A TGF-ß-dominant chemoresistant phenotype of hepatoblastoma associated with aflatoxin exposure in children.

BACKGROUND AND AIMS: Hepatoblastoma (HB) is the most common liver cancer in children, posing a serious threat to children's health. Chemoresistance is the leading cause of mortality in patients with HB. A more explicit definition of the features of chemotherapy resistance in HB represents a fundamental urgent need. APPROACH AND RESULTS: We performed an integrative analysis including single-cell RNA sequencing, whole-exome sequencing, and bulk RNA sequencing in 180 HB samples, to reveal genomic features, transcriptomic profiles, and the immune microenvironment of HB. Multicolor immunohistochemistry staining and in vitro experiments were performed for validation. Here, we reported four HB transcriptional subtypes primarily defined by differential expression of transcription factors. Among them, the S2A subtype, characterized by strong expression of progenitor ( MYCN , MIXL1 ) and mesenchymal transcription factors ( TWIST1 , TBX5 ), was defined as a new chemoresistant subtype. The S2A subtype showed increased TGF-ß cancer-associated fibroblast and an immunosuppressive microenvironment induced by the upregulated TGF-ß of HB. Interestingly, the S2A subtype enriched SBS24 signature and significantly higher serum aflatoxin B1-albumin (AFB1-ALB) level in comparison with other subtypes. Functional assays indicated that aflatoxin promotes HB to upregulate TGF-ß. Furthermore, clinical prognostic analysis showed that serum AFB1-ALB is a potential indicator of HB chemoresistance and prognosis. CONCLUSIONS: Our studies offer new insights into the relationship between aflatoxin and HB chemoresistance and provide important implications for its diagnosis and treatment.

Comparison of clinical efficacy between LAPS and ALPPS in the treatment of hepatitis B virus-related hepatocellular carcinoma.

Background: Insufficient post-operative future liver remnant (FLR) limits the feasibility of hepatectomy for patients. Staged hepatectomy is an effective surgical approach that can improve the resection rate of hepatocellular carcinoma (HCC). This study aimed to compare the safety and efficacy of laparoscopic microwave ablation and portal vein ligation for staged hepatectomy (LAPS) and classical associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in the treatment of hepatitis B virus (HBV)-related HCC. Methods: Clinical data of patients with HBV-related HCC who underwent LAPS or ALPPS in our institute between January 2017 and May 2022 were retrospectively analysed. Results: A total of 18 patients with HBV-related HCC were retrospectively analysed and divided into the LAPS group (n = 9) and ALPPS group (n = 9). Eight patients in the LAPS group and eight patients in the ALPPS group proceeded to a similar resection rate (88.9% vs 88.9%, P = 1.000). The patients undergoing LAPS had a lower total comprehensive complication index than those undergoing ALPPS but there was not a significant different between the two groups (8.66 vs 35.87, P = 0.054). The hypertrophy rate of FLR induced by ALPPS tended to be more rapid than that induced by LAPS (24.29 vs 13.17 mL/d, P = 0.095). The 2-year recurrence-free survival (RFS) was 0% for ALPPS and 35.7% for LAPS (P = 0.009), whereas the 2-year overall survival for ALPPS and LAPS was 33.3% and 100.0% (P = 0.052), respectively. Conclusions: LAPS tended to induce lower morbidity and FLR hypertrophy more slowly than ALPPS, with a comparable resection rate and better long-term RFS in HBV-related HCC patients.

Identification and validation of a plasma metabolomics-based model for risk stratification of intrahepatic cholangiocarcinoma.

BACKGROUND: Liver resection is the mainstay of curative treatment for intrahepatic cholangiocarcinoma (ICC) while the postoperative prognosis varies greatly, with no recognized biomarker. We aimed to identify the plasma metabolomic biomarkers that could be used for preoperative risk stratification of ICC patients. METHODS: 108 eligible ICC patients who underwent radical surgical resection between August 2012 and October 2020 were enrolled. Patients were randomly divided into a discovery cohort (n = 76) and a validation cohort (n = 32) by 7:3. Metabolomics profiling of preoperative plasma was performed and clinical data were collected. The least absolute shrinkage and selection operator (LASSO) regression, Cox regression, and receiver operating characteristic (ROC) analyses were used to screen and validate the survival-related metabolic biomarker panel and construct a LASSO-Cox prediction model. RESULTS: 10 survival-related metabolic biomarkers were used for construction of a LASSO-Cox prediction model. In the discovery and validation cohorts, the LASSO-Cox prediction model achieved an AUC of 0.876 (95%CI: 0.777-0.974) and 0.860 (95%CI: 0.711-1.000) in evaluating 1-year OS of ICC patients, respectively. The OS of ICC patients in the high-risk group was significantly worse than that in the low-risk group (discovery cohort, p < 0.0001; validation cohort: p = 0.041). Also, the LASSO-Cox risk score (HR 2.43, 95%CI: 1.81-3.26, p < 0.0001) was a significant independent risk factor associated with OS. CONCLUSIONS: The LASSO-Cox prediction model has potential as an important tool in evaluating the OS of ICC patients after surgical resection and can be used as prediction tools to implement the best treatment options that could result in better outcomes.

RNA-Seq Analysis Demystify the Pathways of UV-A Supplementation in Different Photoperiods Integrated with Blue and Red Light on Morphology and Phytochemical Profile of Kale.

As an indispensable element in the morphology and phytochemical profile of plants, UV-A has proved to help promote the growth and quality of kale. In this study, UV-A supplementation in different photoperiods (light period supplemental UVA = LS, dark period supplemental UVA = DS, and light-dark period supplemental UVA = LDS) contributed to yielding greater biomass production (fresh weight, dry weight, and plant moisture content), thus improving morphology (plant height, stem diameter, etc.) and promoting higher phytochemicals content (flavonoids, vitamin c, etc.), especially glucosinolates. To fathom its mechanisms, this study, using RNA-seq, verified that UV-A supplementation treatments signally generated related DEGs of plant hormone signal pathway, circadian rhythm plant pathway, glucosinolate pathway, etc. Moreover, 2047 DEGs were obtained in WGCNA, illustrating the correlations between genes, treatments, and pathways. Additionally, DS remarkedly up-regulated related DEGs of the key pathways and ultimately contributed to promoting the stem diameter, plant height, etc., thus increasing the pigment, biomass, vitamin c, etc., enhancing the antioxidant capacity, and most importantly, boosting the accumulations of glucosinolates in kale. In short, this study displayed new insights into UV-A supplementation affected the pathways related to the morphology and phytochemical profile of kale in plant factories.

Effect of Supplemental UV-A Intensity on Growth and Quality of Kale under Red and Blue Light.

Different intensities of UV-A (6, 12, 18 µmol·m-2s-1) were applied in a plant factory to evaluate the combined influences of supplemental UV-A and red and blue light (Red:Blue = 1:1 at PPFD of 250 µmol·m-2 s-1) on the biomass, antioxidant activity and phytochemical accumulation of kale. Supplemental UV-A treatments (T1: 6 µmol·m-2 s-1, T2: 12 µmol·m-2 s-1 and T3: 18 µmol·m-2 s-1) resulted in higher moisture content, higher pigment content, and greater leaf area of kale while T2 reached its highest point. T2 treatment positively enhanced the antioxidant capacity, increased the contents of soluble protein, soluble sugar and reduced the nitrate content. T1 treatment markedly increased the content of aliphatic glucosinolate (GSL), whereas T2 treatment highly increased the contents of indolic GSL and total GSL. Genes related to GSL biosynthesis were down-regulated in CK and T3 treatments, while a majority of them were greatly up-regulated by T1 and T2. Hence, supplemental 12 µmol·m-2 s-1 UV-A might be a promising strategy to enhance the growth and quality of kale in a plant factory.

St13 protects against disordered acinar cell arachidonic acid pathway in chronic pancreatitis.

BACKGROUND: Early diagnosis and treatment of chronic pancreatitis (CP) are limited. In this study, St13, a co-chaperone protein, was investigated whether it constituted a novel regulatory target in CP. Meanwhile, we evaluated the value of micro-PET/CT in the early diagnosis of CP. METHODS: Data from healthy control individuals and patients with alcoholic CP (ACP) or non-ACP (nACP) were analysed. PRSS1 transgenic mice (PRSS1Tg) were treated with ethanol or caerulein to mimic the development of ACP or nACP, respectively. Pancreatic lipid metabolite profiling was performed in human and PRSS1Tg model mice. The potential functions of St13 were investigated by crossing PRSS1Tg mice with St13-/- mice via immunoprecipitation and lipid metabolomics. Micro-PET/CT was performed to evaluate pancreatic morphology and fibrosis in CP model. RESULTS: The arachidonic acid (AA) pathway ranked the most commonly dysregulated lipid pathway in ACP and nACP in human and mice. Knockout of St13 exacerbated fatty replacement and fibrosis in CP model. Sdf2l1 was identified as a binding partner of St13 as it stabilizes the IRE1α-XBP1s signalling pathway, which regulates COX-2, an important component in AA metabolism. Micro-PET/CT with 68Ga-FAPI-04 was useful for evaluating pancreatic morphology and fibrosis in CP model mice 2 weeks after modelling. CONCLUSION: St13 is functionally activated in acinar cells and protects against the cellular characteristics of CP by binding Sdf2l1, regulating AA pathway. 68Ga-FAPI-04 PET/CT may be a very valuable approach for the early diagnosis of CP. These findings thus provide novel insights into both diagnosis and treatment of CP.

Combination Neoantigen-Based Dendritic Cell Vaccination and Adoptive T-Cell Transfer Induces Antitumor Responses Against Recurrence of Hepatocellular Carcinoma.

A high rate of recurrence after curative therapy is a major challenge for the management of hepatocellular carcinoma (HCC). Currently, no effective adjuvant therapy is available to prevent HCC recurrence. We designed a personalized neoantigen-loaded dendritic cell vaccine and neoantigen-activated T-cell therapy, and used it as adjuvant therapy to treat 10 patients with HCC who had undergone curative resection or radiofrequency ablation in the first stage of a phase II trial (NCT03067493). The primary outcomes were safety and neoantigen-specific immune response. Disease-free survival (DFS) was also evaluated. The immunotherapy was successfully administered to all the patients without unexpected delay and demonstrated a reasonable safety profile with no grade ≥3 treatment-related side effects reported. Seventy percent of patients generated de novo circulating multiclonal neoantigen-specific T-cell responses. Induced neoantigen-specific immunity was maintained over time, and epitope spreading was observed. Patients who generated immune responses to treatment exhibited prolonged DFS compared with nonresponders (P = 0.012), with 71.4% experiencing no relapse for 2 years after curative treatment. High expression of an immune stimulatory signature, enhanced immune-cell infiltration (i.e., CD8+ T cells), and upregulated expression of T-cell inflammatory gene profiles were found in the primary tumors of the responders. In addition, neoantigen depletion (immunoediting) was present in the recurrent tumors compared with the primary tumors (7/9 vs. 1/17, P = 0.014), suggesting that immune evasion occurred under the pressure of immunotherapy. Our study indicates that neoantigen-based combination immunotherapy is feasible, safe, and has the potential to reduce HCC recurrence after curative treatment.

Comparison of Hepatic Resection with Percutaneous Ablation for Hepatocellular Carcinoma in the Caudate Lobe Within Milan Criteria.

PURPOSE: We aimed to compare the efficacy of hepatic resection and percutaneous ablation for resectable caudate HCC within Milan criteria and to investigate the prognostic factors. METHODS: Between August 2006 and August 2020, a total of 67 eligible patients with resectable caudate HCC within Milan criteria in three centers were retrospectively analyzed and divided into hepatic resection group (n = 46) and percutaneous ablation group (n = 21). Recurrence-free survival (RFS) and overall survival (OS) rates were compared between groups of hepatic resection and percutaneous ablation for these resectable caudate HCC patients with Kaplan-Meier curves and log-rank test. Univariable and multivariable Cox regression analyses were performed to identify the prognostic factors of RFS and OS. RESULTS: The 1-, 3-, and 5-year OS rates were 97.6%, 83.6%, and 71.5% for the hepatic resection group, and 89.4%, 58.5%, and 48.8% for the percutaneous ablation group (P = 0.032). The corresponding RFS rates were 77.6%, 47.9%, and 42.6% for the hepatic resection group, and 40.5%, 23.2%, and 15.4% for the percutaneous ablation group (P = 0.010). According to the univariable and multivariable analyses, tumor type (first recurrence) (HR = 3.54; 95%CI, 1.49-8.37; P = 0.004) was a significant independent prognostic factor of RFS for caudate HCC patients after resection or ablation, while total bilirubin (HR = 1.02; 95%CI, 1.01-1.04; P = 0.006) and treatment strategy (HR = 5.97; 95%CI, 1.48-24.12; P = 0.012) were significant independent prognostic factors of OS. CONCLUSIONS: Hepatic resection appears to outperform percutaneous ablation for caudate HCC patients within Milan criteria.

Roles and Clinical Significances of ATF6, EMC6, and APAF1 in Prognosis of Pancreatic Cancer.

Background: Pancreatic cancer (PC) is prevalent among malignant tumors with poor prognosis and lacks efficient therapeutic strategies. Endoplasmic reticulum (ER) stress and apoptosis are associated with chronic inflammation and cancer progression. However, the prognostic value of ER stress-related, and apoptosis-related genes in PC remains to be further elucidated. Our study aimed at confirming the prognostic values of the ER stress-related genes, ATF6, EMC6, XBP1, and CHOP, and the apoptosis-related gene, APAF1, in PC patients. Methods: Gene Expression Profiling Interactive Analysis 2 (GEPIA2) was used to evaluate prognosis value of ATF6, EMC6, XBP1, CHOP, and APAF1 in PC. Clinical data from 69 PC patients were retrospectively analyzed. Immunohistochemistry, Western blotting, and qRT-PCR were used for the assessment of gene or protein expression. The cell counting kit-8 (CCK-8) and the Transwell invasion assays were, respectively, used for the assessment of the proliferative and invasive abilities of PC cells. The prognostic values of ATF6, XBP1, CHOP, EMC6, and APAF1 in PC patients were evaluated using Kaplan-Meier and Cox regression analyses. Results: XBP1 and CHOP expressions were not associated with PC recurrence-free survival (RFS), overall survival (OS) and disease-specific survival (DSS). ATF6 upregulation and EMC6 and APAF1 downregulations significantly correlated with the poor RFS, OS, and DSS of PC patients. ATF6 promoted PC cell proliferation and invasion, while EMC6 and APAF1 inhibited these events. Conclusion: ATF6 upregulation and EMC6 and APAF1 downregulations may be valid indicators of poor prognosis of PC patients. Moreover, ATF6, EMC6, and APAF1 may constitute potential therapeutic targets in PC patients.

EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis.

Treatment of acute pancreatitis (AP) and chronic pancreatitis (CP) remains problematic due to a lack of knowledge about disease-specific regulatory targets and mechanisms. The purpose of this study was to screen proteins related to endoplasmic reticulum (ER) stress and apoptosis pathways that may play a role in pancreatitis. Human pancreatic tissues including AP, CP, and healthy volunteers were collected during surgery. Humanized PRSS1 (protease serine 1) transgenic (PRSS1Tg) mice were constructed and treated with caerulein to mimic the development of human AP and CP. Potential regulatory proteins in pancreatitis were identified by proteomic screen using pancreatic tissues of PRSS1Tg AP mice. Adenoviral shRNA-mediated knockdown of identified proteins, followed by functional assays was performed to validate their roles. Functional analyses included transmission electron microscopy for ultrastructural analysis; qRT-PCR, western blotting, co-immunoprecipitation, immunohistochemistry, and immunofluorescence for assessment of gene or protein expression, and TUNEL assays for assessment of acinar cell apoptosis. Humanized PRSS1Tg mice could mimic the development of human pancreatic inflammatory diseases. EMC6 and APAF1 were identified as potential regulatory molecules in AP and CP models by proteomic analysis. Both EMC6 and APAF1 regulated apoptosis and inflammatory injury in pancreatic inflammatory diseases. Moreover, APAF1 was regulated by EMC6, induced apoptosis to injure acinar cells and promoted inflammation. In the progression of pancreatitis, EMC6 was activated and then upregulated APAF1 to induce acinar cell apoptosis and inflammatory injury. These findings suggest that EMC6 may be a new therapeutic target for the treatment of pancreatic inflammatory diseases.

ATF6 aggravates acinar cell apoptosis and injury by regulating p53/AIFM2 transcription in Severe Acute Pancreatitis.

Background: There is no curative therapy for severe acute pancreatitis (SAP) due to poor understanding of its molecular mechanisms. Endoplasmic reticulum (ER) stress is involved in SAP and increased expression of ATF6 has been detected in SAP patients. Here, we aimed to investigate the role of ATF6 in a preclinical SAP mouse model and characterize its regulatory mechanism. Methods: Pancreatic tissues of healthy and SAP patients were collected during surgery. Humanized PRSS1 transgenic mice were treated with caerulein to mimic the SAP development, which was crossed to an ATF6 knockout mouse line, and pancreatic tissues from the resulting pups were screened by proteomics. Adenovirus-mediated delivery to the pancreas of SAP mice was used for shRNA-based knockdown or overexpression. The potential functions and mechanisms of ATF6 were clarified by immunofluorescence, immunoelectron microscopy, Western blotting, qRT-PCR, ChIP-qPCR and luciferase reporter assay. Results: Increased expression of ATF6 was associated with elevated apoptosis, ER and mitochondrial disorder in pancreatic tissues from SAP patients and PRSS1 mice. Knockout of ATF6 in SAP mice attenuated acinar injury, apoptosis and ER disorder. AIFM2, known as a p53 target gene, was identified as a downstream regulatory partner of ATF6, whose expression was increased in SAP. Functionally, AIFM2 could reestablish the pathological disorder in SAP tissues in the absence of ATF6. p53 expression was also increased in SAP mice, which was downregulated by ATF6 knockout. p53 knockout significantly suppressed acinar apoptosis and injury in SAP model. Mechanistically, ATF6 promoted AIFM2 transcription by binding to p53 and AIFM2 promoters. Conclusion: These results reveal that ATF6/p53/AIFM2 pathway plays a critical role in acinar apoptosis during SAP progression, highlighting novel therapeutic target molecules for SAP.

Viral hepatitis B and C infections increase the risks of intrahepatic and extrahepatic cholangiocarcinoma: Evidence from a systematic review and meta-analysis.

BACKGROUND/AIMS: Previous study has shown a positive relationship between the hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and cholangiocarcinoma (CCA); however, their correlation with different anatomical sites of CCA (i.e. ICC and ECC) has not been revealed. This study aims to evaluate the association of HBV or HCV infection with CCA, including the intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC), and to determine the roles of α-1 fetoprotein (AFP), CA19-9, and lymph node involvement in CCA with HBV infection. MATERIALS AND METHODS: Relevant studies published between 2004 and 2016 were systematically searched and retrieved from PubMed, SpringerLink, and Science Direct using key terms such as "cholangiocarcinoma", "bile duct cancer", "extrahepatic cholangiocarcinoma", and "intrahepatic cholangiocarcinoma". The demographic, clinical, and laboratory data were extracted from the included studies, and the meta-analysis was performed using RevMan and STATA 11.0 software. RESULTS: A total of 13 studies with CCA matched the inclusion criteria in this meta-analysis, including 7,113 CCA patients and 24,763 controls. This meta-analysis showed that the HBV or HCV infections can significantly increase the risk of CCA, including ICC and ECC. In addition, the higher levels of AFP, lower levels of CA19-9, and lymph node involvement were detected in the CCA patients with HBV infection as compared to those without. CONCLUSION: The HBV and HCV infections significantly increased the risk of CCA, as well as ICC and ECC. The involvement of AFP, CA19-9, and lymph nodes may play an important role in the diagnosis of CCA.

P53 Activated by ER Stress Aggravates Caerulein-Induced Acute Pancreatitis Progression by Inducing Acinar Cell Apoptosis.

BACKGROUND AND AIMS: Acute pancreatitis (AP) is a severe pancreatic disorder that remains associated with high mortality due to a lack of effective drugs and management strategies. This study aimed to investigate the molecular pathogenic mechanisms of AP involving p53 and endoplasmic reticulum (ER) stress pathways. METHODS: Expression of PRSS1 and p53 in human AP tissues was detected by immunohistochemistry and Western blotting. AP was induced with caerulein in humanized PRSS1 transgenic mice, and its severity was verified by histological imaging, evaluation of edema, serum amylase, and trypsin activity assays. A transferase-mediated d-UTP nick end-labeling assay was performed to evaluate acinar cell apoptosis associated with AP. The expression of ER stress genes was assessed by quantitative RT-PCR (qRT-PCR) and Western blotting. RESULTS: PRSS1 and p53 were highly expressed in human AP tissues. Expression of human PRSS1 in caerulein-treated mice induced significant acinar cell apoptosis and AP progression. P53 knockout significantly suppressed AP progression in humanized PRSS1 transgenic mice. The ER stress pathway was activated by PRSS1 and mediated the progression of AP in mouse pancreatic tissues. Application of a p53 inhibitor effectively ameliorated caerulein-induced AP in PRSS1 transgenic mice, while a p53 activator promoted the progression of AP. CONCLUSION: P53, which was activated by the ER stress pathway, promoted the progression of AP in mice expressing PRSS1 by inducing acinar cell apoptosis.

Risk factors for the concomitant occurrence of alcoholic chronic pancreatitis and alcoholic liver cirrhosis: a 10-years cohort study at a tertiary hospital in China.

OBJECTIVE: Concomitant occurrence of alcoholic chronic pancreatitis (ACP) and alcoholic liver cirrhosis (ALC) is rare with few reported cases. The present study aimed to identify the potential risk factors of chronic pancreatitis (CP) and liver cirrhosis (LC) in ALC patients and ACP patients, respectively. METHODS: A retrospective analysis was performed on 536 patients with CP and 647 ALC patients without CP (Group A). Among the 536 CP patients, 213 ACP cases were divided into two groups: ACP with LC (Group B, n = 52) and ACP without LC (Group C, n = 161). A comparison between Group A and B was carried out to identify the potential risk factors of CP in ALC patients, while Group B and C were compared to determine the independent risk factors of LC in ACP patients. RESULTS: Concomitant occurrence of ACP and ALC accounted for 24.4% (52/213) in this cohort. Significant risk factors for CP in ALC patients included smoking [odds ratio (OR), 2.557; 95% confidence interval (CI): 1.531-5.489; P = 0.003] and multiple bouts of acute pancreatitis (OR, 4.813; 95% CI: 3.625-12.971; P < 0.001). Hepatitis B virus (HBV) infection (OR, 4.237; 95% CI: 1.742-7.629; P = 0.012) was the only independent risk factor associated with LC in ACP patients. CONCLUSION: HBV infection exacerbated liver damage in ACP patients. Alcoholic patients who smoked and suffered from ongoing bouts of acute pancreatitis are prone to develop CP.

Surgical Techniques for the Laparoscopic Treatment of Bile Duct Stones in Patients With a History of Upper Abdominal Operations: Retrospective Cohort Study.

PURPOSE: Few authors have studied applying the laparoscopic approach in patients with previous upper abdominal operations, but no comparison has been made between laparoscopic and open approaches in patients with previous upper abdominal operations. This article aims to introduce surgical techniques and details in treatment to surgeons specialized in minimally invasive surgery. MATERIALS AND METHODS: From January 2010 to January 2018, 460 eligible patients were divided into 3 groups and analyzed retrospectively. Group A: patients with a history of upper abdominal operations who underwent laparoscopy (n=124); group B: patients without a history of upper abdominal operations who underwent laparoscopy (n=140); and group C: patients with a history of upper abdominal operations who underwent an open operation (n=196). Group A was the experimental group; groups B and C served as the control groups. RESULTS: No significant difference was found between groups A and B. Significant differences were found between groups A and C in estimated blood loss (258.3±67.2 vs. 424.7±103.7 mL, P<0.001), postoperative hospitalization (5.7±2.3 vs. 10.2±3.1 d, P<0.001), and postoperative complications (16.1% vs. 42.9%, P=0.013). The final rate of stones clearance was 100% in 3 groups. The total rate of stone recurrence was 7.8%. CONCLUSIONS: Laparoscopy with certain surgical techniques was feasible, effective, and advantageous for patients with previous upper abdominal operations by experienced surgeons. It is necessary for surgeons to have advanced skills and surgical techniques to achieve a successful laparoscopy.

Parecoxib Improves the Outcomes of Acute Mild and Moderate Pancreatitis: A 3-Year Matched Cohort Study Based on a Prospective Database.

OBJECTIVES: The aim of this study was to evaluate the role of parecoxib in patients with different severities of acute pancreatitis (AP). METHODS: A total of 772 eligible patients with AP were divided into 4 groups: mild and moderately AP (MAP) treated with parecoxib (group A, n = 236), MAP without parecoxib treatment (group B, n = 453), severe AP (SAP) treated with parecoxib (group C, n = 28), and SAP without parecoxib treatment (group D, n = 55). Patients in group A were exactly matched with patients in group B by propensity score matching, similar to the matching between group C and group D. RESULTS: The morbidity of abdominal infection in group A was significantly lower as compared with that in group B (P < 0.050). The progression of MAP to SAP significantly decreased in group A than group B (P < 0.050). No significant differences were observed between group C and group D. The risk factors independently related to the progression of MAP included alcoholic/high-fat dietary (P = 0.028) and parecoxib administration (P = 0.011). CONCLUSIONS: Early administration of parecoxib could reduce the morbidity of complications among patients with MAP. Parecoxib may prevent the progression of MAP to SAP and improve its outcomes.

ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis.

Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1ß, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP.

Identification of risk factors for pancreatic pseudocysts formation, intervention and recurrence: a 15-year retrospective analysis in a tertiary hospital in China.

BACKGROUND: Pancreatic pseudocyst (PPC) is a common complication of acute and chronic pancreatitis. To our knowledge no study has systematically reported the risk factors for the formation, intervention and recurrence of PPC. Therefore, the present study aimed to investigate the potential risk factors for PPC, with regards to its formation, intervention and recurrence. METHODS: A database containing 5106 pancreatitis patients was retrospectively analyzed. As a result, a total of 4379 eligible patients were identified and divided into 2 groups: PPC group (group A, n = 759) and non-PPC group (group B, n = 3620). The PPC group was subdivided into 2 groups: intervention PPC (group C, n = 347) and resolution PPC (group D, n = 412). The differences in surgical complication and recurrence rates were compared among 347 PPC patients receiving different interventions, including surgical, endoscopic and percutaneous drainages. Furthermore, group C was subdivided into 2 groups: recurrent PPC (group E, n = 34) and non-recurrent PPC (group F, n = 313). All possible risk factors for PPC formation, intervention and recurrence were determined by multivariate regression analysis. RESULTS: In this study, PPC was developed in 17.3% (759/4379) of pancreatitis patients. The significant risk factors for PPC formation included alcoholic pancreatitis (OR, 6.332; 95% CI, 2.164-11.628; p = 0.031), chronic pancreatitis (CP) (OR, 5.822; 95% CI, 1.921-10.723; p = 0.006) and infected pancreatic necrosis (OR, 4.253; 95% CI, 3.574-7.339; p = 0.021). Meanwhile, the significant risk factors of PPC patients who received intervention were alcoholic pancreatitis (OR, 7.634; 95% CI, 2.125-13.558; p = 0.016), size over 6 cm (OR, 8.834; 95% CI, 2.017-16.649; p = 0.002) and CP (OR, 4.782; 95% CI, 1.897-10.173; p = 0.038). In addition, the recurrence rate in PPC patients treated with percutaneous drainage was found to be the highest (16.3%) among the three intervention groups. Furthermore, percutaneous drainage was the only risk factor of PPC recurrence (OR, 7.812; 95% CI, 3.109-23.072; p = 0.013) identified from this retrospective cohort study. CONCLUSIONS: Alcoholic pancreatitis and CP are the main risk factors for PPC formation and intervention, but not PPC recurrence. A higher recurrence rate is found in PPC patients treated with percutaneous drainage, as compared to endoscopic and surgical interventions.