The ω‐3 fatty acids exert as an antioxidant via the G protein‐coupled receptor 120 (GPR120). Icosapent ethyl, a purified eicosapentaenoic acid, showed a marked reduction in sudden cardiac death. ...Connexin43 is sensitive to redox status. We assessed whether icosapent ethyl attenuates fatal arrhythmias after myocardial infarction, a status of high oxidative stress, through increased connexin43 expression and whether the GPR120 signalling is involved in the protection. Male Wistar rats after ligating coronary artery were assigned to either vehicle or icosapent ethyl for 4 weeks. The postinfarction period was associated with increased oxidative‐nitrosative stress. In concert, myocardial connexin43 levels revealed a significant decrease in vehicle‐treated infarcted rats compared with sham. These changes of oxidative‐nitrosative stress and connexin43 levels were blunted after icosapent ethyl administration. Provocative arrhythmias in the infarcted rats treated with icosapent ethyl were significantly improved than vehicle. Icosapent ethyl significantly increased GPR120 compared to vehicle after infarction. The effects of icosapent ethyl on superoxide and connexin43 were similar to GPR120 agonist GW9508. Besides, the effects of icosapent ethyl on oxidative‐nitrosative stress and connexin43 phosphorylation were abolished by administering AH‐7614, an inhibitor of GPR120. SIN‐1 abolished the Cx43 phosphorylation of icosapent ethyl without affecting GPR120 levels. Taken together, chronic use of icosapent ethyl after infarction is associated with up‐regulation of connexin43 phosphorylation through a GPR120‐dependent antioxidant pathway and thus plays a beneficial effect on arrhythmogenic response to programmed electrical stimulation.
The first-line eradication rate of standard triple therapy for Helicobacter pylori infection has declined to <80%, and alternative therapies with >90% success rates are needed. Inconsistent ...eradication rates were reported for proton pump inhibitor- and amoxicillin-containing high-dose dual therapy.
We performed a prospective, randomized controlled study to assess the efficacy of esomeprazole- and amoxicillin-containing high-dose dual therapy and investigated the influencing clinical factors.
We recruited 240/278 eligible H. pylori-infected patients after exclusion. They were randomly assigned to 14 day high-dose dual therapy (esomeprazole 40 mg three times daily and amoxicillin 750 mg four times daily for 14 days; EA group) or 7 day non-bismuth quadruple therapy (esomeprazole 40 mg twice daily, clarithromycin 500 mg twice daily, amoxicillin 1 g twice daily and metronidazole 500 mg twice daily for 7 days; EACM group). Urea breath tests were followed up 8 weeks later.
The eradication rates for the EA and EACM groups were 91.7% (95% CI = 85.3%-96.0%) and 86.7% (95% CI = 79.3%-92.2%) (P = 0.21) in ITT analysis; and 95.7% (95% CI = 90.2%-98.6%) and 92.0% (95% CI = 85.4%-96.3%) (P = 0.26) in PP analysis. The adverse event rates were 9.6% versus 23.0% in the two groups (P = 0.01). The H. pylori culture positivity rate was 91.8%. The antibiotic resistance rates were amoxicillin, 0%; clarithromycin, 14.6%; and metronidazole, 33.7%.
A 14 day esomeprazole- and amoxicillin-containing high-dose dual therapy achieves a high eradication rate as first-line anti-H. pylori therapy, comparable to that with 7 day non-bismuth quadruple therapy but with fewer adverse events.
Human oral squamous cell carcinoma (OSCC) has been associated with a relatively low survival rate over the years and is characterized by a poor prognosis. C‐X3‐C motif chemokine ligand 1 (CX3CL1) has ...been involved in advanced migratory cells. Overexpressed CX3CL1 promotes several cellular responses related to cancer metastasis, including cell movement, migration and invasion in tumour cells. However, CX3CL1 controls the migration ability, and its molecular mechanism in OSCC remains unknown. The present study confirmed that CX3CL1 increased cell movement, migration and invasion. The CX3CL1‐induced cell motility is upregulated through intercellular adhesion molecule‐1 (ICAM‐1) expression in OSCC cells. These effects were significantly suppressed when OSCC cells were pre‐treated with CX3CR1 monoclonal antibody (mAb) and small‐interfering RNA (siRNA). The CX3CL1‐CX3CR1 axis activates promoted PLCβ/PKCα/c‐Src phosphorylation. Furthermore, CX3CL1 enhanced activator protein‐1 (AP‐1) activity. The CX3CR1 mAb and PLCβ, PKCα, c‐Src inhibitors reduced CX3CL1‐induced c‐Jun phosphorylation, c‐Jun translocation into the nucleus and c‐Jun binding to the ICAM‐1 promoter. The present results reveal that CX3CL1 induces the migration of OSCC cells by promoting ICAM‐1 expression through the CX3CR1 and the PLCβ/PKCα/c‐Src signal pathway, suggesting that CX3CL1‐CX3CR1‐mediated signalling is correlated with tumour motility and appealed to be a precursor for prognosis in human OSCC.
Field‐grown rice (Oryza sativa L.), when exposed to various environmental stresses, produces high amounts of reactive oxygen species, such as H2O2. MicroRNAs (miRNAs) play crucial roles in plant ...stress responses. This study characterized the functions of H2O2‐regulated miRNAs in rice. Small RNA deep sequencing revealed that miR156 levels decreased following H2O2 treatment. Searches of the rice transcriptome and degradome databases indicated that OsSPL2 and OsTIFY11b are miR156‐target genes. Interactions between miR156 and OsSPL2 and OsTIFY11b were confirmed using transient expression assays through agroinfiltration. In addition, the levels of OsSPL2 and OsTIFY11b transcripts were lower in transgenic rice plants overexpressing miR156 than in wild‐type plants. The OsSPL2‐GFP and OsTIFY11b‐GFP proteins were localized to the nucleus. Yeast two‐hybrid and bimolecular fluorescence complementation assays indicated interactions between OsSPL2 and OsTIFY11b. Furthermore, OsTIFY11b interacted with OsMYC2 to regulate the expression of OsRBBI3‐3, which encodes a proteinase inhibitor. The results suggested that H2O2 accumulation in rice suppresses the expression of miR156, and induces the expression of its target genes, OsSPL2 and OsTIFY11b, whose proteins interact in the nucleus to regulate the expression of OsRBBI3‐3, which is involved in plant defense.
Summary Statement
Plants encountering environmental stress produce reactive oxygen species including H2O2 with a relatively long half‐life. Baes on the analyses of small RNA deep sequencing, degradome, and transcriptome, H2O2 represses the expression of miR156, and its target genes OsSPL2 and OsTIFY11b were then induced in rice. The interaction between OsSPL2 and OsTIFY11b in nucleus was verified by yeast two‐hybrid and bimolecular fluorescence complementation assays. OsTIFY11b, a JAZ protein, also interacts with OsMYC2, which further regulates the expression of OsRBBI3‐3 encoding a proteinase inhibitor involved in defense regulation.
•We propose an integrated FMEA-and-AHP framework to select new suppliers.•The MFMEA is based on the six-aspect criteria and supply chain risk.•An IC assembly company is studied to validate the MFMEA ...method.•The MFMEA can categorize new suppliers effectively and select a low-risk supplier.
In the emerging supply chain environment, supply chain risk management plays a more important role than ever. Companies must focus not only on the efficiency of supply chain, but also on its risks. If an unanticipated event occurs, all of the supply chain members will be impacted, and the result will cause significant loss. Therefore, this research proposes a modified failure mode and effects analysis (MFMEA) method to select new suppliers from the supply chain risk’s perspective and applies the analytic hierarchy process (AHP) method to determine the weight of each criterion and sub-criterion for supplier selection. An IC assembly company is then studied to validate this model. The result shows that the case company can categorize its suppliers more effectively and at the same time select a low-risk supply chain partner. Moreover, the case company can provide unsatisfactory suppliers with valuable feedback that will help them improve and become its partners in the future.
Metformin is proposed to have chemopreventive effect of various cancer currently. However, the anti-cancer effect of metformin for diabetic patients with hepatocellular carcinoma (HCC) undergoing ...liver resection remains unclear. The aim of our cohort study was to assess whether metformin influence the recurrence of HCC.
We retrospectively enrolled 857 HCC patients who received primary resection from April 2001 to June 2016. 222 patients were diagnosed with diabetes mellitus (DM) from medical record. Factors influence the overall survival (OS) and recurrence-free survival (RFS) were analyzed by multivariate analysis.
During the follow-up period (mean, 75 months), 471 (54.9%) patients experienced recurrence, and 158 (18.4%) patients died. Multivariate analysis revealed that DM (p = 0.015), elevated AST (p = 0.006), hypoalbuminemia (p = 0.003), tumor number (p = 0.001), tumor size (p < 0.001), vascular invasion (p <0.001), high Ishak fibrosis score (p <0.001), hepatitis B (p = 0.014), hepatitis C (p = 0.001) were independent predictors for RFS. In diabetic patients, only HbA1c>9% (p = 0.033), hypoalbuminemia (p = 0.030) and vascular invasion (p = 0.001) were independent risk factors for HCC recurrence; but the metformin use revealed no significance on recurrence. DM is a risk factor of HCC recurrence after resection. Adequate DM control can reduce the recurrence of HCC. However, the use of metformin does not reduce the risk of HCC recurrence in diabetic patient after initial resection. Hence, metformin may not have protective influences on HCC recurrence in diabetic patients who undergo initial liver resection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
The eradication rates of sequential therapy are high in clinical trials; however, the adherence for follow‐up or the patient population in a real‐world setting might be different from ...those in trails. This study investigates the effectiveness of sequential therapy in a real‐world setting and the factors that lead to treatment failure.
Materials and Methods
In this retrospective study, patients receiving sequential therapy as a first‐line anti‐Helicobacter pylori (H. pylori) treatment in a real‐world setting were reviewed. The age adjusted Charlson Comorbidity Index (age‐CCI) and baseline variety of medications were reviewed to determine factors correlated with nonadherence for post‐treatment testing and H. pylori eradication failure.
Results
A total of 1053 patients were reviewed. A total of 579 patients receiving sequential therapy were included in the analyses. Among them, 462 received post‐treatment testing and were placed into the follow‐up group. Thus, the post‐treatment testing rate was 79.8%. Stroke was an independent factor of nonadherence for post‐treatment testing. In the follow‐up group, the eradication failure rate was 8.2%. Female sex (odds ratio OR 2.41 95% CI 1.16–5.03, p = 0.02) and age‐CCI ≥2 (OR 3.16 1.05–9.48, p = 0.04) were independent factors of H. pylori eradication failure. The eradication failure rates were 14.4%, 7.8%, 7.1%, and 3.1% for the females with age‐CCI ≥2, females with age‐CCI <2, males with age‐CCI ≥2, and males with age‐CCI <2 subgroups, respectively (p = 0.027).
Conclusions
In a real‐world setting, the adherence rate of post‐treatment testing for sequential therapy as a first‐line anti‐H. pylori treatment was found to be suboptimal. Female sex and age‐CCI ≥2 were independent factors of eradication failure.
Polymorphisms in interferon (IFN)L3 (encodes IFNλ3 or interleukin 28B) are associated with outcomes of treatment for hepatitis C virus (HCV) infection. However, there is controversy regarding how ...polymorphisms in IFNL3 affect the risk for development of hepatocellular carcinoma (HCC) in patients treated with pegylated interferon and ribavirin.
In a retrospective study, we analyzed data from 1118 patients with HCV infection (589 men; median age, 60 y; 49.9% infected with genotype 1; 51.3% with advanced fibrosis) treated with pegylated interferon and ribavirin from March 2000 through October 2009 at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan (71.64% achieved sustained virologic response SVR). Baseline samples were collected before therapy. Starting 24 weeks after treatment, clinical and biochemical features were assessed every 3 to 6 months and patients underwent ultrasound examinations. Lesions detected were examined by computed tomography, angiography, or fine-needle aspiration biopsy analyses. Patients were followed up from the initiation of HCV therapy until a diagnosis of HCC (based on published guidelines), death, or March 31, 2013 (median, 60 mo). DNA samples from each patient were analyzed for rs12979860 in IFNL3. Kaplan-Meier analysis was used to determine the risk for development of HCC.
The percentages of patients with the IFNL3 rs12979860 CC, CT, and TT genotypes were 86.4%, 13.2%, and 0.3%, respectively. A total of 108 patients (9.66%) developed HCC. The IFNL3 rs12979860 CT and TT genotypes correlated with high baseline levels of α-fetoprotein (AFP; ≥20 ng/mL), advanced stage of fibrosis, diabetes, or lack of an SVR (all P < .05). Based on multivariate Cox regression analysis, age 60 years and older, low platelet count (<15 × 10(9) cells/L), AFP level of 20 ng/mL or greater, advanced stage fibrosis, diabetes, lack of an SVR, and the IFNL3 rs12979860 CT and TT genotypes were significant risk factors for HCC (P < .05). Age 60 years and older, low numbers of platelets or high AFP level, and advanced fibrosis were risk factors for HCC among patients with a SVR. The IFNL3 rs12979860 genotype did not have a significant effect on risk for HCC among patients with SVRs, although some of these patients (with the CT or TT genotype) did develop HCC. Among patients without SVRs, only fibrosis stage and the IFNL3 rs12979860 CT and TT genotypes (hazard ratio, 1.80; 95% confidence interval, 1.06-3.07; P = .030) were independent risk factors for HCC.
Based on a retrospective study of patients treated for HCV infection, the IFNL3 rs12979860 CT and TT polymorphisms are associated with a risk for HCC, especially in patients without a SVR.
Immune checkpoint inhibitors (ICIs) combined with multitarget tyrosine kinase inhibitors (MTKIs) exert a synergistic effect and are effective in unresectable hepatocellular carcinoma (uHCC). However, ...precise data regarding the real-world clinical applications of these combination therapies in uHCC are lacking. This study compared the treatment efficacy of sorafenib versus lenvatinib in combination with programmed cell death protein-1 (PD-1) inhibitors in patients with uHCC in a clinical setting. Among 208 patients with uHCC treated with PD-1 inhibitors, 88 were administered with ICIs in combination with sorafenib or lenvatinib. The treatment response and survival outcomes were evaluated. Predictors of survival were assessed by multivariate analysis. A total of 49 patients were treated with PD-1 inhibitors combined with sorafenib, and 39 patients were treated with PD-1 inhibitors combined with lenvatinib. The lenvatinib group exhibited a stronger objective response rate (ORR) (20.51% vs. 16.33%) and had a higher disease control rate (41.03% vs. 28.57%) than did the sorafenib group. The median overall survival was longer in the lenvatinib group than the sorafenib group (13.1 vs. 7.8 months; hazard ratio = 0.39,
= 0.017). The incidence of treatment-related adverse events was similar. PD-1 inhibitors combined with lenvatinib can be a feasible treatment strategy for HCC patients receiving MTKI-based combination therapy. PD-1 inhibitors combined with lenvatinib resulted in more favorable survival outcomes without increased toxic effects compared with PD-1 inhibitors with sorafenib. Additional larger-scale and prospective studies should be conducted to verify the study results.
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