OBJECTIVE To investigate the apoptosis-inducing effect of esculetin （Esc） on acute myeloid leukemia （AML） HL-60 cells by regulating the protein kinase B （AKT）/S-phase kinase-associated protein 2 （SKP2）/MutT homolog 1 （MTH1） pathway. METHODS AML HL-60 cells were randomly divided into control group （routine culture）， Esc low-concentration group （L-Esc group， 25 μmol/L Esc）， Esc medium-concentration group （M-Esc group， 50 μmol/L Esc）， Esc high-concentration group （H-Esc group， 100 μmol/L Esc）， and high-concentration of Esc+ SC79 （AKT agonist） group （100 μmol/L Esc+5 μmol/L SC79）. Cell proliferation in each group was detected by MTT assay and colony formation assay. The level of reactive oxygen species （ROS） in cells was measured by using the CM-H2DCFDA fluorescent probe. Cell apoptosis was analyzed by flow cytometry. Western blot assay was performed to detect the expression levels of apoptosis-related proteins [B-cell lymphoma 2 （Bcl-2）， Bcl-2-associated X protein （Bax）， cleaved caspase-3]， AKT/SKP2/MTH1 pathway-related proteins （p-AKT， AKT， SKP2， MTH1）， along with the upstream and downstream proteins of AKT phosphatidylinositol 3-kinase （PI3K）， cyclin-dependent kinase inhibitor 1 （P21） and cyclin-dependent kinase inhibitor 1B （P27）. RESULTS Compared with control group， the cell viability， colony number， and the phosphorylation levels of AKT and PI3K proteins as well as protein expressions of SKP2， MTH1 and Bcl-2 were significantly decreased （P＜0.05）， while ROS level， apoptosis rate， and the expression levels of Bax， cleaved caspase-3， P21 and P27 proteins were significantly increased （P＜0.05）. Moreover， the effects of Esc exhibited concentration-dependence （P＜0.05）. Compared with H-Esc group， above indexes of high-concentration of Esc+ SC79 group were reversed significantly （P＜0.05）. CONCLUSIONS Esc may promote massive ROS production and induce activation of apoptosis in HL-60 cells by inhibiting the AKT/SKP2/MTH1 pathway， thus inhibiting the proliferation of HL-60 cells.

ObjectiveTo investigate the effect and mechanism of transplantation of human umbilical cord mesenchymal stem cell （hUC-MSC） with overexpression of the Numb gene in the treatment of cholestatic liver fibrosis （CLF）. MethodsThe technique of lentiviral transfection was used to induce the overexpression of the Numb gene in hUC-MSC （hUC-MSC^Numb-OE）， and hUC-MSC transfected with empty vector （hUC-MSC^OE-EV） was used as negative control. Bile duct ligation （BDL） was performed to establish a rat model of CLF， and then the rats were randomly divided into BDL group， hUC-MSC group， hUC-MSC^OE-EV group， and hUC-MSC^Numb-OE group， while a sham-operation group was also established. The rats in the intervention groups were given a single splenic injection of the corresponding cells after BDL， and samples were collected at the end of week 4. Related indicators were measured， including serum biochemistry， liver histopathology， the content of hydroxyproline （Hyp） in the liver， hepatic stellate cell activation， ductular reaction， liver regeneration， and the expression levels of key molecules in the Numb-p53 signaling axis. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the BDL group， the hUC-MSC group and the hUC-MSC^OE-EV group had significant reductions in the levels of serum biochemical parameters （aspartate aminotransferase， gamma-glutamyl transpeptidase， total bile acid， total bilirubin， and direct bilirubin）， liver fibrosis markers （the content of Hyp and the expression levels of alpha-smooth muscle actin， tumor necrosis factor-α， and transforming growth factor-beta 1）， and ductular reaction markers （the expression levels of CK7 and CK19） （all P <0.05）， and compared with the hUC-MSC^OE-EV group， the hUC-MSC^Numb-OE group had significantly greater improvements in the above indicators （all P <0.05）. In addition， compared with the hUC-MSC^OE-EV group， the hUC-MSC^Numb-OE group had significant improvements in the expression levels of liver regeneration-related markers （albumin and hepatocyte nuclear factor 4α） and the molecules associated with the Numb-p53 signaling axis （Numb， pNumb， Mdm2， and p53） （all P <0.05）. ConclusionOverexpression of the Numb gene can enhance the therapeutic effect of hUC-MSC on CLF， possibly by activating the Numb-PTB^L-p53-HNF4α axis， promoting the hepatic differentiation of hUC-MSCs and subsequently enhancing liver regeneration.

BACKGROUND:Steroid-induced femoral head necrosis is mostly caused by long-term and extensive use of hormones,but its specific pathogenesis is not yet clear and needs further study. OBJECTIVE:To screen out the differential miRNAs in osteoclast exosomes after the intervention of Panax notoginseng saponins,and on this basis,to further construct an osteogenic-related ferroptosis regulatory network to explore the potential mechanism and research direction of steroid-induced osteonecrosis of the femoral head. METHODS:MTT assay was used to detect the toxic effects of different concentrations of dexamethasone and different mass concentrations of Panax notoginseng saponins on Raw264.7 cell line.Tartrate resistant acid phosphatase staining and TUNEL assay were used to detect the effects of Panax notoginseng saponins on osteoclast inhibition and apoptosis.Exosomes were extracted from cultured osteoclasts with Panax notoginseng saponins intervention.Exosomes from different groups were sequenced to identify differentially expressed miRNAs.CytoScape 3.9.1 was used to construct and visualize the regulatory network between differentially expressed miRNAs and mRNAs.Candidate mRNAs were screened by GO analysis and KEGG analysis.Finally,the differential genes related to ferroptosis were screened out,and the regulatory network of ferroptosis-related genes was constructed. RESULTS AND CONCLUSION:(1)The concentration of dexamethasone(0.1 μmol/L)and Panax notoginseng saponins(1 736.85 μg/mL)suitable for intervention of Raw264.7 cells was determined by MTT assay.(2)Panax notoginseng saponins had an inhibitory effect on osteoclasts and could promote their apoptosis.(3)Totally 20 differentially expressed miRNAs were identified from osteoclast-derived exosome samples,and 11 differentially expressed miRNAs related to osteogenesis were predicted by target mRNAs.The regulatory networks of 4 up-regulated differentially expressed miRNAs corresponding to 155 down-regulated candidate mRNAs and 7 down-regulated differentially expressed miRNAs corresponding to 238 up-regulated candidate mRNAs were constructed.(4)Twenty-four genes related to ferroptosis were screened out from the differential genes.Finally,12 networks were constructed(miR-98-5p/PTGS2,miR-23b-3p/PTGS2,miR-425-5p/TFRC,miR-133a-3p/TFRC,miR-185-5p/TFRC,miR-23b-3p/NFE2L2,miR-23b-3p/LAMP2,miR-98-5p/LAMP2,miR-182-5p/LAMP2,miR-182-5p/TLR4,miR-23b-3p/ZFP36,and miR-182-5p/ZFP36).These results indicate that Panax notoginseng saponins may regulate osteoblast ferroptosis by regulating the expression of miRNAs derived from osteoclast exosomes,thus providing a new idea for the study of the mechanism of steroid-induced femoral head necrosis.

Objective:To investigate the effects of TP53 genetic status(wild-type/mutated/null)on the drug resistance of decitabine(DAC)in myelodysplastic syndromes(MDS)and identify key resistance-associated genes.Methods:Two myeloid cell lines with distinct TP53 status(M-07e:wild-type;SKM-1:mutated;)were treated with gradient DAC concentrations(0-10 μmol/L)for 0-72 h.Cell viability was detected by CCK-8 assay.RNA-Seq transcriptomics,and methylation profiling were integrated to analyze differentially expressed genes.Results:Decitabine(DAC)treatment induced time-and dose-dependent inhibition of cell viability in CCK-8 assays,with SKM-1 cells exhibiting the highest resistance(IC50=5 μmol/L vs M-07e=0.5 μmol/L,P＜0.01).Transcriptomic analysis revealed 662 upregulated and 452 downregulated genes in DAC-treated M-07e cells,while SKM-1 cells showed 515 upregulated and 73 downregulated genes.By proteomic profiling,117 upregulated and 136 downregulated proteins were identified in M-07e cells,while 91 upregulated and 46 downregulated proteins were identified in SKM-1 cells following DAC exposure.Through integrated analysis of upregulated genes and proteins expression profiles,181 candidate genes were screened out,while methylation studies identified 884 hypomethylated genes with high-sensitivity loci and CpG density.Notably,31 genes overlapped between these datasets,and functional annotation indicated these drug-resistance-associated genes are primarily involved in positive regulation of cell differentiation,negative regulation of binding processes,and negative regulation of cellular component organization.Conclusion:TP53 mutations drive DAC resistance via epigenetic reprogramming.Targeting these genes may improve outcomes in TP53-mutated MDS.

Objective:In accordance with the urban spatial structure and functional positioning outlined in the General Plan for the Overall Urban Development of Beijing(2016-2035),this study analyzed the allocation and equity of human resources in the Beijing Center for Disease Control and Prevention(CDC)system from 2019 to 2023,aiming to provide a reference for future planning.Methods:Based on the Plan,Beijing was divided into five structural regions.Descriptive statistical analysis,the Gini coefficient,and the Theil index were used to comprehensively evaluate the allocation and equity of regional human resources.Results:From 2019 to 2023,the total number of human resources in the Beijing CDC system showed a slow growth trend,with an overall shortage in staffing;however,the quality structure of personnel was relatively good.Equity among the structural regions gradually improved,as indicated by the annual decrease in both the Gini coefficient and the total Theil index.The contribution of inter-group differences to the total Theil index was greater than that of intra-group differences.Conclusions:There is a certain gap between the current human resource allocation in the Beijing CDC system and the requirements of non-capital function relocation and functional positioning of each structural region.It is recommended to align with urban planning,increase the number of personnel performing public health functions,and establish human resource allocation standards,plans,and working mechanisms that meet the development needs of each structural region,thereby better serving the functional positioning of the capital city and the health of its residents.

Objective:To investigate the clinical characteristics and hormonal changes in patients with adrenocorticotropic hormone(ACTH)-suppressed and non-suppressed subclinical Cushing′s syndrome(SCS), to evaluate the influencing factors of ACTH suppression, and to assess the diagnostic efficiency of serum dehydroepiandrosterone sulfate(DHEAS) levels in distinguishing these two groups of SCS patients.Methods:Clinical data of patients diagnosed with SCS in the Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical College, between June 2014 and October 2023 were retrospectively collected. A total of 194 cases were included. According to morning(8: 00 AM) plasma ACTH levels, patients were divided into an ACTH-suppressed group(ACTH<2.2 pmol/L) and a non-suppressed group(ACTH≥2.2 pmol/L). Additionally, 194 gender-, age-, and BMI-matched patients with non-functional adrenal tumors(NFA) were enrolled as controls. Clinical characteristics and hormone levels were compared between groups. Logistic regression analysis was performed to identify factors influencing ACTH suppression in SCS patients. Furthermore, receiver operating characteristic(ROC) curve analysis was conducted to evaluate the diagnostic performance of serum DHEAS levels in distinguishing ACTH-suppressed and non-suppressed SCS patients. Results:There were no significant differences in the prevalence of overweight/obesity, hypertension, abnormal glucose metabolism, or bone metabolism disorders between the ACTH-suppressed and non-suppressed groups. The serum cortisol level after the 1 mg-dexamethasone suppression test(DST) was significantly lower in the ACTH non-suppressed group than that in the suppressed group, while the serum DHEAS level was significantly higher in the non-suppressed group(both P<0.01). The area under the curve(AUCs) of serum DHEAS for diagnosing ACTH non-suppressed SCS patients and ACTH-suppressed SCS patients was 0.779(95% CI 0.721-0.837) and 0.874(95% CI 0.831-0.918), respectively. Using a serum DHEAS cutoff of 60.0 μg/dL, the sensitivity and specificity for diagnosing ACTH non-suppressed SCS patients were 66.7% and 76.1%, respectively, while for ACTH-suppressed SCS patients, the sensitivity and specificity were 84.9% and 75.5%, respectively. Conclusion:There were no significant differences in metabolic characteristics between ACTH-suppressed and non-suppressed SCS patients. Serum cortisol level after 1 mg-DST is an independent influencing factor for ACTH suppression status. Low serum DHEAS level serves as a sensitive diagnostic marker for SCS and also demonstrates diagnostic value in ACTH non-suppressed SCS patients.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

Objective To summarize the changing prevalence of carbapenem resistance in Enterobacterales based on the data of CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021 for improving antimicrobial treatment in clinical practice.Methods Antimicrobial susceptibility testing was performed using a commercial automated susceptibility testing system according to the unified CHINET protocol.The results were interpreted according to the breakpoints of the Clinical & Laboratory Standards Institute(CLSI)M100 31st ed in 2021.Results Over the seven-year period(2015-2021),the overall prevalence of carbapenem-resistant Enterobacterales(CRE)was 9.43％(62 342/661 235).The prevalence of CRE strains in Klebsiella pneumoniae,Citrobacter freundii,and Enterobacter cloacae was 22.38％,9.73％,and 8.47％,respectively.The prevalence of CRE strains in Escherichia coli was 1.99％.A few CRE strains were also identified in Salmonella and Shigella.The CRE strains were mainly isolated from respiratory specimens(44.23±2.80)％,followed by blood(20.88±3.40)％and urine(18.40±3.45)％.Intensive care units(ICUs)were the major source of the CRE strains(27.43±5.20)％.CRE strains were resistant to all the β-lactam antibiotics tested and most non-β-lactam antimicrobial agents.The CRE strains were relatively susceptible to tigecycline and polymyxins with low resistance rates.Conclusions The prevalence of CRE strains was increasing from 2015 to 2021.CRE strains were highly resistant to most of the antibacterial drugs used in clinical practice.Clinicians should prescribe antimicrobial agents rationally.Hospitals should strengthen antibiotic stewardship in key clinical settings such as ICUs,and take effective infection control measures to curb CRE outbreak and epidemic in hospitals.

Objective To characterize the changing species distribution and antibiotic resistance profiles of respiratory isolates in hospitals participating in the CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021.Methods Commercial automated antimicrobial susceptibility testing systems and disk diffusion method were used to test the susceptibility of respiratory bacterial isolates to antimicrobial agents following the standardized technical protocol established by the CHINET program.Results A total of 589 746 respiratory isolates were collected from 2015 to 2021.Overall,82.6％of the isolates were Gram-negative bacteria and 17.4％were Gram-positive bacteria.The bacterial isolates from outpatients and inpatients accounted for(6.0±0.9)％and(94.0±0.1)％,respectively.The top microorganisms were Klebsiella spp.,Acinetobacter spp.,Pseudomonas aeruginosa,Staphylococcus aureus,Haemophilus spp.,Stenotrophomonas maltophilia,Escherichia coli,and Streptococcus pneumoniae.Each microorganism was isolated from significantly more males than from females(P＜0.05).The overall prevalence of methicillin-resistant S.aureus(MRSA)was 39.9％.The prevalence of penicillin-resistant S.pneumoniae was 1.4％.The prevalence of extended-spectrum β-lactamase(ESBL)-producing E.coli and K.pneumoniae was 67.8％and 41.3％,respectively.The overall prevalence of carbapenem-resistant E.coli,K.pneumoniae,Enterobacter cloacae,Pseudomonas aeruginosa,and Acinetobacter baumannii was 3.7％,20.8％,9.4％,29.8％,and 73.3％,respectively.The prevalence of β-lactamase was 96.1％in Moraxella catarrhalis and 60.0％in Haemophilus influenzae.The H.influenzae isolates from children(＜18 years)showed significantly higher resistance rates to β-lactam antibiotics than the isolates from adults(P＜0.05).Conclusions Gram-negative bacteria are still predominant in respiratory isolates associated with serious antibiotic resistance.Antimicrobial resistance surveillance should be strengthened in clinical practice to support accurate etiological diagnosis and appropriate antimicrobial therapy based on antimicrobial susceptibility testing results.

Purpose To evaluate the value of tumors invasion in the central airway(TICA)in predicting the severe immune checkpoint inhibitor-related pneumonitis(S-CIP)in lung cancer patients using propensity score matching(PSM).Materials and Methods The intact data of 162 consecutive lung cancer patients who received treatment with immune checkpoint inhibitors in Xi'an International Medical Center Hospital from September 2019 to March 2022 were retrospectively collected.Patients were divided into S-CIP group(23 cases)and non-S-CIP group(139 cases)according to the presence of S-CIP.The demographic information of the patients,including gender,age,history of smoking,thoracic radiotherapy histology,baseline lung diseases,classification,TNM stage,tumor location as well as TICA were collected.A binary Logistic regression was used to analyze the confounding factors and independent risk factors of S-CIP and to predict the development of S-CIP.A 1:1 matching was performed by the nearest neighbor method for PSM.The PSM was used to pair the two groups,and the value of TICA in predicting S-CIP before and after PSM was compared.The receiver operating characteristic curve and the area under the curve were used for model performance based on TICA.Results Before PSM,the proportion of baseline lung diseases(78.3%vs.32.4%,OR=6.802,P=0.001),thoracic radiotherapy history(69.6%vs.30.2%,OR=5.300,P=0.002)and TICA(65.2%vs.27.3%,OR=5.882,P=0.001)in the S-CIP group was higher than those in the non-S-CIP group,and were independent risk factor for predicting S-CIP.After PSM,20 patients were included in each group.The presence of TICA was higher in S-CIP group than that in the non-S-CIP group(60.0%vs.20.0%,OR=6.000,P=0.013).The area under the curves of Logistic regression model based on TICA was 0.700(95%CI 0.534-0.866).Conclusion TICA is an independent risk factor for development of S-CIP,which has moderate degree of accuracy in predicting S-CIP,can be used for risk prediction and early intervention to reduce the poor prognosis of S-CIP patients.