Disulfiram relieves severe acute pancreatitis by inhibiting GSDMD-dependent NETs formation.

OBJECTIVES: Severe acute pancreatitis (SAP) is characterized by pancreatic and systemic inflammation and persistent organ failure. Neutrophil extracellular traps (NETs) are considered to play an important role in the development of SAP. We aimed to explore the effect of disulfiram (DSL), a newly developed anti-inflammatory drug, on NETs in SAP. METHODS: A mouse model of SAP was induced by caerulein and lipopolysaccharide, and the mice were divided into the normal control group, the DSL group, the SAP group, and the SAP treated with 50 mg/kg (50DSLSAP) and 100 mg/kg DSL (100DSLSAP) groups, respectively. The severity of SAP was evaluated based on the morphological and biochemical changes. Gasdermin D (GSDMD) expression was evaluated in vivo and in vitro to verify the effect of DSL. Additionally, the expressions of NETs were also evaluated in vivo and in vitro in SAP with and without DSL treatment to explore the possible mechanism of DSL on SAP. RESULTS: Pancreatic inflammatory injury increased in the SAP group, which was alleviated by DSL. GSDMD, a protein related to the formation of NETs, increased in SAP. Expressions of NETs were also promoted in the in vivo SAP model and by phorbol myristate acetate (PMA) in vitro. Moreover, DSL inhibited the expressions of GSDMD and NETs in vivo. The results were further confirmed in the in vitro experiment. CONCLUSIONS: NETs are highly associated with inflammatory injury in SAP. DSL inhibits NETs formation by downregulating GSDMD, which in turn relieves the inflammation of SAP. Our study may provide a possible therapeutic target for SAP.

Application of artificial intelligence to digital-rapid on-site cytopathology evaluation during endoscopic ultrasound-guided fine needle aspiration: A proof-of-concept study.

BACKGROUND: During endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), cytopathology with rapid on-site evaluation (ROSE) can improve diagnostic yield and accuracy. However, ROSE is unavailable in most Asian and European institutions because of the shortage of cytopathologists. Therefore, developing computer-assisted diagnostic tools to replace manual ROSE is crucial. Herein, we reported the validation of an artificial intelligence (AI)-based model (ROSE-AI model) to substitute manual ROSE during EUS-FNA. METHODS: A total of 467 digitized images from Diff-Quik (D&F)-stained EUS-FNA slides were divided into training (3642 tiles from 367 images) and internal validation (916 tiles from 100 images) datasets. The ROSE-AI model was trained and validated using training and internal validation datasets, respectively. The specificity was emphasized while developing the model. Then, we evaluated the AI model on a 693-image external dataset. We assessed the performance of the AI model to detect cancer cells (CCs) regarding the accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The ROSE-AI model achieved an accuracy of 83.4% in the internal validation dataset and 88.7% in the external test dataset. The sensitivity and PPV were 79.1% and 71.7% in internal validation dataset and 78.0% and 60.7% in external test dataset, respectively. CONCLUSION: We provided a proof of concept that AI can be used to replace manual ROSE during EUS-FNA. The ROSE-AI model can address the shortage of cytopathologists and make ROSE available in more institutes.

Proanthocyanidins suppress NLRP3 inflammasome and M1 macrophage polarization to alleviate severe acute pancreatitis in mice.

The role of reactive oxygen species (ROS) is crucial for the pathogenesis of acute pancreatitis (AP). Proanthocyanidins (PAs) have been confirmed to exert antioxidant activity. Our study aimed to determine whether PAs alleviated SAP via reducing ROS, suppressing NLRP3 inflammasome, and inhibiting M1 macrophage polarization. Our study investigated the protective effects of PAs on pancreatic histopathological injury using SAP mice. The effects of PAs on macrophages were investigated in inflammatory RAW 264.7 cells or mouse bone marrow-derived macrophages (BMDMs) induced by lipopolysaccharide (LPS). Immunofluorescence staining and/or western blot assay were employed to evaluate NLRP3 inflammasome in macrophages and pancreatic tissue. Cell counting kit-8 (CCK-8) was used to access effects of PAs on cell viability and cytometry flow was used to determine the effects of the PAs on the ROS levels of the RAW 264.7 cells. Then, we evaluated M1 macrophage polarization using flow cytometry or real-time quantitative polymerase chain reaction (RT-qPCR). PAs administration alleviated pancreatic inflammation in SAP mice. The PAs depressed NLRP3 inflammasome and inhibited M1 macrophage polarization in pancreatic tissue. We also found that the PAs showed no cellular toxicity but decreased ROS levels in RAW 264.7 cells, downregulated the NLRP3 inflammasome in the macrophages, and inhibited cell M1 macrophage polarization. Our study indicates the anti-inflammatory properties of the PAs on SAP mice by decreasing ROS levels, suppressing NLRP3 inflammasome, and M1 macrophage polarization.

Features of capsule endoscopy in COVID-19 patients with a six-month follow-up: A prospective observational study.

Recently, the coronavirus disease 2019 (COVID-19) has caused a global pandemic. Several studies indicate that the digestive system can also be affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, patients with digestive symptoms should have a capsule endoscopy (CE). COVID-19 patients with gastrointestinal (GI) symptoms who underwent CE were recruited from March 2020 to April 2020. We collected patients' data and performed a prospective follow-up study for 6 months. All 11 COVID-19 cases with GI symptoms who underwent CE presented gastritis. Eight cases (72.7%) had intestinal mucosa inflammation. Among them, two cases showed intestinal ulcers or erosions. Moreover, two cases displayed colonic mucositis. One case was lost during follow-up. At 3-6 months after hospital discharge, five patients underwent CE again, presenting gastrointestinal lesions. Five of the 10 cases had GI symptoms, such as abdominal pain, diarrhea, constipation, and others. Among these five cases, the GI symptoms of three patients disappeared at the last follow-up and two patients still presented diarrhea symptoms. Overall, we observed damaged digestive tract mucosa that could be caused by SARS-CoV-2. Moreover, after discharge, some patients still presented intestinal lesions and GI symptoms.

Actual pressure generated by various suction technique and suctioning liquid weight through endoscopic ultrasound-guided aspiration needles.

OBJECTIVES: Suction pressure is one of the most important factors influencing the amount of tissue obtained during endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB). In this study we aimed to elucidate actual suction pressure generated by various suction methods and the weight of suctioning liquid. METHODS: Different types of fine needles and suction techniques were used, including the slow pull technique (SPT), dry suction technique (DST), wet suction technique (WST), neutralizing negative pressure technique (NNPT), and residual negative pressure technique (RNPT). Actual suction pressure was measured and the amount of suctioning liquid was weighed. RESULTS: Actual suction pressure and weight of the suctioning liquid were lower using SPT than using DST, while they were higher when using WST compared with those using DST. In general, the actual suction pressure increased and the weight of suctioning liquid decreased as the diameter of the FNA needles decreased. While weight of the suctioning liquid using FNB needles was significantly larger than that using FNA needles. In general, the actual suction pressure generated using RNPT was larger than that using NNPT. CONCLUSIONS: WST is superior to SPT and DST in terms of actual suction pressure and weight of suctioning liquid. Diameter of the FNA needle was an important factor that may affect the actual suction pressure and weight of suctioning liquid. FNB needles are superior to FNA needles when it comes to the weight of suctioning liquid. Actual suction pressure obtained by novel suction methods (NNPT and RNPT) may provide a basis for future research.

Identification of potential serum exosomal microRNAs involved in acinar-ductal metaplasia that is a precursor of pancreatic cancer associated with chronic pancreatitis.

BACKGROUNDS: Due to difficulty in early diagnosis of chronic pancreatitis (CP), it is urgent to find novel biomarkers to detect CP. Exosomal microRNAs (Exo-miRNAs) located in the serum may be potential diagnostic and therapeutic targets for CP. OBJECTIVE: To identify differentially expressed Exo-miRNAs (DE-Exo-miRNAs) in the serum of CP patients, we performed a bioinformatics analysis. METHODS: The dataset GSE128508 was downloaded from the Gene Expression Omnibus (GEO) database. The analysis was carried out using BRB-ArrayTools and significance analysis of microarrays (SAM). The target genes of DE-S-Exo-miRNAs were predicted by miRWalk databases. Further gene ontology (GO) term and Kyoto Encyclopedia of Genomes (KEGG) pathway analyses were performed with plug-in ClueGO in Cytoscape software 3.7.0. Subsequently, the interaction regulatory network between encoded proteins of target genes was performed with the Search Tool for the Retrieval of Interacting Genes (STRING) database and analyzed using plug-in Molecular Complex Detection (MCODE) and cytoHubba in Cytoscape software 3.7.0. RESULTS: We identified 227 DE-Exo-miRNAs in the serum. Further analysis using the miRWalk database identified 5164 target genes of these miRNAs. The protein-protein interaction (PPI) regulatory network of 1912 potential target genes for hub 10 up-regulated miRNAs with high degrees and one down-regulated miRNAs were constructed using the STRING database and Cytoscape software. The functional analysis using Cytoscape software tool highlighted that target genes involved in pancreatic cancer. Acinar-ductal metaplasia (ADM) in the inflammatory environment of CP is a precursor of pancreatic cancer. Subsequently, we constructed a network of target genes associated with ADM and their miRNAs. CONCLUSIONS: Exo-miRNAs in the serum as well as their target genes may be promising targets for the early diagnosis and treatment of CP. In addition, we identified potential Exo-miRNAs involved in ADM that is a precursor of pancreatic cancer associated with CP.

Predictors of pain response after endoscopic ultrasound-guided celiac plexus neurolysis for abdominal pain caused by pancreatic malignancy.

BACKGROUND: Endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) has gained popularity as a minimally invasive approach and is currently widely used to treat pancreatic cancer-associated pain. However, response to treatment is variable. AIM: To identify the efficacy of EUS-CPN and explore determinants of pain response in EUS-CPN for pancreatic cancer-associated pain. METHODS: A retrospective study of 58 patients with abdominal pain due to inoperable pancreatic cancer who underwent EUS-CPN were included. The efficacy for palliation of pain was evaluated based on the visual analog scale pain score at 1 wk and 4 wk after EUS-CPN. Univariable and multivariable logistic regression analyses were performed to explore predictors of pain response. RESULTS: A good pain response was obtained in 74.1% and 67.2% of patients at 1 wk and 4 wk, respectively. Tumors located in the body/tail of the pancreas and patients receiving bilateral treatment were weakly associated with a good outcome. Multivariate analysis revealed patients with invisible ganglia and metastatic disease were significant factors for a negative response to EUS-CPN at 1 wk and 4 wk, respectively, particularly for invasion of the celiac plexus (odds ratio (OR) = 13.20, P = 0.003 for 1 wk and OR = 15.11, P = 0.001 for 4 wk). No severe adverse events were reported. CONCLUSION: EUS-CPN is a safe and effective form of treatment for intractable pancreatic cancer-associated pain. Invisible ganglia, distant metastasis, and invasion of the celiac plexus were predictors of less effective response in EUS-CPN for pancreatic cancer-related pain. For these patients, efficacy warrants attention.

Watching Videos of Colonoscopies and Receiving Interpretations Reduce Pain and Anxiety While Increasing the Satisfaction of Patients.

BACKGROUND: Pain associated with colonoscopies is a major barrier to patients participating in colorectal cancer screenings. While sedation and analgesia are used to reduce pain during the procedure, they are associated with increased complications and costs. Thus, it is necessary to identity novel techniques to relieve pain in a safe and cost-effective way. AIMS: To test whether watching real-time videos of colonoscopies while receiving detailed interpretations of the procedures reduces pain and anxiety and increases a patient's satisfaction. METHODS: Patients were randomized into three groups including a group who watched real-time videos of their colonoscopies (Group A), a group who watched real-time videos of their colonoscopies while receiving detailed interpretations of the procedures from the endoscopists (Group B), and a group who did not receive either method (Group C). RESULTS: Pain and anxiety scores were significantly (Group A vs. Group C, [Formula: see text]; Group B vs. Group C, [Formula: see text]) lower in Groups A and B compared to Group C. Additionally, significantly (Group A vs. Group C, [Formula: see text]; Group B vs. Group C, [Formula: see text]) increased satisfaction was observed in Groups A and B compared to Group C. There were no statistically significant differences observed in the pain and anxiety scores when comparing Groups A and B. However, the overall satisfaction score was significantly ([Formula: see text]) higher in Group B compared to Group A. CONCLUSIONS: Real-time videos of colonoscopies as well as videos along with detailed interpretations of the procedures decrease pain and anxiety while improving satisfaction in patients undergoing colonoscopies without sedation. Videos combined with interpretations lead to a greater increase in patient satisfaction.

Liver damage at admission is an independent prognostic factor for COVID-19.

OBJECTIVE: Abnormal liver function is a common form of extra-pulmonary organ damage in patients with coronavirus disease 2019 (COVID-19). Patients with severe COVID-19 have a higher probability and progression of liver injury than those without severe disease. We aimed to evaluate the prognosis of liver injury in patients with COVID-19. METHODS: We retrospectively included 502 patients with laboratory-confirmed SARS-CoV-2 infection. Clinical features and survival of patients with and without liver injury were compared. Cox proportional hazards models were used to determine the variables that might have an effect on survival. RESULTS: Among the 502 patients enrolled, 301 patients had abnormal liver function with increased neutrophil count, C-reactive protein, creatinine, troponin I (TnI), D-dimer, lactose dehydrogenase and creatine kinase. Patients with abnormal liver functions had a higher mortality rate (28.9% vs 9.0%, P < 0.001), a higher ratio of male sex (65.1% vs 40.8%, P < 0.001) and a higher chance of developing systemic inflammatory response syndrome (53.5% vs 41.3%, P = 0.007). Among patients with abnormal liver functions, patients with grade 2 liver damage (with both abnormal alanine aminotransferase or aspartate aminotransferase levels and abnormal alkaline phosphatase or gamma-glutamyl transpeptidase levels) had a higher ratio of male patients, elevated neutrophil count, procalcitonin, D-dimer levels and mortality rate. Multivariate Cox regression analyses suggested that the grade of liver damage (hazard ratio: 1.377, 95% confidence interval: 1.000-1.896, P = 0.049) was an independent predictor of death. CONCLUSIONS: Patients with COVID-19 and abnormal liver functions have a higher mortality than those with normal liver functions. Liver damage is an independent prognostic factor of COVID-19.

Hemophagocytic syndrome as a complication of acute pancreatitis: A case report.

BACKGROUND: Haemophagocytic syndrome (HPS) is rarely seen in patients with acute pancreatitis (AP). HPS as a complication of AP in patients without any previous history has not been elucidated. CASE SUMMARY: A 46-year-old man was admitted for symptom of persistent abdominal pain, nausea, and vomiting for 2 d after heavy drinking. During hospital stay, he suddenly developed skin rash and a secondary fever. The laboratory findings revealed progressive pancytopenia, abnormal hepatic tests, and elevation of serum triglyceride, ferritin, and lactate dehydrogenase levels. However, apparent bacterial or viral infections were not detected. He was also possibly related to autoimmune diseases because of positive expression of various autoimmune antibodies and no remarkable past history. Finally, the bone marrow examination showed a histiocytic reactive growth and prominent hemophagocytosis, which resulted in a diagnosis of HPS. Unexpectedly, the patient responded well to the immunosuppressive therapy. CONCLUSION: HPS is a very rare extrapancreatic manifestation of AP. The diagnosis relies on bone marrow examination and immunosuppressive therapy is effective. For AP with skin changes, the possibility of HPS should be considered during clinical work.

Analysis on survival and prognostic factors in patients with resectable pancreatic adenocarcinoma.

Survival after pancreatic cancer surgery is extremely unfavorable even after curative resection. Prognostic factors have been explored but remain largely undefined. The present study was to identify the role of clinical and laboratory variables in the prognostic significance of resectable pancreatic adenocarcinoma. A total of 96 patients who underwent curative resection for pancreatic cancer were included. Survival was evaluated based on complete follow-up visits and was associated with potential prognostic factors using the Kaplan-Meier method and Cox proportional hazard model survival analyses. The results showed that prognostic variables significantly reduced survival, including old age, poorly differentiated tumors, elevated tumor markers and positive lymph node metastasis (LNM). Age of older than 60 years (HR=1.83, P=0.04), LNM (HR=2.22, P=0.01), lymph node ratio (00.2, HR=1.92, P=0.017), initial CA199 (HR=4.80, P=0.004), and CEA level (HR=2.59, P=0.019) were identified as independent prognostic factors by multivariate analysis. It was concluded that LNR may be potent predictor of survival and suggests that surgeons and the pathologists should thoroughly assess lymph nodes prior to surgery.

Analysis on Survival and Prognostic Factors in Patients with Resectable Pancreatic Adenocarcinoma / 华中科技大学学报（医学）（英德文版）

Survival after pancreatic cancer surgery is extremely unfavorable even after curative resection.Prognostic factors have been explored but remain largely undefined.The present study was to identify the role of clinical and laboratory variables in the prognostic significance of resectable pancreatic adenocarcinoma.A total of 96 patients who underwent curative resection for pancreatic cancer were included.Survival was evaluated based on complete follow-up visits and was associated with potential prognostic factors using the Kaplan-Meier method and Cox proportional hazard model survival analyses.The results showed that prognostic variables significantly reduced survival,including old age,poorly differentiated tumors,elevated tumor markers and positive lymph node metastasis (LNM).Age of older than 60 years (HR=l.83,P=0.04),LNM (HR=2.22,P=0.01),lymph node ratio (0＜LNR≤0.2,HR=1.38,P=0.042;LNR＞0.2,HR=1.92,P=0.017),initial CA199 (HR=4.80,P=0.004),and CEA level (HR=2.59,P=0.019) were identified as independent prognostic factors by multivariate analysis.It was concluded that LNR may be potent predictor of survival and suggests that surgeons and the pathologists should thoroughly assess lymph nodes prior to surgery.