Biomimetic-Structured Cobalt Nanocatalyst Suppresses Aortic Dissection Progression by Catalytic Antioxidation.

As one of the most lethal cardiovascular diseases, aortic dissection (AD) is initiated by overexpression of reactive oxygen species (ROS) in the aorta that damages the vascular structure and finally leads to massive hemorrhage and sudden death. Current drugs used in clinics for AD treatment fail to efficiently scavenge ROS to a large extent, presenting undesirable therapeutic effect. In this work, a nanocatalytic antioxidation concept has been proposed to elevate the therapeutic efficacy of AD by constructing a cobalt nanocatalyst with a biomimetic structure that can scavenge pathological ROS in an efficient and sustainable manner. Theoretical calculations demonstrate that the antioxidation reaction is catalyzed by the redox transition between hydroxocobalt(III) and oxo-hydroxocobalt(V) accompanied by inner-sphere proton-coupled two-electron transfer, forming a nonassociated activation catalytic cycle. The efficient antioxidation action of the biomimetic nanocatalyst in the AD region effectively alleviates oxidative stress, which further modulates the aortic inflammatory microenvironment by promoting phenotype transition of macrophages. Consequently, vascular smooth muscle cells are also protected from inflammation in the meantime, suppressing AD progression. This study provides a nanocatalytic antioxidation approach for the efficient treatment of AD and other cardiovascular diseases.

A Dual-Targeting, Multi-Faceted Biocompatible Nanodrug Optimizes the Microenvironment to Ameliorate Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disease that currently lacks effective pharmacological treatment given the complex pathophysiology of the disease. Here, single-cell RNA-sequencing data from patients with AAA and a mouse model are analyzed, which reveals pivotal pathological changes, including the M1-like polarization of macrophages and the loss of contractile function in smooth muscle cells (SMCs). Both cell types express the integrin αvß3, allowing for their dual targeting with a single rationally designed molecule. To this end, a biocompatible nanodrug, which is termed EVMS@R-HNC, that consists of the multifunctional drug everolimus (EVMS) encapsulated by the hepatitis B virus core protein modifies to contain the RGD sequence to specifically bind to integrin αvß3 is designed. Both in vitro and in vivo results show that EVMS@R-HNC can target macrophages as well as SMCs. Upon binding of the nanodrug, the EVMS is released intracellularly where it exhibits multiple functions, including inhibiting M1 macrophage polarization, thereby suppressing the self-propagating inflammatory cascade and immune microenvironment imbalance, while preserving the normal contractile function of SMCs. Collectively, these results suggest that EVMS@R-HNC presents a highly promising therapeutic approach for the management of AAA.

A biomaterial-based therapy for lower limb ischemia using Sr/Si bioactive hydrogel that inhibits skeletal muscle necrosis and enhances angiogenesis.

Muscle necrosis and angiogenesis are two major challenges in the treatment of lower-limb ischemic diseases. In this study, a triple-functional Sr/Si-containing bioceramic/alginate composite hydrogel with simultaneous bioactivity in enhancing angiogenesis, regulating inflammation, and inhibiting muscle necrosis was designed to treat lower-limb ischemic diseases. In particular, sodium alginate, calcium silicate and strontium carbonate were used to prepare injectable hydrogels, which was gelled within 10 min. More importantly, this composite hydrogel sustainedly releases bioactive Sr2+ and SiO3 2- ions within 28 days. The biological activity of the bioactive ions released from the hydrogels was verified on HUVECs, SMCs, C2C12 and Raw 264.7 cells in vitro, and the therapeutic effect of the hydrogel was confirmed using C57BL/6 mouse model of femoral artery ligation in vivo. The results showed that the composite hydrogel stimulated angiogenesis, developed new collateral capillaries, and re-established the blood supply. In addition, the bioactive hydrogel directly promoted the expression of muscle-regulating factors (MyoG and MyoD) to protect skeletal muscle from necrosis, inhibited M1 polarization, and promoted M2 polarization of macrophages to reduce inflammation, thereby protecting skeletal muscle cells and indirectly promoting vascularization. Our results indicate that these bioceramic/alginate composite bioactive hydrogels are effective biomaterials for treating hindlimb ischemia and suggest that biomaterial-based approaches may have remarkable potential in treating ischemic diseases.

Integrative analysis of platelet-related genes for the prognosis of esophageal cancer.

BACKGROUND: Every year, esophageal cancer is responsible for 509000 deaths and around 572000 new cases worldwide. Although esophageal cancer treatment options have advanced, patients still have a dismal 5-year survival rate. AIM: To investigate the relationship between genes associated to platelets and the prognosis of esophageal cancer. METHODS: We searched differentially expressed genes for changes between 151 tumor tissues and 653 normal, healthy tissues using the "limma" package. To develop a prediction model of platelet-related genes, a univariate Cox regression analysis and least absolute shrinkage and selection operator Cox regression analysis were carried out. Based on a median risk score, patients were divided into high-risk and low-risk categories. A nomogram was created to predict the 1-, 2-, and 3-year overall survival (OS) of esophageal cancer patients using four platelet-related gene signatures, TNM stages, and pathological type. Additionally, the concordance index, receiver operating characteristic curve, and calibration curve were used to validate the nomogram. RESULTS: The prognosis of esophageal cancer was associated to APOOL, EP300, PLA2G6, and VAMP7 according to univariate Cox regression analysis and least absolute shrinkage and selection operator regression analysis. Patients with esophageal cancer at high risk had substantially shorter OS than those with cancer at low risk, according to a Kaplan-Meier analysis (P < 0.05). TNM stage (hazard ratio: 2.187, 95% confidence interval: 1.242-3.852, P = 0.007) in both univariate and multivariate Cox regression and risk score were independently correlated with OS (hazard ratio: 2.451, 95% confidence interval: 1.599-3.756, P < 0.001). CONCLUSION: A survival risk score model and independent prognostic variables for esophageal cancer have been developed using APOOL, EP300, PLA2G6, and VAMP7. OS for esophageal cancer might be predicted using the nomogram based on TNM stage, pathological type, and risk score. The nomogram demonstrated strong predictive ability, as shown by the concordance index, receiver operating characteristic curve, and calibration curve.

Comparison of techniques for left subclavian artery preservation during thoracic endovascular aortic repair: A systematic review and single-arm meta-analysis of both endovascular and surgical revascularization.

Background: Currently, the optimal technique to revascularize the left subclavian artery (LSA) during thoracic endovascular aortic repair (TEVAR) remains controversial. Our study seeks to characterize early and late clinical results and to assess the advantages and disadvantages of endovascular vs. surgical strategies for the preservation of LSA. Methods: PubMed, Embase and Cochrane Library searches were conducted under the PRISMA (Preferred Reporting Items for Systematic review and Meta-Analyses) standards. Only literature published after January 1994 was included. Studies reporting on endovascular revascularization (ER), surgical revascularization (SR) for LSA preservation were included. 30-day mortality and morbidity rates, restenosis rates, and rates of early and late reintervention are measured as outcomes. Results: A total of 28 studies involving 2,759 patients were reviewed. All articles were retrospective in design. Single-arm analysis found no significant statistical differences in ER vs. SR in terms of 30-day mortality and perioperative complication rates. The mean follow-up time for the ER cohort was 12.9 months and for the SR cohort was 26.6 months, respectively. Subgroup analysis revealed a higher risk of perioperative stroke (4.2%) and endoleaks (14.2%) with the chimney technique compared to the fenestrated and single-branched stent approaches. Analysis of the double-arm studies did not yield statistically significant results. Conclusion: Both ER and SR are safe and feasible in the preservation of LSA while achieving an adequate proximal landing zone. Among ER strategies, the chimney technique may presents a greater risk of neurological complications and endoleaks, while the single-branched stent grafts demonstrate the lowest complication rate, and the fenestration method for revascularization lies in an intermediate position. Given that the data quality of the included studies were relatively not satisfactory, more randomized controlled trials (RCTs) are needed to provide convincing evidence for optimal approaches to LSA revascularization in the future.

Development and validation of an epithelial-mesenchymal transition-related gene signature for predicting prognosis.

BACKGROUND: Currently, there are many therapeutic methods for lung adenocarcinoma (LUAD), but the 5-year survival rate is still only 15% at later stages. Epithelial- mesenchymal transition (EMT) has been shown to be closely associated with local dissemination and subsequent metastasis of solid tumors. However, the role of EMT in the occurrence and development of LUAD remains unclear. AIM: To further elucidate the value of EMT-related genes in LUAD prognosis. METHODS: Univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses were applied to establish and validate a new EMT-related gene signature for predicting LUAD prognosis. The risk model was evaluated by Kaplan-Meier survival analysis, principal component analysis, and functional enrichment analysis and was used for nomogram construction. The potential structures of drugs to which LUAD is sensitive were discussed with respect to EMT-related genes in this model. RESULTS: Thirty-three differentially expressed genes related to EMT were found to be highly associated with overall survival (OS) by using univariate Cox regression analysis (log2FC ≥ 1, false discovery rate < 0.001). A prognostic signature of 7 EMT-associated genes was developed to divide patients into two risk groups by high or low risk scores. Kaplan-Meier survival analysis showed that the OS of patients in the high-risk group was significantly poorer than that of patients in the low-risk group (P < 0.05). Multivariate Cox regression analysis showed that the risk score was an independent risk factor for OS (HR > 1, P < 0.05). The results of receiver operator characteristic curve analysis suggested that the 7-gene signature had a perfect ability to predict prognosis (all area under the curves > 0.5). CONCLUSION: The EMT-associated gene signature classifier could be used as a feasible indicator for predicting OS.

Epidemiological and clinical characteristics of road traffic crashes related thoracic traumas: analysis of 5095 hospitalized chest injury patients.

BACKGROUND: Road traffic crashes related (RTCR) chest traumas remain important global public health challenge. The impact of boosting market of automobile vehicles in China during last decade on thoracic injury needs to be defined. This study aimed to review and analyze the demographic and clinical characteristics of RTCR thoracic injuries in China. METHODS: Clinical records of patients with thoracic trauma admitted to thoracic surgery department between January 2003 and June 2020 were retrospectively retrieved and reviewed. Patients' profiles and clinical characteristics were comparatively analyzed between road traffic crashes caused injury and other injury mechanisms, and in RTCR chest trauma patients before January 2011 (2003 group), and after January 2011 (2011 group), when is considered as the beginning year of Chinese household vehicle era. RESULTS: The study included 5095 thoracic trauma patients with mean age of 50.2 years, of whom 79.4% were male. Most of the patients (70.3%, n = 3583) had rib fractures. Associated injuries were present in 52.0% of the patients, of them 78.5% (n = 2080) were extremity fractures. Road traffic crashes accounted for 41.4% (n = 2108) of the injuries, most of them (98.0%) were related to motor vehicles. In comparison with other chest trauma mechanisms, RTCR chest injuries affected females and older males more frequently, with a higher incidence of rib fractures and sternum fractures, and higher injury severity scores (ISS) (all p < 0.05). Surgeries were required in 1495 (70.9%) patients of the RRTCR chest traumas, while the majority of non-RTCR thoracic injuries were managed conservatively or with tube thoracostomy (30.2%, n = 901). RTCR chest traumas caused longer hospital stay (13.0 ± 9.6 days vs. 11.8 ± 7.4 days, p = 0.001), higher ICU usage (30.7% vs. 19.6%, p = 0.001), higher rate of ventilator support (12.9% vs. 7.5%, p = 0.001), and higher mortalities (3.8% vs. 1.6%, p = 0.005) than that of non-RTRA chest injuries. For RTCR patients, when compared with 2003 group, 2011 group had similar patterns in terms of accident category, associated injury and treatment. However, 2011 group had more females (38.5% vs. 18.0%, p = 0.001) and older males (50.6 ± 9.7 vs. 47.9 ± 17.2, p = 0.001), with a higher ISS (18.3 ± 10.2 vs. 17.1 ± 8.9, p = 0.004), and fewer were managed with chest tubes (25.0% vs. 29.2%, p = 0.031). Clinical outcomes were not significantly different between the groups in terms of hospital length of stay, intensive care unit (ICU) usage, ICU length of stay, duration of ventilator hours and mortality. However, the 2011 group had more patients requiring ventilator support (14.4% vs. 10.6%, p = 0.011). CONCLUSIONS: Road traffic crashes remain to be the major etiology of thoracic injuries in China, which usually affects middle-aged males, causing rib fractures with concomitant injuries frequently occurring to other organ systems. Treatments mainly include tube thoracotomy and surgical procedures. Although the clinical characteristics and outcomes of traffic accident related chest traumas are largely unchanged in spite of the rapid increasing numbers of motor vehicles, variations in the pattern of injuries by gender, age, injury severity and ventilator usage may still provide important information for targeted management.

Correction to: SPECT/CT imaging of apoptosis in aortic aneurysm with radiolabeled duramycin.

The original version of this article unfortunately contains errors in Figure 4. An incorrect Figure 4D is published which is actually a repetition of Figure 2C (i.e., apoptosis rate in control vs. H2O2-treated group). The correct Figure 4D should be the aortic diameter of control vs. experimental groups. Also, the order of part figures (a\b\c\d) in Figure 4E is incorrect. The correct Figure 4 is given below.

SPECT/CT imaging of apoptosis in aortic aneurysm with radiolabeled duramycin.

The objective of this research was to estimate whether a [99mTc]duramycin probe can be used for apoptosis imaging in patients with aortic aneurysm (AA). Vascular smooth muscle cell (SMC) apoptosis has an important influence on AA development. Thus, non-invasive imaging of SMC apoptosis may be able to evaluate AA progress and risk stratification. SMCs were treated with hydrogen peroxide (H2O2; 200 µΜ) or culture medium as a control. Apoptosis was measured using flow cytometry and [99mTc]duramycin to detect the binding efficiency to apoptotic SMCs. C57/BL6 mice were administered angiotensin-II and beta-aminopropionitrile (BAPN) subcutaneously to establish an AA model, or saline for controls. Aortic specimens underwent pathological evaluation and their aortic diameters were measured after 6 weeks. Micro-SPECT/CT scanning of [99mTc]duramycin and 18F-FDG PET detection were performed. SMCs treated with H2O2 showed more apoptosis compared with the control group (67.2 ± 3.8% vs. 16.1 ± 0.6%, P < 0.01). The experimental group showed a high rate of AA formation (70%) compared with no AA formation in the control group. The average aorta diameter was higher and [99mTc]duramycin uptake at the AA site was higher in the experimental group compared with the control group. Compared with the normal aorta in the control group, AA in experiment group had more severe medial degeneration, elastic fiber reduction and fracture, and collagen degeneration. TUNEL staining verified the higher apoptosis rate at the AA site in experiment group compared with the control group (63.9 ± 3.7% in ascending AA, 66.4 ± 4.0% in thoracic AA, vs. 3.5 ± 0.3% in normal aorta, P < 0.01). [99mTc]Duramycin may be an effective probe to evaluate apoptosis in AA.

Molecular targets in aortic aneurysm for establishing novel management paradigms.

Aortic aneurysm (AA) is a lethal disease and presents a large challenge for surgeons in the clinic. Although surgical management remains the major choice of AA, operative mortality remains high. With advances in understanding of the mechanisms of AAs, molecular targets, such as matrix metalloproteinases (MMPs), D-dimer, and inflammation markers, including C-reactive protein, interleukins and phagocytes, are important in the pathology of development of AA. These markers may become important for improving the diagnostic quality and provide more therapeutic choices for treatment of AA. Although these new markers require long-term trials before they can be translated into the clinic, they can still be helpful in determining new directions. The main aim of this review is to discuss the current findings of molecular targets in progression of AA and discuss the potential application of these new targets for managing this disease.