Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

OBJECTIVES: To explore the value of serum cystatin C (CysC) levels in evaluating renal prognosis in IgA nephropathy (IgAN) patients. METHODS: We retrospectively collected the clinical data of IgAN patients diagnosed by renal biopsy at Guangdong Provincial People's Hospital from January, 2014 to December, 2018. Based on baseline serum CysC levels, the patients were divided into high serum CysC (>1.03 mg/L) group and normal serum CysC (≤1.03 mg/L) group. The composite endpoint for poor renal prognosis was defined as ≥50% decline in estimated glomerular filtration rate (eGFR) and/or progression to end-stage renal disease (ESRD). Lasso regression, multivariate Cox regression and Kaplan-Meier survival analysis were used to identify the risk factors and compare renal survival rates between the two groups. Smooth curves fitting and threshold effect analysis were used to explore the relationship between serum CysC levels and the outcomes. A nomogram model was constructed and its predictive performance was evaluated using concordance index, calibration curve, receiver operating characteristic (ROC) curve and the area under curve (AUC). RESULTS: A total of 356 IgAN patients were enrolled, who were followed up for 4.65±0.93 years. The composite endpoint occurred in 74 patients. High serum CysC was identified as an independent risk factor for poor renal prognosis in IgAN (HR=2.142, 95% CI 1.222 to 3.755), and the patients with high serum CysC levels had a lower renal survival rate (Log-rank χ²=47.970, P<0.001). In patients with serum CysC below 2.12 mg/L, a higher CysC level was associated with an increased risk of poor renal prognosis (β=3.487, 95% CI: 2.561-4.413, P<0.001), while above this level, the increase of the risk was not significant (β=0.676, 95% CI: -0.642-1.995, P=0.315). The nomogram model based on serum CysC and 3 other independent risk factors demonstrated good internal validity with a concordance index of 0.873 (95% CI: 0.839-0.907) and an AUC of 0.909 (95% CI: 0.873-0.945). CONCLUSIONS Serum CysC levels are associated with renal prognosis in IgAN patients, and high serum CysC an independent risk factor for poor renal prognosis.
Humans ; Glomerulonephritis, IGA/diagnosis* ; Cystatin C/blood* ; Prognosis ; Risk Factors ; Retrospective Studies ; Glomerular Filtration Rate ; Kidney Failure, Chronic ; Male ; Female ; Adult ; Nomograms ; Middle Aged

Objective:To investigate the correlation between the promoter methylation level of Dickkopf-related protein 1 (DKK1) gene and diabetic microangiopaopathy complicated with osteoporosis.Methods:Patients with type 2 diabetes mellitus (T2DM) microangiopathopathy who were admitted to our hospital from Jan. 2019 to Dec. 2022 were collected as research objects, and divided into observation group (44 cases) and control group (58 cases) according to whether they were complicated with osteoporosis. Bone mineral density (BMD) of lumbar spine (L1-4) was measured, and bone metabolism indexes, including serum calcium, serum phosphorus, 25-hydroxy vitamin D3[25-hydroxy vitamin D3, 25- (OH) D3], PTH, C-terminal telopeptide of typeI collagen (CTX), procollagen of aminoterminal propeptide (PINP) and tartrate resistant acid phosphatase (TRACP) levels were detected; The promoter methylation level of DKK1 gene was determined.Results:The methylation level of DKK1 gene promoter in the observation group was 5.17%±0.73%, which was significantly higher than that in the control group (3.81%±0.61%), with statistical significance ( t=5.22, P<0.001). The 25- (OH) D3 level, PTH and lumbar bone density in the observation group were significantly lower than those in the control group, while the CTX and TRACP levels were significantly higher than those in the control group ( t was 5.58, 4.35, 4.12, 4.05 and 4.17, respectively, P<0.001). In all patients, the promoter methylation level of DKK1 gene was significantly positively correlated with CTX and TRACP ( r was 0.41 and 0.39, P was 0.006 and 0.027, respectively), and significantly negatively correlated with PTH and lumbar bone density ( r was -0.38 and -0.43, respectively). P=0.015 and 0.003, respectively). ROC curve analysis showed that the area under the curve of DKK1 methylation level to distinguish type 2 diabetes microangionopathy with and without osteoporosis was 0.841 (0.762-0.921), and the sensitivity and specificity were 86.4% and 72.4%, respectively. Conclusion:The methylation level of DKK1 gene promoter is associated with osteoporosis and bone metabolism in T2DM patients with microangiopathia.

Objective:To study the current status of longitudinal extrauterine growth restriction (EUGR) in extremely preterm infants (EPIs) and to develop a prediction model based on clinical data from multiple NICUs.Methods:From January 2017 to December 2018, EPIs admitted to 32 NICUs in North China were retrospectively studied. Their general conditions, nutritional support, complications during hospitalization and weight changes were reviewed. Weight loss between birth and discharge > 1SD was defined as longitudinal EUGR. The EPIs were assigned into longitudinal EUGR group and non-EUGR group and their nutritional support and weight changes were compared. The EPIs were randomly assigned into the training dataset and the validation dataset with a ratio of 7∶3. Univariate Cox regression analysis and multiple regression analysis were used in the training dataset to select the independent predictive factors. The best-fitting Nomogram model predicting longitudinal EUGR was established based on Akaike Information Criterion. The model was evaluated for discrimination efficacy, calibration and clinical decision curve analysis.Results:A total of 436 EPIs were included in this study, with a mean gestational age of (26.9±0.9) weeks and a birth weight of (989±171) g. The incidence of longitudinal EUGR was 82.3%(359/436). Seven variables (birth weight Z-score, weight loss, weight growth velocity, the proportion of breast milk ≥75% within 3 d before discharge, invasive mechanical ventilation ≥7 d, maternal antenatal corticosteroids use and bronchopulmonary dysplasia) were selected to establish the prediction model. The area under the receiver operating characteristic curve of the training dataset and the validation dataset were 0.870 (95% CI 0.820-0.920) and 0.879 (95% CI 0.815-0.942), suggesting good discrimination efficacy. The calibration curve indicated a good fit of the model ( P>0.05). The decision curve analysis showed positive net benefits at all thresholds. Conclusions:Currently, EPIs have a high incidence of longitudinal EUGR. The prediction model is helpful for early identification and intervention for EPIs with higher risks of longitudinal EUGR. It is necessary to expand the sample size and conduct prospective studies to optimize and validate the prediction model in the future.

OBJECTIVE To establish a determination method for the related substances of LPM3480392, a novel Gi protein-biased opioid receptor(MOR) agonist. METHODS The separation was carried out with Waters Symmetry Shield RP18 (150 mm×4.6 mm, 3.5 μm) by gradient elution method, using a mixture of 0.002 5 mol·L–1 sodium 1-octanesulfonate monohydrate in 0.01 mol·L–1 potassium dihydrogen phosphate-water solution(containing 0.1% triethylamine, adjusted pH to 2.50 with phosphate acid) and acetonitrile as the mobile phase at a flow rate of 1.0 mL·min–1 and the UV detection wavelength was set at 210 nm. RESULTS The chromatographic peaks of LPM3480392 and impurity A, impurity B, impurity C, impurity E and impurity F could be completely separated, the linear relationship of LPM3480392 was good in 0.064 9−5.191 2 μg·mL–1, while impurity A, impurity B, impurity C, impurity E and impurity F showed good linear relationship within 0.066 6−7.610 4 μg·mL–1, 0.166 0−3.794 0 μg·mL–1, 0.209 2−4.463 2 μg·mL–1, 0.167 9−7.672 6 μg·mL–1 and 0.016 4−7.505 7 μg·mL–1, respectively. The recovery rate was within 93.0%−103.2%. CONCLUSION The method is suitable for the determination of related substances in LPM3480392, and can provide valuable reference for the follow-up research and development of LPM3480392.

Objective To investigate the ocular biological parameters of children with idiopathic short stature(ISS)and compare them with those of children with growth hormone deficiency(GHD)and normal children,and to explore the characteristics of ocular biological parameters in this group,so as to provide a reference for the screening of visual acuity and the safety of growth hormone therapy in children with ISS.Methods A total of 15 children aged 5-14 years old with ISS were selected as the observation group,32 children with GHD were selected as the control group,and 47 children of normal height who underwent routine visual acuity screening were selected as normal controls.The ocular biological parameters of children with ISS were studied.The differences of vision-re-lated parameters between the above three groups were compared.The influencing factors affecting the visual devel-opment of children with ISS were analyzed.Results The axial ratio of ISS was significantly higher than that of the GHD group and normal children,and the intraocular pressure of the ISS group was significantly higher than that of the GHD group and normal children.There was no significant difference in axial length between the ISS group and the GHD group,as well as normal children(P＞0.05),but the axial length of the GHD group was significantly shorter than that of normal children.The corneal curvature of ISS was significantly greater than that of normal chil-dren.The axial rate ratio of the ISS group was positively correlated with the peak value and corneal curvature of growth hormone provocation test(β=1.052,P＜0.05;β=0.004,P＜0.05).Conclusion Children with ISS may have high intraocular pressure and high risk of myopia.Higher peak results of growth hormone provocation test and large corneal curvature may be the risk factors for myopia.

Objective To analyze the diagnostic efficacy and clinical significance of magnifying endoscopy combined with narrow-band imaging(ME-NBI),acetate-indigo rouge staining and multi-slice spiral CT for early gastric cancer and precancerous lesions.Methods 202 patients with suspected early gastric cancer and precancerous lesions from February 2019 to March 2022 were regarded as the subjects of this study,all the patients underwent ME-NBI,acetate-indigo rouge staining,and multi-slice spiral CT examination;The diagnostic value of different examination methods for early gastric cancer and precancerous lesions was analyzed using the receiver operator characteristic curve(ROC curve),using the pathological results of gastric cancer as the gold standard,the diagnostic value of ME-NBI,acetate-indigo rouge staining combined with multi-slice spiral CT and their combination in early gastric cancer and precancerous lesions was analyzed using a four grid table.Results The image quality of ME-NBI and acetate-indigo rouge staining combined examinations was significantly higher than that of their respective independent examinations(P<0.05).There was significant difference in the degree of differentiation in the clinical features of patients with early gastric cancer and precancerous lesions(P<0.05).The area under the curve(AUC)of ME-NBI for the diagnosis of early gastric cancer and precancerous lesions was 0.853,the accuracy was 85.64%,the sensitivity was 88.37%,and the specificity was 83.62%.The AUC of acetate-indigo rouge staining for the diagnosis of early gastric cancer and precancerous lesions was 0.814,the accuracy was 81.68%,the sensitivity was 83.72%,and the specificity was 80.17%.The AUC of multi-slice spiral CT for the diagnosis of early gastric cancer and precancerous lesions was 0.804,with an accuracy of 80.69%,a sensitivity of 82.56%,and a specificity of 79.31%.And the AUC of the three methods combined to diagnose early gastric cancer and precancerous lesions was 0.893,with an accuracy of 89.60%,a sensitivity of 93.02%,and a specificity of 87.07%.Conclusion ME-NBI,acetate-indigo rouge staining combined with multi-slice spiral CT has high diagnostic efficacy in early gastric cancer and precancerous lesions,and can be used in clinical practice.

Objective To investigate the distribution and antimicrobial resistance profiles of the common pathogens isolated from urine from 2015 to 2021 in the CHINET Antimicrobial Resistance Surveillance Program.Methods The bacterial strains were isolated from urine and identified routinely in 51 hospitals across China in the CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021.Antimicrobial susceptibility was determined by Kirby-Bauer method,automatic microbiological analysis system and E-test according to the unified protocol.Results A total of 261 893 nonduplicate strains were isolated from urine specimen from 2015 to 2021,of which gram-positive bacteria accounted for 23.8％(62 219/261 893),and gram-negative bacteria 76.2％(199 674/261 893).The most common species were E.coli(46.7％),E.faecium(10.4％),K.pneumoniae(9.8％),E.faecalis(8.7％),P.mirabilis(3.5％),P.aeruginosa(3.4％),SS.agalactiae(2.6％),and E.cloacae(2.1％).The strains were more frequently isolated from inpatients versus outpatients and emergency patients,from females versus males,and from adults versus children.The prevalence of ESBLs-producing strains in E.coli,K.pneumoniae and P.mirabilis was 53.2％,52.8％and 37.0％,respectively.The prevalence of carbapenem-resistant strains in E.coli,K.pneumoniae,P.aeruginosa and A.baumannii was 1.7％,18.5％,16.4％,and 40.3％,respectively.Lower than 10％of the E.faecalis isolates were resistant to ampicillin,nitrofurantoin,linezolid,vancomycin,teicoplanin and fosfomycin.More than 90％of the E.faecium isolates were ressitant to ampicillin,levofloxacin and erythromycin.The percentage of strains resistant to vancomycin,linezolid or teicoplanin was＜2％.The E.coli,K.pneumoniae,P.aeruginosa and A.baumannii strains isolated from ICU inpatients showed significantly higher resistance rates than the corresponding strains isolated from outpatients and non-ICU inpatients.Conclusions E.coli,Enterococcus and K.pneumoniae are the most common pathogens in urinary tract infection.The bacterial species and antimicrobial resistance of urinary isolates vary with different populations.More attention should be paid to antimicrobial resistance surveillance and reduce the irrational use of antimicrobial agents.

Objective To understand the distribution and changing resistance profiles of clinical isolates of Enterococcus in hospitals across China from 2015 to 2021.Methods Antimicrobial susceptibility testing was conducted for the clinical isolates of Enterococcus according to the unified protocol of CHINET program by automated systems,Kirby-Bauer method,or E-test strip.The results were interpreted according to the Clinical & Laboratory Standards Institute(CLSI)breakpoints in 2021.WHONET 5.6 software was used for statistical analysis.Results A total of 124 565 strains of Enterococcus were isolated during the 7-year period,mainly including Enterococcus faecalis(50.7％)and Enterococcus faecalis(41.5％).The strains were mainly isolated from urinary tract specimens(46.9％±2.6％),and primarily from the patients in the department of internal medicine,surgery and ICU.E.faecium and E.faecalis strains showed low level resistance rate to vancomycin,teicoplanin and linezolid(≤3.6％).The prevalence of vancomycin-resistant E.faecalis and E.faecium was 0.1％and 1.3％,respectively.The prevalence of linezolid-resistant E.faecalis increased from 0.7％in 2015 to 3.4％in 2021,while the prevalence of linezolid-resistant E.faecium was 0.3％.Conclusions The clinical isolates of Enterococcus were still highly susceptible to vancomycin,teicoplanin,and linezolid,evidenced by a low resistance rate.However,the prevalence of linezolid-resistant E.faecalis was increasing during the 7-year period.It is necessary to strengthen antimicrobial resistance surveillance to effectively identify the emergence of antibiotic-resistant bacteria and curb the spread of resistant pathogens.

Objective To examine the changing antimicrobial resistance profile of Enterobacter spp.isolates in 53 hospitals across China from 2015 t0 2021.Methods The clinical isolates of Enterobacter spp.were collected from 53 hospitals across China during 2015-2021 and tested for antimicrobial susceptibility using Kirby-Bauer method or automated testing systems according to the CHINET unified protocol.The results were interpreted according to the breakpoints issued by the Clinical & Laboratory Standards Institute(CLSI)in 2021(M100 31st edition)and analyzed with WHONET 5.6 software.Results A total of 37 966 Enterobacter strains were isolated from 2015 to 2021.The proportion of Enterobacter isolates among all clinical isolates showed a fluctuating trend over the 7-year period,overall 2.5％in all clinical isolates amd 5.7％in Enterobacterale strains.The most frequently isolated Enterobacter species was Enterobacter cloacae,accounting for 93.7％(35 571/37 966).The strains were mainly isolated from respiratory specimens(44.4±4.6)％,followed by secretions/pus(16.4±2.3)％and urine(16.0±0.9)％.The strains from respiratory samples decreased slightly,while those from sterile body fluids increased over the 7-year period.The Enterobacter strains were mainly isolated from inpatients(92.9％),and only(7.1±0.8)％of the strains were isolated from outpatients and emergency patients.The patients in surgical wards contributed the highest number of isolates(24.4±2.9)％compared to the inpatients in any other departement.Overall,≤ 7.9％of the E.cloacae strains were resistant to amikacin,tigecycline,polymyxin B,imipenem or meropenem,while ≤5.6％of the Enterobacter asburiae strains were resistant to these antimicrobial agents.E.asburiae showed higher resistance rate to polymyxin B than E.cloacae(19.7％vs 3.9％).Overall,≤8.1％of the Enterobacter gergoviae strains were resistant to tigecycline,amikacin,meropenem,or imipenem,while 10.5％of these strains were resistant to polycolistin B.The overall prevalence of carbapenem-resistant Enterobacter was 10.0％over the 7-year period,but showing an upward trend.The resistance profiles of Enterobacter isolates varied with the department from which they were isolated and whether the patient is an adult or a child.The prevalence of carbapenem-resistant E.cloacae was the highest in the E.cloacae isolates from ICU patients.Conclusions The results of the CHINET Antimicrobial Resistance Surveillance Program indicate that the proportion of Enterobacter strains in all clinical isolates fluctuates slightly over the 7-year period from 2015 to 2021.The Enterobacter strains showed increasing resistance to multiple antimicrobial drugs,especially carbapenems over the 7-year period.