Evaluation of the causal effects of blood metabolites on irritable bowel syndrome: Mendelian randomization.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain, discomfort, and changes in bowel habits. The mechanism underlying IBS remains unclear, and little evidence exists for clarifying the causal relationship between blood metabolites and IBS. METHODS: We conducted a Mendelian randomization (MR) study using two samples. Exposure data for 7824 Europeans were extracted from a genome-wide association study (GWAS) on metabolite levels. The IBS GWAS data from the GWAS database were used for the initial analysis. The primary analysis of causal relationships was conducted using inverse-variance weighting (IVW) with MR-Egger and weighted medians as supplementary analyses. Sensitivity analyses were performed using a combination of the Cochran's Q test, MR-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier, and leave-one-out analysis. For significant associations, replication and meta-analyses were performed using additional independent IBS case GWAS data released by the FinnGen Consortium R9. To identify the metabolites, score regression, confounding analysis, and reverse MR were performed to further assess the causal relationships between the metabolites. RESULTS: After rigorous screening, we identified four known metabolites to be associated with IBS (stearate, odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.59-0.92; arginine, OR: 1.36, 95% CI: 1.07-1.74; 1-palmitoylglycerol, OR:1.49, 95% CI: 1.07-2.07; 1-palmitoylglycerophosphoinositol, OR: 0.84, 95% CI: 0.71-0.99). CONCLUSIONS: MR analysis revealed a causal relationship between the four metabolites and IBS, providing preliminary evidence for the pathogenesis of IBS. Our results provide novel insights into the potential biomarkers of IBS.

LINC00339 accelerates invasion and migration of colorectal cancer via mediating miRNA-30a-5p.

To analyze the biological function of LINC00339 in the progression of colorectal cancer (CRC). We aim to provide directions in the early-stage treatment of CRC. LINC00339 level in 60 paired CRC tissues and paracancerous tissues was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between the LINC00339 level and clinical parameters was analyzed. Moreover, the LINC00339 level in CRC cell lines was determined as well. LINC00339 expression was changed in HCT-8 and HCT-116 cell lines by transfection of LINC00339 overexpression plasmid or anti-LINC00339. The regulatory effects of LINC00339 on the migratory and invasive abilities of CRC cells were evaluated through a series of functional experiments. Dual-luciferase reporter gene assay and rescue experiments were conducted to verify the interaction of LINC00339 and miRNA-30a-5p in mediating the progression of CRC. LINC00339 was upregulated in CRC tissues relative to paracancerous tissues. CRC patients with higher levels of LINC00339 had higher rates of lymph node metastasis and distant metastasis, and worse prognosis than those with lower levels. Knockdown of LINC00339 attenuated migratory and invasive abilities of HCT-116 cells. Overexpression of LINC00339 in HCT-8 obtained the opposite trends. In addition, we verified a negative correlation between LINC00339 and miRNA-30a-5p in CRC tissues. LINC00339 served as a ceRNA to absorb miRNA-30a-5p. Rescue experiments confirmed that miRNA-30a-5p knockdown revered the regulatory effects of LINC00339 on the migratory and invasive abilities of CRC cells. LINC00339 was closely correlated to metastasis and poor prognosis of CRC. It accelerates CRC cells to migrate and invade via mediating miRNA-30a-5p.

Comparison of complications and bowel function among different reconstruction techniques after low anterior resection for rectal cancer: a systematic review and network meta-analysis.

BACKGROUND: Anastomosis for gastrointestinal reconstruction has been contentious after low anterior resection of rectal cancer for the past 30 years. Despite the abundance of randomized controlled trials (RCTs) on colon J-pouch (CJP), straight colorectal anastomosis (SCA), transverse coloplast (TCP), and side-to-end anastomosis (SEA), most studies are small and lack reliable clinical evidence. We conducted a systematic review and network meta-analysis to evaluate the effects of the four anastomoses on postoperative complications, bowel function, and quality of life in rectal cancer. METHODS: We assessed the safety and efficacy of CJP, SCA, TCP, and SEA in adult patients with rectal cancer after surgery by searching the Cochrane Library, Embase, and PubMed databases to collect RCTs from the date of establishment to May 20, 2022. Anastomotic leakage and defecation frequency were the main outcome indicators. We pooled data through a random effects model in a Bayesian framework and assessed model inconsistency using the deviance information criterion (DIC) and node-splitting method and inter-study heterogeneity using the I-squared statistics (I2). The interventions were ranked according to the surface under the cumulative ranking curve (SUCRA) to compare each outcome indicator. RESULTS: Of the 474 studies initially evaluated, 29 were eligible RCTs comprising 2631 patients. Among the four anastomoses, the SEA group had the lowest incidence of anastomotic leakage, ranking first (SUCRASEA = 0.982), followed by the CJP group (SUCRACJP = 0.628). The defecation frequency in the SEA group was comparable to those in the CJP and TCP groups at 3, 6, 12, and 24 months postoperatively. In comparison, the defecation frequency in the SCA group 12 months after surgery all ranked fourth. No statistically significant differences were found among the four anastomoses in terms of anastomotic stricture, reoperation, postoperative mortality within 30 days, fecal urgency, incomplete defecation, use of antidiarrheal medication, or quality of life. CONCLUSIONS: This study demonstrated that SEA had the lowest risk of complications, comparable bowel function, and quality of life compared to the CJP and TCP, but further research is required to determine its long-term consequences. Furthermore, we should be aware that SCA is associated with a high defecation frequency.

The Prognostic Value of a Pathologic Complete Response After Neoadjuvant Therapy for Digestive Cancer: Systematic Review and Meta-Analysis of 21 Studies.

BACKGROUND: Neoadjuvant therapy (NAT) before radical excision has become the preferred initial option for locally advanced digestive cancers such as esophageal cancer (EC), esophagogastric junction adenocarcinoma (EGJAC), gastric adenocarcinoma (GAC), rectal cancer (RC), and pancreatic cancer (PC). Although some patients reportedly achieve a pathologic complete response (pCR) after neoadjuvant therapy, the published data are inconsistent regarding whether pCR yields a survival benefit. The current meta-analysis was performed to assess the potential prognostic value of pCR after preoperative therapy for patients with digestive cancers. METHODS: An extensive electronic search in PubMed, Web of Science, and the Cochrane Library was performed for relevant articles, from which data relative to independent correlations of pCR with overall survival (OS) and disease-free survival (DFS) were extracted for analysis. A random-effects model was used to calculate the pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs). RESULTS: The study identified 6780 patients who met the inclusion and exclusion criteria. The results showed that pCR was significantly correlated with better OS (HR, 0.50; 95% CI, 0.43-0.58; P < 0.001) and DFS (HR, 0.49; 95% CI, 0.40-0.60; P < 0.001) for the digestive cancer patients who achieved pCR than for those who did not achieve pCR. Subgroup analysis showed that the correlation of pCR with OS was significant in EC (HR, 0.57; 95% CI, 0.47-0.69; P < 0.001), EGJAC/GAC (HR, 0.38; 95% CI, 0.17-0.86; P = 0.02), RC (HR, 0.48; 95% CI, 0.28-0.81; P = 0.006), and PC (HR, 0.41; 95% CI, 0.17-0.97; P = 0.04). In addition, the survival benefit for pCR patients was of similar magnitude, irrespective of the type of study, type of NAT, or ethnicity. CONCLUSIONS: A pCR is correlated with favorable survival outcomes compared with a non-pCR for digestive cancer patients after NAT.

[Relationship between mesenchymal stem cells and liver cancer recurrence after liver transplantation in mice].

OBJECTIVE: To explore the relationship between mesenchymal stem cells (MSCs) and liver cancer recurrence after liver transplantation in mice. METHODS: The recurrent murine model of hepatocellular carcinoma (HCC) after liver transplantation was established by transplanting tumor cells of hind paw pads. MSCs labeled with green fluorescent protein (GFP) were injected into the marrow cavity of 615 mice after successful modeling. And the proliferation of MSCs in marrow cavity was observed under stereoscopic fluorescence microscope. MSCs labeled with red fluorescent protein (RFP) were injected into tail vein of mice during tumor dissection. The migration of GFP and RFP- labeled MSCs were tracked before and after tumor recurrence. After recurrence, the mice were sacrificed and the recurrent lesions harvested for conforming pathological type by biopsy. RESULTS: The rate of success modeling was 37.5%. Both gross morphology and pathological examination corresponded to typical HCC manifestations. Thirty mice were detected by GFP/RFP fluorescence for a recurrence of HCC. The outcomes were GFP+RFP (n = 4), GFP (n = 1) and neither (n = 25). CONCLUSIONS: The presence of MSCs in host may be one of important reasons for recurrent HCC after liver transplantation.It helps to support the traditional view of residual tumor cells mediating the relapse and metastasis of HCC.

Yiqi Jiedu Huayu decoction inhibits precancerous lesions of chronic atrophic gastritis by inhibiting NLRP3 inflammasome-mediated pyroptosis.

BACKGROUND: Chronic atrophic gastritis (CAG) is a prevalent chronic gastritis usually accompanied by precancerous lesions such as intestinal metaplasia and dysplasia. The increasing application of traditional Chinese medicine in CAG treatment has shown promising results with low side effects and significant efficacy. AIM: To investigate the pharmacological effects of Yiqi Jiedu Huayu decoction (YJHD) on precancerous lesions of CAG. METHODS: A CAG rat model was established by Helicobacter pylori bacteria solution combined with N-methyl-N'-nitro-N-nitrosoguanidine. Histopathological measurements were conducted by hematoxylin-eosin and alcian blue and periodic acid-Schiff staining. Serum levels of inflammatory factors and gastric mucosal-related factors were examined using enzyme-linked immunosorbent assay. Protein and mRNA levels were quantified via western blot and quantitative real-time polymerase chain reaction analysis, respectively. Molecular interaction was verified by chromatin immunoprecipitation (ChIP) assay. RESULTS: YJHD greatly attenuated pathological changes in the gastric mucosa and precancerous lesions in CAG rats. Meanwhile, YJHD treatment reduced serum levels of inflammatory factors [interleukin (IL)-6, tumor necrosis factor-α and C-reactive protein] and increased serum levels of gastric mucosal-related factors (gastrin, pepsin, somatostatin and prostaglandin E2) in CAG rats. In addition, YJHD administration suppressed NLRP3 inflammasome-mediated cell pyroptosis, as well as the activation of TLR4/NF-κB and IL-6/STAT3 signaling pathways. Mechanically, ChIP experiments confirmed that NLRP3 transcription was regulated by TLR4/NF-κB and IL-6/STAT3 signaling. CONCLUSION: Taken together, YJHD alleviated NLRP3 inflammasome formation and pyroptosis of epithelial cells in CAG, potentially through the inactivation of TLR4/NF-κB and IL-6/STAT3 pathways.

A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis.

Colorectal cancer (CRC) is a common malignant gastrointestinal tumor. Long noncoding RNAs (lncRNAs) are revealed to be critically involved in CRC progression, providing new direction for exploring the pathogenesis of CRC. This study aimed to explore the biological functions and regulatory mechanisms of lncRNA AC125257.1 in CRC. Western blotting and reverse-transcription quantitative polymerase chain reaction were used for the measurement of gene expression. Cell counting kit-8 assay and flow cytometry analysis were used to explore the effects of AC125257.1 on CRC cell viability and apoptosis. RNA pull-down and immunoprecipitation assays were performed for validating the binding between AC125257.1 and its potential downstream microRNA. Results showed that lncRNA AC125257.1 expression was upregulated in CRC cells and tumor tissues. AC125257.1 enhanced cell viability and suppressed apoptosis of CRC cells. Moreover, the knockdown of AC125257.1 suppressed CRC progression in vitro and inhibited tumor growth in vivo. miR-133a-3p was revealed to bind with AC125257.1 in CRC cells. CASC5 was proved to be targeted by miR-133a-3p. Moreover, rescue assays indicated that the knockdown of AC125257.1 suppressed the pathogenic overexpression of CASC5. To conclude, AC125257.1 aggravates CRC development via miR-873-5p/CASC5 axis. Our findings might suggest a novel perspective that AC125257.1 may become the target for CRC treatment.

Wheel drive-based DNA sensing system for highly specific and rapid one-step detection of MiRNAs at the attomolar level.

With the use of DNA as building blocks, a variety of microRNA amplification-based sensing systems have been developed. Nevertheless, ultrasensitive, selective and rapid detection of microRNAs with a high signal-to-background ratio and point mutation discrimination ability remains a challenge. Herein, we propose a novel wheel drive-based DNA sensing system (NWDS) based on a self-assembled, self-quenched nanoprobe (SQP) to conduct highly specific and ultrasensitive one-step measurement of microRNAs. In this work, a signalling recognition DNA hairpin (DH) sequence with a self-complementary stem domain of 14 base pairs was used, which contained three functional regions, namely a recognition region for the target miRNA-21, a sticky region with 9 complementary nucleotides to the 3'terminus of a DNA wheel (DW) and a region for the hybridization with a quenching DNA primer (DP). The SQP was ingeniously self-assembled at room temperature by the DH and DP, which was capable of eliminating unwanted background signals. MiRNA-21 was employed as a target model to specifically activate the SQP, leading to specific hybridization between the HP and DW. With the assistance of a polymerase, an SQP-based wheel driving took place to induce hybridization/polymerization displacement cycles, initiating target recycling and DP displacement. As a result, a large amount of the newly formed hybrid SQP/DW accumulated to generate a substantially enhanced fluorescence signal. In this way, the newly proposed NWDS exhibits ultrasensitivity with a detection limit of 5.62 aM across a wide linear dynamic response range up to 200 nM, excellent selectivity with the capability to discriminate homologous miRNAs and one-base, two-base and three-base mismatched sequences, and an outstanding analytical performance in complex systems. In addition, the significant simultaneous advantages of one-step operation, rapid detection within 15 min and a high signal-to-background ratio of 26 offer a unique opportunity to promote the early diagnosis of cancer-related diseases and molecular biological analysis.

Erratum: Vitexin Inhibits Gastric Cancer Growth and Metastasis through HMGB1-mediated Inactivation of the PI3K/AKT/mTOR/HIF-1α Signaling Pathway.

This corrects the article on p. 439 in vol. 21, PMID: 35079445.

Computed Tomography Texture Features and Risk Factor Analysis of Postoperative Recurrence of Patients with Advanced Gastric Cancer after Radical Treatment under Artificial Intelligence Algorithm.

Computer tomography texture analysis (CTTA) based on the V-Net convolutional neural network (CNN) algorithm was used to analyze the recurrence of advanced gastric cancer after radical treatment. Meanwhile, the clinical characteristics of patients were analyzed to explore the recurrence factors. 86 patients who underwent the advanced radical gastrectomy for gastric cancer were retrospectively selected as the research objects. Patients were divided into the no-recurrence group (30 cases) and the recurrence group (56 cases) according to whether there was recurrence after radical treatment. CTTA was performed before and after surgery in both groups to analyze the risk factors for recurrence. The results showed that the dice coefficient (0.9209) and the intersection over union (IOU) value (0.8392) of the V-CNN segmentation effect were signally higher than those of CNN, V-Net, and context encoder network (CE-Net) (P < 0.05). The mean value of arterial phase and portal phase (65.29 ± 9.23)/(79.89 ± 10.83), kurtosis (3.22)/(3.13), entropy (9.99 ± 0.53)/(9.97 ± 0.83), and correlation (4.12 × 10-5/4.21 × 10-5) of the recurrence group was higher than the no-recurrence group, while the skewness (0.01)/(-0.06) of the recurrence group was lower than that of the no-recurrence group (P < 0.05). Patients aged 60 years old and above, with a tumor diameter of 6 cm and above, and in the stage III/IV in the recurrence group were higher than those in the no-recurrence group, and patients with chemotherapy were lower (P < 0.05). To sum up, age, tumor diameter, whether chemotherapy should be performed, and tumor staging were all the risk factors of postoperative recurrence among patients with gastric cancer. Besides, CT texture parameter could be used to predict and analyze the postoperative recurrence of gastric cancer with good clinical application values.

Vitexin Inhibits Gastric Cancer Growth and Metastasis through HMGB1-mediated Inactivation of the PI3K/AKT/mTOR/HIF-1α Signaling Pathway.

PURPOSE: Gastric cancer (GC) has high morbidity and mortality and is a serious threat to public health. The flavonoid compound vitexin is known to exhibit anti-tumor activity. In this study, we explored the therapeutic potential of vitexin in GC and its underlying mechanism. MATERIALS AND METHODS: The viability, migration, and invasion of GC cells were determined using MTT, scratch wound healing, and transwell assays, respectively. Target molecule expression was determined by western blotting. Tumor growth and liver metastasis were evaluated in vivo using nude mice. Protein expression in the tumor tissues was examined by immunohistochemistry. RESULTS: Vitexin inhibited GC cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT) in a dose-dependent manner. Vitexin treatment led to the inactivation of phosphatidylinositol-3-kinase (PI3K)/AKT/hypoxia-inducible factor-1α (HIF-1α) pathway by repressing HMGB1 expression. Vitexin-mediated inhibition in proliferation, migration, invasion and EMT of GC cells were counteracted by hyper-activation of PI3K/AKT/HIF-1α pathway or HMGB1 overexpression. Finally, vitexin inhibited the xenograft tumor growth and liver metastasis in vivo by suppressing HMGB1 expression. CONCLUSIONS: Vitexin inhibited the malignant progression of GC in vitro and in vivo by suppressing HMGB1-mediated activation of PI3K/Akt/HIF-1α signaling pathway. Thus, vitexin may serve as a promising therapeutic agent for the treatment of GC.

Contribution of interaction between genetic variants of interleukin-11 and Helicobacter pylori infection to the susceptibility of gastric cancer.

BACKGROUND: Gastric cancer (GC) ranks the second leading cause of cancer-related mortality worldwide. We aimed to clarify the relevance of genetic variants of IL-11, a hub of various carcinogenic pathways, as well as their interactions with Helicobacter pylori (H. pylori) infection in the development of GC. METHODS: A case-control study with 880 GC cases and 900 healthy controls was conducted in a Chinese population. Six tagSNPs were detected by Taqman Allelic Discrimination assay, while H. pylori status was detected by Typing Detection Kit for Antibody to H. pylori and serum IL-11 level was measured using ELISA method. RESULTS: We found that rs1126760 (C vs T: OR=1.39, 95% CIs=1.13-1.70, P=0.002) and rs1126757 (C vs T: OR=0.82, 95% CIs=0.72-0.93, P=0.002) were significantly associated with susceptibility of GC. Even adjusted for Bonferroni correction, the results were still significant (P=0.002×6=0.012). IL-11 rs1126760 was significantly associated with higher serum and expression level of IL-11, while rs1126757 was significantly associated with lower serum IL-11 level (P<0.001). Significant interaction with H. pylori infection was identified for rs1126760 (P for interaction =0.005). Higher expression of the IL-11 gene was significant with development and poor prognosis of GC. CONCLUSION: Our study provides strong evidence that genetic variants of the IL-11 gene may interact with H. pylori infection and contribute to the development of GC. Further studies with larger sample size and functional experiments are needed to validate our findings.