Contribution of a Circulating 2'-O-methylated MicroRNA Panel to the Diagnosis of Pancreatic Ductal Adenocarcinoma.

Background: We conducted an assessment of 2'-O-methylated (2'OMe) microRNAs (miRNAs) present in the circulation of individuals suffering from pancreatic ductal adenocarcinoma (PDAC). Subsequently, we devised a set of circulating 2'OMe miRNAs that can be utilized for the screening of PDAC patients within a group at increased risk. Methods: A four-step, multicenter research was carried out. The initial screening phase involved analyzing 10 samples from patients with pancreatic ductal adenocarcinoma (PDAC) and 10 specimens from donors who were in good health. RNA sequencing was performed on these specimens after pre-treatment via NaIO4. The instruction and confirmation phases involved the use of 2'OMe miRNA profiling and multivariate analysis to examine applicant 2'OMe miRNAs in a sample of 248 individuals. In a prospective registration population of 135 individuals, a clinical screening panel was created and confirmed. The performance of individual 2'OMe miRNAs or the biomarker panel was evaluated using the receiver operating characteristic curve. Results: Abnormal circulating 2'OMe miRNAs were detected in individuals suspected of pancreatic ductal adenocarcinoma (PDAC). A circulating panel of 3-2'OMe miRNAs, namely miR-28-3p, miR-143-3p, and miR-151a-3p, was subsequently identified. These miRNAs continually exhibited up-regulation in plasma samples of patients with pancreatic ductal adenocarcinoma (PDAC). The panel's area under the curve (AUC) was 1.0 in the experimental group and 0.928 in the verification cohort when comparing PDAC patients in all clinical stages to normal controls. During the application study, both the specificity and sensitivity were found to be 75.00% and 89.72% respectively, with an AUC value of 0.868. In the comparison between early-stage (I-II) PDAC patients and control subjects, the panel demonstrated an AUC of 1.0 in the training cohort and 0.924 in the validation population. In the application group the AUC was 0.810 (95% CI 0.729-0.876) in comparison to the high-risk symptomatic group. Conclusion: Abnormal circulating 2'OMe miRNAs were detected in individuals with pancreatic ductal adenocarcinoma (PDAC). Consequently, we devised a 2'OMe miRNA biological marker panel that holds promise as an initial detection tool for PDAC.

Current Status of Diagnosis and Treatment of Colorectal Cancer in Asian Countries: A Questionnaire Survey.

INTRODUCTION: Diagnostic and therapeutic methods for colorectal cancer (CRC) have advanced; however, they may be inaccessible worldwide, and their widespread use is challenging. This questionnaire survey investigates the current status of diagnosis and treatment of early-stage CRC in Asian countries. METHODS: Responses to the questionnaire were obtained from 213 doctors at different institutions in 8 countries and regions. The questionnaire consisted of 39 questions on the following four topics: noninvasive diagnosis other than endoscopy (6 questions), diagnosis by magnification and image-enhanced endoscopy (IEE) including artificial intelligence (AI) (10 questions), endoscopic submucosal dissection (ESD), proper use among other therapeutic methods (11 questions), and pathologic diagnosis and surveillance (12 questions). RESULTS: Although 101 of 213 respondents were affiliated with academic hospitals, there were disparities among countries and regions in the dissemination of advanced technologies, such as IEE, AI, and ESD. The NICE classification is widely used for the diagnosis of colorectal tumors using IEE, while the JNET classification with magnification was used in countries such as Japan (65/70, 92.9%) and China (16/22, 72.7%). Of the 211 respondents, 208 (98.6%) assumed that en bloc resection should be achieved for carcinomas, and 180 of 212 (84.9%) believed that ESD was the most suitable in cases with a diameter larger than 2 cm. However, colorectal ESD is not widespread in countries such as Thailand, the Philippines, and Indonesia. CONCLUSION: The promotion of advanced technologies and education should be continual to enable more people to benefit from them.

Combining brushing cytology with simultaneous vacuum aspiration in suspicious biliopancreatic malignancies: A multicenter propensity score-matched study (with video).

BACKGROUND: Brush cytology during endoscopic retrograde cholangiopancreatography (ERCP) is a standard approach in diagnosing biliopancreatic strictures, with yet unsatisfying sensitivity. AIMS: We brought additional simultaneous vacuum aspiration to brushing process and re-evaluate the diagnostic performance. METHODS: This multi-centered retrospective study was conducted in three tertiary centers. Consecutive patients with biliopancreatic strictures were identified. The patients were divided into two arms: the conventional arm (CA) receiving general brushing approach, and the modified arm (MA) being treated with additional vacuum aspiration when performing bushing. The 1:1 propensity-score matching was implemented to tackle the selective biases. RESULTS: A total of 555 patients were identified and 200 patient pairs (193 males, 207 females, with a mean age of 68.1 ± 13.1 years.) fell into the ultimate evaluation. A final diagnosis of malignant stricture was established in 243 patients. The diagnostic yield of the MA group was substantially better than that of the CA group, whether "suspicious malignancies" were considered malignancies or not. The rates of sensitivity, specificity and accuracy were 46.2%, 100%, 68.0% in the MA group, and 15.3%, 98.7%, and 47.0% in the CA group respectively. CONCLUSIONS: Brushing accompanied by simultaneous vacuum aspiration at ERCP improves the diagnostic yield in suspicious biliopancreatic malignancies.

Suppression of Wnt/ß-catenin Signaling in PDAC via METTL16-mediated N6-methyladenosine Modification of DVL2.

Pancreatic cancer is a formidable cause of cancer-related deaths worldwide and has witnessed a more than twofold increase in incidence over the last 25 years. The most frequently occurring form of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), accounting for the majority of pancreatic cancer cases. N6-methyladenosine (m6A), the most abundant transcript modification, has been implicated in the pathogenesis of numerous human cancers, including pancreatic cancer. Despite this, the functional role of methyltransferase-like 16 (METTL16), a critical m6A methyltransferase, in PDAC remains elusive. In this study, we demonstrate that METTL16 expression is significantly diminished in PDAC, rendering it a promising prognostic indicator. Strikingly, both in vitro and in vivo assays revealed accelerated metastasis and invasion of PDAC cells upon METTL16 knockdown, while overexpression of METTL16 exerted an opposite effect. Mechanistically, METTL16 regulates DVL2 expression by suppressing its translation via m6A modification, thereby regulating Wnt/ß-catenin signaling., Our results unveil the downregulation of METTL16 as a concomitant increase in DVL2 levels via m6A modification promoting the progression of PDAC. Thus, we propose METTL16 as a novel therapeutic candidate for targeted PDAC treatment.

Identification of m7G-Related LncRNA Signature for Predicting Prognosis and Evaluating Tumor Immune Infiltration in Pancreatic Adenocarcinoma.

N7-Methylguanosine (m7G) modification holds significant importance in regulating posttranscriptional gene expression in epigenetics. Long non-coding RNAs (lncRNAs) have been demonstrated to play a crucial role in cancer progression. m7G-related lncRNA may be involved in the progression of pancreatic cancer (PC), although the underlying mechanism of regulation remains obscure. We obtained RNA sequence transcriptome data and relevant clinical information from the TCGA and GTEx databases. Univariate and multivariate Cox proportional risk analyses were performed to build a twelve-m7G-associated lncRNA risk model with prognostic value. The model was verified using receiver operating characteristic curve analysis and Kaplan-Meier analysis. The expression level of m7G-related lncRNAs in vitro was validated. Knockdown of SNHG8 increased the proliferation and migration of PC cells. Differentially expressed genes between high- and low-risk groups were identified for gene set enrichment analysis, immune infiltration, and potential drug exploration. We conducted an m7G-related lncRNA predictive risk model for PC patients. The model had independent prognostic significance and offered an exact survival prediction. The research provided us with better knowledge of the regulation of tumor-infiltrating lymphocytes in PC. The m7G-related lncRNA risk model may serve as a precise prognostic tool and indicate prospective therapeutic targets for PC patients.

Colonic mucin-2 attenuates acute necrotizing pancreatitis in rats by modulating intestinal homeostasis.

Mucin-2 (MUC2) secreted by goblet cells participates in the intestinal barrier, but its mechanism in acute necrotizing pancreatitis (ANP) remains unclear. In acute pancreatitis (AP) patients, the functions of goblet cells (MUC2, FCGBP, CLCA1, and TFF3) decreased, and MUC2 was negatively correlated with AP severity. ANP rats treated with pilocarpine (PILO) (PILO+ANP rats) to deplete MUC2 showed more serious pancreatic and colonic injuries, goblet cell dysfunction, gut dysbiosis, and bacterial translocation than those of ANP rats. GC-MS analysis of feces showed that PILO+ANP rats had lower levels of butyric acid, isobutyric acid, isovaleric acid, and hexanoic acid than those of ANP rats. The expression of MUC2 was associated with colonic injury and gut dysbiosis. All these phenomena could be relieved, and goblet cell functions were also partially reversed by MUC2 supplementation in ANP rats. TNF-α-treated colonoids had exacerbated goblet cell dysfunction. MUC2 expression was negatively correlated with the levels of pro-inflammatory cytokines (IL-1ß and IL-6) (p < .05) and positively related to the expression of tight junction proteins (Claudin 1, Occludin, and ZO1) (p < .05). Downregulating MUC2 by siRNA increased the levels of the pro-inflammatory cytokines in colonoids. MUC2 might maintain intestinal homeostasis to alleviate ANP.

METTL14 Facilitates the Metastasis of Pancreatic Carcinoma by Stabilizing LINC00941 in an m6A-IGF2BP2-Dependent Manner.

Pancreatic adenocarcinoma (PC), one of the most fatal diseases, usually generates a poor prognosis in advanced stages. N6-methyladenosine modification has emerged as a crucial participant in tumor development and recurrence. Methyltransferase-like 14 (METTL14), as a core member of methyltransferases, is involved in tumor progression and metastasis. However, the potential mechanism by which METTL14 regulates long noncoding RNAs (lncRNAs) in PC remains unclear. RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation quantitative PCR (MeRIP-qPCR), and fluorescence in situ hybridization (FISH) were used to explore the underlying mechanisms. In our study, we found that METTL14 expression was upregulated in PC patients, and was associated with poor prognosis. In vitro and in vivo experiments, knocking down METTL14 suppressed tumor metastasis. RNA-seq and bioinformatics analyses were used to identify LINC00941 as the downstream target of METTL14. Mechanistically, LINC00941 was upregulated by METTL14 in an m6A-dependent way. LINC00941 was recruited and recognized by IGF2BP2. METTL14 enhanced the affinity of IGF2BP2 for LINC00941, while IGF2BP2 promoted the stabilization of LINC00941, which contributed to the migration and invasion of PC cells. Overall, our research revealed that METTL14 promoted the metastasis of PC through m6A modification of LINC00941. Targeting the METTL14-LINC00941-IGF2BP2 axis may provide promising therapeutic approaches for PC.

Risk factor analysis of malignant adenomas detected during colonoscopy.

Background: Several studies have shown that colorectal adenomas are the most important precancerous lesions. The colonoscopic identification of groups with the high risk of malignant colorectal adenomas remains a controversial issue for clinicians. Aims: To evaluate the basic characteristics of colorectal adenomas with malignancy risk using high-grade dysplasia (HGD) as an alternative marker for malignant transformation. Methods: Data from Shanghai General Hospital between January 2017 and December 2021 were retrospectively analyzed. The primary outcome was the incidence of HGD in adenomas, which was used as a surrogate marker for the risk of malignancy. Odds ratios (ORs) for the HGD rate in adenomas were analyzed in relation to adenoma-related factors. Results: A total of 9,646 patients identified with polyps during 57,445 screening colonoscopies were included in the study. Patients with flat polyps, sessile polyps, and pedunculated polyps represented 27.3% (N = 2,638), 42.7% (N = 4,114), and 30.0% (N = 2,894) of the total number, respectively. HGD was found in 2.41% (N = 97), 0.92% (N = 24), and 3.51% (N = 98) of sessile adenomas, flat adenomas, and pedunculated adenomas, respectively (P < 0.001). Multivariable logistic regression showed that polyp size (P < 0.001) but not shape (P > 0.8), was an independent predictor of HGD. Contrast to the diameter ≤1 cm, the OR value for diameters 1-2, 2-3, and >3 cm was 13.9, 49.3, and 161.6, respectively. The HGD incidence also increased in multiple adenomas (>3 vs. >1, ORs 1.582) and distal adenomas (distal vs. proximal adenomas, OR 2.252). Adenoma morphology (pedunculated vs. flat) was statistically significant in univariate analysis but not when size was included in the multivariate analysis. Besides, the incidence of HGD was also significantly higher in older patients (>64 vs. <50 years old, OR = 2.129). Sex (P = 0.681) was not statistically significant. All these associations were statistically significant (P < 0.05). Conclusion: The malignant potential of polyps is mostly affected by their size but not by their shape. In addition, distal location, multiple adenomas, and advanced age were also correlated with malignant transformation.

Transpapillary Stenting Improves Treatment Outcomes in Patients Undergoing Endoscopic Transmural Drainage of Ductal Disruption-Associated Pancreatic Fluid Collections.

INTRODUCTION: Endoscopic transmural drainage (TMD) has been accepted as the preferred therapy for symptomatic pancreatic fluid collections (PFCs). Recurrence of PFCs presents a unique challenge in patients with disrupted pancreatic duct (PD). We aimed to evaluate whether transpapillary drainage (TPD) provides additional benefits to TMD in patients with PD disruption. METHODS: This was a multicenter retrospective study. Consecutive patients who underwent TMD, TPD, or combined drainage (CD) of PFCs were included. The primary outcome was to compare PFC recurrence among different groups. The secondary outcomes were the technical success rate, length of hospital stay, and procedure-related complications. RESULTS: A total of 153 patients, which consists of 57 patients with pancreatic pseudocysts and 96 patients with walled-off necrosis, were included. PFC recurrence was more common in patients with PD disruption than those with an intact main duct (19% vs 1.4%, P < 0.001). PD disruption was identified as a major risk factor of PFC recurrence by univariable and multivariable analyses. The recurrence rate of CD was significantly lower than TMD only or TPD only (6.5% vs 15.4% vs 22.7%, P < 0.01). The length of hospital stay of CD was significantly shorter than TMD only or TPD only (5 [3.0-9.0] vs 7.0 [5.0-12.0] vs 9 [7.0-16.0], P < 0.001). Dual-modality drainage did not increase procedure-related complications compared with TMD only (13.0% vs 12.8%, P > 0.05). Partial PD disruption was bridged in 87.3% cases while complete PD disruption was reconnected in 55.2% cases. Although statistically not significant, the clinical success rate in walled-off necrosis cases with actively bridged ducts was much higher than those with passively bridged ducts (76.9% vs 40%). DISCUSSION: Transpapillary pancreatic duct stenting seems to improve the efficacy of endoscopic TMD of pancreatic duct disruption-associated PFCs by reducing the recurrence rate and shortening the length of hospital stay.

Peritumoral and Intratumoral Texture Features Based on Multiparametric MRI and Multiple Machine Learning Methods to Preoperatively Evaluate the Pathological Outcomes of Pancreatic Cancer.

BACKGROUND: Radiomics-based preoperative evaluation of lymph node metastasis (LNM) and histological grade (HG) might facilitate the decision-making for pancreatic cancer and further efforts are needed to develop effective models. PURPOSE: To develop multiparametric MRI (MP-MRI)-based radiomics models to evaluate LNM and HG. STUDY TYPE: Retrospective. POPULATION: The pancreatic cancer patients from the main center (n = 126) were assigned to the training and validation sets at a 4:1 ratio. The patients from the other center (n = 40) served as external test sets. FIELD STRENGTH/SEQUENCE: A 3.0 T and 1.5 T/T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast enhancement T1-weighted imaging. ASSESSMENT: A total of 10,686 peritumoral and intratumoral radiomics features were extracted which contained first-order, shape-based, and texture features. The following three-step method was applied to reduce the feature dimensionality: SelectKBest (a function from scikit-learn package), least absolute shrinkage and selection operator (LASSO), and recursive feature elimination based on random forest (RFE-RF). Six classifiers (random forest, logistic regression, support vector machine, K-nearest neighbor, decision tree, and XGBOOST) were trained and selected based on their performance to construct the clinical, radiomics, and combination models. STATISTICAL TESTS: Delong's test was used to compare the models' performance. P value less than 0.05 was considered significant. RESULTS: Twelve significant features for LNM and 11 features for HG were obtained. Random forest and logistic regression performed better than the other classifiers in evaluating LNM and HG, respectively, according to the surgical pathological results. The best performance was obtained with the models that combined peritumoral and intratumoral features with area under curve (AUC) values of 0.944 and 0.892 in the validation and external test sets for HG and 0.924 and 0.875 for LNM. DATA CONCLUSION: Radiomics holds the potential to evaluate LNM and HG of pancreatic cancer. The combination of peritumoral and intratumoral features will make models more accurate. EVIDENCE LEVEL: 4. TECHNICAL EFFICACY: Stage 2.

Preoperative Extrapancreatic Extension Prediction in Patients with Pancreatic Cancer Using Multiparameter MRI and Machine Learning-Based Radiomics Model.

RATIONALE AND OBJECTIVES: Pancreatic cancer is a common malignant tumor with a dismal prognosis. Preoperative differentiation of extrapancreatic extension (EPE) based on radiomics will facilitate treatment decision-making. MATERIALS AND METHODS: This research retrospectively recruited 156 patients from two medical centers. 122 patients from the center A were randomly divided into the training set and the internal test set in a 4:1 ratio. Additionally, 34 patients from the center B served as the external test set. Radiomics features were extracted from multiparametric MRI (MP-MRI), containing axial T2 weighted imaging (T2WI), diffusion weighted imaging (DWI), and dynamic contrast enhancement (DCE) sequences. The three-step method was used for feature extraction: SelecteKBest, least absolute shrinkage and selection operator (LASSO) algorithm, and recursive feature elimination based on random forest (RFE-RF). The model was constructed using six classifiers based on machine learning, and the classifier with the best performance was chosen. Finally, clinical factors associated with EPE were incorporated into the combined model. RESULTS: The classifier with the best performance was XGBoost, which obtained area under curve (AUC) values of 0.853 and 0.848 in the internal and external test sets, respectively. Through SelectKBest, the most relevant clinical factor for EPE was determined to be platelet, which was then added to the combined model, yielding AUC values of 0.880 and 0.848 in the internal and external test sets, respectively. CONCLUSION: Radiomics models had the potential to noninvasively and accurately predict EPE before surgery. Additionally, it would add value to personalized precision treatment.

The Wet Suction Technique Enhances the Diagnostic Efficacy and Aspirate Quality of EUS-FNA for Solid Lesions: A Multicenter Retrospective Study in China.

GOALS: To comprehensively compare the wet suction technique with the conventional dry suction technique for endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in solid lesions. BACKGROUND: Optimal suction techniques for EUS-FNA remain uncertain when approaching solid lesions. STUDY: We performed a retrospective study of EUS-FNA at 3 medical centers in China. A total of 203 patients were enrolled who received 2 passes of EUS-FNA with 22-G needles. If the first pass underwent dry suction, the second pass was wet suction. Otherwise, the order of suction technique is opposite. Diagnostic accuracy, sample quality (including cellularity and blood contamination), and sample quantity (including specimen adequacy, the maximum intact specimen length, and the total specimen length) were compared between wet-suction and dry-suction techniques. RESULTS: The patients included 143 pancreatic lesions and 60 nonpancreatic lesions. Compared with the dry suction technique, the wet suction technique yielded a significantly higher diagnostic accuracy (85.22% vs. 72.41%, P =0.002), better specimen adequacy score and cellularity score ( P <0.0001), and lower blood contamination score ( P <0.0001). In the subgroup analysis, wet suction provided significantly higher diagnostic accuracy in pancreatic cancer without chronic pancreatitis ( P <0.05), and better cellularity score and specimen adequacy score, lower blood contamination score, and longer maximum intact specimen length and total specimen length in various lesions than that in dry suction. CONCLUSIONS: The wet suction technique resulted in significantly higher diagnostic accuracy in pancreatic cancer without chronic pancreatitis, and better cellularity and histologic specimen in most of solid lesions.

RELA-induced MiR-21 Exerts Oncogenic Effects on PDAC via Targeting of ARHGAP24.

Inflammation is one of the inducing factors of pancreatic ductal adenocarcinoma (PDAC), and microRNAs have been confirmed to be involved in the occurrence and development of PDAC. However, whether RELA, an inflammatory regulator, is involved in the regulation of PDAC by miRNA remains to be further studied. In the present study miR-21 was characterized and its upstream regulatory mechanism was investigated, as well as its functional effects and target genes in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis confirmed increased miR-21 expression levels in PDAC tissues. The results of the chromatin immunoprecipitation and dual-luciferase reporter assays demonstrated that transcription factor RELA modulated miR-21 transcription in the PDAC, PANC-1 and MIA PaCa-2 cell lines. Subsequently, a cell viability assay, EdU staining assay and flow cytometry analysis, demonstrated that miR-21 promoted cell proliferation and cell cycle progression, but inhibited cell apoptosis in vitro. Furthermore, a xenograft assay demonstrated that miR-21 accelerated tumor growth in vivo. Mechanistically, miR-21 directly regulated the expression of Rho GTPase activating protein 24 (ARHGAP24), which was indicated to be a tumor suppressor gene. Moreover, both miR-21 and ARHGAP24 were strongly associated with clinical features and may therefore serve as valuable biomarkers in PDAC prognosis.

Identification and Validation of Prognostic Model for Pancreatic Ductal Adenocarcinoma Based on Necroptosis-Related Genes.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a poor prognosis. Recently, necroptosis has been reported to participate in the progression of multiple tumors. However, few studies have revealed the relationship between necroptosis and PDAC, and the role of necroptosis in PDAC has not yet been clarified. Methods: The mRNA expression data and corresponding clinical information of PDAC patients were downloaded from the TCGA and GEO databases. The necroptosis-related genes (NRGs) were obtained from the CUSABIO website. Consensus clustering was performed to divide PDAC patients into two clusters. Univariate and LASSO Cox regression analyses were applied to screen the NRGs related to prognosis to construct the prognostic model. The predictive value of the prognostic model was evaluated by Kaplan-Meier survival analysis and ROC curve. Univariate and multivariate Cox regression analyses were used to evaluate whether the risk score could be used as an independent predictor of PDAC prognosis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and single-sample gene set enrichment analysis (ssGSEA) were used for functional enrichment analysis. Finally, using qRT-PCR examined NRGs mRNA expression in vitro. Results: Based on the TCGA database, a total of 22 differential expressed NRGs were identified, among which eight NRGs (CAPN2, CHMP4C, PLA2G4F, PYGB, BCL2, JAK3, PLA2G4C and STAT4) that may be related to prognosis were screened by univariate Cox regression analysis. And CAPN2, CHMP4C, PLA2G4C and STAT4 were further selected to construct the prognostic model. Kaplan-Meier survival analysis and ROC curve showed that there was a significant correlation between the risk model and prognosis. Univariate and multivariate Cox regression analyses showed that the risk score of the prognostic model could be used as an independent predictor. The model efficacy was further demonstrated in the GEO cohort. Functional analysis revealed that there were significant differences in immune status between high and low-risk groups. Finally, the qRT-PCR results revealed a similar dysregulation of NRGs in PDAC cell lines. Conclusion: This study successfully constructed and verified a prognostic model based on NRGs, which has a good predictive value for the prognosis of PDAC patients.

Paneth Cells Protect against Acute Pancreatitis via Modulating Gut Microbiota Dysbiosis.

Acute pancreatitis (AP) is usually accompanied by intestinal failure, but its mechanism is still unclear. In AP patients, the functions of Paneth cells (lysozyme, HD5, Reg3γ, and Wnt3a) decreased. Compared with AP mice, injuries and inflammation of the pancreas and ileum were aggravated in AP mice treated with dithizone (Dith) (Dith+AP mice). Intestinal permeability and bacterial translocation were also increased. 16S rRNA sequencing showed that the gut microbiota of Dith mice and Dith+AP mice exhibited a marked increase in the pathogenic bacterium Helicobacter and a significant decrease in the probiotic bacterium Blautia. Lysozyme gavage in Dith+AP mice effectively alleviated injuries of the pancreas and small intestine. The beneficial effect of lysozyme was associated with a significant increase in the probiotic bacterium Blautia and a virtual absence of the pathogenic bacterium Helicobacter. The severity of AP in antibiotic-treated mice (ABX mice) was significantly aggravated when receiving feces from Dith mice and was markedly alleviated when receiving feces from lysozyme-gavaged mice. In vitro, lysozyme increased the proliferation of enteroids by promoting the activation of the Wnt pathway and Lgr5 expression in intestinal stem cells. IMPORTANCE We demonstrate that AP patients and experimental AP mice exhibited a dysfunction of Paneth cells. Our in vivo research showed that the severity of AP was exacerbated by the long-term dysfunction of Paneth cells, which was associated with gut microbiota disorder. Restoring part of Paneth cell functions through lysozyme supplementation alleviated the severity of AP and gut microbiota dysbiosis. This study provides novel insight into the link of pancreas-gut interactions in the pathogenesis of AP, providing a new direction for the clinical treatment of intestinal complications during AP.

Circular RNA circ_0047744 suppresses the metastasis of pancreatic ductal adenocarcinoma by regulating the miR-21/SOCS5 axis.

There is increasing evidence that circular RNAs (circRNAs) can serve as microRNA (miRNA) sponges to regulate metastasis of multiple tumors, including pancreatic ductal adenocarcinoma (PDAC). However, the role of the circRNA/miRNA regulatory network in metastasis of PDAC has not been elucidated. The purpose of this study is to explore the role of circ_0047744/miR-21/SOCS5 in the metastasis of PDAC. We found that circRNA_0047744 was weakly expressed in PDAC tissues and cell lines. The expression of circ_0047744 was negatively correlated with lymph node metastasis and positively correlated with overall survival in PDAC patients. Functionally, the overexpression of circ_0047744 suppressed cell migration and invasion in vitro and in vivo. Mechanistically, circ_0047744 could regulate SOCS5 expression by acting as a sponge of miR-21 to inhibit migration and invasion of PDAC cells. Our study demonstrates that circ_0047744 acts as an anti-oncogene to inhibit PDAC metastasis by regulating the miR-21/SOCS5 axis, indicating that circ_0047744 may be a potential novel therapeutic target for PDAC patients.