Bone Marrow Mesenchymal Stem Cells Alleviate Acute Severe Pancreatitis and Promote Lung Repair via Inhibiting NLRP3 Inflammasome in Rat.

BACKGROUND: Acute severe pancreatitis (SAP) is a severe acute abdominal disease, which can lead to pancreatic infection and necrosis as well as distant organ damage. Bone marrow mesenchymal stem cells (BMSCs) can exert anti-inflammatory effect on SAP, while NLRP3 inflammasomes play an important role in the inflammatory response. This study aimed to investigate whether BMSCs exert anti-inflammatory effect on SAP by inhibiting NLRP3 inflammasome. METHODS: The rat SAP model was established. Serum amylase, lipase and inflammatory factor levels were measured by ELISA, and the level of tissue injury was assessed by HE staining. The expression of NLRP3 inflammasome was detected by PCR, Western Blot and immunohistochemistry. ML385 was used to block Nrf2 pathway, aiming to investigate whether Nrf2 pathway was involved in the therapeutic effect of BMSCs on SAP by regulating NLRP3 inflammasome expression. RESULTS: In SAP rats, NLRP3 inflammasome was activated, which became more evident over time. After transplantation of BMSCs, the NLRP3 inflammasome expression decreased at both mRNA and protein levels, the serum levels of amylase, lipase and inflammatory factors decreased, and the pathological scores of the pancreas and lung were both improved. After blocking the Nrf2 pathway, the NLRP3 inflammasome expression increased in the injured pancreas and lung, and the inflammation deteriorated, which inhibited the therapeutic effects of BMSCs on SAP. CONCLUSION: The therapeutic effect of BMSC on SAP is at least partially ascribed to the inhibition of NLRP3 inflammasome, and Nrf2 pathway mediates the therapeutic effect of BMSC on SAP by inhibiting NLRP3 inflammasome.

The efficacy and safety of laparoscopic common bile duct exploration and cholecystectomy for the treatment of difficult common bile duct stones combined with gallstones: a multicenter retrospective study.

PURPOSE: To analyze the benefits of laparoscopic common bile duct exploration and laparoscopic cholecystectomy (LCBDE + LC) versus endoscopic retrograde cholangiopancreatography and/or endoscopic sphincterotomy following laparoscopic cholecystectomy (ERCP/EST + LC) for difficult common bile duct stones combined with gallstones. METHODS: A retrospective analysis of consecutive patients with difficult common bile duct stones combined with gallstones in three hospitals from January 2016 to January 2021 was performed. RESULTS: ERCP/EST + LC contributed to reducing postoperative drainage time. However, LCBDE + LC showed a higher rate of complete clearance, along with lower postoperative hospital stays, expenses and incidence of postoperative hyperamylasemia, pancreatitis, re-operation and recurrence. In addition, LCBDE + LC showed safe and feasible performance in the elderly and patients with previous upper abdominal surgery. CONCLUSION: It is an effective and safe method for LCBDE + LC for difficult common bile duct stones combined with gallstones.

Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis by inhibiting oxidative stress in rats.

To investigate whether bone marrow mesenchymal stem cells (BMSCs) attenuate pancreatic injury via mediating oxidative stress in severe acute pancreatitis (SAP). The SAP model was established in rats. Phosphate buffered saline (PBS) or BMSCs were injected into the rats by tail veins. ML385 was used to down-regulate Nrf2 expression in rats. Pancreatic pathological score was used to evaluated pancreatic injury. Inflammatory-associated cytokines, serum lipase and amylase, levels of myeloperoxidase, malondialdehyde, reactive oxygen species and superoxide dismutase, as well as catalase activity were measured for injury severity evaluation. ML385 aggravates oxidative stress in SAP + ML385 group, compared with SAP + PBS group. BMSCs transplantation alleviated pancreatic injury and enhance antioxidant tolerance in SAP + BMSCs group, while ML385 administration weakened this efficacy in SAP + BMSCs + ML385 group. In addition, BMSCs promoted Nrf2 nuclear translocation via PI3K/AKT signaling pathway. Besides, BMSCs reduced inflammatory response by inhibiting NF-κB signaling pathway in SAP. BMSCs can inhibit oxidative stress and reduce pancreatic injury via inducing Nrf2 nuclear translocation in SAP.

Long noncoding RNAs in cancer-immunity cycle.

The imbalance of immune status in cancer microenvironment plays an important role in the development and progression of cancer. Immunotherapy based on this has become an important field of cancer research in recent years. Many studies on long noncoding RNA (lncRNA) in cancer have focus on its regulation in cancer development and metastasis. Recent studies have suggested that lncRNAs play crucial roles in different phases of cancer immunity, including antigen releasing, antigen presentation, immune activation, immune cells migration, infiltrating into cancer tissues, and killing cancer cells. The functional studies of lncRNAs in cancer immuntity revealed the complicated molecular mechanisms in cancer immunity from a new point of view, which may provide novel potential targets for cancer immunotherapies. Based on the classical cancer-immunity cycle theory, we review the recent studies on the functions and mechanisms of immune-related lncRNAs in different stages of cancer immunity, to summarize the relationship between lncRNAs, and cancer immunity and to provide a framework for further research.

Is T-tube drainage no longer needed for laparoscopic common bile duct exploration? A retrospective analysis and literature review.

Introduction: Primary closure (PC) following laparoscopic common bile duct exploration (LCBDE) is increasingly becoming a safe and effective option for choledocholithiasis. However, whether T-tube drainage (TTD) is no longer needed for LCBDE remains under debate. Aim: To evaluate the safety and efficacy of PC and TTD following LCBDE, and discuss their indications for selection of the procedure, combined with a literature review. Material and methods: 826 consecutive patients who underwent LCBDE with PC or TTD at Shanghai Tenth People's Hospital were reviewed. The clinical data of postoperative outcomes were compared and analyzed. Propensity score matching (PSM) was used to adjust for potential baseline confounding. Results: Of these patients, 796 underwent PC and 30 underwent TTD. Twenty-eight (3.52%) cases occurred in bile leakage in PC, and all of them were treated successfully with conservative therapy. Additionally, there was no evidence of bile duct stricture and death in all PC cases. TTD was mainly performed in patients with a higher rate of cholangitis (50.00%), large stones (26.67%), impacted stones (23.33%) and laser lithotripsy (26.67%). After PSM, 23 cases with PC and TTD were included. In the PC group, the operative time, postoperative stay, hospital expenses and recurrence rate were significantly shorter or less than in the TTD group. However, there were no significant differences between the two groups in postoperative drainage time, complications, reoperations and bile duct stricture rate. Conclusions: PC following LCBDE is safe and effective for choledocholithiasis. TTD is a safe alternative method for bile duct closure in certain special cases, such as acute cholangitis, large stones, impacted stones, and laser lithotripsy.

Chinese and Global Burdens of Gastrointestinal Cancers From 1990 to 2019.

Background: Gastrointestinal (GI) cancers are an important component of the tumor. This study aimed to investigate the burden of six major GI cancers in China and globally from 1990 to 2019. Methods: We conducted a cross-sectional study based on the Global Burden of Disease Study (GBD) 2019. Indicators on incidence, deaths, disability-adjusted life-years (DALYs), and risk factors for esophageal, stomach, liver, pancreatic, colon and rectum, and gallbladder and biliary tract cancers were collected and analyzed for time trends. The contribution of each cancer and the proportion of cases in China among global cases were further reported. Results: Global incidence cases, death cases, and DALYs of GI cancers showed an overall ascending trend over the past 30 years, but there was temporal and geographical variation across cancer types. By 2019, colon and rectum cancer had overtaken stomach cancer as the most burdensome GI cancer globally. However, stomach cancer narrowly continued to be the most burdensome GI in China. In addition, the proportion of incidence and death cases of stomach, pancreatic, colon and rectum, and gallbladder and biliary tract cancers among global cases had further increased. It was noteworthy that the burden of liver cancer in China has been alleviated significantly. Conclusion: GI cancers remain a major public health problem in China and globally. Despite the temporal and geographic diversity of different cancers, targeted primary and secondary prevention are still necessary for the future to face these unknown challenges.

Low aspartate aminotransferase/alanine aminotransferase (DeRitis) ratio assists in predicting diabetes in Chinese population.

Background: Few studies discussed the predictive ability of aspartate aminotransferase/alanine aminotransferase (AST/ALT, DeRitis) ratio for diabetes risk. The aim of this study was to characterize the role of AST/ALT ratio in the prediction of Chinese diabetes. Methods: This retrospective cohort study analyzed a Chinese population comprising 87,883 participants without diabetes at baseline between 2010 and 2016. Cox proportional hazards regression was used to identify independent risk factors. Restricted cubic spline (RCS) was performed to investigate the non-linear correlation between AST/ALT ratio and diabetes risk. Results: During a median follow-up period of 3.01 years, 1,877 participants developed diabetes. Comparing the baseline characteristics, diabetes group exhibited lower AST/ALT ratio. The Kaplan-Meier curve showed that participants with low AST/ALT ratio had higher cumulative incidence, and Cox regression also demonstrated that the lower AST/ALT ratio, the higher diabetes risk (HR: 0.56, 95% CI: 0.37-0.85, P = 0.006). The RCS model revealed a non-linear correlation between AST/ALT ratio and diabetes risk. In the condition of AST/ALT ratio ≤1.18, diabetes risk increased as it decreased (HR: 0.42, 95% CI: 0.19-0.91, P = 0.028). In contrast, AST/ALT ratio did not independently affect diabetes when beyond 1.18. Conclusion: AST/ALT ratio is a valuable predictor of diabetes. Diabetes risk increases rapidly in the condition of AST/ALT ratio ≤1.18.

A nomogram for predicting stones recurrence in patients with bile duct stones undergoing laparoscopic common bile duct exploration.

Background: The recurrence of bile duct stones is a long-term outcome for patients undergoing laparoscopic common bile duct exploration (LCBDE) that is worthy of attention. This study aimed to investigate long-term risk factors for stones recurrence after LCBDE and develop a nomogram for predicting the risk. Methods: The clinical data on consecutive patients with bile duct stones undergoing LCBDE at Shanghai Tenth People's Hospital between January 2014 and February 2019 with a follow-up period longer than 2 years were reviewed. Independent risk factors of stones recurrence identified by the Cox regression model were used to develop a nomogram in predicting stones recurrence after LCBDE. Results: Eight hundred and twenty-two patients were eventually included in this study. Of these patients, 42 (5.11%) developed stones recurrence. The cumulative incidences of stones recurrence at 1, 3, and 5 years after LCBDE were 1.34%, 4.36%, and 7.14%, respectively. Independent risk factors of stones recurrence were identified to be age (HR = 1.04, 95% CI = 1.02-1.07), T-tube drainage (HR = 3.28, 95% CI = 1.23-8.72), fatty liver (HR = 2.69, 95% CI = 1.39-5.20), urinary calculus (HR = 4.68, 95% CI = 2.29-9.56), post-cholecystectomy (HR = 5.21, 95% CI = 2.39-11.33), and post-ERCP + EST (HR = 2.87, 95% CI = 1.18-6.96). By these factors, a developed nomogram showed a C-index of 0.770 to predict stones recurrence. Conclusions: The nomogram, based on identified risk factors, showed good accuracy for predicting stones recurrence, which is valuable to guide these patients' follow-up and prevention.

Serum lipids mediate the relationship of multiple polyaromatic hydrocarbons on non-alcoholic fatty liver disease: A population-based study.

Polyaromatic hydrocarbons (PAHs) are recognized as organic pollutants with liver toxicity. However, the relationship between PAHs and nonalcoholic fatty liver disease (NAFLD) is unclear in humans. The aim of this study was to investigate the levels of PAHs in the US population and their association with the risk of NAFLD. We investigated urinary levels of nine PAHs in 2436 participants from the National Health and Nutrition Examination Survey (NHANES) between 2005 and 2012, including 1-Hydroxynapthalene (1-OHN), 2-Hydroxynapthalene (2-OHN), 3-Hydroxyfluorene (3-OHF), 2-Hydroxyfluorene (2-OHF), 3-Hydroxyphenanthrene (3-OHPhe), 1-Hydroxyphenanthrene (1-OHPhe), 2-Hydroxyphenanthrene (2-OHPhe), 1-Hydroxypyrene (1-OHPyr), 9-Hydroxyfluorene (9-OHF). Logistic regression models were used to estimate the relationship between single PAH and NAFLD. Assessment of the overall effect of multiple PAH mixtures on NAFLD using Bayesian kernel machine regression (BKMR) model. There were 698 participants diagnosed with NAFLD in the study group. After adjusting for related covariates such as sex, age, race, education, marital status, poverty income ratio (PIR), body mass index (BMI), total energy intake, smoking, hypertension, and diabetes, logistic regression analysis showed that compared to the low tertile (T1), the odds ratio of the high tertile (T3) was 1.70 (95%CI: 1.26-2.29, p = 0.001) for total PAHs, 1.50 (95%CI: 1.11-2.03, p = 0.008) for 2-OHN, 1.75 (95%CI: 1.31-2.34, p < 0.001) for 2-OHPhe, 1.59 (95%CI: 1.18-2.14, p = 0.002) for 9-OHF and 0.63 (95%CI: 0.46-0.87, p = 0.004) for 3-OHF. In the BKMR model, we found that the overall effect of the nine PAH mixtures was positively associated with the risk of NAFLD. Mediation analysis showed that HDL and TG mediated the association between PAHs and NAFLD. Our study suggests that multiple PAHs mixtures exposure may induce NAFLD by mediating serum lipids in human metabolism.

The methods of preoperative biliary drainage for resectable hilar cholangiocarcinoma patients: A protocol for systematic review and meta analysis.

OBJECTIVES: To compare the clinical outcomes of endoscopic biliary drainage (EBD) with those of percutaneous transhepatic biliary drainage (PTBD) in patients with resectable hilar cholangiocarcinoma (HCCA) and evaluate the effect of EBD and PTBD on tumor prognosis. MATERIALS AND METHODS: PubMed, EMBASE, and Cochrane Library databases were searched for articles about the comparison between PTBD and EBD. Data were analyzed by Revman 5.3. RESULTS: PTBD showed a lower risk of drainage-related complications than EBD (OR, 2.73; 95%CI, 1.52-4.91; P < .05). PTBD was also associated with lower risk of pancreatitis (OR, 8.47; 95%CI, 2.28-31.45; P < .05). The differences in preoperative cholangitis, R0 resection, blood loss and recurrence showed no statistically significance between EBD and PTBD (all P > .05). Several literatures have reported the tumor implantation metastasis after PTBD. Since no well-designed prospective randomized controlled studies have explored in this depth, this article is unable to draw conclusions on this aspect. CONCLUSION: PTBD is a reasonable choice for PBD, and EBD should only be used as preoperative drainage for HCCA by more experienced physicians. There is a greater need to design prospective randomized controlled studies to obtain high-level evidence-based medicinal proof. It is worth noting that, whether EBD or PTBD, accurate selective biliary drainage should be the trend.

Long noncoding RNA H19 regulates the therapeutic efficacy of mesenchymal stem cells in rats with severe acute pancreatitis by sponging miR-138-5p and miR-141-3p.

BACKGROUND: Patients with severe acute pancreatitis (SAP), which is characterized by high morbidity and mortality, account for an increasing medical burden worldwide. We previously found that mesenchymal stem cells (MSCs) could attenuate SAP and that expression of long noncoding RNA H19 (LncRNA H19) was upregulated in rats receiving MSCs. In the present study, we investigated the mechanisms of LncRNA H19 regulating the therapeutic efficacy of MSCs in the alleviation of SAP. METHODS: MSCs transfected with LncRNA H19 overexpression and knockdown plasmids were intravenously injected into rats 12 h after sodium taurocholate (NaT) administration to induce SAP. RESULTS: Overexpressing LncRNA H19 in MSCs significantly enhanced the anti-inflammatory capacity of the MSCs, inhibited autophagy via promotion of focal adhesion kinase (FAK)-associated pathways, and facilitated cell proliferation by increasing the level of ß-catenin in rats with SAP. LncRNA H19 functioned as a competing endogenous RNA by sponging miR-138-5p and miR-141-3p. Knocking down miR-138-5p in MSCs increased the expression of protein tyrosine kinase 2 (PTK2, encoding FAK) to suppress autophagy, while downregulating miR-141-3p enhanced the level of ß-catenin to promote cell proliferation. CONCLUSIONS: In conclusion, LncRNA H19 effectively increased the therapeutic efficacy of MSCs in rats with SAP via the miR-138-5p/PTK2/FAK and miR-141-3p/ß-catenin pathways.

Mechanisms and therapeutic potentials of cancer immunotherapy in combination with radiotherapy and/or chemotherapy.

Immunotherapies based on T cells have gained significant success in the treatment of diverse cancers, however, several limitations also exist, including low response, acquired resistance and severe side effects, which lead to unfavorable outcomes. Recent studies found that traditional therapies, radiotherapy and/or chemotherapy may affect the immune condition in situ and cause abscopal effect, which may improve the response of immunotherapies, enhance the efficiency, and reduce the untoward effect. Here, we review the mechanisms uncovering the cancer immunotherapy and immunogenic effects of radiotherapy and chemotherapy, aiming to highlight the principles underlying the therapeutic potentials of cancer immunotherapy in combination with radiotherapy and/or chemotherapy and ultimately guide better designs for future synergistic cancer therapies.