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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.

Background Pangenotypic direct-acting antiviral agents (DAAs) glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL) are effective against all hepatitis C virus (HCV) genotype infections. However, data on pangenotypic DAA treatment for mixed genotype HCV infection are sparse. Methods This is a retrospective, single site cohort study analyzing all patients with mixed HCV genotype infections treated with GLE/PIB or SOF/VEL from August 2018 to August 2020 in Chiayi Chang Gung Memorial Hospital, Taiwan. The primary study endpoint was sustained virologic response (SVR) 12 weeks after treatment cessation. We also reported adverse events (AEs). Results A total of 108 patients with mixed infections of any two or three genotypes of 1a, 1b, 2, 3, and 6 received pangenotypic DAAs during the study period. A total of 67 patients received GLE/PIB and 41 received SOF/VEL. The evaluable population analysis revealed SVR rates of 94% (63/67) and 95.1% (39/41) for GLE/PIB and SOF/VEL therapy, respectively, and the per-protocol analysis revealed an SVR of 100% for both regimens. Four patients in the GLE/PIB group and two patients in the SOF/VEL were lost to follow-up. The most common AEs for GLE/PIB versus SOF/VEL therapy included pruritus (14.9% vs 2.4%), fatigue (6.0% vs 7.3%), abdominal discomfort (4.5% vs 7.3%), and acid reflux (3.0% vs 4.9%). DAA-related significant laboratory abnormalities occurred in three patients with > 1.5 × elevated bilirubin level in the GLE/PIB group. None of the above AEs resulted in DAA discontinuation. Conclusions Pangenotypic DAAs are well tolerated by and yield high SVR rates in patients with mixed genotype HCV infection.

Data on direct-acting antiviral agent (DAA) treatment for mixed genotype hepatitis C virus (HCV) infection are scant. This study examined the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) and ledipasvir/sofosbuvir (LDV/SOF) for mixed HCV genotype infection in a real-world setting in Taiwan. We analysed the data from all patients with mixed HCV genotype infections treated with GLE/PIB or LDV/SOF from 2017 to 2019 in three Chang Gung Memorial Hospitals in Taiwan. The primary treatment outcome was sustained virologic response 12 weeks after treatment cessation (SVR12). Adverse events (AEs) were also evaluated. A total of 5190 HCV patients received DAA treatment during this time period. Among them, 116 patients (2.2%) had mixed infections of any 2 or 3 genotypes of 1a, 1b, 2, 3 and 6. Fifty-four patients received GLE/PIB and 62 received LDV/SOF. SVR12 rates for LDV/SOF vs GLE/PIB therapy were 96.6% (56/58) vs 100% (51/51) by the per-protocol analysis and 90.3% (56/62) vs 94.4% (51/54) by the evaluable population analysis. Two patients with 1b + 6 and 1b + 2 genotype infections in the LDV/SOF group had relapse. Evaluating the GLE/PIB vs LDV/SOF groups for the most common AEs revealed pruritus (16.7% vs 4.8%), abdominal discomfort (5.6% vs 8%) and fatigue (5.6% vs 4.8%). One patient with AE-related treatment discontinuation presented with liver decompensation after 4-week GLE/PIB therapy. DAA-related significant laboratory abnormalities occurred in two patients with >3× elevated bilirubin level in the GLE/PIB group. GLE/PIB and LDV/SOF are well tolerated and achieve high SVR12 rates for patients with mixed HCV genotype infection.

Background/Purpose: The major dose-limiting toxicity of ribavirin is hemolytic anemia. We investigated the incidence, risk factors and impact on virological response of anemia in chronic hepatitis C genotype 2 patients receiving sofosbuvir plus ribavirin therapy. Methods: This was a retrospective real-world analysis of a single center including 293 chronic hepatitis C genotype 2 patients treated with sofosbuvir plus ribavirin for 12 weeks. Severe anemia was defined as hemoglobin concentration

PURPOSE To explore the prevalence of hepatitis C virus (HCV) infection as well as the levels of liver health literacy and association with the health status of people with HCV through the nurse-led community health development goal of global elimination. METHODS A community-based, cross-sectional study was conducted between July 2018 and June 2019 in coastal Western Yunlin County, Taiwan. This study was conducted at five townships, and serum HCV antibody (anti-HCV) screening was used for the identification of potentially infected people by a collaborating local hospital. RESULTS Of the 1,963 adults from rural areas enrolled in this study, 321 (16.4%) were anti-HCV positive, 237 (73.8%) reported that they were unaware of their HCV positivity, and none of them were provided information on direct-acting antiviral agent therapy. The levels of anti-HCV positivity were higher among female patients (p < .05), elderly people (p < .001), those with a low education level (p < .001), and those from the Sihu Township within Yunlin County (p < .001). Participants with anti-HCV positivity tended to have lower intakes of vegetables (p < .01) and fruit (p < .05), a greater number of comorbidities (p < .05), as well as a greater incidence of abnormal liver (p < .001) and renal function (p < .001) compared to those with anti-HCV negativity. Multivariable linear regression analysis showed that the presence of HCV infection and a greater number of metabolic syndrome components were associated with poor liver and renal function. CONCLUSIONS These findings showed a high prevalence of HCV infection among adults living in rural areas, who had low literacy levels on hepatitis, unhealthy lifestyles, and abnormal liver and renal function. CLINICAL RELEVANCE Clinicians and primary healthcare providers should initiate efforts to increase the levels of liver health literacy by increasing the accessibility to infection confirmation tests and reducing the number of barriers to the reception of antiviral treatment.

Background The inflammatory cytokine interleukin-6 (IL-6) is critical for the expression of octamer-binding transcription factor 4 (OCT4), which is highly associated with early tumor recurrence and poor prognosis of hepatocellular carcinomas (HCC). DNA methyltransferase (DNMT) family is closely linked with OCT4 expression and drug resistance. However, the underlying mechanism regarding the interplay between DNMTs and IL-6-induced OCT4 expression and the sorafenib resistance of HCC remains largely unclear. Methods HCC tissue samples were used to examine the association between DNMTs/OCT4 expression levels and clinical prognosis. Serum levels of IL-6 were detected using ELISA assays (n = 144). Gain- and loss-of-function experiments were performed in cell lines and mouse xenograft models to determine the underlying mechanism in vitro and in vivo. Results We demonstrate that levels of DNA methyltransferase 3 beta (DNMT3b) are significantly correlated with the OCT4 levels in HCC tissues (n = 144), and the OCT4 expression levels are positively associated with the serum IL-6 levels. Higher levels of IL-6, DNMT3b, or OCT4 predicted early HCC recurrence and poor prognosis. We show that IL-6/STAT3 activation increases DNMT3b/1 and OCT4 in HCC. Activated phospho-STAT3 (STAT-Y640F) significantly increased DNMT3b/OCT4, while dominant negative phospho-STAT3 (STAT-Y705F) was suppressive. Inhibiting DNMT3b with RNA interference or nanaomycin A (a selective DNMT3b inhibitor) effectively suppressed the IL-6 or STAT-Y640F-induced increase of DNMT3b-OCT4 and ALDH activity in vitro and in vivo. The fact that OCT4 regulates the DNMT1 expressions were further demonstrated either by OCT4 forced expression or DNMT1 silence. Additionally, the DNMT3b silencing reduced the OCT4 expression in sorafenib-resistant Hep3B cells with or without IL-6 treatment. Notably, targeting DNMT3b with nanaomycin A significantly increased the cell sensitivity to sorafenib, with a synergistic combination index (CI) in sorafenib-resistant Hep3B cells. Conclusions The DNMT3b plays a critical role in the IL-6-mediated OCT4 expression and the drug sensitivity of sorafenib-resistant HCC. The p-STAT3 activation increases the DNMT3b/OCT4 which confers the tumor early recurrence and poor prognosis of HCC patients. Findings from this study highlight the significance of IL-6-DNMT3b–mediated OCT4 expressions in future therapeutic target for patients expressing cancer stemness-related properties or sorafenib resistance in HCC.

Simple Summary Sorafenib is the first approved targeted therapy for the treatment of advanced hepatocellular carcinoma (HCC). However, HCC resistance to sorafenib has greatly reduced its utility. Yes-associated protein (YAP) is overexpressed in cancers, including HCC. We observed a positive correlation in expression levels of insulin-like growth factor-1 receptor (IGF-1R) and YAP in sorafenib-resistant HCCs. Therefore, the interplay between YAP and IGF-1R signaling and its role in HCC sorafenib resistance will be examined in this study. We found that the YAP-IGF-1R signaling loop was involved in sorafenib resistance in HCC. IGF-1/2 treatment enhanced YAP nuclear translocation. In turn, YAP regulated expression of IGF-1R and epithelial mesenchymal transition (EMT)-related proteins in vitro. Targeting YAP with a specific inhibitor, verteporfin (VP), significantly increased HCC cell sensitivity to sorafenib, with a potential synergistic combination index. These findings highlight the significance of the YAP-IGF-1R signaling loop as a potential therapeutic target for HCC, especially in terms of overcoming sorafenib resistance. Abstract The role of a YAP-IGF-1R signaling loop in HCC resistance to sorafenib remains unknown. Method: Sorafenib-resistant cells were generated by treating naïve cells (HepG2215 and Hep3B) with sorafenib. Different cancer cell lines from databases were analyzed through the ONCOMINE web server. BIOSTORM–LIHC patient tissues (46 nonresponders and 21 responders to sorafenib) were used to compare YAP mRNA levels. The HepG2215_R-derived xenograft in SCID mice was used as an in vivo model. HCC tissues from a patient with sorafenib failure were used to examine differences in YAP and IGF-R signaling. Results: Positive associations exist among the levels of YAP, IGF-1R, and EMT markers in HCC tissues and the levels of these proteins increased with sorafenib failure, with a trend of tumor-margin distribution in vivo. Blocking YAP downregulated IGF-1R signaling-related proteins, while IGF-1/2 treatment enhanced the nuclear translocation of YAP in HCC cells through PI3K-mTOR regulation. The combination of YAP-specific inhibitor verteporfin (VP) and sorafenib effectively decreased cell viability in a synergistic manner, evidenced by the combination index (CI). Conclusion: A YAP-IGF-1R signaling loop may play a role in HCC sorafenib resistance and could provide novel potential targets for combination therapy with sorafenib to overcome drug resistance in HCC.

ObjectivesCommunity-based screening for hepatitis B virus (HBV) and hepatitis C virus (HCV) is essential for hepatitis elimination. This study attempted to increase screening accessibility and efficacy by using alternative tools.DesignPopulation-based prospective cohort study.SettingHepatitis elimination program at Yunlin County, Taiwan.ParticipantsAll 4552 individuals participated in 60 screening sessions of a community-based HBV and HCV screening project in five rural townships with approximately 95 000 inhabitants in central-western Taiwan.InterventionsTo increase accessibility, 60 outreach screening sessions were conducted in 41 disseminative sites. Quantitative HBV surface antigen (qHBsAg) and anti-HCV testing with reflex HCV core antigen (HCV Ag) tests were employed as alternative screening tools.Main outcome measuresCalculate village-specific prevalence of HBsAg, anti-HCV and HCV Ag and establish patient allocation strategies according to levels of qHBsAg HCV Ag and alanine aminotransferase (ALT).ResultsOf 4552 participants, 553, 697 and 290 were positive for HBsAg, anti-HCV and HCV Ag, respectively; 75 of them had both HBsAg and anti-HCV positivity. The average (range) number of participants in each screening session was 98 (31–150). The prevalence rates (range) of HBsAg, anti-HCV and HCV Ag were 12.1% (4.3%–19.4%), 15.3% (2.6%–52.3%) and 6.4% (0%–30.2%), respectively. The HCV Ag positivity rate among anti-HCV-positive participants was 42% (0%–100%). Using cut-off values of >200 IU/mL for qHBsAg, >3 fmol/L for HCV Ag and >40 IU/mL for ALT as criteria for patient referral, we noted an 80.2% reduction in referral burden. Three villages had high anti-HCV prevalences of 52.3%, 53.8% and 63.4% with corresponding viraemic prevalences of 23.2%, 30.1% and 22% and thus constituted newly identified HCV-hyperendemic villages.ConclusionOutreach hepatitis screening increases accessibility for residents in rural communities. Screening HBV and HCV through qHBsAg and HCV Ag tests provides information concerning viral activities, which might be conducive to precise patient allocation in remote communities.

Introduction Real-world data regarding the impact of hepatic fibrosis on the effectiveness of sofosbuvir/velpatasvir (SOF/VEL) treatment is limited in the Asian population. Methods We analyzed data for all 823 patients with hepatitis C virus treated with SOF/VEL from June 2019 to September 2020 at Chang Gung Memorial Hospital in Chiayi, Taiwan. The degree of fibrosis was determined using the fibrosis-4 (FIB-4) index, with advanced fibrosis or cirrhosis defined as a FIB-4 score of > 3.25. The primary treatment outcome was the rate of sustained virologic response 12 weeks after treatment cessation (SVR). Adverse events (AEs) were also evaluated. Results SVR rates did not significantly differ (p > 0.05) between patients with FIB-4 scores of ≤ 3.25 and those with scores of > 3.25. In the per protocol analysis, 99.2% (593/598) of the FIB-4 ≤ 3.25 group and 100% (172/172) of the FIB-4 > 3.25 group achieved SVR; in the evaluable population analysis, 93.4% (593/635) of the FIB-4 ≤ 3.25 group and 91.5% (172/188) of the FIB-4 > 3.25 group achieved SVR. Five patients with FIB-4 scores of ≤ 3.25 did not attain SVR: two relapsed and three had no response. The most common AEs were comparable (p > 0.05) for the FIB-4 ≤ 3.25 group and the FIB-4 > 3.25 group and included abdominal discomfort (4.4% vs. 5.9%), fatigue (4.1% vs. 5.9%), and skin itching (3.6% vs. 3.2%). Laboratory abnormalities were more common in the FIB-4 > 3.25 group (p 3.25 had total bilirubin elevation > 3 × the upper normal limit (UNL). Alanine transaminase elevation > 5 × the UNL was observed in two patients with FIB-4 scores of ≤ 3.25 and one patient with a FIB-4 score of > 3.25. No AEs resulted in treatment discontinuation. Conclusions SOF/VEL treatment is well tolerated and achieves high SVR rates for patients of Taiwanese ethnicity with HCV, regardless of cirrhosis status.

PurposeThe purpose of this study was to identify genes that were epigenetically silenced by STAT3 in gastric cancer.MethodsMBDcap-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).ResultsAs 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).ConclusionsConstitutive 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.

Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.

It remains controversial whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) is associated with different clinical outcomes for chronic hepatitis B (CHB). This study aimed to compare the long-term risk of ETV versus TDF on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in CHB patients from a large multi-institutional database in Taiwan. From 2011 to 2018, a total of 21,222 CHB patients receiving ETV or TDF were screened for eligibility. Patients with coinfection, preexisting cancer and less than 6 months of follow-up were excluded. Finally, 7248 patients (5348 and 1900 in the ETV and TDF groups, respectively) were linked to the National Cancer Registry database for the development of HCC or ICC. Propensity score matching (PSM) (2:1) analysis was used to adjust for baseline differences. The HCC incidence between two groups was not different in the entire population (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.66–1.02, p = 0.078) and in the PSM population (HR 0.83; 95% CI 0.65–1.06, p = 0.129). Among decompensated cirrhotic patients, a lower risk of HCC was observed in TDF group than in ETV group (HR 0.54; 95% CI 0.30–0.98, p = 0.043, PSM model). There were no differences between ETV and TDF groups in the ICC incidence (HR 1.84; 95% CI 0.54–6.29, p = 0.330 in the entire population and HR 1.04; 95% CI 0.31–3.52, p = 0.954 in the PSM population, respectively). In conclusion, treatment with ETV and TDF showed a comparable long-term risk of HCC and ICC in CHB patients.

The use of immune checkpoint inhibitors (ICI) in treating cancer has revolutionized the approach to eradicate cancer cells by reactivating immune responses. However, only a subset of patients benefits from this treatment; the majority remains unresponsive or develops resistance to ICI therapy. Increasing evidence suggests that metabolic machinery in the tumor microenvironment (TME) plays a role in the development of ICI resistance. Within the TME, nutrients and oxygen are scarce, forcing immune cells to undergo metabolic reprogramming to adapt to harsh conditions. Cancer-induced metabolic deregulation in immune cells can attenuate their anti-cancer properties, but can also increase their immunosuppressive properties. Therefore, targeting metabolic pathways of immune cells in the TME may strengthen the efficacy of ICIs and prevent ICI resistance. In this review, we discuss the interactions of immune cells and metabolic alterations in the TME. We also discuss current therapies targeting cellular metabolism in combination with ICIs for the treatment of cancer, and provide possible mechanisms behind the cellular metabolic rewiring that may improve clinical outcomes.

Background Fusobacterium nucleatum was previously found to become a dominant species in the gastric cancer-associated microbiota of patients from Taiwan. However, the prevalence of Fusobacterium nucleatum infection in gastric cancer has not been examined in a larger patient cohort. In addition, whether Fusobacterium nucleatum elicits a cellular response in gastric cancer remains unknown.Methods A study cohort of resected gastric cancer tissue specimens was examined using nested PCR to detect Fusobacterium nucleatum. In vitro coculture of Fusobacterium nucleatum was carried out to identify the alteration in the expression profile of patient-derived gastric cancer cell line.Results approximately one-third of gastric cancer tissues are positive for Fusobacterium nucleatum. Statistical analysis showed that the risk for Fusobacterium nucleatum infection is increased in late-stage cancer tissue specimens and incurs poorer survival in Helicobacter pylori-positive patients. In vitro coculture experiment shows a drastic interferon response activated only by a high multiplicity of infection, and the response peaks within 24 hours and subsides after 72 hours of incubation. Another set of response genes is the continuous increase of actins and their regulators with prolonged time of incubation, activated by both low and high multiplicity of infection.Conclusions Our data indicates that Fusobacterium nucleatum incites an inflammatory response from the cancer cells and promotes cell mobility, likely

Gastric cancer (GC) is among the most treatment-refractory epithelial malignancies. Aberrant activation of Wnt/&beta, 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&ndash, node&ndash, 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/&beta, 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.

Low viral load (LVL) of hepatitis B virus (HBV) is a predictor of chronic HBV infection. However, the usefulness of quantitative hepatitis B surface antigen (qHBsAg) in predicting LVL in community-based screening has not been well studied. We aimed to measure the prevalence of LVL in HBV carriers and validate the efficacy of qHBsAg in predicting LVL.This community-based screening study was conducted in Taiwan. HBV DNA was assayed in HBsAg carriers. Participants were randomized to training and validation sets to determine the ability of qHBsAg to predict LVL. Receiver operating characteristic curves were used to identify the best cutoff values in the training set.Among the 2919 participants, 359 (12.2%) were HBsAg carriers. There were 132 and 137 carriers in the training and validation sets, respectively. Significant correlations were found between qHBsAg and HBV DNA in both training and validation sets. Thirty and 29 participants with qHBsAg8 IU/mL in the training and validation sets, respectively, had LVL. Using 8 IU/mL as the cutoff, negative predictive value (NPV) of qHBsAg for HBV DNA levels2000 IU/mL was 100%. The best cutoff level of qHBsAg to predict HBV LVL was 200 IU/mL, with a sensitivity, specificity, and accuracy of 75.0%, 76.1%, and 75.8%, respectively, in the training set. The positive predictive value and NPV were 70.0% and 77.9%, respectively, in the validation set.Approximately 60% of HBsAg carriers had HBV LVL, and qHBsAg8 IU/mL accurately predicts LVL. This quantitative test provides additional information for community-based screening.

To explore the effectiveness of an oral hygiene programme combined with home phone counselling on hepatitis C patients during antiviral treatment.Hepatitis C virus infection is the leading cause of liver diseases. Evidence indicates that the antiviral treatment for hepatitis C virus infection has been successful, albeit its many side effects, such as discomfort symptoms of oral ulcers, which, in turn, leads to discontinued treatment. Inappropriate oral hygiene may worsen the side effects and increase the risk of dropping out of the treatment.A quasi-experimental pre-post-test design was used.The oral hygiene programme was based on a standardized protocol of oral health care combined with home phone counselling. The participants were recruited from an outpatient clinic between August 2016 and July 2017. The generalized estimating equation was used for repeated measures of oral health behaviour, oral health status and discomfort symptoms.Thirty-four participants completed this study. The findings indicated that the oral hygiene programme significantly improved tooth brushing, use of dental floss and oral comfort. The result showed that the participants' oral health status significantly improved in 3 months.This pilot study supports the finding that an oral hygiene programme can reduce oral discomfort, improve oral hygiene behaviour, and enhance the oral health status of hepatitis C patients receiving treatment. This is a simple and low-cost programme, which can be performed at home easily and boosts the completion of antiviral treatment.目的: 探讨口服卫生计划结合家庭电话咨询对丙型肝炎患者抗病毒治疗期间的效果。 背景: 丙型肝炎病毒感染是引起肝病的主要原因。有证据表明,丙型肝炎病毒感染的抗病毒治疗已取得成功,尽管它有许多副作用,如口腔溃疡的不适症状,这进而导致停止治疗。不适当的口腔卫生可能会加重副作用,增加退出治疗的风险。 设计: 采用准实验前后试验设计。 方法: 口腔卫生方案是根据一项标准化的口腔保健方案,并结合家庭电话咨询。参与者于2016年8月至2017年7月期间从门诊招募。采用广义估计方程对口腔健康行为、口腔健康状况和不适症状进行重复测量。 研究结果: 34名参与者完成了这项研究。研究结果显示,口腔卫生计划显著改善刷牙、使用牙线和口腔舒适度。结果表明,3个月后患者口腔健康状况明显改善。 结论: 这项初步研究证实,口腔卫生计划可减少口腔不适,改善口腔卫生行为,并改善接受治疗的丙型肝炎患者的口腔健康状况。这是一个简单和低成本的项目,可以在家里轻松执行,并促进抗病毒治疗的完成。.

AIM In order to increase diagnostic sensitivity for early disease in rheumatoid arthritis (RA), new classification criteria were approved in 2010 by the American College of Rheumatology and the European League Against Rheumatism. One of the criteria, a high-positive rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA) level, was given a high score of 3. However, the increased prevalence of RF in patients with chronic hepatitis C virus (HCV) infection markedly diminishes the diagnostic specificity of serum RF for RA in these patients. There are no published data on the prevalence and predictive value of high-positive RF and ACPA; thus, we investigated high-positive RF and ACPA levels in nonarthritic patients with chronic HCV infection. METHOD Anti-citrullinated protein antibody and total RF were determined in serum from nonarthritic patients with chronic HCV infection (all had HCV RNA viremia). RESULT In 271 HCV-infected patients, positive RF, positive ACPA, high-positive RF, and high-positive ACPA were detectable in 47.2%, 1.1%, 8.9% and 1.1%, respectively. In these patients, fatty liver was an independent factor for high-positive RF. CONCLUSION In contrast to RF, ACPA is not increased in HCV infection. High-positive RF is not unusually present in nonarthritic patients with chronic HCV infection. ACPA may have improved value for the diagnosis of RA in this patient population. In patients with HCV infection, fatty liver may be a risk factor for high-positive RF.

Current guidelines recommend antibiotic prophylaxis for all patients with various degrees of cirrhosis and upper gastrointestinal (UGI) bleeding. This study assessed the need for antibiotic prophylaxis in patients with low Child–Pugh scores. We retrospectively screened all patients with cirrhosis who underwent upper endoscopies for UGI bleeding in a referral hospital in Taiwan between 2003 and 2014, from which 913 patients were enrolled after excluding patients with active bacterial infections, recent antibiotic use, early death, and Child–Pugh class C cirrhosis. Among them, 73 (8%) received prophylactic antibiotics, and 45 (4.9%) exhibited 14-day bacterial infection. Neither Child–Pugh score nor model for end stage liver disease score were optimal for predicting bacterial infection because their areas under the curves were 0.610 (95% confidence interval [CI]: 0.529–0.691) and 0.666 (95% CI: 0.591–0.742), respectively. Antibiotic prophylaxis did not reduce the risks of 14-day bacterial infection (relative risk [RR]: 0.932, 95% CI: 0.300–2.891, P = 0.902), 14-day rebleeding (RR: 0.791, 95% CI: 0.287–2.181, P = 0.650), or 42-day mortality (RR: 2.710, 95% CI: 0.769–9.524, P = 0.121). The results remained similar after propensity score adjustment. On-demand antibiotic treatment might suffice for patients with Child–Pugh class A/B cirrhosis and UGI bleeding.

Background Hepatitis C virus core antigen (HCV Ag) assay has been proposed as a more economical alternative to HCV RNA detection. This study aimed to investigate the clinical utility of HCV Ag assay in the monitoring of direct-acting antivirals (DAAs) for chronic hepatitis C patients. Methods We analyzed serum samples from 110 patients treated with paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD) with or without ribavirin. The levels for both HCV Ag and HCV RNA assessed by COBAS TaqMan HCV (CTM) Test or Abbott RealTime HCV (ART) assay were evaluated at baseline, week 2, 4, and 12 during treatment and 12 weeks after completion. Results Baseline HCV Ag levels showed good correlations with HCV viral load (r = 0.879; p

The inflammatory cytokine interleukin-6 (IL-6) is critical for the expression of octamer-binding transcription factor 4 (OCT4), which is highly associated with early tumor recurrence and poor prognosis of hepatocellular carcinomas (HCC). DNA methyltransferase (DNMT) family is closely linked with OCT4 expression and drug resistance. However, the underlying mechanism regarding the interplay between DNMTs and IL-6-induced OCT4 expression and the sorafenib resistance of HCC remains largely unclear.HCC tissue samples were used to examine the association between DNMTs/OCT4 expression levels and clinical prognosis. Serum levels of IL-6 were detected using ELISA assays (n = 144). Gain- and loss-of-function experiments were performed in cell lines and mouse xenograft models to determine the underlying mechanism in vitro and in vivo.We demonstrate that levels of DNA methyltransferase 3 beta (DNMT3b) are significantly correlated with the OCT4 levels in HCC tissues (n = 144), and the OCT4 expression levels are positively associated with the serum IL-6 levels. Higher levels of IL-6, DNMT3b, or OCT4 predicted early HCC recurrence and poor prognosis. We show that IL-6/STAT3 activation increases DNMT3b/1 and OCT4 in HCC. Activated phospho-STAT3 (STAT-Y640F) significantly increased DNMT3b/OCT4, while dominant negative phospho-STAT3 (STAT-Y705F) was suppressive. Inhibiting DNMT3b with RNA interference or nanaomycin A (a selective DNMT3b inhibitor) effectively suppressed the IL-6 or STAT-Y640F-induced increase of DNMT3b-OCT4 and ALDH activity in vitro and in vivo. The fact that OCT4 regulates the DNMT1 expressions were further demonstrated either by OCT4 forced expression or DNMT1 silence. Additionally, the DNMT3b silencing reduced the OCT4 expression in sorafenib-resistant Hep3B cells with or without IL-6 treatment. Notably, targeting DNMT3b with nanaomycin A significantly increased the cell sensitivity to sorafenib, with a synergistic combination index (CI) in sorafenib-resistant Hep3B cells.The DNMT3b plays a critical role in the IL-6-mediated OCT4 expression and the drug sensitivity of sorafenib-resistant HCC. The p-STAT3 activation increases the DNMT3b/OCT4 which confers the tumor early recurrence and poor prognosis of HCC patients. Findings from this study highlight the significance of IL-6-DNMT3b-mediated OCT4 expressions in future therapeutic target for patients expressing cancer stemness-related properties or sorafenib resistance in HCC.

Background: Hepatitis C virus (HCV) infection is one of the major causes of liver cirrhosis and hepatocellular carcinoma globally. The advent of direct-acting antivirals (DAAs) with high cure rates provides an opportunity to reduce the rising HCV disease burden. However, few studies have explored the side effects and physiological benefits of DAA therapy in rural areas. The aim of this study was to investigate the subjective reports of discomfort, patient feedback about the course of treatment, and physiological changes after DAA treatment in HCV patients. Methods: A descriptive, prospective, comparative cohort study was conducted from January to August 2019 in western coastal Yunlin County, Taiwan. Data regarding demographic characteristics, subjective discomfort levels, and physiological responses were collected through face to face interviews and from medical records by a cooperating hospital. Results: Six-hundred-and-twenty-three participants with an active HCV infection were identified, 555 (89.1%) had completed treatment, and sustained virologic response was achieved in 99.6% (n = 553). The mean age was 64.9 (standard deviation = 13.1) years, and 35% of patients experienced discomfort during DAA treatment, including fatigue, itching, and dizziness. After three months of treatment, physiological markers, including body weight (p &lt, 0.001), waist circumference (p &lt, 0.05), blood pressure (p &lt, 0.001), alanine aminotransferase (p &lt, 0.001), and aspartate aminotransferase (p &lt, 0.001), had significantly improved. Almost all participants provided positive feedback about the treatment experience and reported manageable side effects. Conclusions: The findings showed that, in an endemic rural area, DAA treatment had a high cure rate and improved physiological markers with few discomforts. These results can be used to reduce the barriers HCV patients face in adopting new medications.

The prognostic significance of various systemic inflammation‐based markers has been explored in different cancers after surgery. This study aimed to investigate whether these markers could predict outcomes in patients with early-stage hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA). One hundred eighteen patients with newly diagnosed HCC within the Milan criteria receiving RFA as initial therapy were retrospectively enrolled. Pretreatment inflammation-based markers including the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and prognostic nutritional index (PNI), together with other clinicopathologic parameters were collected. Cumulative overall survival (OS) and recurrence-free survival (RFS) were estimated by the Kaplan-Meier method and by multivariate analysis using Cox proportional hazard model. The 1-, 3-, and 5-year OS rates of patients were 90%, 67%, and 52%, respectively. Kaplan-Meier curves showed that baseline high NLR ≥ 2.5 (p = 0.006), low PNI p = 0.005), history of end-stage renal disease (ESRD) (p = 0.005), non-Child-Pugh class A (p = 0.001) and elevated alpha-fetoprotein (AFP) ≥ 200 ng/mL (p = 0.005) significantly associated with the poor OS, whereas high PLR ≥ 100 did not. By multivariate analysis, high NLR ≥ 2.5 (hazard ratio (HR) 1.94; 95% confidence interval (CI), 1.05–3.59; p = 0.034), low PNI p = 0.003), ESRD history (HR 3.60; 95% CI, 1.48–8.76; p = 0.005) and elevated AFP ≥ 200 ng/mL (HR 4.61; 95% CI, 1.75–12.13; p = 0.002) were independent factors. An elevated AFP level of ≥200 ng/mL was the significant factor associated with intrahepatic new RFS by univariate and multivariate analyses. In conclusion, pretreatment NLR and PNI are simple and useful predictors for OS in patients with early-stage HCC after RFA.

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/β-catenin signaling, and which plays an important role in transcriptional regulation by β-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.

Corrigendum: Alpha-Fetoprotein Measurement Benefits Hepatocellular Carcinoma Surveillance in Patients With Cirrhosis

More than 200 generic drugs were screened to identify the inhibitory activity on melanogenesis in mouse B16 melanoma cells. Cinnarizine and trazodone were identified as melanogenesis inhibitors. The inhibitory effects of the two drugs on cell survival, melanogenesis, and tyrosinase activity were investigated. The results showed that both cinnarizine and trazodone inhibited melanogenesis in B16 cells by a dose-dependent manner at the non-cytotoxic concentrations. Based on the results of the present study, seeking new melanogenesis inhibitors from generic drugs is an alternative approach to developing new depigmenting agents in cosmeceuticals. Moreover, cinnarizine and trazodone were proven to be good candidates as skin-whitening agents for treatment of skin hyperpigmentation.

Our previous study showed that a methanol extract from Trifolium pratense exerted potent inhibitory activity on melanogenesis in mouse B16 melanoma cells. In the present study, the active compound in this Chinese herb extract was isolated and identified as biochanin A by mass spectrum, (1)H-NMR, and (13)C-NMR analysis. The inhibitory effects of biochanin A on melanogenesis were investigated in vitro in cultured melanoma cells and in vivo in zebrafish and mice. Biochanin A dose-dependently inhibited both melanogenesis and cellular tyrosinase activity in B16 cells and in zebrafish embryos. Application of a cream containing 2% biochanin A twice daily to the skin of mice also increased the skin-whitening index value after 1 week of treatment, and the increase continued for another 2 weeks. Biochanin A was confirmed as a good candidate for use as a skin-whitening agent in the treatment of skin hyperpigmentation disorders.

Purpose: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the leading cause of cancer mortality worldwide. To date, Sorafenib remains the standard of care for advanced HCCs not amenable to curative therapies such as surgery or local ablation. Unfortunately, clinical efficacy of Sorafenib remains marginal as most HCC patients receiving Sorafenib treatment develop Sorafenib resistance. The recently approved regorafenib is the only rescue therapy for patients who fail Sorafenib treatment. However, the effect of regorafenib is also far from satisfactory. Therefore, new strategies to overcome sorefenib resistance are critically warranted. Recently, one FDA-approved drug, here we tentatively named as “FA”, was shown to suppress different cancer malignancy by various mechanisms including inhibiting the development of drug resistance in cancer. These findings provide a rationale for combination treatment of this FA drug with Sorafenib in Sorafenib-resistant HCC. Results: Two Sorafenib-resistant HCC cell lines of Hep3B and HepG2215 were established. The Sorafenib resistance characteristics of the HCC cells were further verified by western blotting assay detecting protein tyrosine phosphorylation. We also demonstarted the resistant HCC cells expressed stemness-related genes and showed high ability of cell migration and metastasis. Combination use of FA drug and Sorafenib significantly suppressed the cell viability as well as the stemness-related properties of Sorafenib-resistant HCC cells, including stemness-related gene/protein expression, secondary sphere formation, and the cell migration. Conclusion: Combination use of FA drug and Sorafenib would be a potential therapeutic strategy for Sorafenib-resistant HCC treatment. Citation Format: Syue-Wei Peng, Yi-Heng Lin, Ming-Hao Teng, Hung-Cheng Lai, Te-Sheng Chang, Yen-Hua Huang. Adjutant therapeutic strategy for sorafenib-resistant hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 896.

Background/Aims: Studies have shown that concurrent infection of hepatitis B virus and hepatitis C virus may be associated with severe forms of chronic liver disease or with rapid progression. However, very little is known about the role and course of concurrent HBV and HCV infection in patients with acute viral hepatitis. Methods: This study retrospectively compared the clinical features of 83 patients diagnosed with HBV- or HCV-related chronic hepatitis with acute exacerbation (12 with concurrent HBV and HCV infection, 46 with HBV infection alone, and 25 with HCV infection alone) encountered at Chia-Yi Chang Gung Memorial Hospital, Taiwan, between January 2003 and December 2005. Results: The clinical course of chronic hepatitis with acute exacerbation in patients with concurrent HBV and HCV infection is similar to patients with single HBV infection, and more severe than patients with single HCV infection, evidenced by increased hepatic decompensation (P = 0.05), failure (P = 0.036), and mortality (P = 0.036). Elevated serum HCVRNA-negative percentage in HBVDNA-positive patients and low serum HBVDNA concentrations in HCVRNA-positive patients imply reciprocal interference of HBV and HCV in patients with concurrent HBV and HCV infections during acute-phase hepatitis. In patients with concurrent HBV and HCV infection, the mortality rate for detectable HBVDNA patients seemed higher than that for undetectable HBVDNA patients, although it did not reach statistical significance (P = 0.066). Conclusions: virus interference existed in chronic hepatitis with acute exacerbation patients with concurrent HBV and HCV infections. Clinical outcome for patients positive for serum HBVDNA was much worse than those negative for serum HBVDNA. When chronic hepatitis with acute exacerbation occurs in patients with concurrent HBV and HCV infection, aggressive management should be investigated and antiviral therapy targeting of HBV infection should be administered early.

To investigate the efficacy and safety of stapled hemorrhoidopexy in treating prolapsed hemorrhoids in patients with liver cirrhosis. Eight consecutive cases of patients with prolapsed hemorrhoids comorbid with liver cirrhosis, who had intractable response to other interventions, were enrolled in this retrospective study between January 2002 and June 2006 at our institute. Six patients (75%) had Child–Pugh class A liver cirrhosis, whereas only two patients (25%) had class B disease. Rectal varices were identified in three patients (37.5%), and esophageal varices were identified in six patients (75%). Concurrent rectal and esophageal varices existed in three patients (37.5%). The patients underwent stapled hemorrhoidopexy with Proximate® PPH-03 in a lithotomy position under spinal/intravenous general anesthesia. There was no procedure-related mortality or major complications except hemorrhage. Two patients (25%) were complicated with postoperative staple-line bleeding, which was managed with conservative treatment without reoperation. There were no leading symptoms of relapsing during a follow-up period of at least 6 months. This study may prove that stapled hemorrhoidopexy is a feasible and safe approach for prolapsed hemorrhoids concurrent with liver cirrhosis.

Background: Bile duct damage and hepatic steatosis are two characteristic histological findings in hepatitis C virus infection; and high prevalence of hepatitis C antibody is noted in patients with cholangiocarcinoma. The purpose of the present study was to examine the relationship between biliary diseases and hepatitis C virus infection. Methods: Persons who received a general checkup in Chang Gung Memorial Hospital between 2000 and 2002 were included. All of them had hemogram, serum biochemistry, hepatitis B surface antigen, hepatitis C antibody and ultrasonography studies. The prevalence of gallbladder stone, bile duct stone and gallbladder polyp/cholesterolosis were compared in different viral infection groups. Results: Of the 28 486 persons, 22 967 were negative for both hepatitis B surface antigen and hepatitis C antibody (group NBNC), 4152 were hepatitis B surface antigen carriers (broup B), 1195 were positive for hepatitis C antibody (group C), and 172 were positive for both markers. The 379 persons (1.3%) having had cholecystectomy were considered to have gallbladder stone at the time when cholecystectomy was done. Gallbladder stone was found in 6.0% persons of group NBNC, 5.4% in group B and 11.7% in group C. The prevalence of gallbladder stone in group C was found especially high for age groups 31–40 years and 61–70 years. The prevalence of bile duct stone was higher in group C (0.4%) than in group NBNC or B (both 0.1%). Stepwise logistic regression analysis showed that age, liver cirrhosis, body mass index, hepatitis C virus infection and gender were independent factors associated with gallbladder stone. Conclusions: Hepatitis C virus infection facilitates gallstone formation. © 2005 Blackwell Publishing Asia Pty Ltd

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, P0.001). 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.

Background Stromal cell-derived factor-1 (SDF-1) (CXC chemokine ligand-12)/CXC chemokine receptor 4 (CXCR4) is involved in the carcinogenesis of human gastric cancer, where it stimulates angiogenesis and favors metastasis of tumor cells to distant organs. In addition, resistin is suggested to be an important link between obesity and the development of gastric cancer. Resistin has identified as an important player in inflammatory responses, and emerged as a mediator in inflammation-associated cancer. A limited number of studies have investigated the association of resistin and SDF-1 with gastric cancer. Herein, we investigated the molecular mechanisms by which resistin influences the expression of SDF-1 in gastric carcinoma cells. Results Human gastric cancer cell lines were exposed to doses of resistin; SDF-1 expression and secretion levels were then determined. Real-time polymerase chain reaction and western blotting analyses were performed to clarify molecular changes. Inhibition of Toll-like receptor 4 (TLR4) by a competitive antagonist inhibited resistin-induced SDF-1 expression. Pharmacological inhibitors and small interfering RNA (siRNA) demonstrated that activation of the p38 mitogen-activated protein kinase (MAPK) pathway is critical for resistin-induced SDF-1 expression mediated by TLR4. The promoter activity and transcription factor enzyme-linked immunosorbent assay revealed that resistin induced expression of SDF-1 mediated by NF-κB in gastric cancer cells. Inhibition of p38 MARK activation blocked the SDF-1-induced expression and the SDF-1 promoter activity in the cancer gastric cells. Chromatin immunoprecipitation assay revealed that inhibition of p38 MARK activation also blocked the resistin-increased NF-κB-DNA-binding activity. Conclusions Resistin-induced SDF-1 upregulation by activation of TLR4, p38 MARK and NF-κB may explain a new role of resistin in the link of obesity and gastric cancer.

Single photon emission computed tomography (SPECT) is a useful tool in measuring dynamic brain functioning. Its potential to reveal the physiological mechanisms of neurotoxicity has not been fully explored. In the present study, the SPECT findings for 25 healthy control subjects were compared to the findings for 25 mixed organic solvent exposure subjects. Specific physiological abnormalities related to regional cerebral blood flow activity (rCBF) were revealed. In the early phase of uptake, significantly decreased uptake was found in the mixed organic solvent group; in the late phase of uptake, a significant increase in uptake was found in specific regions of interest. The discovery of this abnormality in brain functioning may be a significant step toward the creation of a biological marker of neurotoxicity. Early detection of neurotoxicity is important in occupational medicine to prevent neurotoxic illnesses in working populations. Am. J. Ind. Med. 31:4–14 © 1997 Wiley-Liss, Inc.

[This corrects the article DOI: 10.1371/journal.pone.0149897.].

AIM: To verify the usefulness of FibroQ for predicting fibrosis 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 ratio index, 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 significant fibrosis score in chronic hepatitis C compared with other noninvasive tests. CONCLUSION: FibroQ is a simple and useful test for predicting significant fibrosis in patients with chronic hepatitis C.

To evaluate the efficacy of endoscopic submucosal dissection (ESD) for early gastric cancers (EGCs) at a new endoscopic center.ESD is a novel technique that can facilitate en-bloc resection of EGCs, but seldom reported outside Japan.A total of 25 consecutive patients (25 lesions) underwent ESD from June 2004 to March 2006. Patients were divided into 2 groups: group A underwent ESD from June 2004 to May 2005 (introduction stage) and group B from June 2005 to March 2006. The following data were obtained: tumor size, tumor location, operative time, and major complication.The complete resection was achieved in 20 lesions (success rate 80%). Four out of 10 lesions from group A were removed by conventional endoscopic mucosal resection (EMR) piecemeally after ESD failure. Conversely, 14 patients from group B (n=15) were resected by ESD en-bloc (success rate 93.3%). One patient with microscopic residual tumor after ESD was further treated by surgical resection. The time required for resection was significantly longer in group A when compared with group B (130.5 min vs. 81.5 min, P0.05). Postoperative complication rate between the 2 groups were similar. One patient with piecemeal EMR recurred in follow-up, and was further treated successfully by EMR.ESD is an ideal method for EGC treatment, but it may result in a risk of complication. The complete resection rate can be improved by endoscopist's experience. Sophisticated endoscopic hemostasis and clipping skills are essential prior ESD procedures. Conventional EMR techniques are also obligatory during the beginning period.

Purpose: To unravel the role of inflammatory cytokine IL-6 and IGF-1 receptor (IGF-1R) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGF-1R in hepatocellular carcinoma (HCC). Experimental Design: Frozen liver and HCC tissue samples were obtained from 191 patients who received curative hepatectomy between 2004 and 2012. Serum levels of IL-6 were detected using ELISA assays (n = 120). The effects of IL-6/IGF-1 on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGF-1 receptor (p-IGF-1R) in tissues were detected by western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGF-1R expression levels in tissues (n = 191) were analyzed by real-time Q-PCR and was correlated with early tumor recurrence using Kaplan-Meier survival analysis. Results: A high positive correlation between the expression levels of OCT4/NANOG and IGF-1R/p-IGF-1R in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGF-1R was mostly confined to HBV-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL-6 were significantly correlated with high OCT4/NANOG expression. IL-6 stimulated an autocrine IGF-1/IGF-1R expression STAT3-dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGF-1R activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL-6-induced stemness-related properties both in vitro and in vivo. Conclusions: The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL-6-induced IGF/IGF-1R activation, particularly in HBV-HCC. Citation Format: Te-Sheng Chang, Yu-Chih Wu, Ying-Huang Tsai, Yen-Hua Huang. Cancer stemness property incurred by inflammatory cytokine confers poor prognosis of hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1512. doi:10.1158/1538-7445.AM2015-1512

Endometriosis is the eutopic and/or ectopic growth of endometrial tissues. High levels of TGF-β in peritoneal fluid and increased expression of OCT4 have been well documented in endometriosis. However, the molecular mechanism between TGF-β and OCT4 expression in endometriosis still remains largely unknown. In this study, we examined the roles of OCT4 in TGF-β-induced endometrial cell migration and the progression of human ectopic endometriosis. We analyzed the plasma levels of TGF-β (n = 80) and gene expression levels of TGF-βR1 in patient tissues (n = 60) by an ELISA assay and quantitative real-time RT-PCR. The serum TGF-β and tissue TGF-βR1 expressions were significantly increased in the ectopic endometriotic tissues (n = 54, 29 for adenomyosis tissues and 25 for chocolate cysts) comparing with the normal endometrium (n = 5). The TGFβR1 transcriptional level in endometriotic tissues was positively correlated with expressions of OCT4 and genes associated with cell migration, such as VIMENTIN, TWIST, SNAIL and SLUG. TGF-β dose-dependently increased the OCT4 expression both in gene and protein levels in human endometriotic stromal cells and, at a less intensity, in HEC1A endometrial carcinoma cell line. Additionally, TGF-βincreased the expression of migration-associated genes and proteins (SNAIL and N-CAD) dose-dependently both in gene and protein levels in human endometriotic stromal cells. Knockdown of OCT4 significantly suppressed the TGF-β-induced the expressions of migration-associated genes and proteins (N-CAD and SNAIL), and promoted the migration of endometrial cells as evidenced by wound-closure and transwell assays. Conclusions: TGF-β,TGF-βRI, and OCT4 are significantly upregulated in human ectopic endometriotic tissues. The significant OCT4 expression may be involved in the pathology of ectopic endometrial growth through TGF-β-induced migration of endometrial cells. Citation Format: Te-Sheng Chang, Heng-Kien Au, Thai-Yen Ling, Ching-Chi Chi, Chii-Ruey Tzeng, Jui-Hung Chang, Yen-Hua Huang. TGF-β1 enhanced cell migration involving pluripotent transcription factor OCT4 in endometriosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5580. doi:10.1158/1538-7445.AM2014-5580

Expression of cancer stemness in hepatocellular carcinoma (HCC) is linked to drug resistance and tumor relapse which challenge the current therapy. However, mechanisms underlying the regulation of cancer stemness in HCC remain unclear. Effects of interleukin (IL)-6 and insulin-like growth factor I (IGF-I) on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter assays, RNA interference, secondary sphere formation, side population assay, and a xenograft animal model. Western blot analysis and immunohistochemical staining were used to detect the expression of OCT4/NANOG and phospho-IGF-I receptor (p-IGF-IR) in tissues. Levels of OCT4/NANOG and IGF-IR expressions were analyzed by real-time quantitative reverse transcriptase polymerase chain reaction (qPCR) and their association with tumor recurrence of hepatectomized HCC patients (n = 119) was determined using a Kaplan-Meier survival analysis. A high positive correlation between OCT4/NANOG and IGF-IR/p-IGF-IR expressions in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGF-IR was mostly confined to HBV-related HCC (HBV-HCC) and was significantly associated with early tumor recurrence. Investigation of the underlying mechanism showed that IL-6 stimulated the autocrinal IGF-I/IGF-IR expression in a STAT dependent manner, and IGF-I/IGF-IR activation promoted the expression of stemness-related properties of Hep3B cells in both cell lines and xenograft murine models. IL-6 stimulated the expression of stemness-related properties in Hep3B cells, and inhibition of IGF-IR activation significantly suppressed the IL-6’s effects both in vitro and in vivo. Conclusions: Expression of OCT4/NANOG is regulated by IL-6-mediated IGF/IGF-IR signaling in HBV-HCC and is associated with the early recurrence of HCC. Citation Format: Te-Sheng Chang, Thai-Yen Ling, Yu-Chih Wu, Wei-Chi Su, Jaw-Ching Wu, Ching-Chi Chi, Pey-Jium Chang, Jui-Hung Chang, Ya-Ting Yang, Kam-Fai Lee, Jun-Jen Liu, Shui-Yi Tung, Yen-Hua Huang, Liang-Mou Kuo, Hong-Nerng Ho, Yen-Hua Huang. IL-6 and IGF-1 receptor signal in stemness expression of HBV-related hepatocellular carcinoma . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1065. doi:10.1158/1538-7445.AM2013-1065

Hepatocellular carcinoma associated with chronic HBV hepatitis (HBV-HCC) tends to have a poorer prognosis. Inflammation is a common and strong participant in the development of HBV-HCC. However, the mechanism of HBV/inflammation-induced hepatocarcinogenesis still remains largely unknown. Here we demonstrate the potential synergistic role of HBV and proinflammatory cytokines in stemness expression which might associate with HBV-HCC recurrence. In this study, human HCC cell lines including HBV- HCC cells (HepG2.2.15, PLC5, Hep3B, and HA22T), and non-HBV HCC cells (HepG2 and Huh 7) were cultivated with inflammation condition medium (inflam-CM). Inflam-CM significantly increased the expression levels of pluripotent transcription factors (Oct-4, Sox2, and Nanog) and the percentage of side population cells in HBV-HCC but less or not in non-HBV HCC. Furthermore, flow-cytometry and epifluorescence analysis showed that inflam-CM markedly increased the GFP+ cell population in Oct-4 promoter-GFP-HepG2.2.15 cells but not in Oct-4 promoter-GFP-HepG2 cells, supporting the synergistic effect of proinflammatory cytokines and HBV in Oct-4 expression. To test the role of stemness expression in HCC prognosis, HA-Oct-4-HepG2 (HepG2 cells over-expressing HA-Oct-4) were used for drug sensitivity and migration/invasion assay. HA-Oct-4 HepG2 cells showed higher drug resistance and migration/invasion ability comparing with HepG2 cells. The responsible proinflammatory cytokines were to be identified using specific neutralizing antibodies and/or signaling inhibitors. The clinical impact was further analyzed using human HCC frozen tissues and tissue blocks which were collected under IRB approval. Real-time quantitative PCR analysis of HCC frozen tissues (N = 102) revealed a significant difference between HBV-HCC and HCV-HCC for the expression of Oct-4 (p=0.0089), Nanog (p=0.0021) and disease-free interval (DFI) (p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2713. doi:10.1158/1538-7445.AM2011-2713

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Inflammation of various etiologies has been documented to highly associate with the development of HCC. However, the role of inflammation in virus-induced hepatocarcinogenesis still remains largely unknown. Here we demonstrate that the potential synergistic effect of HBV and proinflammatory cytokines might associate with the poor prognosis of HBV-related HCC (HBV-HCC) via IGF-1R signaling activation. In this study, human HCC frozen tissues and tissue blocks were collected for clinical analysis under IRB approval. Real-time quantitative PCR analysis of HCC frozen tissues revealed a reciprocal correlation between the transcriptional levels of IGF-1R and disease-free interval (DFI) in HBV-HCC tissues (N=117). Immunohistochemical staining of HCC tissue blocks also showed a strong correlation between IGF-1R signaling activation (IGF-1R/phospho-IGF-1R) and short DFI. To test the collaborative effect of HBV and inflammation, human HCC cell lines including HBV-related cells (HepG2.2.15, PLC5, Hep3B, and HA22T) and non-HBV-related cells (HepG2 and Huh 7) were cultivated with inflammation condition medium (inflam-CM). We found that inflam-CM treatment significantly increased the levels of pluripotent regulator IGF-1/IGF-1R and IGF-1R signaling (phospho-IGF-1R and phospho-Akt) in HBV- HCC cells (HepG2.2.15 and Hep3B). Additionally, inflam-CM also markedly increased the drug resistance capacity of HepG2.2.15 and Hep3B cells. Blockage of IGF-1R phosphorylation by picropodophyllin (PPP) or down-regulation of IGF-1R by siRNA dramatically increased the drug sensitivity of HBV-HCC cells. Further analysis using neutralizing antibodies against potential proinflamatory cytokines is ongoing to identify the cross-talk between inflammation and IGF-1R signaling in HBV- HCCs. In summary, our works demonstrate that niche inflammation may activate the IGF-1R-Akt signaling and result in poor prognosis of HBV-HCC. This finding may provide a potential therapeutic target for HBV-HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1691. doi:10.1158/1538-7445.AM2011-1691

Background 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. Methods 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. Results 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 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. Conclusions 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.