Ten-Day Vonoprazan-Amoxicillin Dual Therapy vs Standard 14-Day Bismuth-Based Quadruple Therapy for First-Line Helicobacter pylori Eradication: A Multicenter Randomized Clinical Trial.

INTRODUCTION: Whether 10-day short-course vonoprazan-amoxicillin dual therapy (VA-dual) is noninferior to the standard 14-day bismuth-based quadruple therapy (B-quadruple) against Helicobacter pylori eradication has not been determined. This trial aimed to compare the eradication rate, adverse events, and compliance of 10-day VA-dual regimen with standard 14-day B-quadruple regimen as first-line H. pylori treatment. METHODS: This prospective randomized clinical trial was performed at 3 institutions in eastern China. A total of 314 treatment-naive, H. pylori -infected patients were randomly assigned in a 1:1 ratio to either 10-day VA-dual group or 14-day B-quadruple group. Eradication success was determined by 13 C-urea breath test at least 4 weeks after treatment. Eradication rates, adverse events, and compliance were compared between groups. RESULTS: Eradication rates of VA-dual and B-quadruple groups were 86.0% and 89.2% ( P = 0.389), respectively, by intention-to-treat (ITT) analysis; 88.2% and 91.5% ( P = 0.338), respectively, by modified ITT analysis; and 90.8% and 91.3% ( P = 0.884), respectively, by per-protocol (PP) analysis. The efficacy of the VA-dual remained noninferior to B-quadruple therapy in all ITT, modified ITT, and PP analyses. The incidence of adverse events in the VA-dual group was significantly lower compared with that in the B-quadruple group ( P < 0.001). Poor compliance contributed to eradication failure in the VA-dual group ( P < 0.001), while not in the B-quadruple group ( P = 0.110). DISCUSSION: The 10-day VA-dual therapy provided satisfactory eradication rates of >90% (PP analysis) and lower rates of adverse events compared with standard 14-day B-quadruple therapy as first-line H. pylori therapy. TRAIL REGISTRATION NUMBER: ChiCTR2300070100.

RIG-I Promotes Cell Viability, Colony Formation, and Glucose Metabolism and Inhibits Cell Apoptosis in Colorectal Cancer by NF-κB Signaling Pathway.

BACKGROUND: Retinoic acid-inducible gene-I (RIG-I) has crucial effects on various cancers, while RIG-I's detailed roles and mechanism in colorectal cancer (CRC) are uncovered. METHODS: qRT-PCR was used to detect the expression of RIG-I in CRC, adjacent nontumor specimens, and five cell lines. CCK-8, colony formation, and flow cytometry assays were conducted to study CRC cell viabilities. Extracellular acidification rates, lactate analysis, and ATP analysis were conducted to study the cell viabilities and glucose metabolism of CRC cells. Western blot is used to determine the proteins of NF-κBp65 in the nucleus and cytoplasm. RESULTS: This study revealed the upregulation of RIG-I in CRC tissues and cells and that high RIG-I expression was correlated with poor prognosis of CRC patients. In addition, silencing RIG-I inhibited cell viability as well as colony formation and promoted cell apoptosis in CRC cells, while RIG-I knockdown suppressed transplanted tumor growth and facilitated apoptosis in nude mice. Moreover, silencing RIG-I inhibited glucose metabolism by decreasing extracellular acidification rate, lactate production, adenosine triphosphate, and content of hypoxia-inducible factor 1α and pyruvate kinase isoform. 2.2-Deoxy-d-glucose, a glycolysis inhibitor, reduced the growth of CRC cells and promoted apoptosis in vitro and in vivo. In addition, RIG-I knockdown decreased NF-κB nuclear translocation. Besides, inhibiting NF-κB effectively eliminated RIG-I overexpression roles in cell viability and glucose metabolism in CRC cells. CONCLUSION: In summary, this study revealed that RIG-I mediated CRC cell proliferation, apoptosis, and glucose metabolism at least partly by NF-κB signaling pathway.

Impact of tumour size on metastasis and survival in patients with pancreatic neuroendocrine tumours (PNETs): A population based study.

Background: The relationship between tumour size and metastasis rate is poorly recognized in patients with pancreatic neuroendocrine tumours (PNETs). The impact of tumour size on prognosis was controversial in previous investigations. Methods: PNETs cases diagnosed from 1988 to 2013 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic features were retrospectively analyzed. Survival was calculated by the Kaplan-Meier method. Multivariable Cox regression models with hazard ratios (HRs) were constructed to analyze survival outcomes and risk factors. Cubic spline analysis was used to assess relationship between tumor size and probability of metastasis. Results: A total of 5424 patients were identified, 1226 (22.6%) with tumour size of 20mm or less. The probability of metastasis increased in a non-linear fashion with increasing tumour size. Univariate analysis showed that tumour size was significantly correlated with survival (P<0.001), no matter surgery was performed or not. However, subgroup analysis suggested this association to be linear for patients with localized and regional tumours (P<0.001), but stochastic in patients with distant stages (P=0.703). On multivariate analysis, tumour size was an indicator for metastasis (HR=1.010, 95%CI: 1.008-1.013, P<0.001) and size≤20mm was an independent prognostic factor for good survival. For tumours≤20mm, surgical treatment was associated with significantly improved survival (P<0.001). Conclusions: Tumour size affects the probability of metastasis. Its prognostic impact on survival is restricted to patients with localized and regional disease. For patients with tumour size ≤20mm, surgical treatment should be considered preferably.

Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments.

Senescent microenvironments play an important role in tumor progression. Here, we report that doxorubicin (DOX)-pretreated or replicative senescent stromal cells (WI-38 and HUVEC) promote colorectal cancer (CRC) cell growth and invasion in vitro and in vivo. These pro-tumorigenic effects were attenuated by exogenous administration of Klotho, an anti-aging factor. We subsequently identified several senescence-associated secretory phenotype (SASP)-associated genes, including CCL2, which were significantly upregulated in both types of senescent stromal cells during replication and DNA damage-induced senescence. Importantly, we found that the secretion of CCL2 by senescent stromal cells was significantly higher than that seen in nonsenescent cells or in senescent cells pretreated with Klotho. Notably, CCL2 was found to accelerate CRC cell proliferation and invasion, while this effect could be blocked by administration of a specific CCR2 antagonist. We further show that Klotho can suppress NF-κB activation during DOX-induced senescence and thus block CCL2 transcription. Low expression of Klotho, or high expression of CCL2 in patient tumor tissues, correlated with poor overall survival of CRC patients. Collectively, our findings suggest that senescent stromal cells are linked to progression of CRC. Klotho can suppress the senescent stromal cell-associated triggering of CRC progression by inhibiting the expression of SASP factors including CCL2. The identification of key SASP factors such as CCL2 may provide potential therapeutic targets for improving CRC therapy.

[Mechanism of sophocarpine in treating experimental colitis in mice].

To study the preventive effect of sophocarpine (Soc) on dextran sulfate sodium (DSS)-induced colitis in mice, in order to analyze the influence of Soc on toll like receptor 4 (TLR4)/mitogen-activated protein kinases (MAPKs) and janus tyrosine kinase 2 signal transducer and activator of transcription 3 (JAK2/STAT3) signal pathways in mice intestinal tissues. The mice was given 2.5% DSS for 6 days to induce the acute colitis model. The Soc-treated group was intraperitoneally injected with sophocarpine 30 mg · kg(-1) · d(-1) since the day before the experiment to the end. The disease activity index (DAI) was assessed everyday, and the colonic morphology and histological damage were observed with HE staining. The mRNA expressions of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were detected by real-time RT-PCR. The changes in key protein kinase p38 mitogen-activated protein kinase (p38MAPK), c-Jun NH2-terminal protein kinase1/2 (JNK1/2), extracellular signal-regulated kinase1/2 (ERK1/2), JAK2, STAT3 in TLR4/MAPKs and JAK2/STAT3 signaling pathways were detected by western blot. The result showed that the model group showed statistical significance in body weight, DAI, colon length and histopathological changes compared with the normal group (P <0.05); however, the Soc-treated group showed significant improvements in the above indexes compared with the model group (P <0.05). TNF-α, IL-1ß and IL-6 in the model group was significantly higher than that in the normal group (P <0.05), but lowered in the Soc-treated group to varying degrees (P <0.05). In the normal group, the expressions of TLR4 and the phosphorylation of P38, JNK1/2, JAK2, STAT3 were at low levels; in the model group, the phosphorylation of P38, JNK1/2, JAK2, STAT3 increased; the Soc-treated group showed a decrease in TLR4 expression compared with the model group, with notable declines in the phosphorylation of TLR4, P38, JNK1/2, JAK2, STAT3. These findings indicate that Soc can inhibit TLR4/MAPKs, K2/STAT3 signaling pathway activation, reduce the expression of proinflammatory cytokines TNF-α, IL-1ß and IL-6 and relieve inflammatory reactions, so as to effectively prevent experimental colitis.

[Analysis of risk factors for anastomotic infectious complications following bowel resection for Crohn disease].

OBJECTIVE: To investigate the risk factors for anastomotic infectious complications after bowel resection in patients with Crohn disease. METHODS: Clinical data of 124 patients with Crohn disease undergoing bowel resection between January 1990 and October 2012 were analyzed retrospectively. The risk factors were identified by χ(2) test and Logistic regression. RESULTS: Fourteen patients (12.3%, 14/114) developed anastomotic infectious complications in the postoperative period, including anastomotic leak (n=7), intra-abdominal abscess (n=6), and enterocutaneous fistula (n=1). Crohn disease activity index (CDAI)>150 (OR=2.185, 95%CI:1.098-6.256, P=0.040), steroid usage (OR=2.674, 95%CI:1.118-8.786, P=0.027), and the presence of preoperative abscess/fistula (OR=3.447, 95%CI:1.254-10.462, P=0.014) were identified as independent risk factors of anastomotic infectious complications. In the absence of these 3 risk factors, the rate of anastomotic infectious complication was 5.7% (3/53), which increased to 11.4% (4/35) when one risk factor was present, 21.1% (4/19) when two risk factors were present, and 42.9% (3/7) when all the 3 risk factors were present. CONCLUSIONS: CDAI>150, steroid usage and preoperative abscess/fistula are associated with higher rates of anastomotic infectious complications following bowel resection for Crohn disease. A prudent management should be carried out if risk factors can not be eliminated preoperatively.