Antrodin C, a maleimide derivative compound isolated from the ethanol extract of the mycelium of
, is an endemic fungus of Taiwan and a potential chemoprotective agent. However, the molecular ...mechanisms underlying the mode of action of antrodin C on cancer cells, especially in human colorectal cancer (CRC), remain unclear.
The cell death and ROS of the antrodin-C-treated HCT-116 cells were measured by annexin V-FITC/propidium iodide staining, DCFDA, and Fluo-3 fluorescence staining assays. Moreover, signaling molecules regulating TNFα cell death pathways and ROS/AKT/ERK/P38 pathways were also detected in cells treated with antrodin C by Western blotting and chromatin immunoprecipitation. The effects of antrodin C were determined in HCT-116 cell xenograft animal models in terms of tumor volumes and histopathological evaluation.
Treatment with antrodin C triggered the activation of extrinsic apoptosis pathways (TNFα, Bax, caspase-3, and -9), and also suppressed the expression of anti-apoptotic molecules Bcl-2 in HCT-116 cells in a time-dependent manner. Antrodin C also decreased cell proliferation and growth through the inactivation of cyclin D1/cyclin for the arrest of the cell cycle at the G1 phase. The activation of the ROS/AKT/ERK/P38 pathways was involved in antrodin-C-induced transcriptional activation, which implicates the role of the histone H3K9K14ac (Acetyl Lys9/Lys14) of the TNFα promoters. Immunohistochemical analyses revealed that antrodin C treatment significantly induced TNFα levels, whereas it decreased the levels of PCNA, cyclin D1, cyclin E, and MMP-9 in an in vivo xenograft mouse model. Thus, antrodin C induces cell apoptosis via the activation of the ROS/AKT/ERK/P38 signaling modules, indicating a new mechanism for antrodin C to treat CRC in vitro and in vivo.
The findings regarding changes in renal function in patients with hepatitis C virus (HCV) infection treated with direct-acting antivirals (DAAs) are controversial. This study attempted to identify ...the factors associated with the large decline in renal function following DAA treatment. This retrospective cohort study included patients treated with DAAs at Chiayi and Yunlin Chang Gung Hospitals, Taiwan, from 1 January 2017 to 31 October 2020. Estimated glomerular filtration rate (eGFR) data were collected within 90 days prior to DAA therapy and 2 years after the confirmation of a sustained virologic response (SVR). We performed multiple logistic regression to evaluate the clinical or laboratory parameters associated with a large eGFR decline (≥10%). Among the enrolled 606 patients, the mean eGFR at the baseline and endpoint were 84.11 ± 24.38 and 78.88 ± 26.30 mL/min/1.73 m
, respectively (
< 0.001). The factors associated with a large eGFR decline 2 years after the SVR included hypertension (OR: 1.481; 95% CI: 1.010-2.173,
= 0.044) and a higher baseline eGFR (OR: 1.016; 95% CI: 1.007-1.024,
< 0.001). A higher albumin level reduced the risk of a large eGFR decline (OR: 0.546; 95% CI: 0.342-0.872,
= 0.011). In the patients with HCV treated with DAAs, a larger renal function decline was more commonly observed in those with hypertension, a lower (but within normal range) albumin level, and a higher baseline eGFR, while DAA treatment had no effect. The clinical significance of these findings has to be further defined. Although some risk factors associated with chronic kidney disease may be alleviated after DAA treatment, the regular control and follow-up of risk factors and renal function are still recommended in at-risk patients after HCV eradication.
The real-world data of glecaprevir/pibrentasvir (GLE/PIB) therapy for patients with chronic hepatitis C virus (HCV) genotype 2 infection remained limited. We aimed to evaluate the possible predictors ...of virological failure and side effects of GLE/PIB therapy for chronic genotype 2 HCV-infected patients in a real-world setting.
A total of 326 compensated HCV genotype 2 patients treated with GLE/PIB 12 weeks for cirrhotic patients (n = 56) and 8 weeks for non-cirrhotic patients (n = 270) were enrolled.
The sustained virological response 12 weeks off therapy (SVR12) was 98.1%, 100%, and 97.7% in overall, GLE/PIB 12-week, and 8-week group, respectively. There were 6 (1.8%) patients with early withdrawal, and 14.1% patients had pruritus, the major adverse effect. In multivariate analyses, end-stage renal disease (odds ratio (OR) = 4.056, 95% confidence interval (CI) = 1.477–11.14, p = 0.007) and hypertension (OR = 2.325, 95% CI = 1.171–4.616, p = 0.016) were two significant factors associated with pruritus. There were 6 patients with virologic failure. In patients receiving 8-week GLE/PIB therapy, the SVR12 rate was significant lower in high baseline viral load (≥107 IU/ml) group compared to low viral load group (90.6% v.s 98.7%, p = 0.025). Multivariate analyses showed that HCV RNA≥107 IU/ml was one of the independent factors (OR = 0.134, 95% CI = 0.024–0.748; p = 0.022) associated with SVR12.
GIE/PIB is an effective, tolerable and safe agent to treat genotype 2 HCV infected patients. However, high viral load (≥107 IU/ml) may predict virologic failure in non-cirrhotic patients receiving 8 weeks GIE/PIB treatment. This result should be further validated in a large cohort in the future.
The purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer.
MBDcap-Seq and expression microarray were performed to identify genes that were ...epigenetically silenced in AGS gastric cancer cell lines depleted of STAT3. Cell lines and animal experiments were performed to investigate proliferation and metastasis of miR-193a and YWHAZ in gastric cancer cell lines. Bisulfite pyrosequencing and tissue microarray were performed to investigate the promoter methylation of miR-193a and expression of STAT3, YWHAZ in patients with gastritis (n = 8) and gastric cancer (n = 71). Quantitative methylation-specific PCR was performed to examine miR-193a promoter methylation in cell-free DNA of serum samples in gastric cancer patients (n = 19).
As compared with parental cells, depletion of STAT3 resulted in demethylation of a putative STAT3 target, miR-193a, in AGS gastric cancer cells. Although bisulfite pyrosequencing and epigenetic treatment confirmed that miR-193a was epigenetically silenced in gastric cancer cell lines, ChIP-PCR found that it may be indirectly affected by STAT3. Ectopic expression of miR-193a in AGS cells inhibited proliferation and migration of gastric cancer cells. Further expression microarray and bioinformatics analysis identified YWHAZ as one of the target of miR-193a in AGS gastric cancer cells, such that depletion of YWHAZ reduced migration in AGS cells, while its overexpression increased invasion in MKN45 cells
and
. Clinically, bisulfite pyrosequencing revealed that promoter methylation of miR-193a was significantly higher in human gastric cancer tissues (n = 11) as compared to gastritis (n = 8, p < 0.05). Patients infected with H. pylori showed a significantly higher miR-193a methylation than those without H. pylori infection (p < 0.05). Tissue microarray also showed a positive trend between STAT3 and YWHAZ expression in gastric cancer patients (n = 60). Patients with serum miR-193a methylation was associated with shorter overall survival than those without methylation (p < 0.05).
Constitutive activation of JAK/STAT signaling may confer epigenetic silencing of the STAT3 indirect target and tumor suppressor microRNA, miR-193a in gastric cancer. Transcriptional suppression of miR-193a may led to overexpression of YWHAZ resulting in tumor progression. Targeted inhibition of STAT3 may be a novel therapeutic strategy against gastric cancer.
Hepatitis C virus (HCV)-infected patients with chronic kidney disease (CKD) have rarely been studied because they rarely accept interferon-based therapy (IBT) and have been difficult to follow up. We ...investigated long-term outcomes of IBT on the population.
This population-based cohort study used the Taiwan National Health Insurance Research Database as its data source. HCV patients diagnosed with CKD between Jan. 1, 2003, and Dec. 31, 2013, were selected. They were then divided into two groups based on whether they had undergone IBT. All-cause mortality, acute myocardial infarction (AMI), ischemic stroke (IS), hemorrhagic stroke, and new-onset dialysis were evaluated using a Cox proportional hazard regression analysis after propensity score matching.
We enrolled 9872 HCV patients with CKD: 1684 patients in the treated cohort and 8188 patients in the untreated cohort. The annual incidence of all-cause mortality (19.00 vs. 42.89 events per 1000 person-years; p < 0.001) and the incidences of hemorrhagic stroke (1.21 vs. 4.19 events per 1000 person-years; p = 0.006) were lower in the treated cohort. New-onset dialysis was also lower in the treated cohort (aHR: 0.31; 95% CI: 0.20-0.48; p < 0.001).
Antiviral therapy might provide protective benefits on all-cause mortality, hemorrhagic stroke, and new-onset dialysis in HCV-infected patients with CKD.
AIM： To verify the usefulness of FibroQ for predicting fi brosis in patients with chronic hepatitis C, compared with other noninvasive tests. METHODS： This retrospective cohort study included 237 ...consecutive patients with chronic hepatitis C who had undergone percutaneous liver biopsy before treatment. FibroQ, aspartate aminotransferase （AST）/alanine aminotransferase ratio （AAR）, AST to platelet ratioindex, cirrhosis discriminant score, age-platelet index （API）, Pohl score, FIB-4 index, and Lok＇s model were calculated and compared. RESULTS： FibroQ, FIB-4, AAR, API and Lok＇s model results increased significantly as fibrosis advanced （analysis of variance test： P 〈 0.001）. FibroQ trended to be superior in predicting signifi cant fi brosis score in chronic hepatitis C compared with other noninvasive tests. CONCLUSION： FibroQ is a simple and useful test for predicting signifi cant fi brosis in patients with chronic hepatitis C.
BACKGROUNDAn increased amount of Fusobacterium nucleatum (F. nucleatum) is frequently detected in the gastric cancer-associated microbiota of the Taiwanese population. F. nucleatum is known to exert ...cytotoxic effects and play a role in the progression of colorectal cancer, though the impact of F. nucleatum colonization on gastric cancer cells and patient prognosis has not yet been examined. AIMTo identify F. nucleatum-dependent molecular pathways in gastric cancer cells and to determine the impact of F. nucleatum on survival in gastric cancer. METHODSCoculture of F. nucleatum with a gastric cancer cell line was performed, and changes in gene expression were investigated. Genes with significant changes in expression were identified by RNA sequencing. Pathway analysis was carried out to determine deregulated cellular functions. A cohort of gastric cancer patients undergoing gastrectomy was recruited, and nested polymerase chain reaction was performed to detect the presence of F. nucleatum in resected cancer tissues. Statistical analysis was performed to determine whether F. nucleatum colonization affects patient survival. RESULTSRNA sequencing and subsequent pathway analysis revealed a drastic interferon response induced by a high colonization load. This response peaked within 24 h and subsided after 72 h of incubation. In contrast, deregulation of actin and its regulators was observed during prolonged incubation under a low colonization load, likely altering the mobility of gastric cancer cells. According to the clinical specimen analysis, approximately one-third of the gastric cancer patients were positive for F. nucleatum, and statistical analysis indicated that the risk for colonization increases in late-stage cancer patients. Survival analysis demonstrated that F. nucleatum colonization was associated with poorer outcomes among patients also positive for Helicobacter pylori (H. pylori). CONCLUSIONF. nucleatum colonization leads to deregulation of actin dynamics and likely changes cancer cell mobility. Cohort analysis demonstrated that F. nucleatum colonization leads to poorer prognosis in H. pylori-positive patients with late-stage gastric cancer. Hence, combined colonization of F. nucleatum and H. pylori is a predictive biomarker for poorer survival in late-stage gastric cancer patients treated with gastrectomy.
Tissue sampling for biliary stricture is important for differential diagnosis and further treatment. This study aims to assess the differences of transpapillary biliary biopsy for malignant biliary ...strictures between cholangiocarcinoma and pancreatic cancer.
From January 2010 to December 2013, we retrospectively studied 79 patients who suffered from biliary strictures and received transpapillary forceps biopsy after sphincterotomy for tissue sampling. The diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of forceps biopsy were calculated in all cases for both cholangiocarcinoma and pancreatic cancer patients. Possible factors that distinguish malignant strictures from benign strictures and which could affect the accuracy of tissue sampling were analyzed.
There are 65 malignant and 14 benign biliary stricture patients enrolled. The malignant group has a significantly higher serum bilirubin level than the benign group, but age, clinical presentation, level of serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and alkaline phosphatase are not. The sensitivity, specificity, PPV, and NPV of forceps biopsy for biliary stricture are 53.85, 100, 100, and 31.82%, respectively. The cholangiocarcinoma group has a higher sensitivity (73.53 versus 29.17%, p < 0.001), older age, lower CA 19-9 level, and more common hepatic duct strictures than the pancreatic group. The age, serum CEA, CA 19-9 and the alkaline phosphatase level, serum bilirubin level >10 mg/dL, tissue sampling ≧3 are not significant factors affecting diagnostic accuracy in forceps biopsy for pancreatobiliary strictures. There is neither major bleeding nor perforation in our study.
Transpapillary forceps biopsy of biliary strictures after sphincterotomy for tissue sampling is safe and a significantly higher sensitive method in cholangiocarcinoma but not in pancreatic cancer.
Liver cirrhosis is a major risk factor for hepatocellular carcinoma (HCC), and all liver study societies recommend HCC surveillance in patients with cirrhosis. However, no ideal modality for HCC ...surveillance has been determined. The aim of this study is to assess the effectiveness of α-fetoprotein (AFP) measurement in HCC surveillance.
In this retrospective analysis, all patients with cirrhosis, who received HCC surveillance through ultrasound (US) and AFP measurement between January 2002 and July 2010, were followed up until June 2013. The performance effectiveness of surveillance using AFP, US, or both in HCC detection was compared.
Overall, 1,597 patients were followed for a median duration of 4.75 (range 1.42-12) years. Over the 8563.25-person-year follow-up period, 363 patients (22.7%) developed HCCs. For HCC detection, the area under the receiver operator characteristic curve of surveillance AFP was 0.844 (95% confidence interval: 0.820-0.868, P<0.001). When the traditional cutoff value of 20 ng/ml was used, the sensitivity and specificity of AFP were 52.9% and 93.3%, respectively. US exhibited a sensitivity and specificity of 92.0% and 74.2%, respectively. A combination of US and AFP exhibited a sensitivity and specificity of 99.2% and 68.3%, respectively. By using cut-off at 20 ng/ml and AFP level increase ≥2 × from its nadir during the previous 1 year, the combination of US and AFP yielded a sensitivity of 99.2% and an improved specificity of 71.5%.
The complementary use of AFP and US improved the effectiveness of HCC surveillance in patients with cirrhosis.
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