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.
Co-infection of
and
is a microbial biomarker for poor prognosis of gastric cancer patients.
is associated with microsatellite instability and the accumulation of mutations in colorectal cancer. Here, ...we investigated the mutation landscape of
-positive resected gastric cancer tissues using Illumina TruSight Oncology 500 comprehensive panel. Sequencing data were processed to identify the small nucleotide variants, small insertions and deletions, and unstable microsatellite sites. The bioinformatic algorithm also calculated copy number gains of preselected genes and tumor mutation burden. The recurrent genetic aberrations were identified in this study cohort. For gene amplification events, ERBB2, cell cycle regulators, and specific FGF ligands and receptors were the most frequently amplified genes. Pathogenic activation mutations of ERBB2, ERBB3, and PIK3CA, as well as loss-of-function of TP53, were identified in multiple patients. Furthermore,
infection is positively correlated with a higher tumor mutation burden. Survival analysis showed that the combination of
infection and high tumor mutation burden formed an extremely effective biomarker to predict poor prognosis. Our results indicated that the ERBB2-PIK3-AKT-mTOR pathway is frequently activated in gastric cancer and that
and high mutation burden are strong biomarkers of poor prognosis for gastric cancer patients.
Real-world data on the effectiveness of glecaprevir/pibrentasvir (GLE/PIB) for patients with HCV infection and compensated cirrhosis is limited, especially for the 8-week regimen and in an Asian ...population. This retrospective study enrolled 159 consecutive patients with HCV and compensated cirrhosis who were treated with GLE/PIB at a single center in Taiwan. Sustained virological response (SVR) and adverse events (AEs) were evaluated. Among the 159 patients, 91 and 68 were treated with GLE/PIB for 8 and 12 weeks, respectively. In the per protocol analysis, both the 8- and 12-week groups achieved 100% SVR (87/87 vs. 64/64); and in the evaluable population analysis, 95.6% (87/91) of the 8-week group and 94.1% (64/68) of the 12-week group achieved SVR. The most commonly reported AEs, which included pruritus (15.4% vs. 26.5%), abdominal discomfort (9.9% vs. 5.9%), and skin rash (5.5% vs. 5.9%), were mild for the 8- and 12-week groups. Two patients in the 8-week group exhibited total bilirubin elevation over three times the upper normal limit. One of these two patients discontinued GLE/PIB treatment after 2 weeks but still achieved SVR. Both 8- and 12-week GLE/PIB treatments are safe and effective for patients of Taiwanese ethnicity with HCV and compensated cirrhosis.
Abstract
Clinical trials showed pangenotypic direct-acting antivirals’ (DAAs) excellent efficacy and safety when treating hepatitis C virus (HCV). Two pangenotypic regimens were examined, ...glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), in a real-world Taiwanese setting, including all HCV patients treated with GLE/PIB or SOF/VEL from August 2018 to April 2020. The primary endpoint was sustained virologic response 12 weeks after treatment cessation (SVR12), including adverse events (AEs). A total of 1,356 HCV patients received pangenotypic DAA treatment during the study: 742 and 614 received GLE/PIB and SOF/VEL, respectively. The rates of SVR12 for GLE/PIB and SOF/VEL were 710/718 (98.9%) and 581/584 (99.5%), respectively, by per-protocol analysis, and 710/742 (95.7%) and 581/614 (94.6%), respectively, by evaluable population analysis. Eleven (GLE/PIB: 8, SOF/VEL: 3) did not achieve SVR12. The most common AEs for GLE/PIB and SOF/VEL were pruritus (17.4% vs. 2.9%), abdominal discomfort (5.8% vs. 4.4%), dizziness (4.2% vs. 2%), and malaise (3.1% vs. 2.9%). Laboratory abnormalities were uncommon; only < 1% exhibited elevated total bilirubin or aminotransferase levels with both regimens. Five drug discontinuations occurred due to AEs (bilirubin elevation: 3; dermatological issues: 2). Pangenotypic DAAs GLE/PIB and SOF/VEL are effective and well tolerated, achieving high SVR12 rates for patients with all HCV genotypes.
Background/Aims: Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related deaths worldwide. PRDXs are antioxidant enzymes that play an important ...role in cell differentiation, proliferation and apoptosis and have diverse functions in malignancy development. However, the mechanism of aberrant overexpression of PRDX6 in CRC remains unclear. Methods: Boyden chamber assay, flow cytometry and a lentiviral shRNA targeting PRDX6 and transient transfection with pCMV-6-PRDX6 plasmid were used to examine the role of PRDX6 in the proliferation capacity and invasiveness of CRC cells. Immunohistochemistry (IHC) with tissue array containing 40 paraffin- embedded CRC tissue specimens and Western blot assays were used to detect target proteins. Results: PRDX6 was significantly up-expressed in different comparisons of metastasis of colorectal adenomas in node-positive CRC (P = 0.03). In in vitro HCT-116, PRDX6 silencing markedly suppressed CRC cell migration and invasiveness while also inducing cell cycle arrest as well as the generation of reactive oxygen species (ROS); specific overexpression of PRDX6 had the opposite effect. Mechanistically, the PRDX6 inactivation displayed decreased levels of PRDX6, N-cadherin, β-catenin, Vimentin, Slug, Snail and Twist-1 through the activation of the PI3K/ AKT/p38/p50 pathways, but they were also significantly inhibited by PRDX6 transfectants. There was also increased transcriptional activation of dimethylation of histone H3 lysine 4 (H3K4me3) of PRDX6 promoter via the activation of the PI3K/Akt/NFkB pathways. Conclusion: Our findings demonstrated that PRDX6 expression plays a characteristic growth-promoting role in CRC metastasis. This study suggests that PRDX6 may serve as a biomarker of node-positive status and may have a role as an important endogenous regulator of cancer cell tumorigenicity in CRC. PRDX6 may also be an effective therapeutic target.
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 stromal cell-derived factor-1 (SDF-1)/CXC receptor 4 (CXCR4) axis plays an important role in tumor angiogenesis and invasiveness in colorectal cancer (CRC) progression. In addition, metastatic ...CRC remains one of the most difficult human malignancies to treat because of its chemoresistant behavior. However, the mechanism by which correlation occurs between CXCR4 and the clinical response of CRC to chemotherapy remains unknown. We generated chemoresistant cells with increasing doses of oxaliplatin (OXA) and 5-Fluorouracil (5FU) to develop resistance at a clinical dose. We found that the putative markers did not change in the parental cells, but HCT-116/OxR and HCT-116/5-FUR were more aggressive and had higher tumor growth (demonstrated by wound healing, chemotaxis assay, and a nude mice xenograft model) with the use of oxaliplatin. Apoptosis induced by oxaliplatin treatment was significantly decreased in HCT-116/OxR compared to the parental cells. Moreover, HCT-116/OxR cells displayed increased levels of p-gp, p-Akt p-ERK, p-IKBβ, CXCR4, and Bcl-2, but they also significantly inhibited the apoptotic pathways when compared to the parental strain. We evaluated the molecular mechanism governing the signaling pathway associated with anti-apoptosis activity and the aggressive status of chemoresistant cells. Experiments involving specific inhibitors demonstrated that the activation of the pathways associated with CXCR4, ERK1/2 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K)/Akt is critical to the functioning of the HCT-116/OxR and HCT-116/5-FUR characteristics of chemosensitivity. These findings elucidate the mechanism of CXCR4/PI3K/Akt downstream signaling and provide strategies to inhibit CXCR4 mediated signaling pathway in order to overcome CRC's resistance to chemotherapy.
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
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.
Erinacine A, a major active component of a diterpenoid derivative isolated from Hericium erinaceus mycelium, has been demonstrated to exert anticancer effects. Herein, we present an investigation of ...the molecular mechanism of erinacine A induction associated with cancer cells’ aggressive status and death. A proteomic approach was used to purify and identify the differentially expressed proteins following erinacine A treatment and the mechanism of its action in apoptotic and the targets of erinacine A. Our results demonstrate that erinacine A treatment of HCT‐116 and DLD‐1 cells increased cell cytotoxicity and reactive oxygen species (ROS) production as well as decreased cell proliferation and invasiveness. Ten differentially displayed proteins were determined and validated in vitro and in vivo between the erinacine A‐treated and untreated groups. In addition, erinacine A time‐dependent induction of cell death and inhibitory invasiveness was associated with sustained phosphorylation of the PI3K/mTOR/p70S6K and ROCK1/LIMK2/Cofilin pathways. Furthermore, we demonstrated that erinacine A–induced HCT‐116 and DLD‐1 cells viability and anti‐invasion properties by up‐regulating the activation of PI3K/mTOR/p70S6K and production of ROS. Experiments involving specific inhibitors demonstrated that the differential expression of cofilin‐1 (COFL1) and profilin‐1 (PROF1) during erinacine A treatment could be involved in the mechanisms of HCT‐116 and DLD‐1 cells death and decreased aggressiveness, which occurred via ROCK1/LIMK2/Cofilin expression, with activation of the PI3K/mTOR/p70S6K signalling pathway. These findings elucidate the mechanism of erinacine A inhibiting the aggressive status of cells by activating PI3K/mTOR/p70S6K downstream signalling and the novel protein targets COF1 and PROF1; this could be a good molecular strategy to limit the aggressiveness of CRC cells.
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