Cardiovascular outcomes in hepatitis C virus infected patients treated with direct acting antiviral therapy: a retrospective multi-institutional study.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with increased cardiovascular risks. We aimed to investigate the impact of direct acting antiviral (DAA) on HCV-associated cardiovascular events. METHODS: In this retrospective cohort study, patients with the diagnosis of chronic HCV were retrieved from multi-institutional electronic medical records, where diagnosis of HCV was based on serum HCV antibody and HCV-RNA test. The patients eligible for analysis were then separated into patients with DAA treatment and patient without DAA treatment. Primary outcomes included acute coronary syndrome, heart failure (HF), venous thromboembolism (VTE), stroke, cardiovascular death, major adverse cardiovascular event (MACE), and all-cause mortality. Outcomes developed during follow-up were compared between DAA treatment and non-DAA treatment groups. RESULTS: There were 41 565 patients with chronic HCV infection identified. After exclusion criteria applied, 1984 patients in the DAA treatment group and 413 patients in the non-DAA treatment group were compared for outcomes using inverse probability of treatment weighting. Compared to patients in non-DAA treatment group, patients in DAA treatment group were associated with significantly decreased HF (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.44-0.97, P = 0.035), VTE (HR: 0.19, 95% CI: 0.07-0.49, P = 0.001), MACE (HR: 0.73, 95% CI 0.59-0.92, P = 0.007), and all-cause mortality (HR: 0.50, 95% CI: 0.38-0.67, P < 0.001) at 3-year follow-up. CONCLUSIONS: Chronic HCV patients treated with DAA experienced lower rates of cardiovascular events and all-cause mortality than those without treatment. The reduction of VTE was the most significant impact of DAA treatment among the cardiovascular outcomes.

Direct-Acting Antivirals Reduce the De Novo Development of Esophageal Varices in Patients with Hepatitis C Virus Related Liver Cirrhosis.

The real-world benefits of direct-acting antiviral (DAA)-induced sustained virologic response (SVR) on the de novo occurrence and progression of esophageal varices (EV) remain unclear in patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). This is a retrospective cohort study evaluating all patients with Child-Pugh class A HCV-related LC during 2013 to 2020 in the Chang Gung Medical System. A total of 215 patients fit the inclusion criteria and were enrolled. Of them, 132 (61.4%) patients achieved DAA induced-SVR and 83 (38.6%) did not receive anti-viral treatment. During a median follow-up of 18.4 (interquartile range, 10.1−30.9) months, the 2-year incidence of de novo EV occurrence was 8 (7.0%) in the SVR group and 7 (12.7%) in the treatment-naïve group. Compared to the treatment-naïve group, the SVR group was associated with a significantly lower incidence of EV occurrence (adjusted hazard ratio [aHR]: 0.47, p = 0.030) and a significantly lower incidence of EV progression (aHR: 0.55, p = 0.033). The risk of EV progression was strongly correlated with the presence of baseline EV (p < 0.001). To the best of our knowledge, this is the first study to demonstrate that DAA-induced SVR is associated with decreased risk of de novo EV occurrence and progression in the real world.

Fusobacterium nucleatum colonization is associated with decreased survival of helicobacter pylori-positive gastric cancer patients.

BACKGROUND: An 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. AIM: To identify F. nucleatum-dependent molecular pathways in gastric cancer cells and to determine the impact of F. nucleatum on survival in gastric cancer. METHODS: Coculture 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. RESULTS: RNA 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). CONCLUSION: F. 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.

Epigenetic Silencing of STAT3-Targeted miR-193a, by Constitutive Activation of JAK/STAT Signaling, Leads to Tumor Progression Through Overexpression of YWHAZ in Gastric Cancer.

PURPOSE: The purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer. METHODS: 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). RESULTS: 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 in vitro and in vivo. 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). CONCLUSIONS: 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.

Helios Expression in Tumor-Infiltrating Lymphocytes Correlates with Overall Survival of Advanced Gastric Cancer Patients.

Immunotherapy is a highly promising approach for the treatment of gastric cancer, the third-leading cause of overall cancer death worldwide. In particular, tumor-infiltrating lymphocytes and peripheral blood mononuclear cells are believed to mediate host immune responses, although this activity may vary depending on the activation status and/ or their microenvironments. Here, we examined the expression of a specific zinc finger transcription factor, Helios (IKZF2), in gastric tumor-infiltrating lymphocytes by immunohistochemistry and the correlation with survival. Segregation of gastric cancer patients into high- vs. low-Helios-expressing tumor-infiltrating lymphocytes showed those with high expression to exhibit longer survival in gastric cancer patients, Helicobacter pylori-infected gastric cancer patients and advanced stage (III-IV) gastric cancer patients. In particular, Helios expression was an independent factor for survival in advanced gastric cancer patients. We performed immunofluorescence staining to detect Helios expression in tumor-infiltrating lymphocytes and peripheral blood mononuclear cells. We found that Helios is expressed more in CD4+ T cells and little in CD8+ T cells in infiltrated lymphocytes in gastric cancer. In summary, we believe that the study of specific characteristics of tumor-infiltrating lymphocytes can delineate the interactions of immune and tumor cells to improve upon immunotherapy strategies.

2,4-Diamino-Quinazoline, a Wnt Signaling Inhibitor, Suppresses Gastric Cancer Progression and Metastasis.

Gastric cancer (GC) is among the most treatment-refractory epithelial malignancies. Aberrant activation of Wnt/ß-catenin-signaling has been implicated in a variety of human cancers, including gastric cancer. Here we report that the elevated expression of lymphoid enhancer binding factor 1 (Lef1) is associated with the TNM (tumor- node-metastasis) stage of gastric cancer. Subsequently, 2,4-diamino-quinazoline (2,4-DAQ), a selective inhibitor of Lef1, was identified to suppress the expression of Wnt/ß-catenin target genes such as AXIN2, MYC and LGR5 and result in the suppression of gastric cancer cell growth through the apoptotic pathway. The 2,4-DAQ also exhibited an inhibitory effect on the migration/invasion of gastric cancer cells. Importantly, the treatment of human gastric tumor xenograft with 2,4-DAQ suppressed tumor growth in a nude mouse model. Furthermore, 2,4-DAQ appears effective on patient-derived organoids (PDOs). Transcriptome sequencing analysis also revealed that 2,4-DAQ are more effective on the gastric cancers that exhibit higher expression levels of Wnt-signaling pathway-related genes than their adjacent normal gastric tissues.

Nationwide cohort study of outcomes of acute myocardial infarction in patients with liver cirrhosis: A nationwide cohort study.

Liver cirrhotic predisposes patients to coagulopathy and bleeding. Little is known about outcomes of acute myocardial infarction (AMI) in cirrhotic patients.Data from Taiwan National Health Insurance Research Database during 2001 to 2013 were retrieved for patients admitted with cirrhosis and AMI. We excluded patients with missing information, <20 years old, previous AMI, previous coronary intervention, and liver transplant. Patients were separated into cirrhotic and non-cirrhotic. Primary outcomes included all-cause mortality, recurrent myocardial infarction (MI), major cardiac and cerebrovascular events (MACCE: recurrent MI, revascularization, ischemic stroke, and heart failure), and liver outcomes (hepatic encephalopathy, ascites tapping, spontaneous peritonitis, and esophageal varices bleeding).A total of 3217 cirrhotic patients and 6434 non-cirrhotic patients were analyzed, with a mean follow up of 2.8 ±â€Š3.3 years. In cirrhotic patients with AMI, subsequent coronary and cerebrovascular events were lower in comparison to non-cirrhotic patients, with higher all-cause mortality observed from adverse liver related outcomes and bleeding. There were significantly lower cumulative incidence of both recurrent MI and MACCE in cirrhotic patients with AMI compared with non-cirrhotic patients with AMI (hazard ratio [HR] 0.82, confidence interval [CI] 0.71-0.94, P = .006 and HR 0.86, 95% CI 0.79-0.92, P < .001, respectively). There was significantly higher cumulative incidence of liver related outcome in cirrhotic patients with AMI compared with non-cirrhotic patients with AMI (HR 2.27, 95% CI 2.06-2.51, P < .001). And there was significantly higher all-cause mortality in cirrhotic patients with AMI compared with non-cirrhotic patients with AMI (HR 1.30, 95% CI 1.23-1.38, P < .001).In cirrhotic cohort with AMI, a decreased in coronary and cerebrovascular events were observed. However, these patients also had higher all-cause mortality due to adverse liver outcomes and bleeding.

Dual antiplatelet therapy in patients with cirrhosis and acute myocardial infarction - A 13-year nationwide cohort study.

BACKGROUND: Patients with cirrhosis and acute myocardial infarction (AMI) present dilemma whether dual antiplatelet therapy (DAPT) should be used. METHODS: Electronic medical records between 2001-2013 were retrieved from Taiwan National Health Insurance Research Database. Patients were excluded for missing information, age <20 years old, history of AMI, liver transplant, autoimmune disease, coagulopathy, taking DAPT 3 months before index date, follow-up <3 months, anticoagulation user, without DAPT, and events of myocardial infarction (MI), ischemic stroke, major bleeding, and heart failure within 3-month of enrollment. Primary outcomes were 1-year all-cause mortality, recurrent MI, major bleeding, and gastrointestinal bleeding. RESULTS: A total of 150,887 patients with AMI retrieved. After exclusion criteria and propensity score-matching, 914 cirrhotic and 3,656 non-cirrhotic patients with AMI on DAPT were studied. During 1-year follow-up, there was significantly increased mortality in cirrhotic patients compared to non-cirrhotic patients (HR = 1.49, 95% CI = 1.28-1.74). There was significantly decreased recurrent MI in cirrhotic patients compared to non-cirrhotic patients (subdistribution HR [SHR] = 0.71, 95% CI = 0.54-0.92). However, non-significantly increased major bleeding (SHR = 1.23, 95% CI = 0.87-1.73) and significantly increased gastrointestinal bleeding (SHR = 1.49, 95% CI = 1.31-1.70). CONCLUSIONS: In cirrhotic patients with AMI, DAPT offers benefit with decreased recurrent MI at the expense of increased gastrointestinal bleeding.

Nutrition Risk Assessment Using the Modified NUTRIC Score in Cirrhotic Patients with Acute Gastroesophageal Variceal Bleeding: Prevalence of High Nutrition Risk and its Independent Prognostic Value.

Malnutrition is associated with adverse outcomes in patients with liver cirrhosis. Relevant data about nutrition risk in critically ill cirrhotic patients are lacking. The modified Nutrition Risk in Critically Ill (mNUTRIC) score is a novel nutrition risk assessment tool specific for intensive care unit (ICU) patients. This retrospective study was conducted to evaluate the prevalence and prognostic significance of nutrition risk in cirrhotic patients with acute gastroesophageal variceal bleeding (GEVB) using mNUTRIC scores computed on admission to the intensive care unit. The major outcome was 6-week mortality. One-hundred-and-thirty-one admissions in 120 patients were analyzed. Thirty-eight percent of cirrhotic patients with acute GEVB were categorized as being at high nutrition risk (a mNUTRIC score of ≥5). There was a significantly progressive increase in mortality associated with the mNUTRIC score (χ2 for trend, p < 0.001). By using the area under a receiver operating characteristic (ROC) curve, the mNUTRIC demonstrated good discriminative power to predict 6-week mortality (AUROC 0.859). In multivariate analysis, the mNUTRIC score was an independent factor associated with 6-week mortality. In conclusion, the mNUTRIC score can serve as a tool to assess nutrition risk in cirrhotic patients with acute GEVB.

Methylomics analysis identifies a putative STAT3 target, SPG20, as a noninvasive epigenetic biomarker for early detection of gastric cancer.

Gastric cancer is a leading cause of cancer worldwide. Our previous studies showed that aberrant activation of JAK/STAT3 signaling confer epigenetically silences STAT3 target genes in gastric cancer. To further investigate the clinical significance of this phenomenon, we performed Illumina 850K methylation microarray analysis in AGS gastric cancer cells, and cells depleted of STAT3. Integrative computational analysis identified SPG20 as a putative STAT3 epigenetic target, showing promoter hypomethylation in STAT3-depleted AGS cells. Bisulphite pyrosequencing and qRT-PCR confirmed that SPG20 is epigenetically silenced by promoter hypermethylation in a panel of gastric cancer cell lines including AGS cells, but not in immortalized gastric epithelial GES cells. Expression of SPG20 could be restored by the treatment with a DNMT inhibitor, further suggesting that SPG20 is epigenetically silenced by promoter methylation. Clinically, a progressive increase in SPG20 methylation was observed in tissues samples from gastritis (n = 34), to intestinal metaplasia (IM, n = 33), to gastric cancer (n = 53). Importantly, SPG20 methylation could be detected in cell-free DNA isolated from serum samples of gastritis, IM and gastric cancer patients, having a progressive similar to tissues. Taken together, SPG20, a potential STAT3 target, is frequently methylated in gastric cancer, representing a novel noninvasive biomarker for early detection of this deadly disease.

Risk of cardiac arrhythmias in patients with chronic hepatitis B and C infections - A 13-year nationwide population-based study.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is associated with higher risk of cardiovascular events than chronic hepatitis B virus (HBV). We aimed to investigate whether there is higher risk of arrhythmia in HCV infection. METHODS: Electronic medical records from National Health Institute Research Database during 2000-2012 were retrieved for patients with HBV or HCV. Patients with missing information, aged <18 years, diagnosed with HBV or HCV before year 2000, concomitant HBV and HCV, coagulopathy or organ transplant, history of arrhythmia, device implantation, congenital heart disease, rheumatic heart disease, hypertrophic cardiomyopathy, thyroid disease, alcohol or drug abuse, valvular heart disease, or follow-up <6 months were excluded. Primary outcomes were cardiac arrhythmias and all-cause mortality. RESULTS: After 1:1 propensity score matching, 5480 patients with HBV and 5480 patients with HCV were included for study. During a mean follow-up of 6.5 years, the risk of all-cause mortality was higher in the HCV patients than in HBV patients [hazard ratio (HR) 1.35, 95% confidence interval (CI) 1.16-1.58]. There was also a trend toward higher incidence of atrial fibrillation (HR 1.25, 95% 0.98-1.59, p=0.070) and a significantly higher incidence of sick sinus syndrome (HR 1.77, 95% CI 1.07-2.91) in HCV patients. In addition, among patients with all-cause mortality, arrhythmia death was significantly higher with chronic HCV infection. CONCLUSIONS: In patients with chronic viral hepatitis, patients with HCV were associated with significantly increased risks of sick sinus syndrome, and all-cause mortality compared to patients with HBV.

Selection of ß-Blocker in Patients With Cirrhosis and Acute Myocardial Infarction: A 13-Year Nationwide Population-Based Study in Asia.

Background It is not clear whether ß1-selective or nonselective ß-blockers should be used in patients with cirrhosis and acute myocardial infarction. Methods and Results Medical records were retrieved from Taiwan NHIRD (National Health Insurance Research Database) during 2001-2013. Patients were excluded for age <20, previous acute myocardial infarction, contraindication to ß-blockers, chronic obstructive pulmonary disease, asthma, or atrioventricular conduction disease. Patients who died during index admission, had a follow-up <6 months, had a medication ratio of either ß1-selective or nonselective ß-blocker <80%, or who switched between ß-blockers were also excluded. Patients on ß1-selective blockers and nonselective ß-blockers were propensity score matched and compared for outcome. Primary outcomes were 1- and 2-year cardiovascular events, liver adverse outcomes, and all-cause mortality. A total of 203 595 patients with acute myocardial infarction were enrolled, of whom 6355 had cirrhosis. After screening for exclusion criteria, 1769 patients (655 patients on ß-blockers and 1114 patients not on ß-blockers) were eligible for analysis. Among patients on ß-blockers, propensity score matching was performed, and 218 patients on ß1-selective blockers and 218 patients on nonselective ß-blockers were studied. During a 2-year follow-up, patients on ß1-selective blockers had significantly fewer major cardiac and cerebrovascular events (hazard ratio=0.62; 95% confidence interval=0.42-0.91; P=0.014), a trend toward lower all-cause mortality (hazard ratio=0.66; 95% confidence interval=0.38-1.14; P=0.135), and nonworsening liver outcome (hazard ratio=0.66; 95% confidence interval=0.38-1.14; P=0.354). Conclusions In patients with cirrhosis and acute myocardial infarction, selecting a ß-blocker is a clinical dilemma. Our study showed that the use of ß1-selective blockers is associated with lower risks of major cardiac and cerebrovascular events.

Upregulation of bone morphogenetic protein 1 is associated with poor prognosis of late-stage gastric Cancer patients.

BACKGROUND: Gastric cancer is the eighth most common cancer in Taiwan, with a 40% 5-year survival rate. Approximately 40% of patients are refractory to chemotherapy. Currently, the anti-HER2 therapy is the only clinically employed targeted therapy. However, only 7% patients in Taiwan are HER2-positive. Identifying candidate target genes will facilitate the development of adjuvant targeted therapy to increase the efficacy of gastric cancer treatment. METHODS: Clinical specimens were analyzed by targeted RNA sequencing to assess the expression levels of target genes. Statistical significance of differential expression and correlation between specimens was evaluated. The correlation with patient survival was analyzed as well. In vitro cell mobility was determined using wound-healing and transwell mobility assays. RESULTS: Expression of BMP1, COL1A1, STAT3, SOX2, FOXA2, and GATA6 was progressively dysregulated through the stages of gastric oncogenesis. The expression profile of these six genes forms an ubiquitously biomarker signature that is sufficient to differentiate cancer from non-cancerous specimens. High expression status of BMP1 correlates with poor long-term survival of late-stage patients. In vitro, suppression of BMP1 inhibits the mobility of the gastric cancer cell lines, indicating a role of BMP1 in metastasis. CONCLUSIONS: BMP1 is upregulated in gastric cancer and is correlated with poor patient survival. Suppression of BMP1 reduced gastric cancer mobility in vitro. Our finding suggests that anti-BMP1 therapy will likely augment the efficacy of standard chemotherapy and improve the treatment outcome.

Increased Abundance of Clostridium and Fusobacterium in Gastric Microbiota of Patients with Gastric Cancer in Taiwan.

Helicobacter pylori is recognised as a main risk factor for gastric cancer. However, approximately half of the patients with gastritis are negative for H. pylori infection, and the abundance of H. pylori decreases in patients with cancer. In the current study, we profiled gastric epithelium-associated bacterial species in patients with gastritis, intestinal metaplasia, and gastric cancer to identify additional potential pathogenic bacteria. The overall composition of the microbiota was similar between the patients with gastritis and those with intestinal metaplasia. H. pylori was present in half of the non-cancer group, and the dominant bacterial species in the H. pylori-negative patients were Burkholderia, Enterobacter, and Leclercia. The abundance of those bacteria was similar between the cancer and non-cancer groups, whereas the frequency and abundance of H. pylori were significantly lower in the cancer group. Instead, Clostridium, Fusobacterium, and Lactobacillus species were frequently abundant in patients with gastric cancer, demonstrating a gastric cancer-specific bacterial signature. A receiver operating characteristic curve analysis showed that Clostridium colicanis and Fusobacterium nucleatum exhibited a diagnostic ability for gastric cancer. Our findings indicate that the gastric microenvironment is frequently colonised by Clostridium and Fusobacterium in patients with gastric cancer.

Comparison of cardiovascular outcomes and all-cause mortality in patients with chronic hepatitis B and C: A 13-year nationwide population-based study in Asia.

BACKGROUND AND AIMS: Viral hepatitis infection has been linked to increased atherosclerosis. We therefore investigated cardiovascular outcomes in patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. METHODS: Electronic medical records during 2000-2012 were retrieved from the Taiwan National Health Insurance Research Database. Exclusion criteria were age <18, history of coexisting HBV and HCV infection, acute coronary syndrome, coronary intervention, venous thromboembolism, peripheral artery disease, stroke, major or gastrointestinal bleeding, malignancy, and a follow-up period <180 days. Patients with HBV and HCV infection were propensity-matched then compared for outcomes. Primary outcomes were cardiovascular events at the 1-year follow-up, 3-year follow-up, 5-year follow-up, and at the end of follow-up. RESULTS: 41,554 patients with diagnosis of HBV or HCV were retrieved from 2000 to 2012. After exclusion criteria, 31,943 patients were eligible for analysis and propensity score matched. The study population consisted of 6030 patients with HBV infection and 6030 patients with HCV infection. Risk of composite arterial events (acute coronary syndrome, peripheral artery disease, and acute ischemic stroke) was significantly higher in patients with HCV infection compared with patients with HBV infection (p = 0.012 at 5-year follow-up and p = 0.003 at the end of follow-up). All-cause mortality was significantly higher in patients with HCV infection compared with patients with HBV infection (p < 0.001 at 3-year follow-up, 5-year follow-up, and at the end of follow-up). CONCLUSIONS: In patients with chronic viral hepatitis, subjects with HCV infection had a significantly higher risk of composite arterial events and all-cause mortality compared with those with HBV infection.

Dehydroepiandrosterone sulfate and dehydroepiandrosterone sulfate/cortisol ratio in cirrhotic patients with septic shock: another sign of hepatoadrenal syndrome?

BACKGROUND: Cirrhotic patients are susceptible to sepsis and critical illness-related corticosteroid insufficiency (CIRCI). Dehydroepiandrosterone sulfate (DHEAS) is a corticotropin-dependent adrenal androgen, which has immunostimulating and antiglucocorticoid effects. Considering the synchronized synthesis of cortisol and DHEAS and their opposing effects to each other, investigators have proposed measuring these two hormones as a ratio. Severe sepsis has been associated with low DHEAS, especially relative to high cortisol. Despite growing interest in the role of adrenal androgen replacement in critical illness, there have been no data about DHEAS and the DHEAS/cortisol ratio in patients with liver cirrhosis. We studied whether low concentrations of DHEAS and decreased DHEAS/cortisol ratio are associated with poor outcome in patients with liver cirrhosis and septic shock. METHODS: We recruited 46 cirrhotic patients with septic shock, and 46 noncirrhotic counterparts matched by age and sex. We evaluated adrenal function using the short corticotropin stimulation test and analyzed the relation between DHEAS and cortisol. RESULTS: While the nonsurvivors in the cirrhotic group had significantly lower baseline DHEAS, lower baseline DHEAS/cortisol ratio, and reduced increments of both DHEAS and cortisol upon corticotropin stimulation, the survivors had lower baseline cortisol. Cirrhotic patients with lower DHEAS/cortisol ratio (<1.50) had higher levels of interleukin-6 and tumor necrosis factor alpha, higher Sequential Organ Failure Assessment scores, and higher rates of CIRCI and hospital mortality. Using the area under the receiver operating characteristic (AUROC) curve, both DHEAS and the DHEAS/cortisol ratio demonstrated a good discriminative power for predicting hospital survival (AUROC 0.807 and 0.925 respectively). The cirrhotic group had lower DHEAS and DHEAS/cortisol ratio but higher rates of CIRCI and hospital mortality, compared to the noncirrhotic group. CONCLUSIONS: There is dissociation between cortisol (increased) and DHEAS (decreased) in those cirrhotic patients who succumb to septic shock. Low DHEAS/cortisol ratios are associated with more severe diseases, inflammation, and CIRCI and can serve as a prognostic marker. More investigations are needed to evaluate the role of adrenal androgen in this clinical setting.

Inhibition of CCAR1, a Coactivator of ß-Catenin, Suppresses the Proliferation and Migration of Gastric Cancer Cells.

The aberrant activation of Wnt signaling has been implicated in a variety of human cancers, including gastric cancer. Given the current hypothesis that cancer arises from cancer stem cells (CSCs), targeting the critical signaling pathways that support CSC self-renewal appears to be a useful approach for cancer therapy. Cell cycle and apoptosis regulator 1 (CCAR1) is a transcriptional coactivator which has been shown to be a component of Wnt/ß-catenin signaling, and which plays an important role in transcriptional regulation by ß-catenin. However, the function and clinical significance of CCAR1 in gastric cancer have not been elucidated. Here, we show that elevated CCAR1 nuclear expression correlates with the occurrence of gastric cancer. In addition, RNAi-mediated CCAR1 reduction not only suppressed the cell growth and increased apoptosis in AGS and MKN28 cells, but also reduced the migration and invasion ability of these cells. Furthermore, an in vivo xenograft assay revealed that the expression level of CCAR1 was critical for tumorigenesis. Our data demonstrates that CCAR1 contributes to carcinogenesis in gastric cancer and is required for the survival of gastric cancer cells. Moreover, CCAR1 may serve as a diagnostic marker and a potential therapeutic target.

Aberrant JAK/STAT Signaling Suppresses TFF1 and TFF2 through Epigenetic Silencing of GATA6 in Gastric Cancer.

Aberrant Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is crucial to the development of gastric cancer. In this study, we examined the role of STAT3 in the expression and methylation of its targets in gastric cancer patients. Results from RNA sequencing identified an inverse correlation between the expression of STAT3 and GATA6 in 23 pairs of gastric cancer patient samples. We discovered that the expression of GATA6 is epigenetically silenced through promoter methylation in gastric cancer cell lines. Interestingly, the inhibition of STAT3 using a novel STAT3 inhibitor restored the expression of GATA6 and its targets, trefoil factors 1 and 2 (TFF1/2). Moreover, disruption of STAT3 binding to GATA6 promoter by small hairpin RNA restored GATA6 expression in AGS cells. A clinically significant correlation was also observed between the expression of GATA6 and TFF1/2 among tissue samples from 60 gastric cancer patients. Finally, bisulfite pyrosequencing revealed GATA6 methylation in 65% (39/60) of the patients, and those with higher GATA6 methylation tended to have shorter overall survival. In conclusion, we demonstrated that aberrant JAK/STAT signaling suppresses TFF1/2 partially through the epigenetic silencing of GATA6. Therapeutic intervention of STAT3 in reversing the epigenetic status of GATA6 could benefit the treatment of gastric cancer and is worthy of further investigation.