Risk stratification of clinically relevant delayed gastric emptying after pancreaticoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) remains one of the major complications after pancreaticoduodenectomy (PD), with discrepant reports of its contributing factors. This study aimed to develop a nomogram to identify potential predictors and predict the probability of DGE after PD. METHODS: This retrospective study enrolled 422 consecutive patients who underwent PD from January 2019 to December 2021 at our institution. The LASSO algorithm and multivariate logistic regression were performed to identify independent risk and protective factors associated with clinically relevant delayed gastric emptying (CR-DGE). A nomogram was established based on the selected variables. Then, the calibration curve, ROC curve, decision curve analysis (DCA), and clinical impact curve (CIC) were applied to evaluate the predictive performance of our model. Finally, an independent cohort of 45 consecutive patients from January 2022 to March 2022 was enrolled to further validate the nomogram. RESULTS: Among 422 patients, CR-DGE occurred in 94 patients (22.2%). A previous history of chronic gastropathy, intraoperative plasma transfusion ≥ 400 ml, end-to-side gastrointestinal anastomosis, intra-abdominal infection, incisional infection, and clinically relevant postoperative pancreatic fistula (CR-POPF) were identified as risk predictors. Minimally invasive pancreaticoduodenectomy (MIPD) was demonstrated to be a protective predictor of CR-DGE. The areas under the curve (AUCs) were 0.768 (95% CI, 0.706-0.830) in the development cohort, 0.766 (95% CI, 0.671-0.861) in the validation cohort, and 0.787 (95% CI, 0.633-0.940) in the independent cohort. Then, we built a simplified scale based on our nomogram for risk stratification. CONCLUSIONS: Our study identified seven predictors and constructed a validated nomogram that effectively predicted CR-DGE for patients who underwent PD.

Construction of a prognostic model with exosome biogenesis- and release-related genes and identification of RAB27B in immune infiltration of pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and fatal disease. Exosomes are extracellular vesicles that plays a vital rule in the progression and metastasis of PDAC. However, the specific mechanism of exosome biogenesis and release in the tumorigenesis and development of pancreatic cancer remains elusive. The aim of this study is to develop novel biomarkers and construct a reliable prognostic signature to accurately stratify patients and optimize clinical decision-making. Methods: Gene expression and clinical data were acquired from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate Cox regression analysis, random forest analysis, least absolute shrinkage and selection operator (LASSO) regression analysis, and multivariate Cox regression analysis were used to construct the risk signature. The effectiveness of the model was validated by survival point plot, Kaplan-Meier survival analysis, and receiver operating characteristic (ROC) curve in training, testing and entire cohorts. Meanwhile, single sample gene set enrichment analysis (ssGSEA), ESTIMATE and CIBERSORT algorithm were utilized to assess the association of the risk signature with the immune status in the PDAC tumor microenvironment. We also performed functional enrichment, tumor mutation analysis, and DNA methylation analyses based on the risk signature. The function of the core gene was further verified by polymerase chain reaction (PCR), western blot, bicinchoninic acid (BCA), immunohistochemistry (IHC) and in vitro experiments including cell proliferation, migration, and apoptosis experiments. Results: We constructed an exosome biogenesis- and release-related risk model which could serve as an effective and independent prognosis predictor for PDAC patients. The immune infiltration analysis revealed that our signature was related to the PDAC immune microenvironment, mainly associated with a lower proportion of natural killer (NK) cells and CD8+ T cells. Tissue microarray IHC confirmed the association of RAB27B with poor prognosis in PDAC. Knockdown of RAB27B expression promoted PDAC cells' apoptosis, while decreased cellular proliferation and migration. Also, knockdown of RAB27B expression led to reduced exosome secretion, while RAB27B overexpression promoted exosome secretion. Conclusions: The predictive signature can predict overall survival, help elucidate the mechanism of exosome biogenesis and release, and provide immunotherapy guidance for PDAC patients.

IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/ß-catenin signaling.

OBJECTIVES: Previously, Interferon-induced Protein with Tetratricopeptide Repeats 1 (IFIT1) has been shown to promote cancer development. Here, we aimed to explore the role of IFIT1 in the development and progression of pancreatic cancer, including the underlying mechanisms. METHODS: We explored IFIT1 expression in pancreatic cancer samples using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Cell Counting Kit-8 (CCK8), colony formation, scratch wound-healing and Transwell assays were performed to assess the proliferation, migration and invasion abilities of pancreatic cancer cells. Gene Set Enrichment Analysis (GSEA) and Western blotting were performed to assess the regulatory effect of IFIT1 on the Wnt/ß-catenin pathway. RESULTS: We found that upregulation of IFIT1 expression is common in pancreatic cancer and is negatively associated with overall patient survival. Knockdown of IFIT1 expression led to decreased proliferation, migration and invasion of pancreatic cancer cells. We also found that IFIT1 could regulate Wnt/ß-catenin signaling, and that a Wnt/ß-catenin agonist could reverse this effect. In addition, we found that IFIT1 can promote epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. CONCLUSIONS: Our data indicate that IFIT1 increases pancreatic cancer cell proliferation, migration and invasion by activating the Wnt/ß-catenin pathway. In addition, we found that EMT could be regulated by IFIT1. IFIT1 may serve as a potential therapeutic target for pancreatic cancer.

Prognostic value and immune infiltration of ARMC10 in pancreatic adenocarcinoma via integrated bioinformatics analyses.

Background: Armadillo repeat-containing 10 (ARMC10) is involved in the progression of multiple types of tumors. Pancreatic adenocarcinoma (PAAD) is a lethal disease with poor survival and prognosis. Methods: We acquired the data of ARMC10 in PAAD patients from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) datasets and compared the expression level with normal pancreatic tissues. We evaluated the relevance between ARMC10 expression and clinicopathological factors, immune infiltration degree and prognosis in PAAD. Results: High expression of ARMC10 was relevant to T stage, M stage, pathologic stage, histologic grade, residual tumor, primary therapy outcome (P < 0.05) and related to lower Overall-Survival (OS), Disease-Specific Survival (DSS), and Progression-Free Interval (PFI). Gene set enrichment analysis showed that ARMC10 was related to methylation in neural precursor cells (NPC), G alpha (i) signaling events, APC targets, energy metabolism, potassium channels and IL10 synthesis. The expression level of ARMC10 was positively related to the abundance of T helper cells and negatively to that of plasmacytoid dendritic cells (pDCs). Knocking down of ARMC10 could lead to lower proliferation, invasion, migration ability and colony formation rate of PAAD cells in vitro. Conclusions: Our research firstly discovered ARMC10 as a novel prognostic biomarker for PAAD patients and played a crucial role in immune regulation in PAAD.

Phospholipase A/acyltransferase 4 is a prognostic biomarker and correlated with immune infiltrates in pancreatic cancer.

Background: Phospholipase A/acyltransferase (PLAAT) family exhibits O- and N-acyltransferase activity and biosynthesize N-acylated ethanolamine phospholipids. Previously, PLAAT4 was seen as a tumor suppressor, but the exact function of PLAAT4 in pancreatic cancer was still unknown. In this study, we investigated the relationship of PLAAT4 and pancreatic cancer. Methods: Using the data from the cancer genome atlas (TCGA), Genotype-Tissue Expression (GTEx) database and Gene Expression Omnibus (GEO) datasets we compared the expression of PLAAT4 in normal and tumor tissues and analyzed the connections between PLAAT4 and several clinicopathological factors. Further, we conducted Gene ontology (GO) analysis, Gene set enrichment analysis (GSEA), single sample gene set enrichment analysis (ssGSEA) and estimate analysis to explore the association between PLAAT4 and biological function and immune infiltration. In addition, Kaplan-Meier (KM) analysis, univariate and multivariate Cox analysis were used to explore the association between PLAAT4 and prognosis. In addition, we plotted a nomogram according to the multivariate cox analysis visualizing the predictive ability of PLAAT4 on prognosis. In addition, we explore the influence of PLAAT4 on malignant behaviors of the pancreatic cancer cells in vitro. Results: After comparing the expression of PLAAT4 in normal and tumor tissues, we found that the expression of PLAAT4 was significantly high in pancreatic ductal adenocarcinoma (PDAC) samples. In addition, the results of GO and GSEA found that the expression of PLAAT4 was related to cell cycle checkpoints, M phase, regulation by p53, cell cycle mitotic and etc. Further, ssGSEA has shown that PLAAT4 was positively related to the abundance of aDC, Th1 cells, Th2 cells and negatively related to the Th17 cells. Subsequently, KM analysis, univariate and multivariate Cox analysis were used to analyze the correlation between PLAAT4 and prognosis. Additionally, we found that higher expression of PLAAT4 was related to T stage, N stage, histologic grade, etc (P < 0.05) and has a significant correlation with poor Overall Survival (OS), Disease-Specific Survival (DSS) and Progression-Free Interval (PFI). At last, we proved that PLAAT4 contributed to the malignant behaviors of the pancreatic cancer cells. Conclusion: This study indicated PLAAT4 as a novel prognostic biomarker and an important molecular that mediated immune response in pancreatic cancer.

Identification METTL18 as a Potential Prognosis Biomarker and Associated With Immune Infiltrates in Hepatocellular Carcinoma.

Methyltransferase-like 18 (METTL18), a METTL family member, is abundant in hepatocellular carcinoma (HCC). Studies have indicated the METTL family could regulate the progress of diverse malignancies while the role of METTL18 in HCC remains unclear. Data of HCC patients were acquired from the cancer genome atlas (TCGA) and gene expression omnibus (GEO). The expression level of METTL18 in HCC patients was compared with normal liver tissues by Wilcoxon test. Then, the logistic analysis was used to estimate the correlation between METTL18 and clinicopathological factors. Besides, Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) were used to explore relevant functions and quantify the degree of immune infiltration for METTL18. Univariate and Multivariate Cox analyses and Kaplan-Meier analysis were used to estimate the association between METTL18 and prognosis. Besides, by cox multivariate analysis, a nomogram was conducted to forecast the influence of METTL18 on survival rates. METTL18-high was associated with Histologic grade, T stage, Pathologic stage, BMI, Adjacent hepatic tissue inflammation, AFP, Vascular invasion, and TP53 status (P < 0.05). HCC patients with METTL18-high had a poor Overall-Survival [OS; hazard ratio (HR): 1.87, P < 0.001), Disease-Specific Survival (DSS, HR: 1.76, P = 0.015), and Progression-Free Interval (PFI, HR: 1.51, P = 0.006). Multivariate analysis demonstrated that METTL18 was an independent factor for OS (HR: 2.093, P < 0.001), DSS (HR: 2.404, P = 0.015), and PFI (HR: 1.133, P = 0.006). Based on multivariate analysis, the calibration plots and C-indexes of nomograms showed an efficacious predictive effect for HCC patients. GSEA demonstrated that METTL18-high could activate G2M checkpoint, E2F targets, KRAS signaling pathway, and Mitotic Spindle. There was a positive association between the METTL18 and abundance of innate immunocytes (T helper 2 cells) and a negative relation to the abundance of adaptive immunocytes (Dendritic cells, Cytotoxic cells etc.). Finally, we uncovered knockdown of METTL18 significantly suppressed the proliferation, invasion, and migration of HCC cells in vitro. This research indicates that METTL18 could be a novel biomarker to evaluate HCC patients' prognosis and an important regulator of immune responses in HCC.

IFIT1 modulates the proliferation, migration and invasion of pancreatic cancer cells via Wnt/ß-catenin signaling.

OBJECTIVES: Previously, Interferon-induced Protein with Tetratricopeptide Repeats 1 (IFIT1) has been shown to promote cancer development. Here, we aimed to explore the role of IFIT1 in the development and progression of pancreatic cancer, including the underlying mechanisms. METHODS: We explored IFIT1 expression in pancreatic cancer samples using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Cell Counting Kit-8 (CCK8), colony formation, scratch wound-healing and Transwell assays were performed to assess the proliferation, migration and invasion abilities of pancreatic cancer cells. Gene Set Enrichment Analysis (GSEA) and Western blotting were performed to assess the regulatory effect of IFIT1 on the Wnt/ß-catenin pathway. RESULTS: We found that upregulation of IFIT1 expression is common in pancreatic cancer and is negatively associated with overall patient survival. Knockdown of IFIT1 expression led to decreased proliferation, migration and invasion of pancreatic cancer cells. We also found that IFIT1 could regulate Wnt/ß-catenin signaling, and that a Wnt/ß-catenin agonist could reverse this effect. In addition, we found that IFIT1 can promote epithelial-mesenchymal transition (EMT) of pancreatic cancer cells. CONCLUSIONS: Our data indicate that IFIT1 increases pancreatic cancer cell proliferation, migration and invasion by activating the Wnt/ß-catenin pathway. In addition, we found that EMT could be regulated by IFIT1. IFIT1 may serve as a potential therapeutic target for pancreatic cancer.