The ambiguity of etiology makes temporomandibular joint osteoarthritis (TMJOA) "difficult-to-treat". Emerging evidence underscores the therapeutic promise of exosomes in osteoarthritis management. Nonetheless, challenges such as low yields and insignificant efficacy of current exosome therapies necessitate significant advances. Addressing lower strontium (Sr) levels in arthritic synovial microenvironment, we studied the effect of Sr element on exosomes and miRNA selectively loading in synovial mesenchymal stem cells (SMSCs). Here, we developed an optimized system that boosts the yield of SMSC-derived exosomes (SMSC-EXOs) and improves their miRNA profiles with an elevated proportion of beneficial miRNAs, while reducing harmful ones by pretreating SMSCs with Sr. Compared to untreated SMSC-EXOs, Sr-pretreated SMSC-derived exosomes (Sr-SMSC-EXOs) demonstrated superior therapeutic efficacy by mitigating chondrocyte ferroptosis and reducing osteoclast-mediated joint pain in TMJOA. Our results illustrate Alix's crucial role in Sr-triggered miRNA loading, identifying miR-143-3p as a key anti-TMJOA exosomal component. Interestingly, this system is specifically oriented towards synovium-derived stem cells. The insight into trace element-driven, site-specific miRNA selectively loading in SMSC-EXOs proposes a promising therapeutic enhancement strategy for TMJOA.
MicroRNAs/metabolism* ; Mesenchymal Stem Cells/drug effects* ; Osteoarthritis/drug therapy* ; Exosomes/drug effects* ; Strontium/pharmacology* ; Synovial Membrane/cytology* ; Humans ; Animals ; Temporomandibular Joint Disorders/therapy* ; Temporomandibular Joint

Objective To investigate the impact of statistical uncertainty per control point(SUpCP)on dose calculation on volumetric modulated arc therapy(VMAT)for rectum cancer,and to analyze the accuracy and efficiency of calculation.Methods 19 patients with rectum cancer undergoing radiotherapy were selected.The initial VMAT plans were generated on Monaco TPS using SUpCP=3,then changed SUpCP in the dose calculation process as follow:10 SUpCPs(1～10)for each patient,and totally190 VMAT dose distributions were obtained.For plan evaluation,Dmax,Dmean,D95%,V50,homogeneity index(HI),conformity index(CI)of the planning target volume(PTV),dissymmetric variations of bladder,small intestine and femoral head,and time calculation(Time)were analyzed.Patient specific quality assurance(PSQA),dose deviation of isocenter(ΔDISO)and passing rate of three-dimensional dose distribution(γ33,γ32,γ22)between calculated and delivered radiation doses were measured.Results AsSUpC increased,Dmax and HI of PTV,Dmax of bladder were increased,but D95%and V50 of PTV,Time,γ32 and γ22 were decreased(P<0.05).Dmax and CI of PTV,Dmean of bladder,Dmax and Dmean of small intestine and femoral head,ΔDISO and γ33 showed no statistical significance(P>0.05).When ΔDISO<1%,gamma passing rate>90%for all VMAT plan.When SUpCP<6,Dmax of PTV<110%of the prescribed dose was obtained;while SUpCP>2,time for dose calculation was less than 5 min.Conclusion For VMAT plan of rectum cancer on Monaco TPS using XVMC algorithm,3%～5%of statistical uncertainty per control point for dose calculation,and 3%2 mm or 2%2 mm gamma criteria for three-dimensional dose verification is recommended.This study provides clinical application basis for precise dose calculation of VMAT plan of rectum cancer.

OBJECTIVE: To explore the genetic basis for 4 patients with globozoospermia. METHODS: Semen and blood samples were collected from the patients for the determination of sperm concentration, viability, survival rate, morphology and acrosome antigen CD46. Meanwhile, DNA was extracted for whole exome sequencing (WES), and candidate variants were validated by Sanger sequencing. RESULTS: All of the four patients were found to harbor variants of the DPY19L2 gene. Patients 1 ~ 3 had homozygous deletions of the DPY19L2 gene. Sanger sequencing confirmed that the DPY19L2 gene in patient 3 was disrupted at a recombination breakpoint area BP2, resulting in nonallelic homologous recombination and complete deletion of the DPY19L2 gene. Patients 2 and 3 respectively harbored novel homozygous deletions of exons 2 ~ 22 and exons 14 ~ 15. Patient 4 harbored heterozygous deletion of the DPY19L2 gene, in addition with a rare homozygous deletion of the 3' UTR region. CONCLUSION DPY19L2 gene variants probably underlay the globozoospermia in the four patients, which has fit an autosomal recessive pattern of inheritance and the characteristics of genomic diseases.
Male ; Humans ; Teratozoospermia/genetics* ; Homozygote ; Semen ; Sequence Deletion ; 3' Untranslated Regions ; Membrane Proteins

Objective:To explore the effect of triglyceride glucose(TyG) index, single nucleotide polymorphism of Toll-like receptor 4(TLR4) and NOD-like receptor thermal protein domain associated protein 3(NLRP3) genes, and its interaction on the risk of gout.Methods:A total of 315 male patients with gout and 499 men for health checkup at the same period were selected. General data were collected through questionnaires, and peripheral venous blood was collected for biochemical test. Three single nucleotide polymorphisms(SNPs) of NLRP3 and TLR4 were detected with multiplex ligase assay reaction, and logistic regression analysis was applied to compare the correlation between NLRP3 and TLR4 alleles and gout risk. The interaction of SNP and TyG index with gout was analyzed by generalized multi-factor dimensionality reduction(GMDR) model and logistic regression.Results:After adjusting for smoking, drinking, and other factors, the risk of gout increased by 61.1% for each standard deviation increase in TyG index. CC genotypes of rs10754558, rs10759932, and rs7525979 were high risk genotypes of gout in Han ethnicity. GMDR results showed significant differences in the interaction models of rs10754558-TyG index, rs7525979-TyG index, and rs10759932-TyG index between control group and gout group( P<0.05), suggesting an interaction between the three genotypes of SNPs selected and TyG index. Stratified analysis of the three selected SNPs and TyG index showed that after adjusting for age, smoking, and other factors, the high TyG index patients carrying C/C or C/G genotype at rs10754558 displayed an increased risk of gout compared with those carrying GG genotype and low TyG index( OR=2.127, P<0.05). Conclusion:The CC genotypes of rs10754558, rs10759932, and rs7525979 are high risk genotypes for gout in Han ethnicity. The interaction between rs10754558 and TyG index may increase the risk of gout development.

In recent years， with the increasing understanding of the genetic mechanisms of hypertrophic cardiomyopathy， novel molecular-targeted drugs Mavacamten and Aficamten are two cardiac myosin inhibitors currently approved by the FDA for the treatment of hypertrophic obstructive cardiomyopathy. Both of them have a similar mechanism of action and can selectively bind to different variable sites of cardiac myosin to inhibit cardiac myosin， thus reducing myocardial hypercontractility. Relevant clinical studies have also shown that both drugs can reduce patients’ left ventricular outflow tract pressure gradient， the levels of N-terminal pro-B-type natriuretic peptide and cardiac troponin I as cardiac markers， and improve New York Heart Association （NYHA） cardiac function class. They are safe， have mild adverse reactions， and can be tolerated by patients. Compared to Mavacamten， Aficamten， as a structurally optimized product， has a shorter half-life and fewer drug-drug interactions， which is more conducive to drug- targeted dose titration.

Objective To explore the relationship between different obesity indicators and carotid intima-media thickness(CIMT)in patients with type 2 diabetes mellitus(T2DM).Methods A total of 1762 T2DM patients who visited the Endocrinology Department of Changzhou Second People's Hospital Affiliated with Nanjing Medical University and the Integrated Traditional Chinese and Western Medicine Hospital Affiliated with Nanjing University of Traditional Chinese Medicine from January 2019 to February 2022 were enrolled in this study.They were divided into youth group(18～44 years old,n=402),middle aged group(45～59 years old,n=1032),and elderly group(≥60 years old,n=328)according to WHO age classification criteria.The influencing factors for CIMT thickening in T2DM patients were analyzed using binary logistic regression,and the evaluation of the predictive effect of different obesity indicators on CIMT thickening was evaluated by receiver operating characteristic(ROC)curves.Results The subcuta-neous fat area,visceral fat area(VFA),neck circumference(NC),BMI,WC,cardiac metabolic index(CMI),Chinese visceral fat index(CAVI),visceral fat index,triglyceride glucose index,body roundness index,lipid aggregation index,HbA1c,DBP,TC,TG,HDL-C,LDL-C were lower in the middle aged and elderly groups than in youth group(P＜0.05).Binary logistic regression showed that VFA,NC,CMI in young T2DM patients,CAVI in middle aged T2DM patients,and NC in elderly T2DM patients were influ-encing factors for CIMT thickening.ROC curve analysis showed that VFA in young T2DM patients,CAVI in middle aged T2DM patients,and NC in elderly T2DM patients had a better predictive effect on CIMT thickening,with areas under the ROC curve of 0.567,0.574,and 0.573 respectively.Conclusion VFA,CAVI,and NC have a certain predictive effect on CIMT thickening in young,middle aged,and elderly T2DM patients.

Objective:To investigate the characteristics of blood glucose fluctuation and risk factors in type 2 diabetic patients with asymptomatic hypoglycemia.Methods:From September 2018 to July 2021, 342 patients with type 2 diabete mellitus who were hospitalized in the Department of Endocrinology of Hefei Hospital Affilitated to Anhui Medical University were enrolled for a retrospective study. The mean amplitude of glycemic excursions(MAGE), coefficient of variation (CV), 24 hour mean blood glucose level (MG), and time in range (TIR) were obtained by continuous glucose monitoring (CGM). According to the results of CGM and whether the patients have hypoglycemia symptoms, they were divided into three groups: no hypoglycemia group, symptomatic hypoglycemia group, and asymptomatic hypoglycemia group. The differences in blood glucose fluctuations were compared among the three groups. Multivariate logistic regression analysis was used to evaluate the risk factors in type 2 diabete mellitus patients with asymptomatic hypoglycemia. The predictive value of MAGE for asymptomatic hypoglycemia was analyzed by receiver operating characteristic (ROC) curve.Results:Compared with the non-hypoglycemia group, the TIR in asymptomatic hypoglycemia group was higher ( Z=-2.042, P=0.041). The asymptomatic hypoglycemia group had lower MG, higher MAGE and CV compared with the other two groups(all P<0.05). Multivariate logistic regression analysis showed that urinary albumin/creatinine ratio (UACR), MAGE, and CV were the risk factors for asymptomatic hypoglycemia, while MG was the protective factor. After adjustment for other risk factors, MAGE was still associated with asymptomatic hypoglycemia ( OR=1.111, 95% CI 0.999-1.235, P=0.049). The sensitivity and specificity of MAGE in predicting asymptomatic hypoglycemia were 0.769 and 0.776, respectively. Conclusions:Patients with asymptomatic hypoglycemia present with larger TIR and MAGE. MAGE, UACR, and CV were risk factors for asymptomatic hypoglycemia. Moreover, MAGE has some predictive value for the occurrence of asymptomatic hypoglycemia.

Objective:To investigate the joint associations of smoking and insufficient physical activity with hypertension, diabetes and dyslipidemia in male adults.Methods:Based on the data from the 2017 Nanjing Chronic Diseases Risk Factors Surveillance Program, 61 098 Nanjing residents aged 18 and older was randomly recruited from 12 districts, using the multi-stage stratified cluster sampling method. Information about smoking behaviors, physical activity and chronic disease-related indicators within the first 12 months before the survey was obtained through questionnaires.Results:Among the 29 848 valid male samples, the proportions of non-smokers, current smokers and ex-smokers were 59.6%, 37.2% and 3.2%, and the proportions of those who had physically active<600 MET-min/w (insufficient physically active) and ≥600 MET-min/w (adequate physically active) were 18.8% and 82.2%, respectively. In non-smokers, current smokers and ex-smokers, the prevalence of hypertension was 24.7%, 34.0% and 43.8%, and the prevalence of diabetes was 8.8%, 12.3% and 16.5%, and the prevalence of dyslipidemia was 26.8%, 36.1% and 41.9%, respectively. Multivariate logistic regression analysis showed that current smokers had a higher risk of hypertension ( OR=1.164, 95% CI: 1.086-1.248), diabetes ( OR=1.324, 95% CI: 1.207-1.452), and dyslipidemia ( OR=1.291, 95% CI: 1.216-1.371) than non-smokers in male adults. Compared with people who had adequate physical activity, someone with insufficient physical activity had higher hypertension ( OR=1.452, 95% CI: 1.331-1.583), diabetes ( OR=1.170, 95% CI: 1.041-1.315) and dyslipidemia ( OR=1.245, 95% CI: 1.158-1.338). And current smokers with insufficient physical activity had the highest risk of hypertension ( OR=1.749, 95% CI: 1.550-1.974), diabetes ( OR=1.363, 95% CI: 1.165-1.595), and dyslipidemia ( OR=1.614, 95% CI: 1.461-1.782) in male adults. Conclusions:Smoking and insufficient physical activity are risk factors for hypertension, diabetes, and dyslipidemia. People who is characterized by smoking together with insufficient physical activity presents with increased risk on developing hypertension, diabetes, and dyslipidemia.

Tertiary lymphoid structure (TLS) is the ectopic lymphoid tissue around the chronic inflammatory site of tumor, infection diseases, autoimmunity diseases, organ transplantation and so on. TLS is regarded as the vital niche of antitumor immune response in tumor microenvironment for abundant immune cells, and is correlated with better clinical outcomes and immunotherapy response in most solid tumors. As a typical inflammation-driven cancer, hepatocellular carcinoma (HCC) is controversial with the influence of TLS on patients prognosis. In this paper, the composition, formation mechanism, recognition and clinical value of TLS in HCC were briefly reviewed.

Objective:To explore the association between different paths of diabetic progression and dyslipidemia in a Nanjing adult population.Methods:From January 2017 to June 2018, 61, 098 local residents aged ≥18 years were selected from the Chronic Disease and Risk Factor Surveillance database in Nanjing using a five-stage stratified cluster random sampling method. Data were collected through interview surveys, physical measurements, and laboratory examinations. The relationship between different rates of diabetic progression and dyslipidemia was analyzed using complex weighting and multilevel models.Results:In all, 60, 283 participants were finally enrolled in the study. The weighted proportions of normal glucose regulation, pre-diabetes, and diabetes were 71.2%, 17.9%, and 10.9%, respectively. The overall weighted prevalence, awareness, treatment, and control of dyslipidemia were 29.8%, 41.6%, 28.9%, and 22.9%, respectively. The weighted proportion of patients with dyslipidemia combined with diabetes was 52.9%. The weighted prevalence of dyslipidemia in adults with normal glucose regulation, pre-diabetes, and diabetes was 24.0%, 38.8%, and 52.9%, respectively (all P<0.001). Compared to the normal glucose regulation group, subjects with pre-diabetes ( OR = 2.04, 95% CI: 1.95-2.13) or diabetes ( OR= 3.87, 95% CI: 3.66-4.10) had possibly gradually increased risks of dyslipidemia (all P<0.001). In addition, there was an increasing trend toward awareness, treatment, and control of dyslipidemia with increasing levels of glucose (all P<0.001). The weighted awareness of dyslipidemia in adults with normal glucose regulation, pre-diabetes, and diabetes was 36.3%, 42.8%, and 56.2%, respectively; the corresponding rates of treatment and control were 23.7%, 29.2%, and 43.7%, and 20.4%, 22.6%, and 30.1%, respectively. Conclusion:Diabetes and dyslipidemia have become the main chronic diseases in the Nanjing population.