BACKGROUND:Studies have shown that rheumatoid arthritis and osteoporosis are positively correlated,but the causal relationship and related mechanisms have not yet been confirmed.With the cross-fertilization of computer science and life sciences,Mendelian randomization and bioinformatics analyses based on genome-wide association study(GWAS)and transcriptome sequencing data can assess the causal relationship between two diseases,explore the related mechanisms,and mine the therapeutic targets,which will be beneficial to the precision treatment of rheumatoid arthritis combined with osteoporosis.OBJECTIVE:To explore the causal relationship between rheumatoid arthritis and osteoporosis using two-sample Mendelian randomization and to mine potential co-morbid targets and potential targeted drugs through summary-data-based Mendelian randomization and bioinformatics analyses,aiming to provide theoretical basis for mechanism exploration and precision treatment in the field of rheumatoid arthritis combined with osteoporosis.METHODS:(1)Firstly,GWAS data of rheumatoid arthritis,osteoporosis,and cis-expression quantitative trait locus(cis-eQTL)in Asian and European populations were downloaded from the GWAS Catalog,IEU Open GWAS,FinnGen,and eQTLGen databases,and were used for two-sample Mendelian randomization analysis and summary-data-based Mendelian randomization analysis.(2)Transcriptome sequencing data of rheumatoid arthritis(GSE93272 and GSE15573)were downloaded from the GEO database for bioinformatics analysis.(3)Subsequently,forward and inverse Mendelian randomization analyses between rheumatoid arthritis and osteoporosis were performed,and inverse variance weighted was used as the main metric for the analyses,and the results were corroborated with MR Egger,simple mode,weighted median and weighted mode.(4)Then,the genes closely related to rheumatoid arthritis and osteoporosis were identified based on the summary-data-based Mendelian randomization analysis,and the co-disease targets of rheumatoid arthritis and osteoporosis were mined based on cross-analysis.Meanwhile,the biological functions of the co-morbid targets were verified based on bioinformatics analysis and cellular experiments.(5)In addition,a rheumatoid arthritis risk prediction nomogram was constructed based on DYRK2,and its prediction performance was verified by receiver operating characteristic curve,correction curve and decision curve.Finally,the target potential drugs were mined based on Enrichr database and molecular docking was performed.RESULTS AND CONCLUSION:(1)Forward Mendelian randomization analysis of rheumatoid arthritis and osteoporosis showed statistically significant results except for GCST90044540 and GCST90086118,and all other results indicated a significant causal relationship and positive correlation between rheumatoid arthritis and osteoporosis.(2)Inverse Mendelian randomization analysis suggested that no significant causal relationship was seen between osteoporosis and rheumatoid arthritis.(3)Summary-data-based Mendelian randomization analysis identified a total of 412 and 344 genes positively associated with rheumatoid arthritis and osteoporosis,and 421 and 347 genes negatively associated.Based on the cross-analysis,26 co-morbid genes were subsequently obtained.Among them,DYRK2 was a potential therapeutic target,and subsequent bioinformatics analysis and cellular experiments confirmed its important role in the progression of rheumatoid arthritis and osteoporosis.(4)Furthermore,the constructed nomogram has excellent predictive performance.Finally,four potential DYRK2-targeting drugs(undecanoic acid,metyrapone,JNJ-38877605,and ACA)were discovered and molecular docking also demonstrated reliable targeting ability.(5)In conclusion,based on GWAS data from Asian and European populations,we successfully demonstrated that rheumatoid arthritis and osteoporosis are causally related at the genetic level,DYRK2 is a potential therapeutic target,and four small molecules are potential target drugs.

BACKGROUND:Studies have shown that rheumatoid arthritis and osteoporosis are positively correlated,but the causal relationship and related mechanisms have not yet been confirmed.With the cross-fertilization of computer science and life sciences,Mendelian randomization and bioinformatics analyses based on genome-wide association study(GWAS)and transcriptome sequencing data can assess the causal relationship between two diseases,explore the related mechanisms,and mine the therapeutic targets,which will be beneficial to the precision treatment of rheumatoid arthritis combined with osteoporosis.OBJECTIVE:To explore the causal relationship between rheumatoid arthritis and osteoporosis using two-sample Mendelian randomization and to mine potential co-morbid targets and potential targeted drugs through summary-data-based Mendelian randomization and bioinformatics analyses,aiming to provide theoretical basis for mechanism exploration and precision treatment in the field of rheumatoid arthritis combined with osteoporosis.METHODS:(1)Firstly,GWAS data of rheumatoid arthritis,osteoporosis,and cis-expression quantitative trait locus(cis-eQTL)in Asian and European populations were downloaded from the GWAS Catalog,IEU Open GWAS,FinnGen,and eQTLGen databases,and were used for two-sample Mendelian randomization analysis and summary-data-based Mendelian randomization analysis.(2)Transcriptome sequencing data of rheumatoid arthritis(GSE93272 and GSE15573)were downloaded from the GEO database for bioinformatics analysis.(3)Subsequently,forward and inverse Mendelian randomization analyses between rheumatoid arthritis and osteoporosis were performed,and inverse variance weighted was used as the main metric for the analyses,and the results were corroborated with MR Egger,simple mode,weighted median and weighted mode.(4)Then,the genes closely related to rheumatoid arthritis and osteoporosis were identified based on the summary-data-based Mendelian randomization analysis,and the co-disease targets of rheumatoid arthritis and osteoporosis were mined based on cross-analysis.Meanwhile,the biological functions of the co-morbid targets were verified based on bioinformatics analysis and cellular experiments.(5)In addition,a rheumatoid arthritis risk prediction nomogram was constructed based on DYRK2,and its prediction performance was verified by receiver operating characteristic curve,correction curve and decision curve.Finally,the target potential drugs were mined based on Enrichr database and molecular docking was performed.RESULTS AND CONCLUSION:(1)Forward Mendelian randomization analysis of rheumatoid arthritis and osteoporosis showed statistically significant results except for GCST90044540 and GCST90086118,and all other results indicated a significant causal relationship and positive correlation between rheumatoid arthritis and osteoporosis.(2)Inverse Mendelian randomization analysis suggested that no significant causal relationship was seen between osteoporosis and rheumatoid arthritis.(3)Summary-data-based Mendelian randomization analysis identified a total of 412 and 344 genes positively associated with rheumatoid arthritis and osteoporosis,and 421 and 347 genes negatively associated.Based on the cross-analysis,26 co-morbid genes were subsequently obtained.Among them,DYRK2 was a potential therapeutic target,and subsequent bioinformatics analysis and cellular experiments confirmed its important role in the progression of rheumatoid arthritis and osteoporosis.(4)Furthermore,the constructed nomogram has excellent predictive performance.Finally,four potential DYRK2-targeting drugs(undecanoic acid,metyrapone,JNJ-38877605,and ACA)were discovered and molecular docking also demonstrated reliable targeting ability.(5)In conclusion,based on GWAS data from Asian and European populations,we successfully demonstrated that rheumatoid arthritis and osteoporosis are causally related at the genetic level,DYRK2 is a potential therapeutic target,and four small molecules are potential target drugs.

Eightly-four novel thioheterocyclic nucleoside derivatives were designed, synthesized, and evaluated for antitumor activity in vitro and in vivo. Most of the compounds inhibited the growth of HCT116 and HeLa cancer cells in vitro, among them 33a and 36b exhibited potent activity against HCT116 cells (IC₅₀ = 0.27 and 0.49 μmol/L, respectively). Both compounds 33a and 36b inhibited cell metastasis, arrested the cell cycle in the G₂/M phase, and induced apoptosis in vitro. Mechanistic studies revealed that 33a and 36b increased ROS levels, led to DNA damage, ER stress, and mitochondrial dysfunction, and inhibited autophagy in HCT116 cells. Biological information analysis, RNA-sequencing, Gene Set Enrichment Analysis (GSEA), drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and SPR experiments identified that compounds 33a and 36b showed antitumor activity by suppressing the c-MYC pathway. c-MYC silencing assays indicated that c-MYC proteins participated in 33a-mediated anticancer activities in HCT116 cells. More importantly, compound 33a presented favorable pharmacokinetic properties in mice (T _1/2 = 6.8 h) and showed significant antitumor efficacy in vivo without obvious toxicity, showing promising potential for further clinical development.

Objective To analyze the cognition level of health care workers(HCWs)and the management status of various levels of medical institutions towards allergy reactions to commonly used antimicrobial agents.Methods HCWs and clinical pharmacists who were related to the diagnosis and treatment of antimicrobial agents in 14 medical institutions of city-level and autonomous prefectures in Gansu Province were randomly selected for a questionnaire survey.The survey contents included respondents'basic information,criteria for judging antimicrobial allergy,awareness on procedures related to antimicrobial allergy,and antimicrobial management level of different levels of medical institutions.Results A total of 8 670 valid questionnaires from HCWs were collected,including 3 300 phy-sicians,5 024 nurses and 328 pharmacists.160,775,2 123 and 5 612 HCWs were with senior,associate,interme-diate and junior professional titles,respectively.87.66％of the HCWs received relevant training on antimicrobial management in the past two years,the proportion of HCWs from different levels of medical institutions who have received training on antimicrobial management in the past two years was statistically significant different(x2=42.668,P＜0.001).HCWs with senior professional titles had the highest proportion of receiving relevant training(93.75％),there was a statistically significant difference in the proportion of receiving antimicrobial management training among HCWs with different professional titles in the past two years(x2=69.782,P＜0.001).50.98％of HCWs were not clear about penicillin allergy,and most of whom were with junior professional titles,accounting for 68.52％.25.19％of HCWs expressed uncertainty about whether patients with penicillin allergy could use cephalosporins,225 of whom were with associate professional titles,accounting for 29.03％of the total number of HCWs with associate profe-ssional titles.6.11％of HCWs had no experience in skin test procedure;46.94％of HCWs expressed that their medical institutions had no or unclear about whether their medical institutions had an antimicrobial allergy assess-ment team.Conclusion HCWs'judgment on allergy reactions to commonly used antimicrobial agents and aware-ness on antimicrobial application is not high enough,and the overall management level of antimicrobial allergy in all levels of medical institutions is poor.The popularity of antimicrobial allergy assessment teams is not high,and there is an urgent need to strengthen supervision,management,training,et al.

Peroxisome proliferator-activated receptor gamma(PPAR-γ)is a member of the ligand-activated nuclear tran-scription factor superfamily.Activated PPAR-γ is involved in the regulation of many central nervous system(CNS)events,and is involved in cholesterol metabolism by inducing or inhibi-ting a series of gene pathways,thereby inhibiting the deposition of β-amyloid protein(Aβ).It plays an important neuroprotec-tive role in Alzheimer's disease(AD),improves memory and cognition in AD,and is a potential target for AD.Drug develop-ment aimed at restoring cholesterol homeostasis may be a poten-tial strategy to counteract AD.By analyzing the distribution and structure of PPAR-γ,focusing on the biological correlation be-tween PPAR-γ-mediated cholesterol metabolism and AD,this paper describes the mechanism regulation of PPAR-γ on key proteins,genes and their corresponding molecules,providing a new reference for the treatment of AD.

Objective:To detect the expression of L-type amino acid transporter 1(LAT1)in non-Hodgkin's lymphoma(NHL)tissues,and analyze its effect on clinicopathological characteristics and prognosis of patients.Methods:A total of 92 NHL patients who were treated in our hospital from January 2017 to April 2019 were collected.The expression of LAT1 in NHL tissue was detected by immunohistochemistry and compared between patients with different pathological features(including sex,Ann Arbor stage,extranodal infiltration,Ki-67).The risk factors affecting mortality were analyzed using univariate and multivariate Cox proportional hazards regression.Receiver operating characteristic(ROC)curve was used to detect the predictive value of percentage of LAT1-positive cells in NHL tissue for patient mortality,and analyzing the effect of percentage of LAT1-positive cells on survival rate.Results:LAT1 was positively expressed in NHL tissue.The high expression rate of LAT1 in Ann Arbor stage Ⅲ and Ⅳ groups were higher than that in Ann Arbor stage Ⅰ group,that in extranodal infiltration group was higher than non-extranodal infiltration group,and that in Ki-67 positive expression group was higher than Ki-67 negative expression group(all P＜0.05).The remission rate after 3 courses of treatment in high-LAT1 expression group was 70.7％,which was lower than 91.2％in low-LAT1 expression group(P＜0.05).Ann Arbor stage Ⅲ and Ⅳ,extranodal invasion,Ki-67 positive expression and increased expression of LAT1(LAT1-positive cell percentage score ≥ 2)were risk factors for mortality.The cut-off value of percentage of LAT1-positive cells for predicting NHL death was 45.6％,and the area under the ROC curve was 0.905(95％CI:0.897-0.924).The 3-year survival rate of high-LAT1 level group(the percentage of LAT1-positive cells ≥ 45.6％)was 50.00％,which was lower than 78.26％of low-LAT1 level group(P＜0.05).Conclusion:The expression level of LAT1 in NHL tissue increases,which affects Ann Arbor stage and extranodal infiltration of patients.LAT1 is a risk factor for death.

OBJECTIVE: To observe the clinical significance of translocator proteins (TSPO) gene in the treatment of FLT3-ITD/DNMT3A R882 double-mutated acute myeloid leukemia (AML). METHODS: Seventy-six patients with AML hospitalized in the Department of Hematology of the Affiliated People's Hospital of Ningbo University from June 2018 to June 2020 were selected, including 34 patients with FLT3-ITD mutation, 27 patients with DNMT3A R882 mutation, 15 patients with FLT3-ITD/DNMT3A R882 double mutation, as well as 19 patients with immune thrombocytopenia (ITP) hospitalized during the same period as control group. RNA was routinely extracted from 3 ml bone marrow retained during bone puncture, and TSPO gene expression was detected by transcriptome sequencing (using 2-deltadeltaCt calculation). RESULTS: The expression of TSPO gene in FLT3-ITD group and DNMT3A R882 group at first diagnosis was 2.02±1.04 and 1.85±0.76, respectively, which were both higher than 1.00±0.06 in control group, but the differences were not statistically significant (P=0.671, P=0.821). The expression of TSPO gene in the FLT3-ITD/DNMT3A R882 group was 3.98±1.07, wich was significantly higher than that in the FLT3-ITD group and DNMT3A R882 group, the differences were statistically significant (P=0.032, P=0.021). The expression of TSPO gene in patients who achieved complete response after chemotherapy in the FLT3-ITD/DNMT3A R882 group was 1.19±0.87, which was significantly lower than that at first diagnosis, and the difference was statistically significant (P=0.011). CONCLUSION TSPO gene may be used as an indicator of efficacy in FLT3-ITD /DNMT3A R882 double-mutated AML.
Humans ; DNA (Cytosine-5-)-Methyltransferases/genetics* ; DNA Methyltransferase 3A ; Mutation ; Leukemia, Myeloid, Acute/drug therapy* ; Nucleophosmin ; Prognosis ; fms-Like Tyrosine Kinase 3/genetics* ; Receptors, GABA/therapeutic use*

Abstract: Objective　To further investigate the underreporting of mortality surveillance data among permanent residents in Hainan Province in 2020, and to explore the application of Application of the Analysis of National Causes of Death for Action (ANACONDA) in the quality analysis of mortality surveillance. Methods　The data were collected from the Death Information Monitoring and Management System of Hainan Center for Disease Control and Prevention, and mainly included 33 418 deaths reported from 19 cities and counties in Hainan Province from January 1, 2020 to December 31, 2020. All the data were analyzed by the application of ANACONDA, and the causes of death were classified by the International Classification of Diseases, 10th Revision (ICD-10). Results　A total of 33 418 deaths were reported in Hainan Province in 2020, with a crude mortality rate of 3.6‰. The proportion of deaths in males under 85 years old was higher than that in females, while the proportion of deaths in 85 years old and above was opposite. The quality analysis of cause of death surveillance showed that there was under-reporting of death surveillance in Hainan Province in 2020, with an under-reporting rate of 30.1%. There were differences in the age composition and GBD regional composition ratio of deaths of the three major categories of diseases, and the misreporting of causes of death in the middle and high age groups was more significant. The Vital Statistics Performance Index (VSPI) score of death data in Hainan Province in 2020 was 52.8, the score of cause of death reporting quality was 85.5, and the score of specific cause of death level that could be used was 88.4. The completeness of death reports in the priority action areas for improving cause of death data quality accounted for the largest share, followed by the quality of cause of death reports. There was a difference in the proportion of specific causes of death between males and females after the survey, but the change in order was not obvious. Conclusions　The data integrity of cause-of-death surveillance is low in Hainan Province in 2020. It is suggested to improve the completeness of reporting data, strengthen the training of cause-of-death surveillance system, and regularly evaluate and supervise the system.

Stable isotope tracer metabolomics tracks and analyzes the whole metabolic process of the body through the tracer atoms, which belongs to the frontier technology in the field of biomedicine. This technology is of great significance and value for explaining the pathogenesis of diseases, finding biomarkers of diseases and drug action targets. Taking the mechanism of glucose catabolism disorder in depression as an example, this paper systematically expounds the stable isotope tracer metabolomics technology and its application. The research idea of stable isotope tracer metabolomics based on unmarked metabolomics was put forward, and the research strategy of biological significance interpretation from four dimensions of metabolite isotope abundance, key metabolic enzymes, metabolic flow direction and metabolite flow was given, which broke through the bottleneck of stable isotope tracer metabolomics research technology based on overall animal experiment, and provided scientific basis for the promotion and application of this technology.

Objective: To compare the 5-year follow-up outcomes of radiofrequency catheter ablation (RFCA) combined with left atrial appendage closure (LAAC) and long-term oral anticoagulant (OAC) after RFCA in patients with atrial fibrillation. Methods: This retrospective cross-sectional study included patients with atrial fibrillation who underwent"one-stop"procedure in the First Affiliated Hospital of Ningbo University from September 2015 to December 2017 (RFCA+LAAC group). Baseline data of patients were collected. Propensity score matching at the ratio of 1∶1 was used to select patients with atrial fibrillation who took long-term OAC after RFCA (RFCA+OAC group). The maintenance rate of sinus rhythm and the incidence of adverse events during follow-up were compared between the two groups. Results: A total of 110 patients were enrolled in the RFCA+LAAC group and RFCA+OAC group, respectively. Age of patients was (67.4±8.8) years in RFCA+LAAC group, and there were 42 (38.2%) female patients. Age of patients was (67.3±7.9) years in RFCA+OAC group, and there were 47 (42.7%) female patients. The patients were followed up for mean of (5.3±1.1) years. There was no significant difference in the maintenance rate of sinus rhythm (log-rank: χ²=0.277, P=0.602) and incidence of ischemic stroke events (2.7% (3/110) vs. 4.5% (5/110), P=0.719) during follow-up between the two groups. The incidence of bleeding events (6.4% (7/110) vs. 18.2% (20/110), P=0.008) and major bleeding events (1.8% (2/110) vs. 8.2% (9/110), P=0.030) was significantly higher in the RFCA+OAC group than in the RFCA+LAAC group. Conclusion: There is no significant difference between RFCA+LAAC group and RFCA+OAC group in maintenance rate of sinus rhythm and incidence of ischemic stroke events. Patients in the RFCA+LAAC group have a lower risk of bleeding events compared to the RFCA+OAC group.
Humans ; Female ; Middle Aged ; Aged ; Male ; Atrial Fibrillation/surgery* ; Cross-Sectional Studies ; Follow-Up Studies ; Retrospective Studies ; Anticoagulants/therapeutic use* ; Catheter Ablation ; Ischemic Stroke