Purpose: This study aimed to evaluate the safety and efficacy of gemcitabine and cisplatin (GP) regimen in combination with immune checkpoint inhibitor sintilimab as neoadjuvant therapy for muscle-invasive bladder cancer (MIBC) patients and the feasibility of the following selective bladder sparing surgery. Materials and Methods: Patients with histopathologically confirmed urothelial carcinoma without distant metastases (T2-4a, N ≤ 1, M0, American Joint Committee of Cancer 8th) and with adequate organ function will be enrolled. The therapeutic regimen was sintilimab 200 mg once on day 8, gemcitabine 1,000 mg/m2 and cisplatin 35 mg/m2 once on days 1 and 8, every 21 days for four cycles. The primary endpoint was pathologic complete response (pCR, pT0N0) rate. The secondary end points were ypT < 2 rate, R0 resection rate, event-free survival, and safety. Results: From May 4, 2020, to May 20, 2023, 55 patients were enrolled. Forty-six patients were evaluated for efficacy. Among the 42 patients who underwent surgery, 16 patients (38.0%) achieved pCR. Thirty-three patients (78.6%) achieved pT < 2. With a median follow-up of 15.7 months, the 1-year event-free survival was 91.3%. Notwithstanding the poor pathological baseline characteristic of a high T3-T4a proportion (39.1%), a promising bladder preservation (including 22 patients transurethral resection of bladder tumor, 5 patients partial cystectomy, and 4 surveillances) rate was achieved (67.4%). The most common grade ≥ 3 treatment-related adverse events was neutropenia (n=15, 27.3%), which was related to chemotherapy. There were no grade 3 immune-related adverse events. Conclusion Neoadjuvant GP plus sintilimab is a promising regimen for MIBC patients, with relatively high pT < 2 rate and triggering the emerging roles for the multi-disciplinary team decision-making for bladder sparing surgery.

Osteoporosis is a common bone disease， whose incidence is still on the rise， posing great challenges to patients and society. This review mainly studies the pathogenesis of osteoporosis from the aspects of oxidative stress， inflammatory response， and glucolipotoxicity-induced injury and clarifies the efficacy and mechanism of some active ingredients of traditional Chinese medicine against osteoporosis through the integration of in vitro and in vivo experiments. The experimental results suggest that some active ingredients can improve bone resorption markers and maintain bone homeostasis by modulating inflammation， oxidative stress， etc. These active ingredients regulate osteoporosis through the receptor activator of nuclear transcription factor-κB （NF-κB） ligand （RANKL） pathway， osteoprotegerin （OPG） pathway， Wnt/β-catenin pathway， NF-κB pathway， mitogen-activated protein kinase （MAPK） pathway， adenosine monophosphate （AMP）-activated protein kinase （AMPK）/mammalian target of rapamycin （mTOR） pathway， and oxidative stress pathway. This review provides ideas for the progress of the prevention and treatment of osteoporosis with the active ingredients of traditional Chinese medicine， aiming to provide new potential lead compounds and reference for the development of innovative drugs and clinical therapy for the treatment of osteoporosis.

Objective To investigate the effect and mechanisms of celecoxib on right heart function in mice with acute high-altitude hypoxia exposure.Methods Male C57BL/6J mice(7 weeks old)were housed in a hypobaric chamber simulating an altitude of 5 800 m for 2 d to establish an animal model of acute hypobaric hypoxia.①Eighteen mice were randomly assigned to plain+saline(P+S),high-altitude hypoxia exposure+saline(H+S),and high-altitude hypoxia exposure+celecoxib(H+Cel).Body weight and routine blood indicators were measured,and cardiac ultrasound examination were performed for heart rate(HR),pulmonary artery acceleration time to ejection time ratio(AT/ET),tricuspid annular plane systolic excursion(TAPSE),tricuspid annular systolic velocity(S'),and left ventricular ejection fraction(LVEF)and fractional shortening(FS).Targeted metabolomic profiling was applied to detect the cardiac arachidonic acid(AA)metabolite levels.The contents of 12,13-dihydroxy-9Z-octadecenoic acid(12,13-diHOME)in the heart,liver,brown adipose tissue,and plasma were quantified by ELISA.② Eighteen mice were randomly assigned into plain+saline(P+S),high-altitude hypoxia exposure+saline(H+S)and high-altitude hypoxia exposure+12,13-diHOME(H+di)groups.Body weight,routine blood tests,and echocardiography were performed as above.③ Thirty-two mice were randomly divided into high-altitude hypoxia exposure+saline(H+S),high-altitude hypoxia exposure+celecoxib(H+Cel),high-altitude hypoxia exposure+soluble epoxide hydrolase inhibitor(sEHI)(H+sEHI),and high-altitude hypoxia exposure+sEHI+celecoxib(H+sEHI+Cel)groups.Body weight,routine blood tests,and echocardiography were performed as above.Cardiac and plasma contents of 12,13-diHOME and epoxyeicosatrienoic acids(EETs)were measured by ELISA.Results ① Compared to the P+S group,the H+S group exhibited significantly reduction of cardiac 12,13-diHOME level(P<0.001),increased counts of white blood cells(WBC)and neutrophils(P<0.01)and decreased TAPSE,S'and AT/ET both at resting state and under stress(P<0.01,P<0.001).Compared to the H+S group,the H+Cel group exhibited significantly increase of cardiac 12,13-diHOME level(P<0.05),reduced WBC and lymphocyte counts(P<0.01,P<0.05)and improved TAPSE and S'levels at resting state and under stress(P<0.01,P<0.001).② Compared to the H+S group,the H+di group demonstrated significantly improvement of TAPSE at basal and under stress(P<0.001)and a trend towards improved TAPSE at resting state(P=0.0532),but no obvious differences was observed in WBC and neutrophil counts between the H+di group and the H+S group.③ Compared to the H+Cel group,both the H+sEHI and H+sEHI+Cel groups exhibited significantly reduction of cardiac 12,13-diHOME level(P<0.01,P<0.05)though no statistical changes in cardiac function indicators.Compared to the H+S group,WBC counts and lymphocyte were decreased,and serum EETs level was incrased in the H+Cel group,H+sEHI group and H+sEHI+Cel group(P<0.01,P<0.001).Conclusion Celecoxib can elevate cardiac level of 12,13-diHOME and improves right heart function in mice after acute high-altitude hypoxia exposure through the CYP450-sEH metabolic pathway.

Objective:To study the association between subtypes of hypertension and risk for all-cause mortality and cardio-cerebrovascular mortalities in the elderly in communities of Beijing.Methods:The data were collected from the Beijing Healthy Aging Cohort Study. The elderly in 5 urban areas (former Xicheng, former Xuanwu, Fangshan, Haidian and Tongzhou) and 4 rural areas (Yanqing, Miyun, Huairou and Daxing) in Beijing were selected as the study subjects by multi-stage stratified cluster random sampling. The baseline survey was conducted from July 2009 to September 2015. The follow-up was conducted until March 31, 2021, and a total of 6 326 participants were enrolled. Cox proportional hazard regression model was used to analyze the association of SBP, DBP, normal blood pressure, high normal blood pressure, simple systolic hypertension, simple diastolic hypertension and systolic diastolic hypertension with all-cause mortality and cardio-cerebrovascular mortality.Results:By March 31, 2021, the median follow-up time was 6.30 years, the all-cause mortality density was 201.67/10 000 person-years, and the cardio-cerebrovascular mortality density was 90.20/10 000 person-years. Multivariate Cox proportional hazard regression model analysis showed that the risk for all-cause mortality increased by 5.6% ( HR=1.056, 95% CI: 1.020-1.092), and the risk for cardio-cerebrovasculvar mortality increased by 12.5% ( HR=1.125, 95% CI: 1.071-1.182) for every 10 mmHg increase in SBP. The risk for all-cause mortality increased by 8.6% ( HR=1.086, 95% CI: 1.023-1.152), and the risk for cardio-cerebrovascular mortality increased by 19.9% ( HR=1.199, 95% CI: 1.101-1.306) for every 10 mmHg increase in DBP. Compared with the normal blood pressure group, the risk for all-cause mortality increased by 64.8% ( HR=1.648, 95% CI: 1.049-2.591) and the risk for cardio- cerebrovascular mortality increased by 112.8% ( HR=2.128, 95% CI: 1.069-4.233) in the simple diastolic hypertension group. The risk for all-cause mortality increased by 34.4% ( HR=1.344, 95% CI: 1.023-1.467) and the risk for cardio-cerebrovascular mortality increased by 111.3% ( HR=2.113, 95% CI: 1.384-3.225) in the systolic-diastolic hypertension group. Conclusions:In the elderly in communities of Beijing, beside systolic-diastolic hypertension. It is necessary to pay close attention to the simple diastolic hypertension, which has lower prevalence, and give targeted prevention and treatment.

Objective:To investigate the association of urinary albumin-to-creatinine ratio (UACR) in normal range and cardiovascular health (CVH) score with cardio-cerebroascular and all-cause mortality in urban elderly residents in Beijing.Methods:Based on Beijing Healthy Aging Cohort Study, data from 1 817 elderly participants with normal UACR were analyzed, and UACR was used as both continuous and categorical variable. "Life's Essential 8" was used to develop a CVH score. Statistical analysis was performed by using software SPSS 26.0 and R 4.2.1, including two independent samples t-test, χ2 test and non-parametric test. Multivariable Cox proportional hazard regression models stratified by CVH score and the restricted cubic spline were used to analyse the association of UACR with the risk for cardio-cerebrovascular and all-cause mortality. Results:By March 31, 2021, the median follow-up time M ( Q1, Q3) was 11.28 (10.84, 11.36) years, a total of 308 deaths were recorded during follow-up, and the mortality density was 163.87/10 000 person-years. The age of the participants was (71.4±6.6) years, and 1 070 participants were women. The results showed that the risk for both cardio-cerebrovascular disease and all-cause mortality decreased with the decrease of UACR in the low CVH score group ( HR=0.500, 95% CI: 0.341-0.734; HR=0.793, 95% CI: 0.647-0.971), and in the high CVH score group, there was a decreasing trend in the risk for cardio-cerebrovascular mortality with the decrease of UACR ( HR=0.665, 95% CI: 0.447-0.990). Compared with the participants with low CVH score and higher UACR, the risk for cardio-cerebrovascular and all-cause mortality decreased by 68.9% and 45.6%, respectively, in the participants with high CVH score and lower UACR ( HR=0.311, 95% CI: 0.131-0.739; HR=0.544, 95% CI: 0.360-0.822), and the risk for all-cause mortality decreased by 26.7% in the participants with high CVH score and higher UACR ( HR=0.733, 95% CI: 0.542-0.993). Conclusions:In urban elderly residents in Beijing, higher UACR were associated with a significantly increased risk for cardio-cerebrovascular and all-cause mortality, and in the low-CVH score group, decreased UACR was protective factor against cardio-cerebrovascular and all-cause mortality. The combined effect of cardiovascular health status and normal UACR had a greater protection against the risk for cardio-cerebrovascular and all-cause mortality.

Objective:To describe and analyze the distribution characteristics of a body shape index (ABSI) and its association with all-cause mortality in the elderly in communities of Beijing.Methods:The baseline and follow-up data of 10 423 subjects in Beijing Healthy Aging Cohort Study were used. The endpoint outcome was all-cause mortality in follow-up. The associations of ABSI, BMI and waist circumference with all-cause mortality were analyzed with a Cox proportional hazard regression model.Results:The mean follow-up time in this cohort was 6.36 years and the all-cause mortality was 15.27%. The restricted cubic spline results showed that ABSI showed a "U" association with all-cause mortality in the total population. After adjustment for confounding factors, compared with the normal ABSI group, the risk for all-cause mortality was higher in the low ABSI group ( HR=1.69, 95% CI: 1.32-2.17) and high ABSI group ( HR=1.75, 95% CI: 1.40-2.18). Compared with the normal BMI group, low BMI was associated with an increased risk for all-cause mortality ( HR=1.70, 95% CI: 1.40-2.08). Compared with the normal waist circumference group, central obesity was associated with a decreased risk for all-cause mortality ( HR=0.89, 95% CI: 0.80-0.99). The results of gender specific analysis on ABSI association with all-cause mortality were similar to that in total population, but the strength of association varied among different age groups. Cross-grouping results showed that older people with normal BMI and waist circumference and abnormal ABSI had an increased risk of all-cause mortality ( HR=1.91, 95% CI: 1.22-2.99). Conclusions:In Beijing, ABSI is correlated with the risk for all-cause mortality in the elderly population, which is more sensitive and specific than the traditional indicators (BMI and waist circumference). They can be used as one of the physical measurement indicators for all-cause mortality risk prediction in the health risk assessment and management in the elderly.

Objective:To explore the association between physical activity (PA) level and all-cause mortality in the elderly with different obesity status in Beijing.Methods:The study subjects were from the Cardiovascular and Cognitive Healthy Study in Middle-Aged and Elderly Residents of Beijing, a total of 3 746 individuals aged ≥60 years in the baseline survey between 2013 and 2015 were included in the study. Questionnaire survey and physical examination were conducted to collect the basic information of the individuals. The metabolic equivalent of the elderly was used to calculate the PA level, and an international PA questionnaire was used to determine the PA intensity. BMI, waist-to-height ratio (WHtR) and a body shape index (ABSI) were used to evaluate individuals' obesity status. The distribution of different PA levels under different obesity states was described by using bar chart and cumulative percentage bar chart. Cox proportional hazard regression model was used to analyze the correlation between the level of PA and all-cause mortality risk in different types of obesity status.Results:By December 31, 2019, the median follow-up time was 5.46 years, and the mortality density was 244.55/10 000 person-years. Compared with the individuals in high-PA intensity group, the all-cause mortality risk increased by 41% ( HR=1.41, 95% CI: 1.14-1.76) and 122% ( HR=2.22, 95% CI: 1.76-2.81), respectively, in moderate and low PA intensity groups. Compared with the individuals in high-PA intensity-high-obesity group, based on the BMI, the all-cause mortality risk increased by 85% ( HR=1.85, 95% CI: 1.08-3.16) and 250% ( HR=3.50, 95% CI: 2.01-6.10) in those in moderate-PA intensity-high-obesity group and in low-intensity-high-obesity group. Based on the WHtR, the all-cause mortality risk increased by 53% ( HR=1.53, 95% CI: 1.02-2.29) and 218% ( HR=3.18, 95% CI: 2.09-4.86), respectively, in those with moderate-PA intensity-high-obesity and those with low-PA intensity-high-obesity. According to the ABSI, the all-cause mortality risk increased by 120% in those in low-PA intensity-high-obesity group ( HR=2.20, 95% CI: 1.53-3.18). Based on any one of the indicators BMI, WHtR, or ABSI, there was no significant difference in all-cause mortality risk between high-intensity-moderate-obesity group and high-intensity-low-obesity group (all P>0.05). Conclusions:PA level is closely associated with the all-cause mortality risk in the elderly in communities of Beijing. Increasing PA level can not only reduce the all-cause mortality risk but also reduce even eliminate the excess all-cause mortality risk associated with obesity.

Objective:To analyze the association between different lipid indicators and cardio-cerebrovascular mortality in the elderly, identify a better lipid indicator for the risk for cardio-cerebrovascular mortality in the elderly in communities of Beijing.Methods:The elderly aged 60 years and above were selected from the Beijing Healthy Aging Cohort Study from July 2009 to September 2015. Remnant cholesterol (RC) was derived by calculation. The Cox proportional hazard regression models determined the HR and 95% CI incidating the associations of baseline different lipid indicators with cardio-cerebrovascular and all-cause mortality. Results:By March 31, 2021, with a mean follow-up duration of 6.88 years in the study population, a total of 492 cardio-cerebrovascular deaths and 1 056 all-cause deaths wre recorded. The HR values indicating the association between LDL-C, HDL-C, and RC were 0.87 (95% CI: 0.78-0.97), 0.46 (95% CI: 0.35-0.62), and 1.29 (95% CI: 1.14-1.45) for cardio-cerebrovascular mortality, respectively, and 0.93 (95% CI: 0.86-1.00), 0.66 (95% CI: 0.55-0.80) and 1.22 (95% CI: 1.12-1.33) for all-cause mortality. The associations of RC and HDL-C with cardio-cerebrovascular mortality were consistent regardless of hyperlipidemia in the elderly. Subgroup analyses showed that elevated RC was associated with increased risk for cardio-cerebrovascular mortality, and elevated HDL-C was associated with decreased risk for cardio-cerebrovascular mortality in the elderly in different gender, age, smoking status, drinking status, and diabetes status groups in communities of Beijing. Conclusion:RC might be a better potential lipid indicator for the risk for cardio-cerebrovascular mortality in the elderly in communities compared with traditional cholesterol indicator.

Objective:To investigate the diagnostic value of umbilical cord blood lactic acid and base excess for multi-organ dysfunction following neonatal asphyxia.Methods:A retrospective analysis was conducted on the clinical data of 244 patients at high risk for perinatal asphyxia who received treatment at Dongyang People's Hospital from January 2021 to December 2023.Based on the presence of organ dysfunction, the infants were divided into three groups: a single organ dysfunction group (Group A, n = 55), a multi-organ dysfunction group (Group B, n = 16), and a no organ dysfunction group (Group C, n = 173). Lactic acid levels and base excess values were compared among the three groups. Receiver operating characteristic curves were used to validate the predictive value of lactic acid and base excess values for organ dysfunction. Results:There were no statistically significant differences in general data among the three groups ( P > 0.05). In Group B, the lactic acid level was 15.10 (13.85, 16.83) mmol/L, and the base excess value was 9.80 (6.65, 15.18) mmol/L. In Group A, the lactic acid level was 7.70 (6.25, 11.70) mmol/L, and the base excess value was 5.70 (3.85, 9.60) mmol/L. In Group C, the lactic acid level was 6.80 (4.30, 9.00) mmol/L, and the base excess value was 4.00 (3.00, 6.50) mmol/L. The lactic acid level and base excess value in Group B were significantly higher than those in both Group A and Group C. Additionally, the lactic acid level and base excess value in Group A were significantly greater than those in Group C ( t = 2.60, 20.19, 2.95, 1.92, all P < 0.05). Receiver operating characteristic curve analysis revealed that the combined assessment of base excess value and lactic acid level was more effective than evaluating each parameter individually in predicting the presence of organ damage and multiple organ dysfunction syndrome. Additionally, the detection of base excess value was found to be superior to the measurement of lactic acid level. The areas under the curve values for the combined assessment of base excess value and lactic acid level for the presence of organ damage and multiple organ dysfunction syndrome were 0.694 and 0.856, respectively. In comparison, the AUC values for base excess value detection were 0.678 and 0.846, while the AUC values for lactic acid level measurement were 0.633 and 0.797, respectively. Conclusions:Umbilical cord blood lactic acid and base excess are correlated with organ dysfunction following neonatal asphyxia, and both parameters have clinical value in assessing organ damage.

Fucoidan(FUC)is a natural seaweed-derived drug.Previously,our experiments have shown that FUC can significantly inhibit the cell viability of human osteosarcoma 143B cells and induce cell death,but the mechanism remains unclear.Ferroptosis,a novel form of cell death,has emerged as an important target for tumor therapy.This study aims to investigate whether FUC induces ferroptosis of 143B cells and elucidate its underlying molecular mechanisms.CCK-8 and LDH assays result showed that FUC(10,100,400 μg/mL)significantly reduced cell viability of 143B cells and induced cell death.Calce-in-AM staining,FeRhoNox-1 staining,and C11 BODIPY 581/591 staining indicated that FUC obviously increased the levels of labile iron pool(LIP),Fe2+,and lipid reactive oxygen species(Lip ROS)in 143B cells.Chemical colorimetric analysis revealed that FUC markedly decreased intracellular Glutathi-one(GSH)contents.Real-time quantitative PCR showed that FUC dramatically reduced the mRNA lev-els of ferroptosis-related factors solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4),while increasing the mRNA levels of prostaglandin endoperoxide synthase 2(PTGS2)and acyl-CoA synthetase long-chain family member 4(ACSL4).Western blotting analysis demonstrated that FUC significantly reduced the protein levels of SLC7A11 and GPX4,and the ratios of p-PI3K/PI3K,p-AktSer473/Akt,and p-AktThr308/Akt,but increased the protein level of ACSL4.Immunofluorescence staining showed that FUC obviously inhibited the nuclear translocation of p-AktSer473.The ferroptosis in-hibitor ferrostatin-1(Fer-1)and iron chelator deferoxamine(DFO)remarkably suppressed cell death in-duced by FUC in 143B cells.Additionally,the PI3K/Akt pathway activator 740Y-P significantly inhibi-ted FUC-induced iron overload and lipid peroxidation in 143B cells,and restored the protein levels of SLC7A11 and GPX4.In conclusion,FUC can induce ferroptosis of 143B cells by inhibiting the PI3K/Akt signaling pathway,which may be a potential target for the prevention and treatment of osteosarcoma.