BACKGROUND: Knee osteoarthritis (OA) is still challenging to prevent or treat. Enhanced endoplasmic reticulum (ER) stress and increased pyroptosis in chondrocytes may be responsible for cartilage degeneration. This study aims to investigate the effect of ER stress on chondrocyte pyroptosis and the upstream regulatory mechanisms, which have rarely been reported. METHODS: The expression of the histone methyltransferase enhancer of zeste homolog 2 (EZH2), microRNA-142-3p (miR-142-3p), and high mobility group box 1 (HMGB1) and the levels of ER stress, pyroptosis, and metabolic markers in normal and OA chondrocytes were investigated by western blotting, quantitative polymerase chain reaction, immunohistochemistry, fluorescence in situ hybridization, fluorescein amidite-tyrosine-valine-alanine-aspartic acid-fluoromethyl ketone (FAM-YVAD-FMK)/Hoechst 33342/propidium iodide (PI) staining, lactate dehydrogenase (LDH) release assays, and cell viability assessments. The effects of EZH2, miR-142-3p, and HMGB1 on ER stress and pyroptosis and the hierarchical regulatory relationship between them were analyzed by chromatin immunoprecipitation, luciferase reporters, gain/loss-of-function assays, and rescue assays in interleukin (IL)-1β-induced OA chondrocytes. The mechanistic contribution of EZH2, miR-142-3p, and HMGB1 to chondrocyte ER stress and pyroptosis and therapeutic prospects were validated radiologically, histologically, and immunohistochemically in surgically induced OA rats. RESULTS: Increased EZH2 and HMGB1, decreased miR-142-3p, enhanced ER stress, and activated pyroptosis in chondrocytes were associated with OA occurrence and progression. EZH2 and HMGB1 exacerbated and miR-142-3p alleviated ER stress and pyroptosis in OA chondrocytes. EZH2 transcriptionally silenced miR-142-3p via H3K27 trimethylation, and miR-142-3p posttranscriptionally silenced HMGB1 by targeting the 3'-UTR of the HMGB1 gene. Moreover, ER stress mediated the effects of EZH2, miR-142-3p, and HMGB1 on chondrocyte pyroptosis. In vivo experiments mechanistically validated the hierarchical regulatory relationship between EZH2, miR-142-3p, and HMGB1 and their effects on chondrocyte ER stress and pyroptosis. CONCLUSIONS A novel EZH2/miR-142-3p/HMGB1 axis mediates chondrocyte pyroptosis and cartilage degeneration by regulating ER stress in OA, contributing novel mechanistic insights into OA pathogenesis and providing potential targets for future therapeutic research.
Enhancer of Zeste Homolog 2 Protein/genetics* ; Osteoarthritis, Knee/pathology* ; Chondrocytes/metabolism* ; Pyroptosis/physiology* ; HMGB1 Protein/genetics* ; MicroRNAs/metabolism* ; Endoplasmic Reticulum Stress/genetics* ; Humans ; Animals ; Rats ; Male ; Rats, Sprague-Dawley ; Middle Aged

Objective:To evaluate the epidemiological characteristics and influencing factors of out-of-hospital sudden cardiac death (SCD) in Hangzhou from 2016 to 2019.Methods:SCD events recorded by Hangzhou Emergency Center from January 1, 2016 to December 31, 2019 were reviewed. Demographic and mortality data were recorded, and the distribution patterns of SCD events in terms of date, time, and population with different characteristics were observed. Time series analysis method and a distributed lag nonlinear model based on quasi-Poisson distribution were used to explore the possible nonlinear association between ambient temperature and SCD incidence.Results:A total of 4 744 out-of-hospital sudden death events were recorded by Hangzhou Emergency Center from January 1, 2016 to December 31, 2019. After excluding non-SCD events and observed events with missing items, 3 743 SCD events were finally included in the study. The survey results showed that the incidence of out-of-hospital SCD in Hangzhou was 96.5 cases per 100 000 person-years. Most of the people who experienced SCD were aged ≥60 years. The incidence in males (2 462 cases, 66%) was significantly higher than that in females (1 281 cases, 34%), and the proportion of events occurring during the day (2 737 cases, 73%) was significantly higher than that at night (1 006 cases, 27%), mainly occurring between 7: 00 and 9: 00. High temperature was associated with an increased risk of SCD. When the average daily temperature was higher than 25.5 ℃, the risk of SCD increased with the further increase of average daily temperature.Conclusions:SCD events mainly occur in the elderly population aged ≥60 years, with a significantly higher incidence in males than in females, and more frequently during the day than at night, mainly between 7: 00 and 9: 00 in the morning. High temperature is closely related to the risk of SCD. It is particularly important to carry out targeted SCD screening and prevention for different populations and implement appropriate prevention strategies for high-risk groups of SCD in high-temperature weather.

Objective To use a physics-informed neural network(PINN)-based model to predict hemodynamics in intracranial aneurysms and address the problems of long simulation time and high computational cost in traditional computational fluid dynamics(CFD)simulations.Methods The PINN model was trained using only the computational domain coordinates and sparse velocity measurement points from CFD data of clinical patients.The predicted blood flow velocity,pressure,and wall shear stress(WSS)from the PINN model were compared with CFD simulation results.Results The proposed method was used to test and validate data from four different patients.For velocity prediction,the average mean absolute error(MAE),average mean relative error(MRE),average mean squared error(MSE)was 4.60％,6.61％,and 0.229％,respectively.For WSS prediction,the average MAE,MRE and MSE was 5.54％,8.58％,and 0.510％,respectively.The PINN model demonstrated a good generalization capability across different aneurysm models and could reduce the computation time of hemodynamics from several hours to just a few seconds.Conclusions The PINN model can effectively compensate for incomplete measurement data through physical constraints,even when boundary conditions are unknown and measurement data are sparse.It can rapidly and accurately simulate the hemodynamics of intracranial aneurysms.This method has the potential to provide effective support for clinical risk prediction in intracranial aneurysms.

Adhering to the guidance of party building is an essential requirement for comprehensively promoting the high-quality development of public hospitals.How to solve the problem of"two skins"of party building and business,further promote the deep integration of the party and business has become an important topic for the party building of public hospitals in the new era.Taking Jieyang People's Hospital as an example,this paper introduces the innovation and exploration experience on the par-ty building work round in the hospital,the working mechanism of which is"1+5+5+4"of"Party building leading,five re-sponsibility coordination,five-step linkage and four-type integration".This approach effectively promotes the deep integration and promotion of the party and business,which further lead the high-quality development of various work in the hospital.It can pro-vide reference for exploring and improving the system and mechanism of the integration of party and business,and further promote party leadership in promoting high-quality development in public hospitals.

BACKGROUND:Studies have confirmed that up-regulation of microRNA-140 expression can partially inhibit osteoarthritis-like changes in knee cartilage tissues and cells and delay the progression of osteoarthritis,suggesting that microRNA-140 is involved in the pathogenesis of osteoarthritis.OBJECTIVE:To further analyze the mechanism of microRNA-140 involvement in osteoarthritis by loading exosomes overexpressing microRNA-140 with sodium alginate/collagen hydrogel.METHODS:Lentivirus was used to infect rat bone marrow mesenchymal stem cells to overexpress microRNA-140,then exosomes were isolated and exosomes overexpressing microRNA-140 were obtained.Sodium alginate/collagen hydrogels loaded with exosomes were prepared.Thirty-two SD rats were randomly divided into four groups,with 8 rats in each group.Normal control group did not receive any treatment.The osteoarthritis model was established by injecting sodium iodoacetate into the knee cavity in the osteoarthritis group,the non-transfected exosome group and the transfected exosome group.Two weeks later,PBS was injected into the knee cavity in the osteoarthritis group.Sodium alginate/collagen hydrogel carrying non-overexpressing microRNA-140 and overexpressing microRNA-140 exosomes were injected into the knee cavity of the non-transfected exosome group and transfected exosome group.At 6 weeks after modeling,the threshold of mechanical foot withdrawal response,the concentration of inflammatory factors in synovial fluid,the expression of chondrogen-related genes,the histological changes of knee cartilage and the expression of pyroptosis related proteins were detected in rats.RESULTS AND CONCLUSION:(1)Compared with normal control group,the threshold value of mechanical stimulation foot contraction response,type Ⅱ collagen,SOX9 mRNA expression levels,and Type Ⅱ collagen immunofluorescence intensity were decreased in the osteoarthritis group(P<0.05),and proinflammatory cytokine levels were increased in synovial fluid(P<0.05).The mRNA expressions of matrix metalloproteinase 13 and a disintegrin and metalloproteinase with thrombospondin motifs-5(ADAMTS-5)were increased(P<0.05),and the protein expression levels of NLRP3,ASC,GSDMD p30,caspase-1 p20,interleukin-1β,and interleukin-18 were increased(P<0.05).Immunofluorescence intensity of GSDMD and cleaved caspase-1 was increased(P<0.05),and cartilage tissue was severely damaged.(2)Compared with osteoarthritis group,the threshold value of mechanical stimulation foot contraction response,type Ⅱ collagen,SOX9 mRNA expression levels,and type Ⅱ collagen immunofluorescence intensity in the non-transfected and transfected exosome groups were increased(P<0.05);proinflammatory cytokine levels were decreased in synovial fluid(P<0.05).The mRNA expression of matrix metalloproteinase 13 was decreased(P<0.05),and the protein expression levels of NLRP3,ASC,GSDMD p30,caspase-1 p20,interleukin-1β,and interleukin-18 were decreased(P<0.05).The immunofluorescence intensity of GSDMD and cleaved caspase-1 decreased(P<0.05),and the cartilage tissue damage was reduced(P<0.05),and the effect was stronger in the transfected exosome group.(3)These results conclude that microRNA-140 can reduce the pain response of rats with osteoarthritis by inhibiting inflammation,maintaining cartilage homeostasis,and inhibiting cartilaginous pyroptosis,thereby reducing cartilage damage and playing a therapeutic role in osteoarthritis.

Objective:To analyze the incidence and influencing factors of lymphopenia in prostate cancer patients undergoing pelvic radiotherapy.Methods:A retrospective analysis was conducted on 123 prostate cancer patients treated at the Department of Radiation Oncology, Peking University First Hospital, from November 2011 to May 2015. Radiotherapy was administered using conventional fractionated intensity-modulated radiotherapy. Blood routine, including absolute lymphocyte count (ALC), was performed on patients before radiotherapy, weekly during radiotherapy, and at the end of radiotherapy. Severe lymphopenia was defined as an ALC <500 cells/μl. Based on whether the minimum ALC during radiotherapy was lower than 500 cells/μl, the entire cohort and 55 patients (excluding those with undelineated pelvic bone marrow due to radiotherapy planning system issues) with delineated pelvic bone marrow (divided into pelvic bone marrow, iliac bone marrow, and lower pelvic bone marrow) were stratified into a severe lymphopenia group (33 cases and 16 cases, respectively) and a mild lymphopenia group (90 cases and 39 cases, respectively). Differences in clinical factors and dosimetric parameters were compared between the groups using the chi-square test (or Fisher's exact test), t-test, and Wilcoxon rank-sum test. Univariate and multivariate logistic regression analyses were performed to identify the clinical and dosimetric factors influencing severe lymphopenia. Results:All 123 prostate cancer patients experienced lymphopenia during radiotherapy, with a median minimum ALC of 0.6×10 9/L [range: (0.2-2.3)×10 9/L]. Severe lymphopenia occurred in 26.8% (33 cases) of patients. Univariate analysis of the entire cohort showed that pre-radiotherapy baseline ALC, initial neutrophil-to-lymphocyte ratio, prostate-specific antigen value, Gleason score, and pelvic radiotherapy were promoting factors for severe lymphopenia ( P<0.05). Multivariate analysis identified pre-radiotherapy baseline ALC ( OR=0.217, 95% CI: 0.072-0.650, P=0.006) and pelvic radiotherapy ( OR=23.852, 95% CI: 2.834-200.787, P=0.004) as promoting factors for severe lymphopenia. In patients with delineated pelvic bone marrow, univariate analysis showed that pelvic bone marrow V 30 Gy and V 40 Gy, iliac bone marrow V 30 Gy and V 40 Gy, lower pelvic bone marrow V 30 Gy and V 40 Gy were promoting factors for severe lymphopenia during treatment ( P<0.05). Conclusions:Lymphopenia is common in prostate cancer patients undergoing radiotherapy, with a high incidence of severe lymphopenia. Pre-radiotherapy baseline ALC, as well as pelvic, iliac, and lower pelvic bone marrow V 30 Gy and V 40 Gy, are promoting factors for severe lymphopenia during radiotherapy.

Objective:To investigate the predictive value of elevated calprotectin S100A9 (S100A9) concentration during living-donor liver transplantation (LDLT) for early acute lung injury (ALI) in children with biliary atresia.Method:A retrospective analysis was conducted on 280 pediatric patients with biliary atresia who underwent LDLT using hyperreduced left lateral segment grafts at Tianjin First Central Hospital between January 2019 and January 2021. Based on intraoperative serum S100A9 levels at 30 minutes after graft reperfusion, patients were divided into the high S100A9 group (≥9.05 μg/L, 141 cases) and the low S100A9 group (<9.05 μg/L, 139 cases). General clinical characteristics were compared between the two groups. Univariate and multivariate logistic regression analyses were performed to examine the correlation between S100A9 levels and early postoperative ALI. The predictive value of risk factors was assessed using receiver operating characteristic (ROC) curve analysis with calculation of the area under the curve (AUC) .Result:A total of 280 eligible children were included in the study, with 141 in the high S100A9 group and 139 in the low S100A9 group. The incidence of ALI was significantly higher in the high S100A9 group (31.2%) compared to the low S100A9 group (10.8%). Multivariate regression analysis identified elevated preoperative creatinine levels ( OR=1.191, 95% CI: 1.069~1.321, P=0.002), increased intraoperative S100A9 concentrations ( OR=1.426, 95% CI: 1.272~1.599, P=0.021), and higher intraoperative blood transfusion volume ( OR=0.985, 95% CI: 0.973~0.997, P=0.017) as independent risk factors for postoperative ALI in pediatric LDLT. The predictive value of intraoperative S100A9 levels for ALI was significant, with an AUC of 0.816 (95% CI: 0.758~0.874), a sensitivity of 80.5%, a specificity of 73.7%, and an optimal cutoff value of 9.49 μg/L. Furthermore, preoperative albumin and creatinine levels were found to be correlated with increased intraoperative S100A9 levels. Conclusion:Elevated intraoperative S100A9 levels, increased preoperative creatinine levels, and higher intraoperative blood transfusion volumes are independent risk factors for early ALI following pediatric LDLT. S100A9 levels have strong predictive value for ALI occurrence, highlighting the need for perioperative monitoring and intervention strategies to improve postoperative outcomes.

Objective To find the molecular mechanism underlying the effect of congenital cataract related 129th single-site mutation G129C on the thermal stability of human γC crystallin(HγC)protein structure.Methods HγC-WT and HγC-G129C were expressed and purified in vitro.The changes of intrinsic fluorescence intensity and static light scattering intensity of proteins with temperature were measured,and the temperature dependence of the folding and aggregation structures of HγC-WT and HγC-G129C was compared.Results When temperature was be-low 65 ℃,the barycentric mean of the intrinsic fluorescence of HγC-WT and HγC-G129C shifted towards a longer wavelength and the fluorescence intensity decreased with the increasing temperature,which was believed to be the evidence of unfolded protein conformation.When the temperature was higher than 65 ℃,the static light scattering intensity increased significantly with the temperature,indicating the protein aggregation upon heating.The wild-type HγC-G129C showed a stronger aggregation potency.During the thermal de-naturation process of HγC-WT and HγC-G 129C,the crossing-point temperatures were 74.5 ℃ and 55.5 ℃,respectively.HγC-WT showed higher thermal stability.Conclusions The congenital cataract-associated G129C mutation significantly weakens conforma-tional stability of γC-crystallin.

Objective:To investigate the role of calcium-binding protein S100A9 in acute lung injury induced by hepatic ischemia-reperfusion (HIR) in mice, and to explore its relationship with nuclear factor erythroid 2-related factor 2 (Nrf2).Methods:A total of 12 specific pathogen-free (SPF) male wild-type (WT) and 12 S100A9 knockout (S100A9 KO) C57BL/6J mice aged 6~8 weeks and weighing 20-25 g were randomly divided into four groups using a random number table: WT+Sham group, S100A9 KO+Sham group, WT+HIR group, and S100A9 KO+HIR group ( n=6 per group). The HIR model was established by clamping the portal vein and hepatic artery of the left and median liver lobes for 60 minutes followed by reperfusion. At 6 hours post-reperfusion, mice were anesthetized again, and blood samples were collected from the inferior vena cava. Both lungs were harvested. The lung wet-to-dry (W/D) weight ratio was measured. Hematoxylin and eosin (HE) staining was used to assess histopathological changes and calculate lung injury scores. The levels of inflammatory markers—S100A9, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) —as well as oxidative stress indicators including myeloperoxidase (MPO), reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) in serum and lung tissue were measured. Western blotting was used to assess the expression levels of nuclear and cytoplasmic Nrf2, and cytoplasmic HO-1. Results:Compared with the WT+Sham group, both the WT+HIR and S100A9 KO+HIR groups showed significantly increased lung injury scores, W/D ratio, TNF-α, IL-6, ROS, MPO, and MDA levels (all P<0.05). Compared with the WT+HIR group, the S100A9 KO+HIR group exhibited significantly reduced levels of these indicators (all P<0.05). Moreover, the S100A9 KO+HIR group showed elevated nuclear Nrf2 expression and decreased cytoplasmic Nrf2 expression, accompanied by increased expression of HO-1, Gclm, Gclc, and Nqo1 (all P<0.05). Conclusion:Upregulation of S100A9 is involved in the development of HIR-induced acute lung injury, possibly through inhibition of Nrf2 nuclear translocation.

Objective:To examine the prevalence of malnutrition and evaluate the impact of nutritional support on clinical outcomes in elderly patients diagnosed with gastric and colorectal cancer.Methods:A retrospective cohort study was conducted, analyzing elderly patients with gastrointestinal tumors who underwent surgical treatment in the general surgery department from January 2019 to June 2020.The Global Leadership Initiative on Malnutrition(GLIM)criteria were utilized to diagnose malnutrition, and the effects of malnutrition and nutritional support on clinical prognosis were investigated.Results:A total of 426 elderly hospitalized patients with gastric and colorectal tumors who underwent surgical treatment were included in this study.This cohort comprised 199 cases of gastric cancer and 227 cases of colorectal cancer, with ages ranging from 65 to 91 years(mean age: 72.05±5.99).According to the GLIM criteria, 43.7%(186/426)of the patients were diagnosed with malnutrition, of which 25.6%(109/426)were moderately malnourished and 18.1%(77/426)were severely malnourished.Among the gastric cancer patients, 73.4%(146/199)were identified as having nutritional risk, with 48.7%(97/199)being malnourished and 22.6%(45/199)experiencing severe malnutrition.In the colorectal cancer group, 63.9%(145/227)were at nutritional risk, 39.2%(89/227)were malnourished, and 14.1%(32/227)had severe malnutrition.Additionally, 60.3%(257/426)of the patients received nutritional support therapy: 25.4%(108/426)received parenteral nutrition(PN), 11.3%(48/426)received enteral nutrition(EN), 23.7%(101/426)received a combination of EN and PN, while 39.7%(169/426)did not receive any nutritional support.Regardless of the presence or degree of malnutrition, patients who received nutritional support had significantly shorter total hospital stays compared to those who did not receive nutritional support, and this difference was statistically significant( t=5.58, 3.69, 2.21, 3.03, all P<0.05). Conclusions:Providing nutritional support to malnourished patients can reduce the length of hospital stay and improve clinical outcomes.