Background and purpose:Cytotoxic T lymphocyte (CTL) plays a vital role in the process of anti-tumor immunology. The aim of this study was to investigate whether changes in concentration of IL-2 (50, 200 and 1 000 U/mL) would affect the sub-population and cytotoxic function of cells cultivated by peptide-specific CTL induction systemin vitro and also observe whether using the concentration of IL-2 at a range of 50-1 000 U/mL isbeneifcial to regulatory cells (Tregs) enrichment.Methods:Peripheral blood from 10 healthy donors and 10 cancer patients that were HLA-A2 positive, were collected in the study. HLA-A2 restricted CTL epitope P321 (ILIGETIKI) derived from COX-2 pulsed with different concentrations of IL-2 were used to induce peptides-speciifc CTLin vitro. Flow cytometry was performed to analyze the proliferative capability, the proportion of different T-cell subsets, and secretion of perforin, granzyme B and IFN-γ. IFN-γ secretion was assessed by ELISpot assay.Results:High concentration of IL-2 increased the proliferative activity. The percentage of CD4+ T cells of cancer patient group was signiifcantly higher than that of healthy donor group, while the percentage of CD8+ T cells of cancer patient group was signiifcantly lower than that of healthy donor group. And there was no signiifcant difference in the percentages of CD4+ T cells, CD8+ T cells and Tregs among groups with different IL-2 concentrations. No difference was seen in cytokine (perforin, granzyme B, IFN-γ) secretion capacity of CD8+ T cells. ELISpot study revealed that high-dose IL-2 resulted in the increasing of IFN-γ secretion.Conclusion:The sub-population and the function of cells cultured by peptide-speciifc CTL induction systemin vitro are not affected by different concentrations of IL-2. Furthermore, high concentrations of IL-2 (50-1 000 U/mL) do not provide the enrichment for Tregs. Higher concentration of IL-2 is likely to cause high secretion of IFN-γ in ELISpot assay. In order to exclude the distraction of NK cells or NKT cells, the concentration of 50 U/mL is better choice.

Objective:To observe and analyze the function of intestinal barrier in patients with pouchitis, and to explore the role of nucleotide oligomerization domain 2 (NOD2) in ileal pouchitis, so as to provide new ideas for the pathogenesis of pouchitis.Methods:From January 2011 to December 2016, the clinical pathological data of patients with ileal pouch-anal anastomosis who underwent pouch mucosa biopsy at the Endoscopy Center of General Hospital of Tianjin Medical University were retrospectively analyzed. According to the disease activity index of pouchitis, patients were divided into pouchitis group (20 cases) and non-pouchitis group (30 cases). In addition, UC patients who did not undergo surgery were selected as the control group (10 cases). The intestinal structure of patients of the pouchitis group and non-pouchitis group was observed under transmission electron microscope. The positive expression rates of occludin, alpha human defensin and NOD2 in the control group, non-pouchitis group and pouchitis group were detected and calculated by immunohistochemistry. Levene test, independent sample t test and Spearman correlation analysis were used for statistical analysis. Results:Under the transmission electron microscope, the tight junction epithelial structure and microvilli of intestinal mucosal of patients in the pouchitis group were severely injured. The results of immunohistochemistry showed that the positive expression rates of occludin, alpha human defensin and NOD2 in the intestinal mucosa of patients in the pouchitis group were all lower than those of the control group and non-pouchitis groups ((19.3±0.4)% vs. (84.0±0.3)% and (77.9±0.5)%; (60.0±1.3)% vs. (85.0±0.1)% and (77.3±0.4)%; (46.1±1.6)% vs. (72.0±0.7)% and (60.7±0.5)%), and the differences were statistically significant ( t=-8.451, -7.514, -3.943, -2.970, -5.115 and -2.982, all P<0.05). The correlation analysis showed that the expression level of NOD2 was positively correlated with occludin and alpha human defensin ( r=0.671 and 0.628, both P<0.01). Conclusions:Intestinal barrier function is impaired in patients with ileal pouchitis, and NOD2-related intestinal barrier injury may play an important role in the pathogenesis of ileal pouchitis.

HMGB1's role in tumors is complex and diverse,and it exerts its biological function by combining with different receptors.One of the receptors is called RAGE,which is localized to the cell membrane and binds to HMGB1 released outside the cell.The HMGB1/RAGE axis promotes tumor development,moreover,tumor development and its drug resistance are closely related to inflammation.This article mainly reviews the molecular mechanism of HMGB1/RAGE axis in pro-inflammatory and protumor effects in pancreatic,colorectal and liver cancers.We also summarize the research progress of papaverine and its derivatives for the treatment of HMGB1/RAGE axis in tumor inflammation,with aims of providing new ideas for exploring the molecular mechanism of action in tumor inflammation,and providing a new theoretical basis for the research of HMGB1/RAGE axis therapeutics.

Objective:To evaluate the value of preoperative prediction of vessel invasion (VI) of locally advanced gastric cancer by machine learning model based on the venous phase enhanced CT radiomics features.Methods:A retrospective analysis of 296 patients with locally advanced gastric cancer confirmed by pathology in the First Affiliated Hospital of Zhengzhou University from July 2011 to December 2020 was performed. The patients were divided into VI positive group ( n=213) and VI negative group ( n=83) based on pathological results. The data were divided into training set ( n=207) and test set ( n=89) according to the ratio of 7∶3 with stratification sampling. The clinical characteristics of patients were recorded, and the independent risk factors of gastric cancer VI were screened by multivariate logistic regression. Pyradiomics software was used to extract radiomic features from the venous phase enhanced CT images, and the minimum absolute shrinkage and selection algorithm (LASSO) was used to screen the features, obtain the optimal feature subset, and establish the radiomics signature. Four machine learning algorithms, including extreme gradient boosting (XGBoost), logistic, naive Bayes (GNB), and support vector machine (SVM) models, were used to build prediction models for the radiomics signature and the screened clinical independent risk factors. The efficacy of the model in predicting gastric cancer VI was evaluated by the receiver operating characteristic curve. Results:The degree of differentiation (OR=13.651, 95%CI 7.265-25.650, P=0.003), Lauren′s classification (OR=1.349, 95%CI 1.011-1.799, P=0.042) and CA199 (OR=1.796, 95%CI 1.406-2.186, P=0.044) were independent risk factors for predicting the VI of locally advanced gastric cancer. Based on the venous phase enhanced CT images, 864 quantitative features were extracted, and 18 best constructed radiomics signature were selected by LASSO. In the training set, the area under the curve (AUC) of XGBoost, logistic, GNB and SVM models for predicting gastric cancer VI were 0.914 (95%CI 0.875-0.953), 0.897 (95%CI 0.853-0.940), 0.880 (95%CI 0.832-0.928) and 0.814 (95%CI 0.755-0.873), respectively, and in the test set were 0.870 (95%CI 0.769-0.971), 0.877 (95%CI 0.788-0.964), 0.859 (95%CI 0.755-0.961) and 0.773 (95%CI 0.647-0.898). The logistic model had the largest AUC in the test set. Conclusions:The machine learning model based on the venous phase enhanced CT radiomics features has high efficacy in predicting the VI of locally advanced gastric cancer before the operation, and the logistic model demonstrates the best diagnostic efficacy.

Purpose To observe the right ventricle and left ventricle blood pool T2 map in chronic thromboembolic pulmonary hypertension(CTEPH)and healthy controls,and to analyze the value of T2 mapping technique in evaluating CTEPH.Materials and Methods A total of 42 patients with CTEPH and 42 healthy volunteers had been prospectively recruited from January 2020 to January 2022 in China-Japan Friendship Hospital.All CTEPH patients underwent cardiac magnetic resonance with T2 mapping and right heart catheterization.Cardiac magnetic resonance was performed on healthy controls.Diastolic T2 mapping was performed in cardiac magnetic resonance,and then the ratio of right ventricular to left ventricular T2 values(RVT2/LVT2)between the CTEPH group and the healthy group was calculated and compared.Meanwhile,the correlation between RVT2/LVT2 and hemodynamic parameters in the CTEPH group was analyzed.Results RVT2/LVT2 in the CTEPH group was significantly lower than that in the healthy group(0.74±0.16 vs.0.86±0.12;t=3.673,P<0.001).RVT2/LVT2 in CTEPH group was negatively correlated with pulmonary vascular resistance(r=-0.534,P<0.001);while it was positively correlated with cardiac index,right atrium oxygen saturation,right ventricle oxygen saturation and pulmonary arteries oxygen saturation(r=0.600,0.603,0.648,0.582,P<0.001).Conclusion RVT2/LVT2 in the CTEPH group is positively correlated with right cardiac oxygen saturation and negatively correlated with pulmonary vascular resistance.T2 mapping may be a noninvasive evaluation of hemodynamics in CTEPH.

Objective:To explore the contents and methods of clinical comprehensive evaluation of microecologics, with the example of Bifidobacterium quadruple viable tablet, in order to provide evidence for clinical rational use of microecologics, and microecologics research, development and related decision-making, and to promote rational use of medications. Methods:Based on the research data collected from systematic literature search, health technology assessment methods such as evidence-based medicine and pharmacoeconomics evaluation were used to estimate the safety, efficacy, economics, suitability, accessibility and innovation of Bifidobacterium quadruple viable tablet. Results:In terms of efficacy, Bifidobacterium quadruple viable tablet showed significant therapeutic effects in the treatment of pediatric diarrhea, antibiotic-related diarrhea, diarrhea-predominant irritable bowel syndrome, and secondary diarrhea caused by diseases such as ulcerative colitis, as well as constipation and functional dyspepsia. It can also be used in the treatment of various diseases such as Helicobacter pylori related gastritis, liver cirrhosis, non-alcoholic fatty liver disease. In terms of safety, the incidence of adverse effects of this medication was low, and most were mild to moderate and transient symptoms. In terms of economics, compared with mesalazine alone in the treatment of ulcerative colitis, the incremental cost-effectiveness ratio of combination of Bifidobacterium quadruple viable tablet and mesalazine was 1 743.2. Besides, the daily treatment cost of Bifidobacterium quadruple viable tablet was lower than that of combination of Bifidobacterium triple viable and Bacillus licheniformis (1.87 to 2.80 yuan vs. 2.08 to 5.78 yuan). In terms of innovation, this medication had multiple patents and had been identified as a high-tech product in Zhejiang Province. In terms of suitability, the overall suitability of use and technical characteristics of medication were good. It could be further improved in the aspects of dosage form and system. In terms of accessibility, the price of the medication was stable, affordable and accessible to the general public. Conclusions:Based on the existing evidence, Bifidobacterium quadruple viable tablet presented effective with supported evidences, good safety, accessibility and innovation. The suitability can be further optimized. However, more in-depth and targeted research is needed in terms of economics and innovation in different clinical applications, and there is space for optimization in medication suitability.

Objective:To investigate the protective effects and mechanisms of targeted inhibition of type 3 deiodinase (Dio3) on skeletal muscle mitochondria in sepsis.Methods:① In vivo experiments: adeno-associated virus (AAV) was employed to specifically target Dio3 expression in the anterior tibial muscle of rats, and a septic rat model was generated using cecal ligation and puncture (CLP). The male Sprague-Dawley (SD) rats were divided into shNC+Sham group, shD3+Sham group, shNC+CLP group, and shD3+CLP group by random number table method, with 8 rats in each group. After CLP modeling, tibial samples were collected and Western blotting analysis was conducted to assess the protein levels of Dio3, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), and silence-regulatory protein 1 (SIRT1). Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was utilized to examine mRNA expression of genes including thyroid hormone receptors (THRα, THRβ), monocarboxylate transporter 10 (MCT10), mitochondrial DNA (mtDNA), and PGC1α. Transmission electron microscopy was employed to investigate mitochondrial morphology. ② In vitro experiments: involved culturing C2C12 myoblasts, interfering with Dio3 expression using lentivirus, and constructing an endotoxin cell model by treating cells with lipopolysaccharide (LPS). C2C12 cells were divided into shNC group, shD3 group, shNC+LPS group, and shD3+LPS group. Immunofluorescence colocalization analysis was performed to determine the intracellular distribution of PGC1α. Co-immunoprecipitation assay coupled with Western blotting was carried out to evaluate the acetylation level of PGC1α. Results:① In vivo experiments: compared with the shNC+Sham group, the expression of Dio3 protein in skeletal muscle of the shNC+CLP group was significantly increased (Dio3/β-Tubulin: 3.32±0.70 vs. 1.00±0.49, P < 0.05), however, there was no significant difference in the shD3+Sham group. Dio3 expression in the shD3+CLP group was markedly reduced relative to the shNC+CLP group (Dio3/β-Tubulin: 1.42±0.54 vs. 3.32±0.70, P < 0.05). Compared with the shNC+CLP group, the expression of T3-regulated genes in the shD3+CLP group were restored [THRα mRNA (2 -ΔΔCt): 0.67±0.05 vs. 0.33±0.01, THRβ mRNA (2 -ΔΔCt): 0.94±0.05 vs. 0.67±0.02, MCT10 mRNA (2 -ΔΔCt): 0.65±0.03 vs. 0.57±0.02, all P < 0.05]. Morphology analysis by electron microscopy suggested prominent mitochondrial damage in the skeletal muscle of the shNC+CLP group, while the shD3+CLP group exhibited a marked improvement. Compared with the shNC+Sham group, the shNC+CLP group significantly reduced the number of mitochondria (cells/HP: 10.375±1.375 vs. 13.750±2.063, P < 0.05), while the shD3+CLP group significantly increased the number of mitochondria compared to the shNC+CLP group (cells/HP: 11.250±2.063 vs. 10.375±1.375, P < 0.05). The expression of mtDNA in shNC+CLP group was markedly reduced compared with shNC+Sham group (copies: 0.842±0.035 vs. 1.002±0.064, P < 0.05). Although no difference was detected in the mtDNA expression between shD3+CLP group and shNC+CLP group, but significant increase was found when compared with the shD3+Sham group (copies: 0.758±0.035 vs. 0.474±0.050, P < 0.05). In the shD3+CLP group, PGC1α expression was significantly improved at both transcriptional and protein levels relative to the shNC+CLP group [PGC1α mRNA (2 -ΔΔCt): 1.49±0.13 vs. 0.68±0.06, PGC1α/β-Tubulin: 0.76±0.02 vs. 0.62±0.04, both P < 0.05]. ② In vitro experiments: post-24-hour LPS treatment of C2C12 cells, the cellular localization of PGC1α became diffuse; interference with Dio3 expression promoted PGC1α translocation to the perinuclear region and nucleus. Moreover, the acetylated PGC1α level in the shD3+LPS group was significantly lower than that in the shNC+LPS group (acetylated PGC1α/β-Tubulin: 0.59±0.01 vs. 1.24±0.01, P < 0.05), while the expression of the deacetylating agent SIRT1 was substantially elevated following Dio3 inhibition (SIRT1/β-Tubulin: 1.04±0.04 vs. 0.58±0.03, P < 0.05). When SIRT1 activity was inhibited by using EX527, PGC1α protein expression was notably decreased compared to the shD3+LPS group (PGC1α/β-Tubulin: 0.92±0.03 vs. 1.58±0.03, P < 0.05). Conclusion:Inhibition of Dio3 in skeletal muscle reduced the acetylation of PGC1α through activating SIRT1, facilitating nuclear translocation of PGC1α, thereby offering protection against sepsis-induced skeletal muscle mitochondrial damage.

Objectives:To investigate the prevalence,clinical characteristics and risk factors of coronavirus disease-2019(COVID-19)in patients with pulmonary hypertension(PH). Methods:A questionnaire survey was conducted from December 30,2022 to January 6,2023 through the WeChat official account of the PH Patients Mutual Aid Organization.PH patients aged≥18 years from 26 province(municipality/autonomous region)were recruited to fill in the electronic survey questionnaire. Results:A total of 293 valid questionnaires were collected from PH patients.The mean age of patients was(40.6±12.7)years,and 226 patients(77.1%)of them were female.The vaccination rate was 59.7%(175/293),117 patients(39.9%)received three or more doses of vaccine,145 patients(49.5%)received inactivated vaccine.242 patients(82.6%)had COVID-19.The most common symptoms during infection were fever(85.5%),cough(77.7%),and fatigue(66.5%).10.7%of the patients had severe or critical COVID-19.Age(OR =1.057,95%CI:1.027-1.087,P<0.001)and comorbid pulmonary disease(OR=3.341,95%CI:1.215-9.184,P=0.019)were associated with severe or critical COVID-19.After adjusting for confounding factors,age was an independent risk factor for severe or critical COVID-19(OR=1.049,95%CI:1.019-1.080,P=0.001).Severe or critical COVID-19 was an independent risk factor for worsening heart failure in PH patients during COVID-19 pandemic(OR=10.522,95%CI:4.311-25.682,P<0.001). Conclusions:The immunization coverage of PH patients is insufficient.PH patients have a higher risk of developing severe or critical COVID-19 than general population.Ageing is an independent risk factor for severe or critical COVID-19,and the risk of worsening heart failure in PH patients with severe or critical COVID-19 is significantly increased during COVID-19 pandemic.

Objective To understand the incidence and characteristics of adverse drug reactions(ADRs)of carbapenems,explore the relevant risk signals,and provide a reference for clinically safe drug use.Methods All spontaneous reports of carbapenem drug-related ADRs from January 2008 to October 2022 in the Adverse Drug Reaction Monitoring Center,PLA General Hospital's ADR database were retrieved,and information such as patients'general conditions,involved systems and organs damage,and the names of ADRs involved were retrospectively analysed.Using the reporting odd ratio method,the proportional reporting ratio method,the Medicines and Healthcare Products Regulatory Agency method,and information component method to obtain risk signals of carbapenem antimicrobial drug-related ADR.Results A total of 2 642 ADR reports of carbapenems were reported,of which 410 serious ADR reports(15.52％)were serious ADR reports,five cabapenem antimirobial drug species were mainly involved.In descending order of composition were imipenem cilastatin(51.28％),meropenem(32.13％),biapenem(8.10％),ertapenem(7.68％),and panipenem(0.79％).The male to female ratio of patients was 1.74:1,with the most age＞60 years(59.69％).A total of 14"drug-ADR name"combinations generated risk signals in all four data mining methods,with meropenem being the most signals,and imipenem cilastatin and ertapenem had a high number of reported ADR in nervous system.Conclusion The results of risk signal mining are basically consistent with the known carbapenem ADR information,during the use of carbapenem antimicrobial drugs in the clinic,it is recommended to monitor patients'liver and kidney functions as well as blood biochemical indexes,so as to strengthen the awareness of vigilance in the clinical use of carbapenem antimicrobial drugs,and timely recognize and deal with ADRs in a timely manner,and to avoid the occurrence of serious ADRs.

Objective To construct a module for drug-induced central nervous system adverse reactions(CNS-ADR)within the Clinical Adverse Drug Event Active Monitoring and Intelligent Assessment Alert System-Ⅱ(ADE-ASAS-Ⅱ),and to conduct a large-scale,real-world active monitoring and evaluation of CNS-ADR specifically related to imipenem/cilastatin.Methods Based on literature review,spontaneous report evaluation,and initial word set of CNS-ADR related descriptions in electronic medical records,text recognition technology was used to construct and optimize the condition settings of the CNS-ADR automatic monitoring module.Hospitalized patients using imipenem/cilastatin were retrospectively monitored from 2017 to 2021,and the positive patients which had CNS-ADR were statistically described in terms of the demographic characteristics,CNS symptoms,and hospital departments.Results Based on a repeated testing optimization using 1 185 manually monitored results,the best setting for the determined module includes 62 sets of keywords,with a positive predictive value(PPV)of 13.63％and a recall rate of 100％.Expanding the monitoring to 8 222 medication users using this module,281 cases of positive causality were identified,with an incidence rate of 3.42％.Among them,patients over 60 years old accounted for 50.17％,and the main manifestations of CNS-ADR were epileptic seizures,headaches,mania,and delirium.Conclusion The CNS-ADR automatic monitoring module established based on ADE-ASAS-Ⅱ provides fast and reliable text data mining support for conducting real-world research on CNS-ADR.