2023年 · 第136卷第20期

Osteosarcoma (OS) is the most common primary malignant bone tumor that more commonly occurs in children and adolescents. The most commonly used treatment for OS is surgery combined with chemotherapy, but the treatment outcomes are typically unsatisfactory. High rates of metastasis and post-treatment recurrence rates are major challenges in the treatment of OS. This underlines the need for studying the in-depth characterization of the pathogenetic mechanisms of OS and development of more effective therapeutic modalities. Previous studies have demonstrated the important role of the bone microenvironment and the regulation of signaling pathways in the occurrence and development of OS. In this review, we discussed the available evidence pertaining to the mechanisms of OS development and identified therapeutic targets for OS. We also summarized the available treatment modalities for OS and identified future priorities for therapeutics research.

Background: Hypertensive heart disease (HHD) poses a public health challenge, but data on its burden and trends among older adults are scarce. This study aimed to identify trends in the burden of HHD among older adults between 1990 and 2019 at the global, regional, and national levels. Methods: Using the Global Burden of Diseases study 2019 data, we assessed HHD prevalence, death, and disability-adjusted life-year (DALY) rates for individuals aged 60-89 years at the global, regional, and national levels and estimated their average annual percentage changes (AAPCs) between 1990 and 2019 using joinpoint regression analysis. Results: In 2019, there were 14.35 million HHD prevalent cases, 0.85 million deaths, and 14.56 million DALYs in older adults. Between 1990 and 2019, the prevalence of HHD increased globally {AAPC, 0.38 (95% confidence interval [CI], 0.36, 0.41)} with decreases observed in mortality (AAPC, - 0.83 [95% CI, - 0.99, - 0.66]) and the DALY rate (AAPC, - 1.03 [95% CI, - 1.19, - 0.87]). This overall global trend pattern was essentially maintained for sex, age group, and sociodemographic index (SDI) quintile except for non-significant changes in the prevalence of HHD in those aged 70-74 years and in the middle SDI quintile. Notably, males had a higher HHD prevalence rate. However, HHD-related mortality and the DALY rate were higher in females. The middle SDI quintile experienced the largest decreases in mortality and the DALY rate, with a non-significant decline in prevalence between 1990 and 2019. There were significant discrepancies in the HHD burden and its trends across regions and countries. Conclusions: In the past three decades, there has been an overall increasing trend in the prevalence of HHD among older adults worldwide despite decreasing trends in mortality and the DALY rate. Better management of hypertension, and prevention and control of HHD are needed in older adults.

Background: Understanding the changing profiles of cardiovascular disease (CVD) and modifiable risk factors is essential for CVD prevention and control. We aimed to report the comprehensive trends in CVD and risk factors in China from 1990 to 2019. Methods: Data on the incidence, death, and disability-adjusted life years (DALYs) of total CVD and its 11 subtypes for China were obtained from the Global Burden of Disease Study 2019. The CVD burden attributable to 12 risk factors was also retrieved. A secondary analysis was conducted to summarize the leading causes of CVD burden and attributable risk factors. Results: From 1990 to 2019, the number of CVD incidence, death, and DALYs considerably increased by 132.8%, 89.1%, and 52.6%, respectively. Stroke, ischemic heart disease, and hypertensive heart disease accounted for over 95.0% of CVD deaths in 2019 and remained the top three causes during the past 30 years. Between 1990 and 2019, the age-standardized rate of stroke decreased significantly (percentage of decreased incidence: -9.3%; death: -39.8%; DALYs: -41.6%), while the rate of ischemic heart disease increased (percentage of increased incidence: 11.5%; death: 17.6%; DALYs: 2.2%). High systolic blood pressure, unhealthy diet, tobacco, and air pollution continued to be the major contributors to CVD deaths and DALYs (attributing to over 70% of the CVD burden), and the high body mass index (BMI)-associated CVD burden had the largest increase between 1990 and 2019. Conclusions: The significant increases in the number of CVD incident cases, deaths, and DALYs suggest that the CVD burden is still a concern. Intensified strategies and policies are needed to maintain promising progress in stroke and to reduce the escalating burden of ischemic heart disease. The CVD burden attributable to risk factors has not yet made adequate achievements; even worse, high BMI has contributed to the increasing CVD burden.

Background: Atherosclerosis-related diseases represent significant health issues among adults globally. Despite their widespread impact, comprehensive data concerning the global and national burden and trends of these diseases remain sparse. Our objective is to examine the trends in the burden of atherosclerosis among adults from 1990 to 2019 at both global and national levels. Methods: We reported the average annual percentage changes (AAPCs) in prevalence, incidence, mortality, and disability-adjusted life years (DALYs) of atherosclerosis-related diseases (ischemic heart disease [IHD], ischemic stroke, and peripheral arterial disease [PAD]) at the global and national levels among individuals based on a trend analysis of the Global Burden of Diseases Study (GBD) 2019. We further analyzed these global trends as a function of age, gender, and the social development index. We also used joinpoint regression analysis to identify the year with the most substantial changes in global trends. Results: Globally, the AAPC of IHD incidence rose from 1990 to 2019 (0.20; 95% confidence interval [CI], 0.12-0.28), with substantial surges in 1995, 2001, 2005, 2010, and 2017. Conversely, AAPC of IHD mortality rates exhibited a different trend until a rise in 2014. The AAPC of incidence rates of ischemic stroke and PAD also escalated during the same period, with respective 0.43 (95% CI, 0.39-0.48) and 0.13 (95% CI, 0.06-0.21). For ischemic stroke, both incidence and mortality soared in 2014, while PAD incidence declined in 1994 and 1998, then sharply climbed in 2016. Nationally, the Northern Mariana Islands experienced the steepest increase in IHD and PAD incidence and mortality between 1990 and 2019. China saw a significant rise in ischemic stroke incidence, whereas the highest mortality rate increase occurred in Timor-Leste. By sociodemographic index (SDI) quintile, low-middle-, middle-, and high-middle-SDI countries all showed upward trends in IHD, ischemic stroke, and PAD incidence. Simultaneously, IHD and ischemic stroke mortality rates, as well as DALYs, dropped in the low-, high-middle-, and high-SDI nations. However, PAD mortality rates and DALYs saw an uptick across all SDI quintiles. Regarding age demographics, a global decrease in the AAPC IHD incidence as noted in individuals above 55 years old, in contrast to an increase in the 20-55 age group during this period. AAPC of mortality rates for IHD, ischemic stroke, and PAD decreased across all ages. The AAPC showed an increase in IHD incidence in both genders. Conversely, IHD’s DALYs saw a reduction in both males and females. Ischemic stroke patterns mirrored these trends, whereas all measures for PAD exhibited growth for both sexes. Conclusions: From 1990 to 2019, there was an overall increasing trend in the global incidence of all three clinical manifestations of atherosclerosis. Between 1990 and 2019, both the mortality rate and DALYs for IHD and ischemic stroke declined across all age groups. Overall, the burden of atherosclerosis-related diseases has not significantly decreased and even shows signs of trending upward. These findings strongly suggest that despite some progress made, efforts to control atherosclerosis diseases globally need to be intensified.

Background: The age, biomarkers, and clinical history (ABC)-atrial fibrillation (AF)-Stroke score have been proposed to refine stroke risk stratification, beyond what clinical risk scores such as the CHA2DS2-VASc score can offer. This study aimed to identify risk factors associated with thromboembolism and evaluate the performance of the ABC-AF-Stroke score in predicting thromboembolism in non-anticoagulated AF patients following successful ablations. Methods: A total of 2692 patients who underwent successful ablations with discontinued anticoagulation after a 3-month blanking period in the Chinese Atrial Fibrillation Registry (CAFR) between 2013 and 2019 were included. Cox regression analysis was conducted to present the association of risk factors with thromboembolism risk. The ABC-AF-Stroke score was evaluated in terms of discrimination, including concordance index (C-index), net reclassification improvement (NRI) and integrated discrimination improvement (IDI), clinical utilization by decision curve analysis (DCA), and calibration by comparing the predicted risk with the observed annualized event rate. Results: After a median follow-up of 3.5 years, 64 patients experienced thromboembolism events. Age, prior history of stroke/transient ischemic attack (TIA), high-sensitivity cardiac troponin T (cTnT-hs), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were independently associated with thromboembolism risk. The ABC-AF-Stroke score performed statistically significantly better than the CHA2DS2-VASc score in terms of C-index (0.67, 95% confidence interval [CI]: 0.59–0.74 vs. 0.60, 95% CI: 0.52–0.67, P = 0.030) and reclassification capacity. The DCA implied that the ABC-AF-Stroke score could identify more thromboembolism events without increasing the false positive rate compared to the CHA2DS2-VASc score. The calibration curve showed that the ABC-AF-Stroke score was well calibrated in this population. Conclusions: In this real-world study enrolling non-anticoagulated AF patients following successful ablations, age, prior history of stroke/TIA, level of NT-proBNP, and cTnT-hs were independently associated with an increased risk of thromboembolism. The ABC-AF-Stroke score was well-calibrated and statistically significantly outperformed the CHA2DS2-VASc score in predicting thromboembolism risk.

Background: We have recently developed a new Coronary Artery Tree description and Lesion EvaluaTion (CatLet) angiographic scoring system. Our preliminary studies have demonstrated its superiority over the the Synergy between percutaneous coronary intervention (PCI) with Taxus and Cardiac Surgery (SYNTAX) score with respect to outcome predictions for acute myocardial infarction (AMI) patients. The current study hypothesized that the residual CatLet (rCatLet) score predicts clinical outcomes for AMI patients and that a combination with the three clinical variables (CVs)—age, creatinine, and ejection fraction, will enhance its predicting values. Methods: The rCatLet score was calculated retrospectively in 308 consecutively enrolled patients with AMI. Primary endpoint, major adverse cardiac or cerebrovascular events (MACCE) including all-cause mortality, non-fatal AMI, transient ischemic attack/stroke, and ischemia-driven repeat revascularization, was stratified according to rCatLet score tertiles: rCatLet_low ≤3, rCatLet_mid 4-11, and rCatLet_top ≥12, respectively. Cross-validation confirmed a reasonably good agreement between the observed and predicted risks. Results: Of 308 patients analyzed, the rates of MACCE, all-cause death, and cardiac death were 20.8%, 18.2%, and 15.3%, respectively. Kaplan-Meier curves for all endpoints showed increasing outcome events with the increasing tertiles of the rCatLet score, with P values <0.001 on trend test. For MACCE, all-cause death, and cardiac death, the area under the curves (AUCs) of the rCatLet score were 0.70 (95% confidence intervals [CI]: 0.63-0.78), 0.69 (95% CI: 0.61-0.77), and 0.71 (95% CI: 0.63-0.79), respectively; the AUCs of the CVs-adjusted rCatLet score models were 0.83 (95% CI: 0.78-0.89), 0.87 (95% CI: 0.82-0.92), and 0.89 (95% CI: 0.84-0.94), respectively. The performance of CVs-adjusted rCatLet score was significantly better than the stand-alone rCatLet score in terms of outcome predictions. Conclusion: The rCatLet score has a predicting value for clinical outcomes for AMI patients and the incorporation of the three CVs into the rCatLet score will enhance its predicting ability. Trial Registration: http://www.chictr.org.cn, ChiCTR-POC-17013536.

Background: The hemoglobin glycation index (HGI) was developed to quantify glucose metabolism and individual differences and proved to be a robust measure of individual glycosylated hemoglobin (HbA1c) bias. Here, we aimed to explore the relationship between different HGIs and the risk of 5-year major adverse cardiovascular events (MACEs) by performing a large multicenter cohort study in China. Methods: A total of 9791 subjects from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: a Longitudinal Study (the REACTION study) were divided into five subgroups (Q1-Q5) with the HGI quantiles (≤5th, >5th and ≤33.3th, >33.3th and ≤66.7th, >66.7th and ≤95th, and >95th percentile). A multivariate logistic regression model constructed by the restricted cubic spline method was used to evaluate the relationship between the HGI and the 5-year MACE risk. Subgroup analysis between the HGI and covariates were explored to detect differences among the five subgroups. Results: The total 5-year MACE rate in the nationwide cohort was 6.87% (673/9791). Restricted cubic spline analysis suggested a U-shaped correlation between the HGI values and MACE risk after adjustment for cardiovascular risk factors (χ2 = 29.5, P <0.001). After adjustment for potential confounders, subjects with HGIs ≤-0.75 or >0.82 showed odds ratios (ORs) for MACE of 1.471 (95% confidence interval [CI], 1.027-2.069) and 2.222 (95% CI, 1.641-3.026) compared to subjects with HGIs of >-0.75 and ≤-0.20. In the subgroup with non-coronary heart disease, the risk of MACE was significantly higher in subjects with HGIs ≤-0.75 (OR, 1.540 [1.039-2.234]; P = 0.027) and >0.82 (OR, 2.022 [1.392-2.890]; P <0.001) compared to those with HGIs of ≤-0.75 or >0.82 after adjustment for potential confounders. Conclusions: We found a U-shaped correlation between the HGI values and the risk of 5-year MACE. Both low and high HGIs were associated with an increased risk of MACE. Therefore, the HGI may predict the 5-year MACE risk.

Background: Several studies have reported that polygenic risk scores (PRSs) can enhance risk prediction of coronary artery disease (CAD) in European populations. However, research on this topic is far from sufficient in non-European countries, including China. We aimed to evaluate the potential of PRS for predicting CAD for primary prevention in the Chinese population. Methods: Participants with genome-wide genotypic data from the China Kadoorie Biobank were divided into training (n = 28,490) and testing sets (n = 72,150). Ten previously developed PRSs were evaluated, and new ones were developed using clumping and thresholding or LDpred method. The PRS showing the strongest association with CAD in the training set was selected to further evaluate its effects on improving the traditional CAD risk-prediction model in the testing set. Genetic risk was computed by summing the product of the weights and allele dosages across genome-wide single-nucleotide polymorphisms. Prediction of the 10-year first CAD events was assessed using hazard ratios (HRs) and measures of model discrimination, calibration, and net reclassification improvement (NRI). Hard CAD (nonfatal I21-I23 and fatal I20-I25) and soft CAD (all fatal or nonfatal I20-I25) were analyzed separately. Results: In the testing set, 1214 hard and 7201 soft CAD cases were documented during a mean follow-up of 11.2 years. The HR per standard deviation of the optimal PRS was 1.26 (95% CI:1.19-1.33) for hard CAD. Based on a traditional CAD risk prediction model containing only non-laboratory-based information, the addition of PRS for hard CAD increased Harrell’s C index by 0.001 (-0.001 to 0.003) in women and 0.003 (0.001 to 0.005) in men. Among the different high-risk thresholds ranging from 1% to 10%, the highest categorical NRI was 3.2% (95% CI: 0.4-6.0%) at a high-risk threshold of 10.0% in women. The association of the PRS with soft CAD was much weaker than with hard CAD, leading to minimal or no improvement in the soft CAD model. Conclusions: In this Chinese population sample, the current PRSs minimally changed risk discrimination and offered little improvement in risk stratification for soft CAD. Therefore, this may not be suitable for promoting genetic screening in the general Chinese population to improve CAD risk prediction.

Background: Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) are the main causes of restenosis (RS) in diabetic lower extremity arterial disease (LEAD). However, the relevant pathogenic mechanisms are poorly understood. Methods: In this study, we introduced a "two-step injury protocol" rat RS model, which started with the induction of atherosclerosis (AS) and was followed by percutaneous transluminal angioplasty (PTA). Hematoxylin-eosin (HE) staining and immunohistochemistry staining were used to verify the form of RS. Two-step transfection was performed, with the first transfection of Lin28a followed by a second transfection of let-7c and let-7g, to explore the possible mechanism by which Lin28a exerted effects. 5-ethynyl-2′-deoxyuridine (EdU) and Transwell assay were performed to evaluate the ability of proliferation and migration of VSMCs. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to detect the expression of Lin28a protein and let-7 family members. Results: Using a combination of in vitro and in vivo experiments, we discovered that let-7c, let-7g, and microRNA98 (miR98) were downstream targets of Lin28a. More importantly, decreased expression of let-7c/let-7g increased Lin28a, leading to further inhibition of let-7c/let-7g. We also found an increased level of let-7d in the RS pathological condition, suggesting that it may function as a protective regulator of the Lin28a/let-7 loop by inhibiting the proliferation and migration of VSMCs. Conclusion: These findings indicated the presence of a double-negative feedback loop consisting of Lin28a and let-7c/let-7g, which may be responsible for the vicious behavior of VSMCs in RS.

Background: Sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) is a key protein that maintains myocardial Ca2+ homeostasis. The present study aimed to investigate the mechanism underlying the SERCA2a-SUMOylation (small ubiquitin-like modifier) process after ischemia/reperfusion injury (I/RI) in vitro and in vivo. Methods: Calcium transient and systolic/diastolic function of cardiomyocytes isolated from Serca2a knockout (KO) and wildtype mice with I/RI were compared. SUMO-relevant protein expression and localization were detected by quantitative real-time PCR (RT-qPCR), Western blotting, and immunofluorescence in vitro and in vivo. Serca2a-SUMOylation, infarct size, and cardiac function of Senp1 or Senp2 overexpressed/suppressed adenovirus infected cardiomyocytes, were detected by immunoprecipitation, triphenyltetrazolium chloride (TTC)-Evans blue staining, and echocardiography respectively. Results: The results showed that the changes of Fura-2 fluorescence intensity and contraction amplitude of cardiomyocytes decreased in the I/RI groups and were further reduced in the Serca2a KO + I/RI groups. Senp1 and Senp2 messenger ribose nucleic acid (mRNA) and protein expression levels in vivo and in cardiomyocytes were highest at 6 h and declined at 12 h after I/RI. However, the highest levels in HL-1 cells were recorded at 12 h. Senp2 expression increased in the cytoplasm, unlike that of Senp1. Inhibition of Senp2 protein reversed the I/RI-induced Serca2a-SUMOylation decline, reduced the infarction area, and improved cardiac function, while inhibition of Senp1 protein could not restore the above indicators. Conclusion: I/RI activated Senp1 and Senp2 protein expression, which promoted Serca2a-deSUMOylation, while inhibition of Senp2 expression reversed Serca2a-SUMOylation and improved cardiac function.