carcinoma (HCC) in the baseline. Three hundred and fifty-five patients received SOF/RBV, forty-seven patients received SOF/DCV and sixty-two patients received SOF/DCV/RBV. The SOF/DCV group featured a greater HCV viral load than the SOF/RBV or SOF/DCV/RBV groups. SVR12 was achieved in 94.6% of the SOF/RBV group, 95.7% of the SOF/DCV group and 96.8% of then SOF/DCV/RBV group (P = NS). Thirteen out of 352 patients (3.7%) in the SOF/RBV group, 1 out of 62 patients (1.6%) in the SOF/DCV/RBV group and 1 out of 47 patients (2.1%) in the SOF/DCV group developed virological failure. There are no differences in virological failure between the three groups (P = NS). Multi-variate analysis shows that history of HCC is an independent factor that is associated with the failure of treatment in the SOF/RBV group (odds ratio:4.905, 95% confidence interval (CI): 1.321-18.205, P = 0.017). Hemoglobin levels at 12 weeks are significantly lower in the SOF/RBV and the SOF/RBV/DCV group than in the SOF/DCV group (P<0.05). Serious adverse events (SAE) occurred in six patients (1.6%) in the SOF/RBV group and in one patient (1.6%) in the SOF/RBV/DCV group. No patients in the SOF/DCV group experienced SAE.

Conclusions: SOF/RBV, SOF/DCV or SOF/DCV/RBV for 12 weeks all achieve very high SVR rates and are equally effective in the treatment of genotype 2 CHC patients in the real world in Taiwan. Patients in the SOF/RBV group who have a history of HCC exhibit a lower SVR rate.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227424PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953822PMC
April 2020

Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma.

Cancers (Basel) 2019 Nov 23;11(12). Epub 2019 Nov 23.

Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.

Oral squamous cell carcinoma (OSCC) is one of the major leading causes of cancer death worldwide due to the limited availability of biomarkers and therapeutic targets. Autophagy related protease 4B (ATG4B) is an essential protease for the autophagy machinery, and ATG4B phosphorylation at Ser383/392 increases its proteolytic activity. ATG4B expression and activation are crucial for cancer cell proliferation and invasion. However, the clinical relevance of ATG4B and phospho-Ser383/392-ATG4B for OSCC remains unknown, particularly in buccal mucosal SCC (BMSCC) and tongue SCC (TSCC). With a tissue microarray comprising specimens from 498 OSCC patients, including 179 BMSCC and 249 TSCC patients, we found that the protein levels of ATG4B and phospho-Ser383/392-ATG4B were elevated in the tumor tissues of BMSCC and TSCC compared with those in adjacent normal tissues. High protein levels of ATG4B were significantly associated with worse disease-specific survival (DSS) in OSCC patients, particularly in patients with tumors at advanced stages. In contrast, phospho-Ser383/392-ATG4B expression was correlated with poor disease-free survival (DFS) in TSCC patients. Moreover, ATG4B protein expression was positively correlated with phospho-Ser383/392-ATG4B expression in both BMSCC and TSCC. However, high coexpression levels of ATG4B and phospho-Ser383/392-ATG4B were associated with poor DFS only in TSCC patients, whereas they had no significant association with DSS in BMSCC and TSCC patients. In addition, silencing ATG4B with an antisense oligonucleotide (ASO) or small interfering RNA (siRNA) diminished cell proliferation of TW2.6 and SAS oral cancer cells. Further, knockdown of ATG4B reduced cell migration and invasion of oral cancer cells. Taken together, these findings suggest that ATG4B might be a biomarker for diagnosis/prognosis of OSCC and a potential therapeutic target for OSCC patients.
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http://dx.doi.org/10.3390/cancers11121854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966594PMC
November 2019

High-Quality Conformal Homogeneous All-Vacuum Deposited CsPbCl Thin Films and Their UV Photodiode Applications.

ACS Appl Mater Interfaces 2019 Dec 3;11(50):47054-47062. Epub 2019 Dec 3.

Department of Materials Science and Engineering , National Tsing Hua University , Hsinchu 30013 , Taiwan.

A sensitive and fast ultraviolet (UV) photodetector is strongly desirable because of its wide range of applications in chemical/biological sensing and imaging. CsPbCl-based thin film photodetectors have not been constructed previously owing to their extremely poor precursor solubility; however, vapor deposition allows for thin film fabrication without the limitation of solubility. Therefore, this work is the first to demonstrate the optoelectronic properties of inorganic CsPbCl perovskite thin films and UV photodiodes using all-vacuum deposition. The perovskites annealed at 120 °C exhibited outstanding performance, including a notable external quantum efficiency value of 797.1% with an applied bias of -2 V, an outstanding detectivity of 1.4 × 10 Jones, a short response time as low as ∼ 50 μs, and a large linear dynamic range of up to 136 dB. CsPbCl thin films manufactured by this vacuum-deposited approach were also found to be moisture-resistant and demonstrated high durability. The devices maintained excellent performance and demonstrated less than 10% degradation after 30 days. Thus, thin film visible-blind UV detectors can potentially be used in transparent smart displays, window-integrated electronic circuits, and sensor applications.
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http://dx.doi.org/10.1021/acsami.9b16264DOI Listing
December 2019
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