Immune checkpoint inhibitor-associated gastritis: Patterns and management.

Immune checkpoint inhibitors (ICIs) are widely used due to their effectiveness in treating various tumors. Immune-related adverse events (irAEs) are defined as adverse effects resulting from ICI treatment. Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects, such as diarrhea and colitis, which may lead to the cessation of ICIs. Although irAE gastritis is rarely reported, it may lead to serious complications such as gastrorrhagia. Furthermore, irAE gastritis is often difficult to identify early due to its diverse symptoms. Although steroid hormones and immunosuppressants are commonly used to reverse irAEs, the best regimen and dosage for irAE gastritis remains uncertain. In addition, the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered. In this editorial, strategies such as early identification, pathological diagnosis, management interventions, and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.

Hypertriglyceridemia as a risk factor for complications of acute pancreatitis and the development of a severity prediction model.

BACKGROUND: Hypertriglyceridemia (HTG) is a major cause of acute pancreatitis (AP). We aimed to determine whether HTG is an independent risk factor for AP complications and construct a prediction model for non-mild AP. METHODS: We conducted a multi-center cohort study including 872 patients with AP and divided them into HTG-AP and non-HTG-AP groups. Multivariate logistic regression was performed, and a prediction model for non-mild HTG-AP was developed. RESULTS: HTG-AP patients had a higher risk of systemic complications, including systemic inflammatory response syndrome [odds ratio (OR): 1.718; 95% confidence interval (CI): 1.286-2.295], shock (OR: 2.103; 95%CI: 1.236-3.578), acute respiratory distress syndrome (OR: 2.231; 95%CI: 1.555-3.200), acute renal failure (OR: 1.593; 95%CI: 1.036-2.450), and local complications such as acute peripancreatic fluid collection (OR: 2.072; 95%CI: 1.550-2.771), acute necrotic collection (OR: 1.996; 95%CI: 1.394-2.856), and walled-off necrosis (OR: 2.157; 95%CI: 1.202-3.870). The area under curve of our prediction model was 0.898 (95%CI: 0.857-0.940) and 0.875 (95%CI: 0.804-0.946) in the derivation and validation datasets respectively. CONCLUSION: HTG is an independent risk factor for AP complications. We constructed a simple and accurate prediction model for progression of non-mild AP.

Characterization of inulolytic enzymes from the Jerusalem artichoke-derived Glutamicibacter mishrai NJAU-1.

The rhizosphere context of inulin-accumulating plants, such as Jerusalem artichoke (Helianthus tuberosus), is an ideal starting basis for the discovery of inulolytic enzymes with potential for bio fructose production. We isolated a Glutamicibacter mishrai NJAU-1 strain from this context, showing exo-inulinase activity, releasing fructose from fructans. The growth conditions (pH 9.0; 15 °C) were adjusted, and the production of inulinase by Glutamicibacter mishrai NJAU-1 increased by 90% (0.32 U/mL). Intriguingly, both levan and inulin, but not fructose and sucrose, induced the production of exo-inulinase activity. Two exo-inulinase genes (inu1 and inu2) were cloned and heterologously expressed in Pichia pastoris. While INU2 preferentially hydrolyzed longer inulins, the smallest fructan 1-kestose appeared as the preferred substrate for INU1, also efficiently degrading nystose and sucrose. Active site docking studies with GFn- and Fn-type small inulins (G is glucose, F is fructose, and n is the number of ß (2-1) bound fructose moieties) revealed subtle substrate differences between INU1 and INU2. A possible explanation about substrate specificity and INU's protein structure is then suggested. KEY POINTS: • A Glutamicibacter mishrai strain harbored exo-inulinase activity. • Fructans induced the inulolytic activity in G. mishrai while the inulolytic activity was optimized at pH 9.0 and 15 °C. • Two exo-inulinases with differential substrate specificity were characterized.

Development and external validation of models to predict acute respiratory distress syndrome related to severe acute pancreatitis.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a major cause of death in patients with severe acute pancreatitis (SAP). Although a series of prediction models have been developed for early identification of such patients, the majority are complicated or lack validation. A simpler and more credible model is required for clinical practice. AIM: To develop and validate a predictive model for SAP related ARDS. METHODS: Patients diagnosed with AP from four hospitals located at different regions of China were retrospectively grouped into derivation and validation cohorts. Statistically significant variables were identified using the least absolute shrinkage and selection operator regression method. Predictive models with nomograms were further built using multiple logistic regression analysis with these picked predictors. The discriminatory power of new models was compared with some common models. The performance of calibration ability and clinical utility of the predictive models were evaluated. RESULTS: Out of 597 patients with AP, 139 were diagnosed with SAP (80 in derivation cohort and 59 in validation cohort) and 99 with ARDS (62 in derivation cohort and 37 in validation cohort). Four identical variables were identified as independent risk factors for both SAP and ARDS: heart rate [odds ratio (OR) = 1.05; 95%CI: 1.04-1.07; P < 0.001; OR = 1.05, 95%CI: 1.03-1.07, P < 0.001], respiratory rate (OR = 1.08, 95%CI: 1.0-1.17, P = 0.047; OR = 1.10, 95%CI: 1.02-1.19, P = 0.014), serum calcium concentration (OR = 0.26, 95%CI: 0.09-0.73, P = 0.011; OR = 0.17, 95%CI: 0.06-0.48, P = 0.001) and blood urea nitrogen (OR = 1.15, 95%CI: 1.09-1.23, P < 0.001; OR = 1.12, 95%CI: 1.05-1.19, P < 0.001). The area under receiver operating characteristic curve was 0.879 (95%CI: 0.830-0.928) and 0.898 (95%CI: 0.848-0.949) for SAP prediction in derivation and validation cohorts, respectively. This value was 0.892 (95%CI: 0.843-0.941) and 0.833 (95%CI: 0.754-0.912) for ARDS prediction, respectively. The discriminatory power of our models was improved compared with that of other widely used models and the calibration ability and clinical utility of the prediction models performed adequately. CONCLUSION: The present study constructed and validated a simple and accurate predictive model for SAP-related ARDS in patients with AP.

E3 ubiquitin ligase ITCH improves LPS-induced chondrocyte injury by mediating JAG1 ubiquitination in osteoarthritis.

ITCH is an E3 ubiquitin ligase associated with some inflammatory diseases, but its role in osteoarthritis (OA) remains to be explored. Here, we investigated the effects of ITCH in OA-induced chondrocyte damage and its potential mechanisms. Here, we found that ITCH was downregulated, while JAG1 was upregulated in OA tissues compared to normal cartilaginous tissues. And primary human chondrocytes were induced by LPS to simulate OA condition. Overexpressing ITCH or silencing JAG1 promoted proliferation, and restrained apoptosis, inflammation and extracellular matrix (ECM) degradation in LPS-stimulated chondrocytes. Mechanistically, ITCH bound to JAG1 protein through the WW-PPXY motif and degraded it via K48 ubiquitination. JAG1 overexpression reversed the protective effect of ITCH on LPS-induced chondrocyte damage. ITCH prevented LPS-caused Notch1 signaling activation by suppressing JAG1. Furthermore, GSI (a Notch specific inhibitor) abrogated the effects of ITCH knockdown on chondrocyte injury. Additionally, a mouse OA model was established by destabilization of the medial meniscus operation, and H&E and Safranin O-fast green staining was used to evaluate articular cartilage damage. And ITCH overexpression alleviated OA-induced articular cartilage damage in vivo. In conclusion, ITCH mitigated LPS-induced chondrocyte injury and OA-induced articular cartilage damage through attenuating Notch1 pathway activation by degrading JAG1 via ubiquitination, which provides a novel strategy for the treatment of OA.

Protein-Protein Interaction Sites Prediction Based on an Under-Sampling Strategy and Random Forest Algorithm.

The computational methods of protein-protein interaction sites prediction can effectively avoid the shortcomings of high cost and time in traditional experimental approaches. However, the serious class imbalance between interface and non-interface residues on the protein sequences limits the prediction performance of these methods. This work therefore proposed a new strategy, NearMiss-based under-sampling for unbalancing datasets and Random Forest classification (NM-RF), to predict protein interaction sites. Herein, the residues on protein sequences were represented by the PSSM-derived features, hydropathy index (HI) and relative solvent accessibility (RSA). In order to resolve the class imbalance problem, an under-sampling method based on NearMiss algorithm is adopted to remove some non-interface residues, and then the random forest algorithm is used to perform binary classification on the balanced feature datasets. Experiments show that the accuracy of NM-RF model reaches 87.6% and 84.3% on Dtestset72 and PDBtestset164 respectively, which demonstrate the effectiveness of the proposed NM-RF method in differentiating the interface or non-interface residues.

Proton Pump Inhibitors Were Associated With Reduced Pseudocysts in Acute Pancreatitis: A Multicenter Cohort Study.

Background: Acute pancreatitis (AP) is a systemic inflammatory disorder with a wide spectrum of clinical symptoms that can range from mild to severe. Previous preclinical study results suggest that proton pump inhibitors (PPIs) can inhibit exocrine pancreatic secretion and exert anti-inflammatory properties, which might in turn improve the outcome of AP. Aim: We conducted this multicenter, retrospective cohort study to investigate the potential effects of PPIs on the mortality, and total duration of hospital stay and local complication occurrence of patients with AP. Methods: A total of 858 patients with AP were included. All patients presented to the hospital within 48 h of symptom onset and were divided into the following two groups: patients who were treated with PPIs (n = 684) and those not treated with PPIs (n = 174). We used propensity score matching (PSM) analysis to reduce confounding bias before comparing the outcomes between the two groups. Results: Before PSM analysis, there were significant differences in a number of parameters between the two groups, including age, sex, hematocrit, blood urea nitrogen, peritonitis signs, Ranson's score, and Acute Physiology Chronic Health Evaluation II score and organ failure occurrence. Before PSM, the PPIs group had a higher rate of mortality than the control group [RR = 1.065; 95% confidence ratio (CI) 1.045-1.086; p = 0.001]. After PSM, there was no significant difference in mortality (RR = 1.009; 95% CI, 0.999-1.019; p = 0.554) or total hospital stay (p = 0.856), although the PPIs group had a lower occurrence of pancreatic pseudocyst (RR = 0.416; 95% CI 0.221-0.780; p = 0.005). Conclusion: This study showed that PPIs therapy was not associated with reduced mortality or total hospital stay, but was associated with a reduction in the occurrence of pseudocysts in patients with acute pancreatitis.

Contrast-enhanced ultrasound using SonoVue mixed with oral gastrointestinal contrast agent to evaluate esophageal hiatal hernia: Report of three cases and a literature review.

BACKGROUND: Due to a thicker abdominal wall in some patients, ultrasound artifacts from gastrointestinal gas and surrounding tissues can interfere with routine ultrasound examination, precluding its ability to display or clearly show the structure of a hernial sac (HS) and thereby diminishing diagnostic performance for esophageal hiatal hernia (EHH). Contrast-enhanced ultrasound (CEUS) imaging using an oral agent mixture allows for clear and intuitive identification of an EHH sac and dynamic observation of esophageal reflux. CASE SUMMARY: In this case series, we report three patients with clinically-suspected EHH, including two females and one male with an average age of 67.3 ± 16.4 years. CEUS was administered with an oral agent mixture (microbubble-based SonoVue and gastrointestinal contrast agent) and identified a direct sign of supradiaphragmatic HS (containing the hyperechoic agent) and indirect signs [e.g., widening of esophageal hiatus, hyperechoic mixture agent continuously or intermittently reflux flowing back and forth from the stomach into the supradiaphragmatic HS, and esophagus-gastric echo ring (i.e., the "EG" ring) seen above the diaphragm]. All three cases received a definitive diagnosis of EHH by esophageal manometry and gastroscopy. Two lesions resolved upon drug treatment and one required surgery. The recurrence rate in follow-up was 0%. The data from these cases suggest that the new non-invasive examination method may greatly improve the diagnosis of EHH. CONCLUSION: CEUS with the oral agent mixture can facilitate clear and intuitive identification of HS and dynamic observation of esophageal reflux.

Investigations on system integration method and dynamic performance of electromechanical actuator.

A highly integrated electromechanical actuator was developed in this article, which aims at fulfilling the requirements of high power-to-weight ratio, high efficiency, high integration and low volume in military equipment. Three different transmission schemes were proposed for the integrated electromechanical actuator according to the differences in integration methods. Comparative analysis was conducted on the specific structures of the integrated electromechanical actuator and the categories and performance of the planetary roller screw, which is the key unit of the integrated electromechanical actuator. An integrated electromechanical actuator was designed based on the project requirements. A mathematical model was established and the system transfer function was derived. Based on this, a simulation model of the position loop system was established using the AMESim software and the effects of some related parameters, such as friction, backlash and stiffness, on the dynamic performance of the system were investigated. The related theory and simulation results were experimentally validated by a self-developed integrated electromechanical actuator research prototype combined with the related test system. The data obtained from the step response tests, sinusoidal response tests and repeat locating accuracy tests indicated that the developed integrated electromechanical actuator prototype is of rapid, accurate and stable position tracking capability.

NF-κB Phosphorylation Inhibition Prevents Articular Cartilage Degradation in Osteoarthritis Rats via 2-Aminoquinoline.

BACKGROUND Osteoarthritis is a chronic degenerative disease of the joints that is common in older people worldwide. The characteristic features of osteoarthritis include cartilage degradation, synovitis, and remodelling of subchondral bone. The present study investigated the effect of 2-aminoquinoline on knee articular cartilage degradation in an osteoarthritis rat model. MATERIAL AND METHODS The rat model of osteoarthritis was established in Wistar rats by intra-articular injection of monosodium iodoacetate. The rats were randomly divided into 6 groups of 10 rats each: a normal control group, an untreated group, and 4 (5, 10, 15 and 20 mg/kg) treatment groups. The rats in treatment groups received 5, 10, 15, or 20 mg/kg doses of 2-aminoquinoline on day 2 of monosodium iodoacetate injection. RESULTS The 2-aminoquinoline treatment of monosodium iodoacetate-injected rats markedly decreased weight-bearing asymmetry, inhibited edema formation, and improved paw withdrawal thresholds. The expression of inflammatory cytokines was markedly higher in the osteoarthritis rats. Treatment with 2-aminoquinoline led to a significant reduction in inflammatory cytokine expression in osteoarthritis rats in a dose-dependent manner. In osteoarthritis rats, the expressions of prostaglandin E2 (PGE2), matrix metalloproteinase-13 (MMP-13), and substance P were also higher in comparison to the control group. The 2-aminoquinoline treatment supressed PGE2, MMP-13, and substance P levels in osteoarthritis rats. Moreover, the expression of phosphorylated nuclear factor kappaB (p-NF-kappaB) was markedly higher in the untreated rats. However, activation of NF-kappaB was downregulated in the osteoarthritis rats by treatment with 2-aminoquinoline. CONCLUSIONS The present study demonstrated that 2-aminoquinoline prevents articular cartilage damage in osteoarthritis rats through inhibition of inflammatory factors and downregulation of NF-kappaB activation, suggesting that 2-aminoquinoline would be effective in treatment of osteoarthritis.

CTRP9 protects against MIA-induced inflammation and knee cartilage damage by deactivating the MAPK/NF-κB pathway in rats with osteoarthritis.

C1q/TNF-related protein 9 (CTRP9), the closest paralog of adiponectin, has been reported to protect against inflammation-related diseases. However, its role in regulating osteoarthritis (OA) has not been fully elucidated. First, a rat model of OA was generated. Furthermore, rats with OA were injected with different doses of recombinant CTRP9 protein (rCTRP9), and the knee cartilage damage was evaluated. Finally, the phosphorylation of p38 and the secretion of matrix metalloproteinases (MMPs) were detected by Western blotting and enzyme-linked immunosorbent assay. Results revealed that CTRP9 was highly expressed in adipose tissue, followed by skeletal muscle and cartilage tissue, and less expressed in liver, kidney and lung. Moreover, the expression of CTRP9 significantly decreased in the monosodium iodoacetate (MIA) group in the knee cartilage and knee synovial fluid, and the contents of interleukin-1ß (IL-1ß) and IL-6 significantly increased in knee synovial fluid. In addition, rCTRP9 alleviated MIA-induced inflammation, oxidative stress and knee cartilage damage in a dose-dependent way. In addition, rCTRP9 could attenuate the expression of p38MAPK and p-p38 and suppress the expression of nuclear factor-kappa B (NF-κB), p65 and MMPs. Collectively, the results of the present study suggested that CTRP9 alleviates the inflammation of MIA-induced OA through deactivating p38MAPK and NF-κB signaling pathways in rats.

Health education program improves QOL in students with irritable bowel syndrome after the Wenchuan earthquake: a five-year multi-center study.

BACKGROUND: Stress is a common contributing factor for irritable bowel syndrome (IBS). This study was to evaluate the efficacy of the centralized health education program in improving the quality of life (QOL) of middle school students with IBS who experienced the Wenchuan earthquake on May 12, 2008. METHODS: A multi-center, randomized and open evaluation study design was adopted. A total of 584 students who met the Rome III criteria for IBS in four middle schools were identified. Of these students, 29 were excluded for various reasons, and the remaining 555 students were randomly assigned to either the health education group (n = 277) or the control group (n = 278, received no health education). De-identified data were collected via the IBS quality of life (IBS-QOL) questionnaire and abdominal pain was assessed during the 5-year follow-up survey. RESULTS: The IBS-QOL mean total score was comparable at baseline between no-education group and education group no matter in quake-unaffected areas or quake-affected areas (52.27 vs 51.43, t = 1.15, P > 0.05; 51.02 vs 50.64, t = 1.98, P > 0.05). During the 5-year study period, 84 students opted out during follow-up. After 5 years, a significant difference of the IBS-QOL mean total score was observed between the no-education group and education group in quake-unaffected areas (80.53 vs 93.67, t = - 55.45, P < 0.01), which was also observed in quake-affected areas (64.23 vs 93.80, t = - 188.10, P < 0.01). In addition, there was a reciprocal action between factor 1(health education or not) and factor 2(affected by the earthquake or not) regarding IBS-QOL for dysphoria(Q1), interference with activity(Q2), food avoidance(Q5) and relationships(Q8)(P < 0.001) at year 1, 3 and 5. In all students, abdominal pain scores gradually reduced from baseline in each subgroup over 5 years (P < 0.001).The improvement was greater in the education group than in the control group no matter in quake-unaffected area and in quake-affected areas(P < 0.001). There was a reciprocal action between factor 1(health education or not) and factor 2(duration of follow-up) regarding the mean abdominal pain symptom score irrespective of quake-unaffected or quake-affected areas (P = 0.029 and P < 0.001). CONCLUSION: The health education program improved quality of life and abdominal pain in middle school IBS students in Wenchuan quake-affected areas.

[Reliability and validity of the screen for child anxiety related emotional disorders in high school students in the 5.12 Wenchuan earthquake stricken areas].

OBJECTIVE: To test the reliability and validity of the Screen for Child Anxiety Related Emotional Disorders (SCARED-41) in high school students in the 5.12 Wenchuan Earthquake stricken areas. METHODS: A multistage cluster random sampling method was adopted to select 2729 year 10 and year 11 students from three high schools in the earthquake stricken areas for the questionnaire survey using SCARED-41. The internal consistency and construct validity of the SCARED-41 were evaluated through Cronbach's alpha and exploratory and confirmatory factor analyses, respectively. RESULTS: The Guttman split-half correlation for the SCARED-41 was 0.940, with the five subscales ranging from 0.734 to 0.860. The Cronbach's alpha for the SCARED-41 was 0.937, with the five subscales ranging from 0.646 to 0.862. Seven common factors were extracted from the exploratory factor analysis, with a percentage of cumulative explained variance of 49.9%. Social phobia contributed the most, which accounted for 11.9% of the total variance and retained all prior assigned items. Somatic/panic and general anxiety came second. The confirmatory factor analysis showed that a modified model combining the somatic/panic and general anxiety factors as one generated a better fit than the originally assumed construct. RESULTS: SCARED-41 has good psychometrics properties. With adequate reliability and validity, SCARED-41 can be widely applied for assessing anxiety of students in earthquake stricken areas.

[Effects of PreS2 synthetic peptides on infiltrating T lymphocyte subgroups expression in hepatocellular carcinoma].

OBJECTIVES: To explore whether PreS2 can change the percentage of T lymphocyte subgroups and the ration of CD4+/CD8+ in hepatocellular carcinoma (HCC) caused by HBV. METHODS: The P120-146 region composed by the way of Merrifield, which was the most intensive antigen in PreS2 peptides, served as the antigen after dissolved in 0.01 mol/L PBS. 12 patients were chosed as the subjects, who were pathologically diagnosed as HCC after operation, were HBsAg-, HBeAg-, anti-HBc, and HBV DNA positive in serum, and expressed HBsAg in HCC tissue. The monocytes were isolated and cultured in 96 microplate with 1x 10(6) cells in every well, then the PreS2 synthetic peptides was added in at the doses of 1microg, 5microg, and 10microg, also IL-2 with 500 U was added in. Seven days later, the percentage of CD3+, CD4+, CD8+, and the ratio of CD4+/CD8+ were detected. RESULTS: It was found that the percentage of CD4+ increased significantly (t = 3.508, P < 0.01), and the ratio of CD4+/CD8+ decreasedly obviously (t = 2.235, P < 0.05) in the 5microg PreS2 synthetic peptides group, compared with those in the control group. The percentage of CD3+ rised markedly in the IL-2 group, compared with that in the control group. CONCLUSION: With proper doses, PreS2 is capable of changing the expression of T lymphocyte subgroups in HCC tissue, increasing the percentage of CD4+ obviously and changing the motionless state of CD8+, to make the carcinoma cell killed through the action of CD4+ and CD8+.