PD-1/PD-L1 and coronary heart disease: a mendelian randomization study.

Introduction: It has been found that programmed cell death protein-1 (PD-1) or its ligand PD-L1 may play an important role in the onset and progression of coronary heart disease (CHD). Thus, we conducted this mendelian randomization analysis (MR) to estimate the causal relationship between PD-1/PD-L1 and 5 specific CHDs (chronic ischemic heart disease, acute myocardial infarction, angina pectoris, coronary atherosclerosis, and unstable angina pectoris), complemented by gene set enrichment analysis (GSEA) for further validation. Methods: Publicly available summary-level data were attained from the UK Biobank with genetic instruments obtained from the largest available, nonoverlapping genome-wide association studies (GWAS). Our analysis involved various approaches including inverse variance-weighted meta-analysis, alternative techniques like weighted median, MR-Egger, MR-multipotency residuals and outliers detection (PRESSO), along with multiple sensitivity assessments such as MR-Egger intercept test, Cochran's Q test, and leave-one-out sensitivity analysis to evaluate and exclude any anomalies. Results: Gene expression profile (GSE71226) was obtained from Gene Expression Omnibus (GEO) database for GSEA. IVW analysis showed a causal association between PD-1 and chronic ischemic heart disease (OR, 0.997; 95%CI, 0.995-0.999; P, 0.009), chronic ischemic heart disease and PD-1 (beta, -3.1; 95%CI, -6.017 to -0.183; P, 0.037), chronic ischemic heart disease and PD-L1 (beta, -3.269; 95%CI, -6.197 to -0.341; P, 0.029). No significant causal relationship was found between PD-1/PD-L1 and other 4 CHDs. The accuracy and robustness of these findings were confirmed by sensitivity tests. GSEA found that the KEGG pathway and related core genes of "PD-L1 expression and PD-1 checkpoint pathway in cancer" pathway were downregulated in CHD. Discussion: This study provided evidence of a bidirectional causal relationship between PD-1 and chronic ischemic heart disease and a protective association between chronic ischemic heart disease and PD-L1.

Long-term and short-term cardiovascular disease mortality among patients of 21 non-metastatic cancers.

INTRODUCTION: Previous studies on cardiovascular disease (CVD) death risk in cancer patients mostly focused on overall cancer, age subgroups and single cancers. OBJECTIVES: To assess the CVD death risk in non-metastatic cancer patients at 21 cancer sites. METHODS: A total of 1,672,561 non-metastatic cancer patients from Surveillance, Epidemiology, and End Results (SEER) datebase (1975-2018) were included in this population-based study, with a median follow-up of 12·7 years. The risk of CVD deaths was assessed using proportions, competing-risk regression, absolute excess risks (AERs), and standardized mortality ratios (SMRs). RESULTS: In patients with localized cancers, the proportion of CVD death and cumulative mortality from CVD in the high-competing risk group (14 of 21 unique cancers) surpassed that of primary neoplasm after cancer diagnosis. The SMRs and AERs of CVD were found higher in patients with non-metastatic cancer than the general US population (SMR 1·96 [95 %CI, 1·95-1·97]-19·85[95 %CI, 16·69-23·44]; AER 5·77-210·48), heart disease (SMR 1·94[95 %CI, 1·93-1·95]-19·25[95 %CI, 15·76-23·29]; AER 4·36-159·10) and cerebrovascular disease (SMR 2·05[95 %CI, 2·02-2·08]-24·71[95 %CI, 16·28-35·96]; AER 1·01-37·44) deaths. In the high-competing risk group, CVD-related SMR in patients with localized stage cancer increased with survival time but followed a reverse-dipper pattern in the low-competing risk group (7 of 21 cancers). The high-competing risk group had higher CVD-related death risks than the low-competing risk group. CONCLUSION: The CVD death risk in patients with non-metastatic cancer varied by cancer stage, site and survival time. The risk of CVD mortality is higher in 14 out of 21 localized cancers (high-competing cancers). Targeted strategies for CVD management in non-metastatic cancer patients are needed.

Gastrodin alleviates cisplatin nephrotoxicity by inhibiting ferroptosis via the SIRT1/FOXO3A/GPX4 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Cisplatin (CP) results in acute kidney injury (AKI) and negatively affects patients' therapy and survival. The dried rhizome of Gastrodia elata Blume has been used to treat clinical kidney diseases. Gastrodin (GAS) is an active ingredient of the G. elata tuber. It is unknown whether GAS can alleviate CP-induced AKI. AIM OF THE STUDY: This study aimed to investigate whether GAS, an active ingredient of G. elata Blume, can alleviate CP-induced AKI and to explore its underlying mechanisms. MATERIALS AND METHODS: Experiments were conducted with a CP-induced AKI mouse model and an immortalized human renal tubular epithelial cell line (HK-2). Serum creatinine, Periodic acid-Schiff staining, tissue iron, glutathione, malondialdehyde, and 4-Hydroxynonenal were detected in serum and kidney samples to observe whether GAS inhibits CP-induced tubule ferroptosis. The drug target was verified by detecting the effects of GAS on sirtuin-1 (SIRT1) activity in vitro. Transcriptional regulation of glutathione peroxidase 4 (GPX4) by forkhead box O3A (FOXO3A) was verified by siRNA knockdown, overexpression, and chromatin immunoprecipitation. The effects of FOXO3A, SIRT1, and GAS on CP-induced ferroptosis were measured with propidium iodide, dihydroethidium, monobromobimane, and dipyrromethene boron difluoride staining in HK-2 cells. The relationship between GAS and the SIRT1/FOXO3A/GPX4 pathway was studied using Western blotting. RESULTS: GAS treatment inhibited CP-induced reactive oxygen species, lipid peroxidation, and tubule death in the cell and animal models. GAS activated SIRT1 in vitro. The SIRT1 inhibitor blocked the protective role of GAS in reducing lipid peroxidation in HK-2 cells. FOXO3A transcriptionally regulated GPX4 expression and inhibited CP-induced cell ferroptosis. Compared to CP-damaged mouse kidneys, GAS-treated mice demonstrated significantly increased SIRT1 and GPX4 expression levels, decreased CP-induced acetylation of FOXO3A, and inhibited lipid peroxidation and cell death. CONCLUSIONS: GAS alleviated CP-induced AKI by inhibiting ferroptosis via the SIRT1/FOXO3A/GPX4 signaling pathway. The results offer new insights into the development of new anti-AKI drugs from traditional Chinese medicine.

Cardiovascular mortality by cancer risk stratification in patients with localized prostate cancer: a SEER-based study.

Purpose: The risk of cardiovascular disease (CVD) mortality in patients with localized prostate cancer (PCa) by risk stratification remains unclear. The aim of this study was to determine the risk of CVD death in patients with localized PCa by risk stratification. Patients and methods: Population-based study of 340,806 cases in the Surveillance, Epidemiology, and End Results (SEER) database diagnosed with localized PCa between 2004 and 2016. The proportion of deaths identifies the primary cause of death, the competing risk model identifies the interaction between CVD and PCa, and the standardized mortality rate (SMR) quantifies the risk of CVD death in patients with PCa. Results: CVD-related death was the leading cause of death in patients with localized PCa, and cumulative CVD-related death also surpassed PCa almost as soon as PCa was diagnosed in the low- and intermediate-risk groups. However, in the high-risk group, CVD surpassed PCa approximately 90 months later. Patients with localized PCa have a higher risk of CVD-related death compared to the general population and the risk increases steadily with survival (SMR = 4.8, 95% CI 4.6-5.1 to SMR = 13.6, 95% CI 12.8-14.5). Conclusions: CVD-related death is a major competing risk in patients with localized PCa, and cumulative CVD mortality increases steadily with survival time and exceeds PCa in all three stratifications (low, intermediate, and high risk). Patients with localized PCa have a higher CVD-related death than the general population. Management of patients with localized PCa requires attention to both the primary cancer and CVD.

The impact of tumor characteristics on cardiovascular disease death in breast cancer patients with CT or RT: a population-based study.

Background: Previous studies focused on the impact of cardiovascular diseases (CVD) risk factors in breast cancer patients with chemotherapy (CT) or radiotherapy (RT). This study aimed to identify the impact of tumor characteristics on CVD death in these patients. Methods: Data of female breast cancer patients with CT or RT between 2004 and 2016 were included. The risk factors of CVD death were identified using Cox regression analyses. A nomogram was constructed to evaluate the predicted value of tumor characteristics, and then validated by the concordance indexes (C-index) and calibration curves. Result: A total of 28,539 patients were included with an average follow-up of 6.1 years. Tumor size > 45 mm (adjusted HR = 1.431, 95% CI = 1.116-1.836, P = 0.005), regional (adjusted HR = 1.278, 95% CI = 1.048-1.560, P = 0.015) and distant stage (adjusted HR = 2.240, 95% CI = 1.444-3.474, P < 0.001) were risk factors of CVD death for breast cancer patients with CT or RT. The prediction nomogram of tumor characteristics (tumor size and stage) on CVD survival was established. The C-index of internal and external validation were 0.780 (95% Cl = 0.751-0.809), and 0.809 (95% Cl = 0.768-0.850), respectively. The calibration curves showed consistency between the actual observation and nomogram. The risk stratification was also significant distinction (P < 0.05). Conclusion: Tumor size and stage were related to the risk of CVD death for breast cancer patients with CT or RT. The management of CVD death risk in breast cancer patients with CT or RT should focus not only on CVD risk factors but also on tumor size and stage.

Long-term risks of cardiovascular death in a population-based cohort of 1,141,675 older patients with cancer.

BACKGROUND: previous studies have focused on the risk of cardiovascular disease (CVD)-related death in individual cancers, adolescents or all cancers. OBJECTIVE: to evaluate the risk of CVD-related death in older patients with cancer. METHODS: older patients with cancer (over 65 years) of 16 cancers diagnosed between 1975 and 2018 were screened out from the Surveillance, Epidemiology and End Results program. The proportion of deaths, competing risk regression models, standardized mortality ratios (SMRs) and absolute excess risks (AERs) were used to assess the risk of CVD-related death. RESULTS: this study included 1,141,675 older patients (median follow-up: 13.5 years). Of the 16 individual cancers, the risk of CVD death exceeded primary neoplasm death in older patients with cancers of the breast, endometrium, vulva, prostate gland, penis and melanoma of the skin over time (high competing risk group). Compared to the general older population, older patients with cancer had higher SMR and AER of CVD-related death (SMR: 1.58-4.23; AER: 21.16-365.89), heart disease-related death (SMR: 1.14-4.16; AER: 16.29-301.68) and cerebrovascular disease-related death (SMR: 1.11-4.66; AER: 3.02-72.43), with the SMR trend varying with CVD-related death competing risk classifications. The risk of CVD-related death in the high-competing risk group was higher than in the low-competing risk group. CONCLUSIONS: for older patients with cancer, six of 16 individual cancers, including breast, endometrium, vulva, prostate gland, penis and melanoma of the skin was at high risk of CVD-related death. Management for long-term cardiovascular risk in older patients with cancer is needed.

Non-cancer-specific survival in patients with primary central nervous system lymphoma: A multi-center cohort study.

Objective: The study aimed to evaluate the non-cancer-specific death risk and identify the risk factors affecting the non-cancer-specific survival (NCSS) in patients with primary central nervous system lymphoma (PCNSL). Methods: This multi-center cohort study included 2497 patients with PCNSL in the Surveillance, Epidemiology and End Results (SEER) database from 2007 to 2016, with a mean follow-up of 4.54 years. The non-cancer-specific death risk in patients with PCNSL and primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) was evaluated using the proportion of deaths, standardized mortality ratio (SMR), and absolute excess risk (AER). Univariate and multivariate competing risk regression models were utilized to identify the risk factors of NCSS. Results: PCNSL was the most frequent cause of death in PCNSL patients (75.03%). Non-cancer-specific causes constituted a non-negligible portion of death (20.61%). Compared with the general population, PCNSL patients had higher risks of death from cardiovascular disease (CVD) (SMR, 2.55; AER, 77.29), Alzheimer's disease (SMR, 2.71; AER, 8.79), respiratory disease (SMR, 2.12; AER, 15.63), and other non-cancer-specific diseases (SMR, 4.12; AER, 83.12). Male sex, Black race, earlier year of diagnosis (2007-2011), being unmarried, and a lack of chemotherapy were risk factors for NCSS in patients with PCNSL and PCNS-DLBCL (all P < 0.05). Conclusion: Non-cancer-specific causes were important competing causes of death in PCNSL patients. More attention is recommended to non-cancer-specific causes of death in the management of PCNSL patients.

Psychometric evaluation of the inventory of dimensions of emerging adulthood (IDEA) in China.

Background/Objective: Emerging adulthood (EA, age range between 18 to 29 years) is an important developmental stage that is characterized by marked social and psychological changes. Currently, its developmental features are quantified by the Inventory of the Dimensions of Emerging Adulthood (IDEA) but a validated Chinese version of this questionnaire (IDEA-C) is lacking. Thus, this research, which consists of two consecutive studies, aimed to investigate the psychometric properties of the translated IDEA in a Chinese sample of emerging adults. Method: Firstly, a forward-backward translation of the IDEA-C scale was conducted. Item analysis and exploratory factor analysis were performed in Sample 1a (n = 2438), followed by structural validity test in Sample 1b (n = 2461). Concurrent validity and internal consistency were evaluated in Sample 1(n = 4899). Finally, test-retest reliability was tested in Sample 2 (n = 185). Then, the second study aimed to test the factor structure proposed by study 1 in the non-student sample (n = 2200) by confirmatory factor analysis. In addition, the second study also investigated whether the attainment of college education influenced the EA experience of non-student emerging adults in China. And the association was examined between the socioeconomic status of emerging adults and the subscales of IDEA. Results: In the college sample, the IDEA-C scale presented a four-factor structure different from the original five-factor structure (χ2(190)=1116.84, p < 0.001; CFI = 0.97; TLI = 0.96; SRMR = 0.039; RMSEA = 0.050 [90%CI=0.047-0.052]). In addition, IDEA-C exhibited good internal consistency reliability (Cronbach's alpha >0.77), test-retest reliability (r>0.49, p < 0.01) and concurrent validity. And the CFA in non-student sample also showed an adequate fit indices (χ2(158) =710.10, p < 0.001, TLI=0.93, CFI=0.94, SRMR=0.038, RMSEA=0.04 [90%CI=0.037-0.040]) and an adequate internal consistency (Cronbach's alpha >0.64) and test-retest reliability (r>0.43, p < 0.01). Conclusion: The results of the present study confirmed that the Chinese version of the IDEA is found to be valid for measuring psychological characteristics of EA in Chinese-speaking samples of emerging adults.