Low-intensity pulsed ultrasound improves myocardial ischaemia‒reperfusion injury via migrasome-mediated mitocytosis.

During myocardial ischaemia‒reperfusion injury (MIRI), the accumulation of damaged mitochondria could pose serious threats to the heart. The migrasomes, newly discovered mitocytosis-mediating organelles, selectively remove damaged mitochondria to provide mitochondrial quality control. Here, we utilised low-intensity pulsed ultrasound (LIPUS) on MIRI mice model and demonstrated that LIPUS reduced the infarcted area and improved cardiac dysfunction. Additionally, we found that LIPUS alleviated MIRI-induced mitochondrial dysfunction. We provided new evidence that LIPUS mechanical stimulation facilitated damaged mitochondrial excretion via migrasome-dependent mitocytosis. Inhibition the formation of migrasomes abolished the protective effect of LIPUS on MIRI. Mechanistically, LIPUS induced the formation of migrasomes by evoking the RhoA/Myosin II/F-actin pathway. Meanwhile, F-actin activated YAP nuclear translocation to transcriptionally activate the mitochondrial motor protein KIF5B and Drp1, which are indispensable for LIPUS-induced mitocytosis. These results revealed that LIPUS activates mitocytosis, a migrasome-dependent mitochondrial quality control mechanism, to protect against MIRI, underlining LIPUS as a safe and potentially non-invasive treatment for MIRI.

Independent prognostic biomarker FERMT3 associated with immune infiltration and immunotherapy response in glioma.

BACKGROUND: Adult glioma progresses rapidly and has a poor clinical outcome. The focal adhesion protein Kindlin-3 (encoded by the FERMT3 gene) participates in tumor development, drug resistance, and progression. However, the relationship between Kindlin-3 and glioma prognosis or immune microenvironment is poorly understood. METHODS: We comprehensively analyzed the expression, prognostic value, mutation landscape, functional enrichment, immune infiltration, and therapeutic role of FERMT3 in glioma using multiple datasets and validated Kindlin-3 expression in clinical tissue specimens by immunohistochemistry and multiple immunofluorescence staining. RESULTS: FERMT3 is an independent predictor of glioma prognosis and is highly expressed in glioblastoma tissues. Functional enrichment analyses indicated that FERMT3 participates in multiple immune-related pathways such as immune response and cytokine production. Furthermore, FERMT3 expression was positively correlated with the infiltration of several immune cells, immune scores, and the expression of genes related to immune checkpoints. Further analyses revealed that overexpression of FERMT3 was linked to a better response to anti-PD1 therapy. Data from single-cell RNA-seq reveal that FERMT3 was largely expressed in microglial cells and tissue-resident macrophages. Multiple immunofluorescence staining confirmed the overexpression of Kindlin-3 in the glioma-associated microglia/macrophages (GAMs). CONCLUSION: The findings of this study provide a new perspective on the role of Kindlin-3 in glioma and may have a significant impact on the discovery of novel biomarkers and targeting of GAMs in the future.

The overexpression and clinical significance of TBX15 in human gliomas.

T-box transcription factor 15 (TBX15) is upregulated in a variety of tumors and has been reported to promote uncontrolled proliferation of tumor cells and induce tumor cells to avoid apoptosis, thus accelerating the malignant transformation of malignant tumors. However, the prognostic value of TBX15 in glioma and its relationship with immune infiltration remain unknown. In this study, we intended to explore the prognostic value of TBX15 and its link to glioma immune infiltration and examine TBX15 expression in pan-cancer using RNAseq data in TPM format from TCGA and GTEx. TBX15 mRNA and protein expressions in glioma cells and adjacent normal tissue were detected and compared by RT-qPCR and Western blot. The effect of TBX15 on survival was assessed by Kaplan-Meier Method. The correlation between TBX15 upregulation and the clinicopathological characteristics of glioma patients was assessed by using TCGA databases, and the relationship between TBX15 and other genes in glioma was evaluated by using TCGA data. The top 300 genes most significantly associated with TBX15 were selected to establish a PPI network through the STRING database. The relationship between TBX15 mRNA expression and immune cell infiltration was explored by using ssGSEA and the TIMER Database. It was found that TBX15 mRNA expression in glioma tissues was significantly higher than that in the adjacent normal tissues, and this difference was most obvious in high-grade gliomas. TBX15 expression was increased in human gliomas and associated with worse clinicopathological characteristics and poorer survival prognosis in glioma patients. In addition, elevated TBX15 expression was linked to a collection of genes involved in immunosuppression. In conclusion, TBX15 played an important role in immune cell infiltration in glioma and may prove to be a predictor of the prognosis in glioma patients.

Identification of High-Risk Coronary Lesions by 3-Vessel Optical Coherence Tomography.

BACKGROUND: Optical coherence tomography (OCT) may provide a method for detecting histologically defined high-risk plaques in vivo. OBJECTIVES: The authors aimed to investigate the prognostic value of OCT for identifying patients and lesions that are at risk for adverse cardiac events. METHODS: Between January 2017 and May 2019, OCT of all the 3 main epicardial arteries was performed in 883 patients with acute myocardial infarction (MI) who were referred for primary percutaneous coronary intervention. The primary endpoint was the composite of cardiac death, nonculprit lesion-related nonfatal MI, and unplanned coronary revascularization. Patients were followed for up to 4 years (median 3.3 years). RESULTS: The 4-year cumulative rate of the primary endpoint was 7.2%. In patient-level analysis, thin-cap fibroatheroma (TCFA) (adjusted HR: 3.05; 95% CI: 1.67-5.57) and minimal lumen area (MLA) <3.5 mm2 (adjusted HR: 3.71; 95% CI: 1.22-11.34) were independent predictors of the primary endpoint. In lesion-level analysis, nonculprit lesions responsible for subsequent events were not angiographically severe at baseline (mean diameter stenosis 43.8% ± 13.4%). TCFA (adjusted HR: 8.15; 95% CI: 3.67-18.07) and MLA <3.5 mm2 (adjusted HR: 4.33; 95% CI: 1.81-10.38) were predictive of events arising from each specific lesion. TCFAs with an MLA <3.5 mm2 carried a higher risk and were sufficient for identifying patients at risk for the composite of cardiac death and nonculprit lesion-related nonfatal MI. CONCLUSIONS: OCT imaging of angiographically nonobstructive territories in patients with acute MI can aid in identifying patients and lesions at increased risk for adverse cardiac events.

Predictors of Adverse Prognosis in Patients With Acute Coronary Syndrome Caused by Plaque Erosion With a Nonstent Strategy.

Background The EROSION (Effective Anti-Thrombotic Therapy Without Stenting: Intravascular Optical Coherence Tomography-Based Management in Plaque Erosion) study demonstrated that antithrombotic therapy without stenting was safe and feasible in selected patients with acute coronary syndrome caused by plaque erosion. However, the factors related to the prognosis of these patients are not clear. This study aimed to explore the predictors of an adverse prognosis of a nonstent strategy in a larger sample size. Methods and Results A total of 252 (55 patients were from the EROSION study) patients with acute coronary syndrome with plaque erosion who met the inclusion criteria of the EROSION study and completed clinical follow-up were enrolled. Patients were divided into 2 groups according to the occurrence of major adverse cardiovascular events (MACE), which were defined as the composite of cardiac death, recurrent myocardial infarction, ischemia-driven target lesion revascularization, rehospitalization because of unstable or progressive angina, major bleeding, and stroke. Among 232 patients with acute coronary syndrome included in the final analysis, 50 patients (21.6%) developed MACE at a median follow-up of 2.9 years. Compared with patients without MACE, patients with MACE were older and had a higher degree of percentage of area stenosis (72.2%±9.4% versus 64.2%±15.7%, P<0.001) and thrombus burden (24.4%±10.4% versus 20.4%±10.9%, P=0.010) at baseline. Multivariate Cox regression analysis confirmed that age, percentage of area stenosis, and thrombus burden were predictors of MACE. The best cutoff values of predictors were age ≥60 years, percentage of area stenosis ≥63.5%, and thrombus burden ≥18.5%, respectively, and when they were all present, the rate of MACE rose to 57.7%. Conclusions The nonstent treatment strategy of patients with acute coronary syndrome caused by plaque erosion was heterogeneous, and patients aged ≥60 years, percentage of area stenosis ≥63.5%, and thrombus burden ≥18.5% may predict a worse clinical outcome.

Ferroptosis: A potential opportunity for intervention of pre-metastatic niche.

It is widely thought that the tumor microenvironment (TME) provides the "soil" for malignant tumors to survive. Prior to metastasis, the interaction at the host site between factors secreted by primary tumors, bone-marrow-derived cells, with stromal components initiates and establishes a pre-metastatic niche (PMN) characterized by immunosuppression, inflammation, angiogenesis and vascular permeability, as well as lymphangiogenesis, reprogramming and organotropism. Ferroptosis is a non-apoptotic cell death characterized by iron-dependent lipid peroxidation and metabolic constraints. Ferroptotic cancer cells release various signal molecules into the TME to either suppress or promote tumor progression. This review highlights the important role played by ferroptosis in PMN, focusing on the relationship between ferroptosis and PMN characteristics, and discusses future research directions.

Clinical Outcomes of Different Calcified Culprit Plaques in Patients with Acute Coronary Syndrome.

Background: Previous studies have found that coronary artery calcification is closely associated with the occurrence of major adverse cardiac events (MACE). This study aimed to investigate the characteristics and clinical outcomes of different calcified plaques in patients with acute coronary syndrome (ACS) by using optical coherence tomography (OCT). Methods: 258 ACS patients with calcified culprit plaques who underwent OCT-guided stent implantation were enrolled. They were divided into three subtypes based on the calcified plaque morphology, including eruptive calcified nodules, calcified protrusion, and superficial calcific sheet. Results: Compared with superficial calcific sheet and calcified protrusion, eruptive calcified nodules had the greatest calcium burden and a higher rate of stent edge dissection (p < 0.001) and incomplete stent apposition (p < 0.001). In a median follow-up period of 2 years, 39 (15.1%) patients experienced MACE (a composite event of cardiac death, target-vessel myocardial infarction, ischemia-driven revascularization), with a significantly higher incidence in the eruptive calcified nodules group (32.1% vs. 10.1% vs. 13.0%, p = 0.001). A multivariate Cox analysis demonstrated that the eruptive calcified nodules (hazard ratio 3.14; 95% confidence interval, 1.64−6.02; p = 0.001) were an independent predictor of MACE. Conclusions: MACE occurred more frequently in ACS patients with eruptive calcified nodules, and the eruptive calcified nodules were an independent predictor of MACE.

Optical Coherence Tomographic Features of Pancoronary Plaques in Patients With Acute Myocardial Infarction Caused by Layered Plaque Rupture Versus Layered Plaque Erosion.

Atherosclerotic plaque instability could occur on the basis of healed plaque which has a layered appearance on optical coherence tomography. This study aimed to investigate pancoronary plaque features of layered plaque rupture (LPR) and layered plaque erosion (LPE) in patients with acute myocardial infarction. Among 388 patients with acute myocardial infarction who underwent preintervention optical coherence tomography imaging of three coronary arteries, 190 patients with layered culprit plaque (49.0%) were identified and further divided into 2 groups: LPR group and LPE group. Clinical characteristics, pancoronary plaque features and clinical outcomes were compared between the 2 groups. Patients with LPR were older, less often male and current smoker, and had a lower coronary flow grade than those with LPE. At the culprit lesion, LPR group had a higher prevalence of lipid plaque, thin-cap fibroatheroma (TCFA), macrophage, and microchannel, and presented with more severe lumen area stenosis than LPE group. At nonculprit lesions, LPR group had a higher prevalence of TCFA and had greater layered tissue thickness and area than LPE group. The ischemia-driven revascularization rate was higher in LPR group. Moreover, we found that TCFA, diameter stenosis >56.5%, and mean lipid arc >179.1° were predictors for layered culprit plaque. In conclusion, patients with LPR had more vulnerable plaque features at culprit and nonculprit lesions and had higher incidence of ischemia-driven revascularization than those with LPE. TCFA, diameter stenosis >56.5%, and mean lipid arc >179.1° were predictors of layered culprit plaque.

Culprit and Non-Culprit Plaque Characteristics With vs. Without a Healed Phenotype in Patients With Acute Myocardial Infarction Caused by Plaque Erosion　- A 3-Vessel OCT Study.

BACKGROUND: Plaque erosion can occur quietly without causing clinical symptoms, followed by a healing process resulting in healed plaque. This study aimed to assess culprit and non-culprit plaque characteristics of patients with acute myocardial infarction (AMI) caused by plaque erosion with vs. without healed phenotype at the culprit plaque using optical coherence tomography (OCT).Methods and Results: A total of 117 AMI patients caused by plaque erosion who underwent OCT imaging of 3 coronary arteries were included. Patients were divided into 2 groups based on presence or absence of a healed phenotype at the culprit site. Culprit and non-culprit plaque characteristics were compared between the 2 groups. A healed phenotype at the culprit lesion was identified in 47.9% of AMI patients caused by plaque erosion. Patients with a healed phenotype at the culprit site were more frequently with hyperlipidemia, and had a higher prevalence of macrophage infiltration, microchannels, cholesterol crystals, and calcification at the culprit lesion. Moreover, patients with a healed phenotype at the culprit site had more non-culprit plaques and more characteristics of plaque vulnerability at the non-culprit lesion. In addition, patients with a healed phenotype at the culprit site presented with more severe luminal stenosis at both the culprit and non-culprit lesion. CONCLUSIONS: A healed phenotype was identified in 47.9% of AMI patients caused by plaque erosion at the culprit site. A healed phenotype within eroded culprit plaque was associated with signs of pancoronary vulnerability and advanced atherosclerosis.