Beyond inhibition against the PD-1/PD-L1 pathway: development of PD-L1 inhibitors targeting internalization and degradation of PD-L1.

Tumor cells hijack the programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway to suppress the immune response through overexpressing PD-L1 to interact with PD-1 of T cells. With in-depth ongoing research, tumor-intrinsic PD-L1 is found to play important roles in tumor progression without interaction with PD-1 expressed on T cells, which provides an additional important target and therapeutic approach for development of PD-L1 inhibitors. Existing monoclonal antibody (mAb) drugs against the PD-1/PD-L1 pathway generally behave by conformationally blocking the interactions of PD-1 with PD-L1 on the cell surface. Beyond general inhibition of the protein-protein interaction (PPI), inhibitors targeting PD-L1 currently focus on the functional inhibition of the interaction between PD-1/PD-L1 and degradation of tumor-intrinsic PD-L1. This perspective will clarify the evolution of PD-L1 inhibitors and provide insights into the current development of PD-L1 inhibitors, especially targeting internalization and degradation of PD-L1.

Diabetic kidney disease as an independent predictor of long-term adverse outcomes in patients with coronary artery disease and diabetic mellitus.

Background: Diabetic kidney disease (DKD) had been proposed as a contributor in the pathogenesis of coronary artery disease (CAD). However, the relationship of DKD and the long-term adverse outcomes in patients with CAD after percutaneous coronary intervention (PCI) was still undiscovered. Methods: Approximately 892 patients with CAD enrolled from January 2012 to December 2016. The patients were divided into two groups, the DKD group (n = 341) and the None DKD group (n = 551). The primary outcome was major adverse cardiac events (MACE) after PCI. The average follow-up time was 1,897 ± 1,276 days. Results: Baseline data showed that some factors were significantly different between the two groups, including age, body mass index, gender (female), hypertension, smoking, stroke history, heart failure, duration of diabetic mellitus (DM), low-density lipoprotein cholesterol, urinary protein/creatinine ratio, serum creatinine, hemoglobin, platelet, antiplatelet, beta blocker, statin, antihypertensive drugs, and insulin (all p < 0.005). There were significant differences between the two groups in MACE, 40.3% vs. 52.2% (p = 0.001), and in cardiovascular death events and all-cause death events (5.6% vs. 20.5%, p < 0.001 and 4.4% vs. 13.5%, p < 0.001, respectively). In the DKD group, the risk of MACE was elevated to 141.9% [hazard ratio (HR) = 1.419, 95% confidence interval (CI): 1.164-1.730, p = 0.001] in the Cox univariable regression analyses; after adjusting co-variables, the Cox multivariable regression analyses demonstrated that DKD was an independent predictor for MACE (HR = 1.291, 95% CI: 1.027-1.624, p = 0.029) in patients with CAD after PCI, as well as in cardiovascular death events (HR = 2.148, 95% CI: 1.292-3.572, p = 0.003) and all-cause death events (HR = 2.229, 95% CI: 1.325-3.749, p = 0.003). Conclusion: This study suggests that DKD is an independent and novel predictor of long-term adverse outcomes in patients with CAD and DM who underwent PCI.

Extracellular vesicles in atherosclerosis and vascular calcification: the versatile non-coding RNAs from endothelial cells and vascular smooth muscle cells.

Atherosclerosis (AS) is characterized by the accumulation of lipids, fibrous elements, and calcification in the innermost layers of arteries. Vascular calcification (VC), the deposition of calcium and phosphate within the arterial wall, is an important characteristic of AS natural history. However, medial arterial calcification (MAC) differs from intimal calcification and cannot simply be explained as the consequence of AS. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) are directly involved in AS and VC processes. Understanding the communication between ECs and VSMCs is critical in revealing mechanisms underlying AS and VC. Extracellular vesicles (EVs) are found as intercellular messengers in kinds of physiological processes and pathological progression. Non-coding RNAs (ncRNAs) encapsulated in EVs are involved in AS and VC, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). The effects of ncRNAs have not been comprehensively understood, especially encapsulated in EVs. Some ncRNAs have demonstrated significant roles in AS and VC, but it remains unclear the functions of the majority ncRNAs detected in EVs. In this review, we summarize ncRNAs encapsulated in EC-EVs and VSMC-EVs, and the signaling pathways that are involved in AS and VC.

Systemic immune-inflammation index as a prognostic marker for advanced chronic heart failure with renal dysfunction.

AIMS: We aim to investigate the correlation between high levels of the systemic immune-inflammation index (SII) and long-term mortality and major cardiovascular adverse events in advanced chronic heart failure patients with renal dysfunction. METHODS AND RESULTS: Seven hundred seventeen advanced chronic heart failure patients with renal dysfunction, who visited the First affiliated hospital of Zhengzhou University from September 2019 to December 2020, were included. All-cause mortalities (ACM) were selected as primary endpoints and major cardiovascular adverse events (MACEs) as the secondary endpoints. Based on the receiver operating characteristic (ROC) curve and the Youden index, the optimal cut-off values of SII for ACM and MACEs were 1228 and 1406. In the group where ACM were the primary endpoint, patients were categorized into the low-SII group (n = 479) and the high-SII group (n = 238). Patients in the group using MACEs as the secondary endpoint were also categorized into the low-SII groups (n = 514) and the high-SII groups (n = 203). Univariate and multivariate COX regression were used to screen the independent predictors for ACM and MACEs, revealing the relationship between SII levels and endpoints. According to the univariate COX analysis, SII was the risk factor (hazard ratio [HR] = 2.144, 95% confidence interval [CI]: 1.565-2.938, P < 0.001) for the ACM subgroup. It was also the risk factor (HR = 1.625, CI: 1.261-2.905, P < 0.001) for the MACEs subgroup. Multivariate COX regression analysis indicated that the occurrence of ACM and MACEs in high-level SII and low-level SII patients had statistical differences. The incidence of ACM increased by 70.3% (HR = 1.703; 95% CI: 1.200-2.337; P = 0.002) in patients of the high SII level group, the incidence of MACEs increased by 58.3% (HR = 1.583, 95% CI: 1.213-2.065, P = 0.001). Kaplan-Meier (K-M) survival analysis further suggested that patients with a high SII level had an increased risk of having ACM (log-rank P < 0.001) and MACEs (log-rank P < 0.001) within 30 months. SII could be considered as a novel predictor of the occurrence of ACM and MACEs for patients with advanced chronic heart failure and renal dysfunction. CONCLUSIONS: This study suggested that SII is a novel independent predictor of mortality in advanced chronic heart failure patients with renal dysfunction, and it should be considered in current clinical management.

The hemoglobin glycation index predicts the risk of adverse cardiovascular events in coronary heart disease patients with type 2 diabetes mellitus.

Background: Previous studies have shown that the hemoglobin glycation index (HGI) can be used as a predictor of diabetic complications. However, limited information is currently available to indicate the correlation between HGI and comorbidity of coronary heart disease (CHD) and diabetes. This study aimed to evaluate the potential of HGI to predict major adverse cardiovascular events (MACEs) in CHD patients with type 2 diabetes mellitus (T2DM) undergoing percutaneous coronary intervention (PCI). Materials and methods: A total of 918 CHD patients with T2DM were enrolled in a 3-year retrospective cohort study, from December 2017 to December 2020 at the First Affiliated Hospital of Zhengzhou University. Data including fasting blood glucose (FPG/FBG) and glycated hemoglobin A1c (HbA1c) were collected. HGI was calculated as actual measured HbA1c minus predicted HbA1c. Three groups were further divided based on the levels of HGI, including low, medium, and high levels. Result: Kaplan Meier analysis indicated that elevated HGI was strongly associated with the occurence of MACE (log-rank P < 0.001). Multivariate Cox regression analysis revealed that elevated HGI was an independent risk factor for incident MACE in CHD patients with T2DM [adjusted hazard ratio (HR): 1.473; 95% confidence interval (CI): 1.365-1.589, P < 0.001]. Conclusions: Hemoglobin glycation index is an independent predictor of MACE events in CHD patients with T2DM. High HGI indicates a higher risk of MACE occurrence.

Combination of TyG Index and GRACE Risk Score as Long-Term Prognostic Marker in Patients with ACS Complicated with T2DM Undergoing PCI.

Objective: We aimed to investigate the prognostic value of the triglyceride-glucose (TyG) index combined the with Global Registry of Acute Coronary Events (GRACE) score in adult acute coronary syndrome (ACS) patients with type 2 diabetes mellitus (T2DM) who underwent percutaneous coronary intervention (PCI). Methods: The study enrolled total 899 ACS patients with T2DM who underwent PCI. TyG index and the GRACE risk score were calculated and assessed by median. The correlation was analyzed by Spearman's rank correlation coefficient. The cumulative major adverse cardiovascular event (MACE) curve was generated using the Kaplan-Meier method. Multivariate Cox regression was used to identify predictors of MACEs. Additionally, the receiver operating characteristic curve (ROC), net reclassification index (NRI) and Integrated Discrimination Improvement (IDI) were applied to analyze the performance of each single factor index and combined multivariate index in predicting MACE. Results: In the ACS patients with T2DM after PCI, there were significant differences in the TyG index and GRACE risk score between the MACE group and the MACE-free group (P < 0.001). Kaplan-Meier analysis showed that the TyG index combined with the GRACE risk score was positively correlated with the occurrence of MACEs (log rank P < 0.001). Multivariate Cox regression analyses showed that the TyG index, the GRACE risk score, and the TyG index combined with the GRACE risk score were independent predictors of long-term MACEs (adjusted HR: 1.805; 95% CI: 1.479-2.203, P < 0.001; adjusted HR: 1.012; 95% CI: 1.009-1.016, P < 0.001; and adjusted HR: 2.337; 95% CI: 1.805-3.025, P < 0.001, respectively). Correlation analysis indicated that the TyG index was positively correlated with the GRACE risk score (R = 0.140, P < 0.001). The analysis of AUC, NRI and IDI revealed that the combined multivariate index performed better prognostic role than each single factor index in predicting the occurrence of MACE. Conclusion: Both the GRACE risk score and the TyG index could be significant and independent predictors of clinical outcomes in ACS patients with T2DM after PCI. A combination of them could be enhanced predictions of clinical outcomes in these patients.