Lipopolysaccharide-regulated RNF31/NRF2 axis in colonic epithelial cells mediates homeostasis of the intestinal barrier in ulcerative colitis.

BACKGROUND: Although previous studies have shown that the Ring Finger Protein 31 (RNF31) gene confers susceptibility to inflammatory disease and colorectal cancer, the exact function of this protein in ulcerative colitis (UC) has not been determined. METHODS: A mouse dextran sulfate sodium (DSS)-induced experimental colitis model was used to study RNF31 and NRF2 in colitis. RNF31 silencing or overexpression in vitro was applied to address the role of RNF31 in colonic mucosal barrier damage. Immunohistochemistry and silico analysis was performed to investigate the expression of RNF31 via taking advantage of UC tissue samples and Gene Expression Omnibus (GEO) data, respectively. The cycloheximide (CHX)-chase experiment and Co-Immunoprecipitation (Co-IP) assays were conducted to explore the association of RNF31 protein with NRF2 and P62. RESULTS: RNF31 is highly expressed in UC patients, in inflamed murine colon induced DSS and Lipopolysaccharide (LPS)-treated epithelial cells, while the express of NRF2 was Tabdecreased. RNF31-knockdown mice in the DSS-induced colitis model had a less severe phenotype, which was associated with a more integrated barrier of colon epithelial cells. While depletion of NRF2 in colitis model exacerbated intestinal inflammation. Mechanistically, RNF31 promoted the degradation of NRF2 by regulating its ubiquitination. Upon stimulation by RNF31, NRF2 is K63 ubiquitinated, which is associated with the C871 residue of RNF31. Moreover, downregulated NRF2 mediates inflammation by promoting the secretion of IL1ß and IL18, leading to damage of the intestinal barrier. Upon LPS stimulation, the interaction of the PUB domain of RNF31 with the UBA domain of P62 increased, resulting in decreased degradation of the RNF31 protein via autophagy. CONCLUSION: Overall, depletion of RNF31 effectively relieves DSS-induced colitis in mice by inhibiting NRF2 degradation, suggesting that RNF31 may be a potential therapy for human ulcerative colitis.

Radiomics analysis based on CT for predicting lymph node metastasis and prognosis in duodenal papillary carcinoma.

OBJECTIVES: Radiomics has been demonstrated to be strongly associated with TNM stage and patient prognosis. We aimed to develop a model for predicting lymph node metastasis (LNM) and survival. METHODS: For radiomics texture selection, 3D Slicer 5.0.3 software and the least absolute shrinkage and selection operator (LASSO) algorithm were used. Subsequently, the radiomics model, computed tomography (CT) image, and clinical risk model were compared. The performance of the three models was evaluated using receiver operating characteristic (ROC) curves, decision curve analysis (DCA), calibration plots, and clinical impact curves (CICs). RESULTS: For the LNM prediction model, 224 patients with LNM information were used to construct a model that was applied to predict LNM. According to the CT data and clinical characteristics, we constructed a radiomics model, CT imaging model and clinical model. The radiomics model for evaluating LNM status showed excellent calibration and discrimination in the training cohort (AUC = 0.926, 95% CI = 0.869-0.982) and the validation cohort (AUC = 0.872, 95% CI = 0.802-0.941). DeLong's test demonstrated that the difference among the three models was significant. Similarly, DCA and CIC showed that the radiomics model has better clinical utility than the CT imaging model and clinical model. Our model also exhibited good performance in predicting survival-in line with the findings of the model built with clinical risk factors. CONCLUSIONS: CT radiomics models exhibited better predictive performance for LNM than models built based on clinical risk characteristics and CT imaging and had comparative clinical utility for predicting patient prognosis. CRITICAL RELEVANCE STATEMENT: The radiomics model showed excellent performance and discrimination for predicting LNM and survival of duodenal papillary carcinoma (DPC). KEY POINTS: LNM status determines the most appropriate treatment for DPC. Our radiomics model for evaluating the LNM status of DPC performed excellently. The radiomics model had high sensitivity and specificity for predicting survival, exhibiting great clinical value.

Are Radiomic Spleen Features Useful for Assessing the Response to Infliximab in Patients With Crohn's Disease? A Multicenter Study.

INTRODUCTION: To develop and validate a radiomics nomogram for assessing the response of patients with Crohn's disease (CD) to infliximab. METHODS: Radiomics features of the spleen were extracted from computed tomography enterography images of each patient's arterial phase. The feature selection process was performed using the least absolute shrinkage and selection operator algorithm, and a radiomics score was calculated based on the radiomics signature formula. Subsequently, the radiomic model and the clinical risk factor model were separately established based on the radiomics score and clinically significant features, respectively. The performance of both models was evaluated using receiver operating characteristic curves, decision curve analysis curves, and clinical impact curves. RESULTS: Among the 175 patients with CD, 105 exhibited a clinical response, and 60 exhibited clinical remission after receiving infliximab treatment. Our radiomic model, comprising 20 relevant features, demonstrated excellent predictive performance. The radiomic nomogram for predicting clinical response showed good calibration and discrimination in the training cohort (area under the curve [AUC] 0.909, 95% confidence interval [CI] 0.840-0.978), the validation cohort (AUC 0.954, 95% CI 0.889-1), and the external cohort (AUC = 0.902, 95% CI 0.83-0.974). Accordingly, the nomogram was also suitable for predicting clinical remission. Decision curve analysis and clinical impact curves highlighted the clinical utility of our nomogram. DISCUSSION: Our radiomics nomogram is a noninvasive predictive tool constructed from radiomic features of the spleen. It also demonstrated good predictive accuracy in evaluating CD patients' response to infliximab treatment. Multicenter validation provided high-level evidence for its clinical application.

Exploring the Molecular Targets and Therapeutic Potential of Coptisine in Colon Cancer: A Network Pharmacology Approach.

INTRODUCTION: Colon cancer is a frequent malignancy, and surgery is still the primary therapy for people with colon cancer. Other treatments, including radiation, chemotherapy, and biologic therapy, may be utilized as a supplement. Chemotherapy, a prominent treatment for colon cancer, has failed to provide positive outcomes. This necessitates the development of more effective and less harmful treatment drugs. Coptisine was discovered to inhibit the development of colon cancer cell line HCT-116 in vivo, decrease the growth of HCT-116 cells, and cause apoptosis in vitro in colon cancer. Coptisine (COP) has shown antitumor activity in colon cancer, but its molecular mechanism and its molecular targets have not been fully understood. METHODS: In this study, the biological behavior was verified in vitro. The targets of Huanglian alkaloids on colon cancer were predicted, and the protein-protein interaction (PPI) network was constructed. The core targets of safranine for colon cancer were extracted and analyzed by GO and KEGG enrichment to identify the possible molecular mechanisms of safranine treatment. Western blot was used to detect the changes of related pathway proteins in colon cancer cells. The differential expression of hub genes in colon cancer was analyzed using the GEPIA2 website. The binding ability of safranine to the target was verified by molecular docking. Finally, the targets were preliminarily verified by q-PCR analysis. RESULTS: Coptisine can inhibit the survival, migration, and proliferation of colon cancer cells DLD1 and HCT-116. Based on network pharmacology, ninety-one targets for colon cancer were screened. ESR1, ALB, AR, CDK2, PARP1, HSP90AB1, IGF1R, CCNE1, and CDC42 were found in the top 10. Enrichment analysis showed that these targets were mainly related to pathways in cancer, FC γ R-mediated phagocytosis, prostate cancer, progesterone-mediated oocyte maturation, the oestrogen signal pathway, proteoglycan in cancer and the PI3K-Akt signal pathway. WB results showed that after the treatment of colon cancer DLD1 cells with coptisine, the expression of P-AKT and AKT decreased, that of its downstream protein Bcl-2 decreased, and that of BAX increased. Differential expression analysis of hub genes showed that CCNE1, CDK2, HSP90AB1, and CHEK2 were upregulated in colon cancer samples, and molecular docking showed that these targets had a good ability to bind to coptisine. After the treatment of colon cancer DLD1 cells with coptisine, q-PCR results showed that CCNE1 and HSP90AB1 were significantly downregulated, while CDK2 and CHEK2 had no significant changes. CONCLUSION: Coptisine may be a candidate drug for the treatment of colon cancer, and its therapeutic effect may be related to the cancer pathway and PI3K-Akt signalling pathway. CCNE1 and HSP90AB1 may be potential targets of coptisine in the treatment of colon cancer.

The E3 ubiquitin ligase RNF31 mediates the development of ulcerative colitis by regulating NLRP3 inflammasome activation.

Ulcerative colitis (UC) is characterized by dysregulated inflammation and disruption of the intestinal barrier. The NLRP3 inflammasome, which is composed of NLRP3, ASC, and caspase-1, plays a crucial role in UC pathogenesis by triggering the production of proinflammatory cytokines. In this study, we investigated the regulatory role of RNF31 in NLRP3 inflammasome activation during UC development. Through comprehensive analysis of ulcerative colitis tissues using the GEO database and immunohistochemistry, we found that RNF31 expression was elevated in UC tissues, which prompted further investigation into its function. We constructed an RNF31 knockdown cell model and observed a significant reduction in NLRP3 inflammasome activation, indicating the involvement of RNF31 in regulating NLRP3. Mechanistically, RNF31 could interact with NLRP3 through the RBR structural domain, leading to increased K63-linked ubiquitination of NLRP3 and consequent stabilization. Coimmunoprecipitation experiments revealed a mutual interaction between RNF31 and NLRP3, substantiating their functional association. Finally, an in vivo mouse model with RNF31 knockdown showed a notable reduction in NLRP3 expression, which was accompanied by a decrease in the proinflammatory cytokines IL-18 and IL-1ß. The successful attenuation of DSS-induced tissue inflammation by this treatment confirmed the physiological relevance of RNF31-mediated regulation of NLRP3. This study unveils a novel regulatory pathway by which RNF31 affects NLRP3 inflammasome activation, providing new insights into UC pathogenesis and potential therapeutic targets for UC treatment.

Prediction model for lymph node metastasis in superficial colorectal cancer: a better choice than computed tomography.

BACKGROUND: Risk evaluation of lymph node metastasis (LNM) in superficial colorectal cancer resected by endoscopic surgery is critical for determining subsequent therapeutic strategies, but the role of existing clinical methods, including computed tomography, remains limited. METHODS: Features of the nomogram were determined by logistic regression analysis, and the performance was validated by calibration plots, ROC curves and DCA curves in both the training set and the validation set. RESULTS: A total of 608 consecutive superficial CRC cases were randomly divided into 426 training and 182 validation cases. Univariate and multivariate logistic regression analyses revealed that age < 50, tumour budding, lymphatic invasion and lower HDL levels were risk factors for LNM. Stepwise regression and the Hosmer‒Lemeshow goodness of fit test showed that the nomogram had good performance and discrimination, which was validated by ROC curves and calibration plots. Internal and external validation demonstrated that the nomogram had a higher C-index (training group, 0.749, validation group, 0.693). DCA and clinical impact curves graphically show that the use of the nomogram to predict LNM had remarkable predictive power. Finally, in comparison with CT diagnosis, the nomogram also visually showed higher superiority, as demonstrated by ROC, DCA and clinical impact curves. CONCLUSION: Using common clinicopathologic factors, a noninvasive nomogram for individualized prediction of LNM after endoscopic surgery was conveniently established. Nomograms have great superiority in the risk stratification of LNM compared with traditional CT imaging.

Overexpression of RAB31 in gastric cancer is associated with released exosomes and increased tumor cell invasion and metastasis.

BACKGROUND: Gastric cancer (GC) is one of most common cancers worldwide. Several studies have suggested that Rab31 functions as a membrane vesicle transport regulator; however, the mechanism by which RAB31 regulates exosome secretion and promotes metastasis remains to be clarified. METHODS: We examined the expression of RAB31 protein and mRNA in GC tissue samples via immunohistochemistry and reverse transcription-polymerase chain reaction assays, respectively. We elucidated the function of RAB31 in GC cells by constructing a cell model and a pulmonary metastatic model of GC with overexpression of RAB31. Protein mass spectrometry was used to identify the exosomal protein. RESULTS: RAB31 expression increased at both the protein and mRNA levels with the development of GC. Cells overexpressing RAB31 showed an enhanced ability to migrate in both the in vitro cell model and the pulmonary metastatic model of GC. Exosome nanoparticle tracking analysis and electron microscopy revealed that the both the number and size of the exosomes secreted by GC cells were reduced when RAB31 expression was depleted. Injection of exosomes derived from RAB31 overexpressing cells promoted pulmonary metastasis in vivo. Analysis of the exosomal proteins revealed that PSMA1 was overexpressed in GC tissue in accordance with RAB31 expression. PSMA1 overexpression was highly associated with poor prognosis of GC patients. CONCLUSION: Our findings revealed a key role for RAB31 in GC metastasis through regulation of exosome secretion.

Endoscopic Submucosal Dissection Versus Radical Surgery for T1 Superficial Esophageal Cell Carcinoma: a Subgroup Survival Analysis.

BACKGROUND: With the continuous advent of magnifying endoscopy, endoscopic submucosal dissection (ESD) has gradually become the mainstream treatment for early esophageal cancer. We aimed to compare the outcomes of patients with T1 superficial esophageal cell carcinoma treated with ESD vs. esophagectomy. METHODS: We retrospectively analyzed patients who underwent ESD or radical surgery at the First Affiliated Hospital of Nanchang University from January 1, 2010, to December 31, 2018. The purpose of propensity score matching is to reduce selection bias. Precise subgroup analysis according to depth of invasion was performed to reduce the influence of confounding factors. RESULT: We reviewed patients who underwent ESD (n = 117) or radical surgery (n = 217) at the First Affiliated Hospital of Nanchang University from 2010 to 2018. The OS rate and progression-free survival rate in the ESD group were better than those in the surgery group (OS, P = 0.002. PFS, P = 0.004). The ESD group had a lower early adverse event rate (74.6% vs. 91%, P = 0.012), shorter hospital stays (median 10 days vs. 18 days, P < 0.001), and lower hospitalization costs (median 15,455 vs. 62,376 RMB, P < 0.001). Multivariate Cox regression analysis found that the treatment method was an independent risk factor affecting the prognosis of patients with superficial esophageal cancer, and the death risk of patients in the ESD group was 0.377 times that of the radical surgery group (HR = 0.377, P = 0.023). We conducted a subgroup analysis of patients again according to the depth of invasion; 37 pairs of patients were included in the T1a stage, and 19 pairs of patients were included in the T1b stage. In T1a and T1b patients, the difference in OS rate and PFS rate between the two treatments was statistically significant (T1a, OS, P = 0.002, PFS, P = 0.004; T1b, OS, P = 0.019, PFS, P = 0.022), and the OS rates in the ESD group were better than those in the radical surgery group. CONCLUSION: For patients with T1b superficial esophageal cancer, ESD has a longer overall survival and progression-free survival compared with radical surgery. These results support ESD as the preferred treatment for stage T1b superficial esophageal cancer.

Comparison of some biochemical markers between early-onset and late-onset colorectal precancerous lesions: A single-center retrospective study.

OBJECTIVE: Given that the onset of diseases including colorectal cancer precursors is affecting younger individuals and that obesity is an important risk factor for early-onset, we conducted a study to explore the biochemical profile of differences in serum between early-onset patients and late-onset colorectal precancerous lesions. METHODS: A total of 1447 patients, including 469 early-onset patients and 978 late-onset patients, were enrolled from the First Affiliated Hospital of Nanchang University (FAHNU), of which there were 311 sessile serrated adenoma/polyps (SSA/P) and 1136 normal adenomas. The distribution of the included categorical variables was compared via Pearson's chi-squared test, whereas continuous variables were compared by using the nonparametric Kruskal-Wallis test and ANOVA. RESULTS: Compared with late-onset patients, the levels of total bilirubin and HDL-C were lower (p < 0.05), whereas triglyceride and uric acid levels were higher, in early-onset patients. Interestingly, in the subgroup analysis, triglyceride and uric acid levels remained at higher levels, whereas HDL-C remained at lower levels, in early-onset patients than in late-onset patients. Other characteristics, such as LDL-C, drinking, γ-GT, and the N/L ratio, were similar between the two groups. An additional analysis of the association of tumor size with markers showed that lower levels of HDL-C and higher levels of uric acid were associated with increased tumor size (p < 0.05). CONCLUSIONS: Early-onset CRC precursor cases exhibit higher levels of triglycerides and lower levels of HDL-C than late-onset cases. Additionally, levels of HDL-C are negatively associated with tumor size, whereas uric acid was positively correlated with tumor size.

Different lipid metabolic profiles and their associated genes in sessile serrated adenoma or polyps compared to hyperplastic polyps.

The serrated pathway is important in the development of colorectal cancer; currently, knowledge about the lipid metabolism profiles of serrated lesions is limited. Clinical characteristics were compared via Pearson's chi-squared test, nonparametric Kruskal-Wallis test and ANOVA. For some missing values, the MCAR test and multiple imputations were performed. Compared to patients with HP, the rates of younger patients (<50) and male patients with SSA or SSP were increased (P<0.05). Additionally, the BMI index and triglyceride levels were increased in patients with SSA or SSP. Inversely, patients with SSA/P had lower levels of HDL (P<0.05). Interestingly, the value of uric acid and tumor size in SSA/P patients tended to be greater than those in HP patients, and the ratio of patients who smoked was also increased. Other characteristics, such as LDL, ALB, γ-GT, and the N/L ratio, were similar among the subtypes of serrated lesions. Analysis of GEO data (GSE43841) showed that 9 genes were associated with lipid metabolism, including ADRB3, DEGS2, PRKACB, SLC44A1, and CA4. PRKACB was downregulated in SSA/P tissue compared to HP tissue samples from the GSE76987 dataset and our hospital. In conclusion, compared to benign HP, lower HDL levels and higher triglyceride levels tended to occur in CRC precursor SSA/P lesions, and these factors may be associated with metabolic genomic markers, such as PRKACB.

Molecular mechanisms of Huanglian jiedu decoction on ulcerative colitis based on network pharmacology and molecular docking.

Huanglian jiedu decoction (HLJDD) is a heat-clearing and detoxifying agent composed of four kinds of Chinese herbal medicine. Previous studies have shown that HLJDD can improve the inflammatory response of ulcerative colitis (UC) and maintain intestinal barrier function. However, its molecular mechanism is not completely clear. In this study, we verified the bioactive components (BCI) and potential targets of HLJDD in the treatment of UC using network pharmacology and molecular docking, and constructed the pharmacological network and PPI network. Then the core genes were enriched by GO and KEGG. Finally, the bioactive components were docked with the key targets to verify the binding ability between them. A total of 54 active components related to UC were identified. Ten genes are very important to the PPI network. Functional analysis showed that these target genes were mainly involved in the regulation of cell response to different stimuli, IL-17 signal pathway and TNF signal pathway. The results of molecular docking showed that the active components of HLJDD had a good binding ability with the Hub gene. This study systematically elucidates the "multi-component, multi-target, multi-pathway" mechanism of anti-UC with HLJDD for the first time, suggesting that HLJDD or its active components may be candidate drugs for the treatment of ulcerative colitis.

Development and validation of a nomogram for primary duodenal carcinoma: a multicenter, population-based study.

Aim: This study aimed to develop a predictive model for patients with duodenal carcinoma. Methods: Duodenal carcinoma patients from the Surveillance, Epidemiology, and End Results database (2010-2015) and the First Affiliated Hospital of Nanchang University (2010-2021) were enrolled. A nomogram was constructed according to least absolute shrinkage and selection operator regression analysis, the Akaike information criterion approach and Cox regression analysis. Results: Five independent prognostic factors were significantly associated with the prognosis of the duodenal carcinoma patients. A nomogram was constructed with a C-index in the training and validation cohorts of 0.671 (95% CI: 0.578-0.716) and 0.662 (95% CI: 0.529-0.773), respectively. Conclusion: The established nomogram model provided visualization of the risk of each prognostic factor.

Higher LNM rate and poorer prognosis of early-onset compared to late-onset T1 stage colorectal cancer: a large-population based study.

As for T1 stage CRC, there is little knowledge of differences in lymph node metastasis (LNM) and prognosis between early-onset and late-onset CRC. To know that, we included 13,084 patients from the SEER database and 476 patients in T1 stage from our hospital to analyze difference of LNM and prognosis. Univariate and multivariate logistic analyses revealed that early-onset CRC was more likely than late-onset CRC to be positive for LNM. In addition, we found that T1b stage, poor differentiation and lymphatic invasion were risk factors for LNM. Specifically, we found that black race was a risk factor. Before propensity-score matching (PSM), we also found that early-onset CRC patients had better survival, as demonstrated by SEER data. After adjusting for confounding factors by PSM, we found that early onset remained a risk factor for LNM. Moreover, we found that patients diagnosed with early-onset CRC had a poorer prognosis than those diagnosed with late-onset CRC, which was demonstrated by analysis of SEER data and our own data. In conclusion, our study was the first to find that early-onset T1 stage CRC more frequently developed LNM, suggesting that endoscopic submucosal resection should be performed more carefully in these patients. Moreover, early-onset patients in the T1 stage also had poorer survival, suggesting that clinical doctors should pay more attention to early-onset patients.

Taraxasterol acetate targets RNF31 to inhibit RNF31/p53 axis-driven cell proliferation in colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer worldwide. Several studies have suggested that taraxasterol acetate (TA) can inhibit the growth of tumor cells. However, to date, it remains unclear how TA inhibits cell growth and how RNF31 functions as an oncogene. We examined the expression of RNF31 in CRC tissue samples via immunohistochemistry and elucidated the function of RNF31 in CRC cells by constructing a cell model with RNF31 depletion. A cycloheximide (CHX)-chase analysis and immunofluorescence assays were conducted to demonstrate that TA can promote RNF31 degradation by activating autophagy. We used the PharmMapper website to predict targets of TA and identified RNF31. CHX-chase experiments showed that TA could facilitate RNF31 degradation, which was inhibited by the administration of chloroquine. Immunofluorescence assays showed that RNF31 protein was colocalized with LC3I/II and p62, suggesting that TA promoted RNF31 degradation by activating autophagy. We also found that CRC patients with RNF31 overexpression had poorer survival than those with low RNF31 expression. The results of the CHX-chase experiment showed that depletion of RNF31 alleviated p53 degradation, which was inhibited by MG132. A series of co-immunoprecipitation (Co-IP) assays revealed that RNF31 interacts with p53 and promotes p53 ubiquitination and degradation. A Co-IP assay performed with a truncated RNF31 plasmid showed that the PUB domain interacts with p53. Moreover, the PUB domain is the key structure in the induction of p53 ubiquitination. Our findings reveal a key role of RNF31 in CRC cell growth and indicate a mechanism through which TA inhibits cell growth.

Prognostic Value of S100P Expression in Patients With Digestive System Cancers: A Meta-Analysis.

BACKGROUND: Digestive system cancers (DSCs) are associated with high morbidity and mortality. S100P has been reported as a prognostic biomarker in DSCs, but its prognostic value remains controversial. Accordingly, we conducted a meta-analysis to investigate whether S100P is correlated with overall survival (OS) of patients with DSCs. The relationship between S100P and clinicopathological features was also evaluated. METHODS: We systematically searched PubMed, Embase, Web of Science and Cochrane Library for eligible studies up to January 2020. In total, 16 publications with 1,925 patients were included. RESULTS: S100P overexpression was associated with poor OS of patient with DSCs (HR=1.54, 95% CI: 1.14-2.08, P=0.005). When stratified by anatomic structure, S100P overexpression was associated with poor prognosis in non-gastrointestinal tract cancers (HR=1.98, 95% CI: 1.44-2.72, P<0.001) but not in gastrointestinal tract cancers (HR=1.09, 95% CI: 0.66-1.81, P=0.727). When stratified by tumor type, S100P overexpression predicted poor OS in cholangiocarcinoma (HR=2.14, 95% CI: 1.30-3.50, P=0.003) and hepatocellular carcinoma (HR=1.91, 95% CI: 1.22-2.99, P =0.005) but not in gastric cancer (HR=0.97, 95% CI: 0.65-1.45, P=0.872), colorectal cancer (HR=1.18, 95% CI: 0.32-4.41, P=0.807), gallbladder cancer (HR=1.40, 95% CI: 0.84-2.34, P=0.198), and pancreatic cancer (HR=1.92, 95% CI: 0.99-3.72, P=0.053). Furthermore, high S100P expression was significantly associated with distant metastasis (OR=3.58, P=0.044), advanced clinical stage (OR=2.03, P=0.041) and recurrence (OR=1.66, P=0.007). CONCLUSION: S100P might act as a prognostic indicator of non-gastrointestinal tract cancers.

Analyzing and predicting the LNM rate and prognosis of patients with intraductal papillary mucinous neoplasm of the pancreas.

BACKGROUND: Current the surveillance and management are controversial for patients with IPMN. We aimed to develop an alternative nomogram to individualize IPMN prognosis and LNM. METHODS: Based on the data from SEER database of patients diagnosed with IPMN between 2004 and 2015, a nomogram predicting the survival and LNM of IPMN based on univariate and multivariate and Lasso regression analysis was performed, internally and externally validated, and measured by C-index, and decision curve analysis (DCA), and compared to the 7th TNM stage. RESULTS: A total of 941 patients were included. Age, T stage examined nodes, tumor size, and pathology grade were identified as an independent factor for predicting LNM. The nomogram we established to predict LNM had a high predicting value with a C-index value of 0.735 and an AUC value of 0.753. Interestingly, including T1 stage, we found an inverse correlation was between age and LNM. In addition, nomogram for predicting CSS also performed better than TNM stage both in the internal validation group (1-year AUC:0.753 vs. 0.693, 3-year AUC: 0.801 vs. 0.731, 5-year AUC: 0.803 vs. 0.733) and external validation group (1-year AUC: 0.761 vs. 0.701, 3-year AUC: 0.772 vs. 0.713, 5-year AUC:0.811 vs. 0.735). DCA analysis showed the nomogram showed a greater benefit across the period of follow-up compared to 7th TNM stage. CONCLUSION: A nomogram based on multivariate and Lasso regression analysis showed great clinical usability compared with current criteria. Also, for LNM of IPMN, younger age patients with IPMN should be attached more importance.

Higher Lymph Node Metastasis Rate and Poorer Prognosis of Intestinal-Type Gastric Cancer Compared to Diffuse-Type Gastric Cancer in Early-Onset Early-Stage Gastric Cancer: A Retrospective Study.

Background: The incidence of early-onset gastric cancer (GC) that was diagnosed at <50 years is increasing, but there is a knowledge gap on early-onset early-stage GC (EEGC) that was defined as early-onset GC limited to the mucosa or submucosa. Therefore, we comprehensively analysed the clinical features based on Lauren type. Methods: Logistic and Cox analyses were used to investigate risk factors for lymph node metastasis (LNM) and prognosis, respectively. Propensity score matching (PSM) was used to adjust confounding factors. Protein mass spectrometry analysis was used to explore the molecular mechanism of LNM. Result: Our study included 581 patients with EEGC from the Surveillance, Epidemiology, and End Results (SEER) database and 226 patients with EEGC from our own centre. We identified intestinal type, T1b stage, and tumour size (>3 cm) as risk factors for LNM using SEER and our own data. We also found that the prognosis of patients with intestinal-type EEGC was poorer than patients with diffuse-type EEGC, and T1b stage and positive LNM were hazard factors for survival. After analysing the expression of proteins between positive and negative LNM in the intestinal or diffuse type, we found no similar proteins between these groups. The differentially expressed genes (DEGs) in the intestinal type functioned as epithelial cell signalling in Helicobacter pylori. The DEGs in the diffuse type functioned in the tricarboxylic acid cycle (TCA cycle) and oxidative phosphorylation. Conclusion: For EEGC, our study was the first report to demonstrate that the intestinal type was a risk factor for LNM and survival compared to the diffuse type, and the oncogenic expression promoting the occurrence of LNM was different. These findings suggest that clinicians should pay more attention to intestinal-type EEGC than diffuse-type EEGC.

Prognostic analysis of gastric signet ring cell carcinoma and mucinous carcinoma: a propensity score-matched study and competing risk analysis.

BACKGROUND: Limited evidence and contradictory results have been reported regarding the impact of signet ring cell carcinoma (SRC) and mucinous gastric cancer (MGC) classifications on the prognosis of gastric cancer (GC). RESULTS: Information on 6017 patients and 266 patients was extracted from the SEER database and our hospital records, respectively. We found that patients with MGC had a better survival rate than those with SRC (P=0.012), but in the early stage, MGC was a risk factor for a poor prognosis. After PSM, for both patients from the SEER database and our hospital, the prognosis of patients with SRC was poorer than that of patients with MGC (P<0.05), but patients with MGC in early-stage GC showed poorer survival. Additionally, SRC was demonstrated to be a risk factor in the multivariate competing risk regression model for cancer-specific survival. CONCLUSION: Patients with SRC may have a worse prognosis than those with MGC, but for early-stage GC, patients with SRC have a better prognosis than those with MGC. METHOD: Patients from the SEER database and from our hospital diagnosed with SRC or MGC were included in a Cox regression analysis, multivariate competing risk model and propensity score matching (PSM) analysis.

TLR9 induces colitis-associated colorectal carcinogenesis by regulating NF-κB expression levels.

Chronic colorectal inflammation has been associated with colorectal cancer (CRC); however, its exact molecular mechanisms remain unclear. The present study aimed to investigate the effect of Toll-like receptor 9 (TLR9) on the development of colitis-associated CRC (CAC) through its regulation of the NF-κB signaling pathway. By using a CAC mouse model and immunohistochemistry, the present study discovered that the protein expression levels of TLR9 were gradually upregulated during the development of CRC. In addition, the expression levels of TLR9 were revealed to be positively correlated with NF-κB and Ki67 expression levels. In vitro, inhibiting TLR9 expression levels using chloroquine decreased the cell viability, proliferation and migration of the CRC cell line HT29, and further experiments indicated that this may occur through downregulating the expression levels of NF-κB, proliferating cell nuclear antigen and Bcl-xl. In conclusion, the findings of the present study suggested that TLR9 may serve an important role in the development of CAC by regulating NF-κB signaling.

Analysis of the Incidence and Survival of Gastric Cancer Based on the Lauren Classification: A Large Population-Based Study Using SEER.

Background: Limited evidence exists on the incidence of gastric cancer (GC), and contradictory results exist for the prognosis of GC based on the Lauren classification. We analyzed the incidence and survival of GC based on the Lauren classification. Methods: The Surveillance, Epidemiology, and End Results (SEER) database from 1975 through 2015 was used to identify all patients with surgically resected, histologically diagnosed intestinal or diffused-type GC. Propensity score matching was used to analyze the association between the Lauren classification type and prognosis. Results: The trend of total GC incidence showed an obvious decrease (APC = -1.51, 95% CI: -2.31 to -1.01) as well as that of the intestinal type (APC = -1.43, 95% CI: -2.01 to -1.12). However, we found that the relative incidence of the diffused type was increased (APC = 0.6, 95% CI: 0.41-0.82). The trend of the total incidence of GC (APC = -1.31, 95% CI: -1.91 to -1.03) and that of the intestinal type (APC = -1.11, 95% CI: -1.53 to -0.98) was decreased in 40-49-year-olds, but that of the diffused type was increased (APC = 1.5, 95% CI: 1.2-1.72). We found that trends in GC incidence exhibited a similar pattern in the regional and distant stages and showed a decrease from 1975 through 2015. However, the incidence rate of the local stage was increased, with an APC of 0.5 (95% CI: 0.3-0.7). We identified 15,989 GC cases from the SEER database, including 13,852 intestinal-type and 2,138 diffused-type cases. The 1,336 intestinal-type cases were matched with 1,336 diffused-type cases using propensity score matching (PSM), and patients with the diffused type had a better prognosis than patients with the intestinal type (HR = 0.56, 95% CI: 0.45-0.78). However, we found that patients with diffused-type GC had worse survival than patients with intestinal-type GC in the cohort from Renji Hospital (P < 0.001). Conclusion: The total incidence of GC and that of the intestinal-type GC decreased, but the incidence of diffused-type GC increased in 40-49-year-olds. Diffused types of GCs may have a different prognosis compared to intestinal-type GCs in different patient cohorts. Nevertheless, these results should be interpreted with caution in assessing the prognosis in combination with other factors.