Efficacy of catheter ablation for atrial fibrillation in heart failure: a meta-analysis of randomized controlled trials.

The study aims to evaluate whether rhythm control by catheter ablation is superior to medical therapy for the patients with atrial fibrillation (AF) and heart failure (HF). The literatures were searched by using PubMed, Cochrane Library, Embase, and Web of Science databases up to 12 October 2023. The randomized controlled trials (RCTs) comparing rhythm control using catheter ablation vs. medical therapy in AF patients with HF were pooled. The primary outcomes included all-cause mortality, HF re-hospitalization, and stroke, and the secondary outcomes included left ventricular ejection fraction (LVEF), atrial tachyarrythmia recurrence, quality of life (Minnesota Living with Heart Failure Questionnaire score, MLHFQ score), 6 min walking distance (6MWD), the level of N-terminal B-type natriuretic peptide precursor (NT-proBNP), and adverse events. Nine RCTs involving in 2293 patients met the inclusion criteria. Compared with medical therapy, catheter ablation reduced all-cause mortality [10.07% (121/1201) vs. 15.26% (175/1147), risk ratio (RR):0.60, 95% confidence interval (CI): 0.48-0.74, P < 0.00001, I2 = 0%] and the rate of HF re-hospitalization (RR: 0.65, P = 0.02, 95% CI: 0.45 to 0.94, I2 = 74%), but had no obvious difference in incidence of stroke (RR: 0.67, P = 0.27, 95% CI: 0.32 to 1.38, I2 = 0%). Catheter ablation enhanced LVEF [mean difference (MD), 6.26%, P < 0.00001, I2 = 89%], reduced AT recurrence (RR: 0.37, P < 0.00001, 95% CI: 0.26 to 0.52, I2 = 89%), improved the quality of life (MLHFQ score) (MD: -6.83, P = 0.003, I2 = 67%), elevated 6MWD (MD: 15.92, P = 0.006, I2 = 76%), and diminished the level NT-proBNP (MD: -44.19, P < 0.00001, I2 = 75%), but had no significant difference in adverse events [25.81% (310/1201) vs. 30.25% (347/1147), RR: 0.81, 95% CI: 0.65-1.01, P = 0.06, I2 = 55%]. Catheter ablation as rhythm control strategy substantially enhances the survival rate, reduces HF re-hospitalization, increases the rate of sinus rhythm maintenance, improves the left ventricular function and the quality of life for AF patients with HF, and has similar safety, compared with medical therapy. The rhythm control by catheter ablation may be a better strategy for the AF patients with HF.

Correlation of oxidative stress and vascular endothelial dysfunction with hippocampal perfusion in atrial fibrillation patients with cognitive impairment.

Objectives: To evaluate the correlation of oxidative stress and vascular endothelial dysfunction with hippocampal perfusion in patients with atrial fibrillation and cognitive impairment. Methods: In total, 41 atrial fibrillation patients with cognitive impairment were compared to 45 atrial fibrillation patients without cognitive impairment. Oxidative stress, vascular endothelial dysfunction, hippocampal perfusion, and cognitive function were measured. Results: Serum level of oxidized low-density lipoprotein was significantly higher in the atrial fibrillation + cognitive impairment group than in the atrial fibrillation group. Serum levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were significantly higher, and nitric oxide was lower, in the atrial fibrillation + cognitive impairment group than in the atrial fibrillation group. The regional cerebral blood volume, mean transit time, and time to peak were significantly higher in the atrial fibrillation + cognitive impairment group than in the atrial fibrillation group. Moreover, regional cerebral blood flow was significantly lower in the atrial fibrillation + cognitive impairment group than in the atrial fibrillation group. Age, left atrial diameter, and regional cerebral blood volume were negatively correlated with the cognitive function score in the atrial fibrillation + cognitive impairment group. Serum levels of oxidized low-density lipoprotein, regional cerebral blood volume, regional cerebral blood flow, mean transit time, and time to peak were significantly correlated with cognitive impairment in atrial fibrillation patients after multivariate logistic regression analysis. Conclusion: Hippocampal perfusion and oxidative stress were significantly correlated with cognitive impairment in atrial fibrillation patients.

ERCC4: a potential regulatory factor in inflammatory bowel disease and inflammation-associated colorectal cancer.

The pathogenesis of inflammatory bowel disease (IBD) remains unclear and is associated with an increased risk of developing colitis-associated cancer (CAC). Under sustained inflammatory stimulation in the intestines, loss of early DNA damage response genes can lead to tumor formation. Many proteins are involved in the pathways of DNA damage response and play critical roles in protecting genes from various potential damages that DNA may undergo. ERCC4 is a structure-specific endonuclease that participates in the nucleotide excision repair (NER) pathway. The catalytic site of ERCC4 determines the activity of NER and is an indispensable gene in the NER pathway. ERCC4 may be involved in the imbalanced process of DNA damage and repair in IBD-related inflammation and CAC. This article primarily reviews the function of ERCC4 in the DNA repair pathway and discusses its potential role in the processes of IBD-related inflammation and carcinogenesis. Finally, we explore how this knowledge may open novel avenues for the treatment of IBD and IBD-related cancer.

Research progress of Ustekinumab in the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, recurrent gastrointestinal disorder with elusive etiology. Interleukin-12 (IL-12) and IL-23 have emerged as key proinflammatory mediators/cytokines in IBD pathogenesis. Ustekinumab (UST), targeting IL-12 and IL-23, has demonstrated promising efficacy and safety in the treatment of IBD. Recently, UST has become increasingly favored as a potential first-line treatment option. This review delineates UST's mechanism of action, its clinical applications in IBD, including the response rates, strategies for dose optimization for case of partial or lost response, and potential adverse events. This review aims to offer a comprehensive understanding of UST's role as a therapeutic option in IBD management.

Variation and disparity in awareness of atrial fibrillation in China: A national cross-sectional study.

BACKGROUND: The latest information regarding the awareness of atrial fibrillation (AF) remains limited in China. OBJECTIVES: The present study aimed to understand the variation and disparity in awareness of AF in China. METHODS: The cross-sectional study used data from the 2020 nationwide epidemiology survey on AF among adults aged 18 years or older in mainland China to assess the prevalence of AF awareness. The awareness of AF diagnostic methods and outcomes was also assessed using an interviewer-administered questionnaire. RESULTS: Of the 114,039 adults responding to the survey, 1463 (age-standardized prevalence, 55.3% (95% confidence interval [CI], 47.7-62.9%) and 10,202 (8.2%, 95%CI 5.4-10.9%) were aware of AF in participants with and without AF, respectively. Of these, 36.4% (95%CI 30.0-42.9%) and 6.3% (95%CI 3.6-9.1%) considered electrocardiogram as a method of diagnosing AF, and 30.0% (95% CI 3.2-8.2%) and 5.2% (95%CI 2.7-7.6%) considered stroke as an outcome of AF. The proportion of participants who being aware of AF varied significantly across sociodemographic and cardiovascular disease subgroups, and was almost consistently lower in rural areas than those in urban areas. Overall, lack of AF awareness was associated with rural areas, geographical region, lower education levels, and without history and had no risk factors of cardiovascular disease. CONCLUSIONS: Nearly half of adults with AF, and >90% non-AF population are unaware of AF in China, with significant variation and disparity. Focused public health initiatives are needed to improve awareness and knowledge of AF among high-risk populations.

A novel nomogram for predicting endoscopic remission in refractory Crohn's disease with ustekinumab administration.

Ustekinumab (UST) is a human IgG1 monoclonal antibody that targets to the share p40 subunit of interleukin-12(IL-12) and IL-23. Evidence has shown that UST therapy is well tolerated and effective in inducing clinical response in refractory CD(Crohn's disease) and dose escalation is effective in recapturing response in over half of the patients. However, no predictive factor has been reported to be helpful for UST treatment in clinical practice. Additionally, there were few reports about therapeutic drug monitoring (TDM) of UST administration in China due to its late launch time in Chinese market and lack of experience in clinical use. Herein, we establish and validate the first UST-trough concentrations (TCs) -related nomogram in China for predicting endoscopic remission in refractory CD to facilitate clinical decision making.

Comparison of clinical outcomes of Ibutilide-guided cardioversion and direct current synchronized cardioversion after radiofrequency ablation of persistent atrial fibrillation.

Backgroup: Ibutilide has already been used for cardioversion of persistent atrial fibrillation (PsAF) after radiofrequency catheter ablation (RFCA). The purpose of this study was to determine the effect of Ibutilide-guided cardioversion on clinical outcomes after individualized ablation of PsAF. Methods: From October 2020 to September 2021, consecutive patients with PsAF accepted for RFCA were prospectively enrolled. After individualized ablation including pulmonary vein isolation plus left atrial roof line ablation and personalized linear ablation based on left atrial low-voltage zones, patients were divided into the spontaneous conversion (SCV) group, direct current synchronized cardioversion (DCC) group and Ibutilide group according to different cardioversion types during ablation. The rates of freedom from atrial tachyarrhythmia (ATT) among the three groups were evaluated after follow-up. Results: In this study, 110 patients were enrolled, including 12 patients with SCV, 50 patients receiving DCC and 48 patients receiving Ibutilide cardioversion after individualized ablation. Among the three groups, the SCV group had shorter AF duration {12 months [interquartile range (IQR) 12-16], P = 0.042} and smaller left atrial diameter (LAD) [35 mm (IQR: 33-42), P = 0.023]. A 12-month freedom from ATT rate was 83.3% in SCV group, 69.4% in DCC group, and 79.2% in Ibutilide group, respectively (Log-rank, P = 0.745). During the follow-up [17 months (IQR: 15-19)], the rate of freedom from ATT of SCV group (83.3%), and Ibutilide group (72.9%) were both higher than that of DCC group (53.1%, P = 0.042). Moreover, Kaplan-Meier analysis showed a significantly higher sinus rhythm (SR) maintenance in Ibutilide group than in DCC group (Log-rank, P = 0.041). After adjusting for risk factors of AF recurrence, the hazard ratio for AF recurrence of the DCC group with reference to the Ibutilide group was 4.10 [95% confidence interval (CI) (1.87-8.98), P < 0.001]. Furthermore, subgroup analysis showed that freedom from ATT rate in effective Ibutilide subgroup was significantly higher than noneffective Ibutilide subgroup (Log-rank, P < 0.001). Conclusion: For the treatment of the patients with PsAF, Ibutilide-guided cardioversion after individualized RFCA may be benefit for maintenance of SR compared to conventional DCC, especially for the patients who are effective for administration of Ibutilide.

Targeted splicing therapy: new strategies for colorectal cancer.

RNA splicing is the process of forming mature mRNA, which is an essential phase necessary for gene expression and controls many aspects of cell proliferation, survival, and differentiation. Abnormal gene-splicing events are closely related to the development of tumors, and the generation of oncogenic isoform in splicing can promote tumor progression. As a main process of tumor-specific splicing variants, alternative splicing (AS) can promote tumor progression by increasing the production of oncogenic splicing isoforms and/or reducing the production of normal splicing isoforms. This is the focus of current research on the regulation of aberrant tumor splicing. So far, AS has been found to be associated with various aspects of tumor biology, including cell proliferation and invasion, resistance to apoptosis, and sensitivity to different chemotherapeutic drugs. This article will review the abnormal splicing events in colorectal cancer (CRC), especially the tumor-associated splicing variants arising from AS, aiming to offer an insight into CRC-targeted splicing therapy.

Research progress on the mechanism of cholesterol-25-hydroxylase in intestinal immunity.

Inflammatory bowel disease (IBD), a general term encompassing Crohn's disease (CD) and ulcerative colitis (UC), and other conditions, is a chronic and relapsing autoimmune disease that can occur in any part of the digestive tract. While the cause of IBD remains unclear, it is acknowledged that the disease has much to do with the dysregulation of intestinal immunity. In the intestinal immune regulatory system, Cholesterol-25-hydroxylase (CH25H) plays an important role in regulating the function of immune cells and lipid metabolism through catalyzing the oxidation of cholesterol into 25-hydroxycholesterol (25-HC). Specifically, CH25H focuses its mechanism of regulating the inflammatory response, signal transduction and cell migration on various types of immune cells by binding to relevant receptors, and the mechanism of regulating lipid metabolism and immune cell function via the transcription factor Sterol Regulator-Binding Protein. Based on this foundation, this article will review the function of CH25H in intestinal immunity, aiming to provide evidence for supporting the discovery of early diagnostic and treatment targets for IBD.

PILRA is associated with immune cells infiltration in atrial fibrillation based on bioinformatics and experiment validation.

Background and aims: inflammation plays an important role in atrial fibrillation (AF). In this study, we investigated the significance of immune cell infiltration in AF and identified the potential Hub genes involved in the regulation of immune cell infiltration in AF. Methods: we obtained AF datasets from the GEO database and analyzed them for obtaining differentially expressed genes (DEGs) by R software. Then, we performed GO, KEGG, and GSEA enrichment analyses of DEGs. The Hub genes of AF were determined by least absolute shrinkage selection operator (LASSO) regression analysis and weighted gene co-expression network analysis (WGCNA). Their validation was verified by using quantitative polymerase chain reaction (qPCR) in the AF rat model. Finally, we used a single sample GSEA (ssGSEA) to analyze immune cell infiltration and its relationship with hub genes. Results: We obtained 298 DGEs from the heatmap and found that DGEs were closely related to inflammation, immunity, and cytokine interactions by enrichment analyses. We obtained 10 co-expression modules by WGCNA. Among them, the module including CLEC4A, COTL1, EVI2B, FCER1G, GAPT, HCST, NCF2, PILRA, TLR8, and TYROBP had the highest correlation with AF. Four Hub genes (PILRA, NCF2, EVI2B, GAPT) were obtained further by LASSO analysis. The results suggested that the expression level of PILRA was significantly elevated in the rats with AF by qPCR, compared to the rats without AF. The results revealed that the infiltration of neutrophils, macrophages, monocytes, mast cells, immature B cells, myeloid-derived suppressor cell (MDSC), dendritic cell, and T cells and their partial subpopulations were closely related to AF by ssGSEA analysis, and PILRA was positively correlated with immature B cell, monocyte, macrophage, mast cell, dendritic cell, and T cells and their partial subpopulations by Spearman correlation analysis. Conclusions: PILRA was closely related to multiple types of immune cell infiltration, which may be associated with AF. PILRA may be a novel target of intervention for AF.

Quantum recurrent neural networks for sequential learning.

Quantum neural network (QNN) is one of the promising directions where the near-term noisy intermediate-scale quantum (NISQ) devices could find advantageous applications against classical resources. Recurrent neural networks are the most fundamental networks for sequential learning, but up to now there is still a lack of canonical model of quantum recurrent neural network (QRNN), which certainly restricts the research in the field of quantum deep learning. In the present work, we propose a new kind of QRNN which would be a good candidate as the canonical QRNN model, where, the quantum recurrent blocks (QRBs) are constructed in the hardware-efficient way, and the QRNN is built by stacking the QRBs in a staggered way that can greatly reduce the algorithm's requirement with regard to the coherent time of quantum devices. That is, our QRNN is much more accessible on NISQ devices. Furthermore, the performance of the present QRNN model is verified concretely using three different kinds of classical sequential data, i.e., meteorological indicators, stock price, and text categorization. The numerical experiments show that our QRNN achieves much better performance in prediction (classification) accuracy against the classical RNN and state-of-the-art QNN models for sequential learning, and can predict the changing details of temporal sequence data. The practical circuit structure and superior performance indicate that the present QRNN is a promising learning model to find quantum advantageous applications in the near term.

Glycemic variability and the risk of atrial fibrillation: a meta-analysis.

Background: Glycemic variability (GV) has been associated with vascular complications in patients with diabetes. However, the relationship between GV and risk of atrial fibrillation (AF) remains not fully determined. We therefore conducted a systematic review and meta-analysis to evaluate the above association. Methods: Medline, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure were searched for longitudinal follow-up studies comparing the incidence of AF between patients with higher versus lower GV. A random-effects model incorporating the potential heterogeneity was used to pool the results. Results: Nine cohort studies with 6,877,661 participants were included, and 36,784 (0.53%) participants developed AF during follow-up. Pooled results showed that a high GV was associated with an increased risk of AF (risk ratio [RR]: 1.20, 95% confidence interval [CI]: 1.11 to 1.30, p < 0.001, I2 = 20%). Subgroup analyses suggested consistent association between GV and AF in prospective (RR: 1.29, 95% CI: 1.05 to 1.59, p = 0.01) and retrospective studies (RR: 1.18, 95% CI: 1.08 to 1.29, p = 0.002), in diabetic (RR: 1.24, 95% CI: 1.03 to 1.50, p = 0.03) and non-diabetic subjects (RR: 1.13, 95% CI: 1.00 to 1.28, p = 0.05), in studies with short-term (RR: 1.25, 95% CI: 1.11 to 1.40, p < 0.001) and long-term GV (RR: 1.18, 95% CI: 1.05 to 1.34, p = 0.006), and in studies with different quality scores (p for subgroup difference all > 0.05). Conclusion: A high GV may predict an increased risk of AF in adult population.

Construction and integrated analysis of the ceRNA network hsa_circ_0000672/miR-516a-5p/TRAF6 and its potential function in atrial fibrillation.

Atrial fibrosis is a crucial contributor to initiation and perpetuation of atrial fibrillation (AF). This study aimed to identify a circRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) regulatory network related to atrial fibrosis in AF, especially to validate hsa_circ_0000672/hsa_miR-516a-5p/TRAF6 ceRNA axis in AF preliminarily. The circRNA-miRNA-mRNA ceRNA network associated with AF fibrosis was constructed using bioinformatic tools and literature reviews. Left atrium (LA) low voltage was used to represent LA fibrosis by using LA voltage matrix mapping. Ten controls with sinus rhythm (SR), and 20 patients with persistent AF including 12 patients with LA low voltage and 8 patients with LA normal voltage were enrolled in this study. The ceRNA regulatory network associated with atrial fibrosis was successfully constructed, which included up-regulated hsa_circ_0000672 and hsa_circ_0003916, down-regulated miR-516a-5p and five up-regulated hub genes (KRAS, SMAD2, TRAF6, MAPK11 and SMURF1). In addition, according to the results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, these hub genes were clustered in TGF-beta and MAPK signaling pathway. In the patients with persistent AF, hsa_circ_0000672 expression in peripheral blood monocytes was significantly higher than those in controls with SR by quantitative real-time polymerase chain reaction (p-value < 0.001). Furthermore, hsa_circ_0000672 expression was higher in peripheral blood monocytes of persistent AF patients with LA low voltage than those with LA normal voltage (p-value = 0.002). The dual-luciferase activity assay confirmed that hsa_circ_0000672 exerted biological functions as a sponge of miR-516a-5p to regulate expression of its target gene TRAF6. Hsa_circ_0000672 expression in peripheral blood monocytes may be associated with atrial fibrosis. The hsa_circ_0000672 may be involved in atrial fibrosis by indirectly regulating TRAF6 as a ceRNA by sponging miR-516a-5p.

The First Case of Cribriform-Morular Thyroid Carcinoma and FAP with APC Gene Mutation in China: A Case Report and Brief Review.

The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is now designated as morular cribriform thyroid carcinoma (CMTC) according to the 5th edition of the World Health Organization (WHO) Classification of Thyroid Tumors. CMTC can appear within a familial adenomatous polyposis (FAP) or be sporadic. We report the first case of a young female patient in China who was diagnosed with FAP and CMTC with a mutation in exon 16 of the APC gene underlying the disease. The main purpose of this case report is to provide a special pathological type of thyroid tumors, which is expected to be helpful for clinical work in the future.

Effects of heat shock protein 90 on complement activation in myocardial ischemia/reperfusion injury after pioglitazone preconditioning.

BACKGROUND: Heat shock protein 90 (HSP90) appears to have a pivotal function in ischemic preconditioning. Pioglitazone preconditioning (PioC) attenuates myocardial ischemia/reperfusion (I/R) injuries. OBJECTIVES: The current study aims to investigate the role of HSP90, complement C3 and C5a, and nuclear factor kappa-B (NF-κB) in PioC-induced cardioprotection. MATERIAL AND METHODS: A total of 80 rats were randomly categorized into 4 groups, as follows: sham, I/R, PioC, and PioC+HSP90 inhibitor geldanamycin (PioC+GA). The sham group rats had a thoracotomy, in which the ligature was passed by the heart with no ligation (150 min). The other 3 groups were exposed to ischemia (30 min) followed by reperfusion (2 h). In the PioC group, pioglitazone (3 mg/kg) was administered intravenously 24 h before ischemia. In the PioC+GA group, after being pretreated with pioglitazone, GA was administered (intraperitoneally, 1 mg/kg) 30 min before ischemia. Myocardial infarct sizes (ISs), apoptosis rates, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and cardiac troponin I (cTnI) serum levels were determined. The HSP90, C3, NF-κB, C5a, B-cell lymphoma-2 (Bcl-2), and Bax expression levels, as well as interleukin (IL)-1ß, IL-6, intercellular cell adhesion molecule-1 (ICAM-1), and tumor necrosis factor alpha (TNF-α) mRNA levels were measured. RESULTS: The myocardial ISs, serum CK-MB, cTnI and LDH levels, apoptosis rates, IL-1ß, IL-6, TNF-α, ICAM-1 release, as well as Bax, C5a, C3, and NF-κB protein expression were considerably lower in the PioC group than in the I/R group (p < 0.05). The Bcl-2 and HSP90 expression was higher in the PioC group than in the I/R group (p < 0.05). Geldanamycin inhibited the effects of PioC. These data strongly demonstrate that the PioC-induced is dependent upon HSP90 activity. CONCLUSIONS: The HSP90 is indispensable for PioC-mediated cardioprotection. The HSP90 attenuates I/R-induced ISs, apoptosis of cardiomyocytes and myocardial inflammation through C3, C5a and NF-κB activation inhibition.

An approach for carbon content measurement in marine sediment: Application of organic and elemental carbon analyzer.

Organic and Elemental Carbon (OEC) is widely applied in the atmospheric sciences for determining carbon content and distinguishing black carbon contents of aerosols, with an advantage that OEC-based approach can provide thermograms derived from carbonaceous material. It is potential to adopt the advantage to measure the content and composition of organic carbon (OC)% in marine sediments. Here, we utilized the OEC analyzer to measure the OC% in marine sediment based on the pyrolytic oxidation principle, and obtain the OC-derived carbon dioxide (CO2) thermograms. We examined marine sediments and reference materials to understand the stability and reproducibility of OC% measurements using our approach. The findings indicate that the OC% results (ranging from 1.44 to 1.59%, ave. 1.55 ± 0.03%, n = 64) based on this approach are accurate. In addition, CO2 concentration thermograms obtained by repeated measurements exhibit a strong reproducibility. Our approach can thus provide the concentrations of thermally-evolved CO2 with increasing heating temperature to deeply understand the reactivities of OC and the compositions in sediments. We suggest that the OEC-based OC% measurement is credible when samples preparation is well-performed (e.g., suitable sample mass and uniformly distributed loading). To sum up, we provide a means to accurately determine the OC% in marine sediments in terms of the ramped-pyrolysis principle.

Identification of a novel circRNA-miRNA-mRNA regulatory axis in hepatocellular carcinoma based on bioinformatics analysis.

In recent years, circular RNAs (circRNAs) have been found to play an essential regulatory role in hepatocellular carcinoma (HCC) through various mechanisms, particularly the endogenous competitive RNA (ceRNA) mechanism. Therefore, it is significant to explore the circRNAs in hepatoma. In this study, we constructed the ceRNA and survival network using Cytoscape. We also used R, Perl software, and multiple online databases and platforms, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), to perform overall survival, immune cell infiltration, immune checkpoints, pathway activity, and anticancer drug sensitivity analysis of the genes. Finally, the receiver operator characteristic curve (ROC) analysis was performed to identify the diagnosis value of the genes. KEGG analysis revealed the T cell receptor signaling pathway as the main enrichment pathway. A total of 29 genes related to survival and prognosis were screened out. The findings suggest that ZNF544, WDR76, ACTG1, RASSF3, E2F3, ASRGL1, and POGK are associated with multilevel immune cell infiltration. Additionally, immune checkpoint analysis screened out the ACTG1, E2F3, RASSF3, and WDR76. It was also revealed that the WDR76, E2F3, ASRGL1, and POGK mainly activated the cell cycle and DNA damage response (DDR) pathway. The results suggest that the sensitivity toward trametinib, refametinib (RDEA119), and selumetinib correlates to the expression of WDR76. ROC analysis showed that the area under the curve (AUC) of all genes in the regulatory axis was greater than 0.7. The identified hsa_circ_0000417/hsa_circ_0002688/hsa_circ_0001387--hsa-miR-199a-5p--WDR76 regulatory axis may provide new insights into the progression, clinical diagnosis, and treatment of HCC.

Exosomal HSP90 induced by remote ischemic preconditioning alleviates myocardial ischemia/reperfusion injury by inhibiting complement activation and inflammation.

BACKGROUND/AIMS: The activation of the complement system and subsequent inflammatory responses are important features of myocardial ischemia/reperfusion (I/R) injury. Exosomes are nanoscale extracellular vesicles that play a significant role in remote ischemic preconditioning (RIPC) cardioprotection. The present study aimed to test whether RIPC-induced plasma exosomes (RIPC-Exo) exert protective effects on myocardial I/R injury by inhibiting complement activation and inflammation and whether exosomal heat shock protein 90 (HSP90) mediates these effects. METHODS: Rat hearts underwent 30 min of coronary ligation followed by 2 h of reperfusion. Plasma exosomes were isolated from RIPC rats and injected into the infarcted myocardium immediately after ligation. Sixty rats were randomly divided into Sham, I/R, I/R + RIPC-Exo (50 µg/µl), and RIPC-Exo + GA (geldanamycin, 1 mg/kg, administration 30 min before ligation) groups. Cardiomyocyte apoptosis, the release of myocardial markers (LDH, cTnI and CK-MB), infarct size, the expression of HSP90, complement component (C)3, C5a, c-Jun N-terminal kinase (JNK), interleukin (IL)-1ß, tumor necrosis factor (TNF)-alpha and intercellular adhesion molecule -1 (ICAM-1) were assessed. RESULTS: RIPC-Exo treatment significantly reduced I/R-induced cardiomyocyte apoptosis, the release of myocardial markers (LDH, cTnI and CK-MB) and infarct size. These beneficial effects were accompanied by decreased C3 and C5a expression, decreased inflammatory factor levels (IL-1ß, TNF-α, and ICAM-1), decreased JNK and Bax, and increased Bcl-2 expression. Meanwhile, the expression of HSP90 in the exosomes from rat plasma increased significantly after RIPC. However, treatment with HSP90 inhibitor GA significantly reversed the cardioprotection of RIPC-Exo, as well as activated complement component, JNK signalling and inflammation, indicating that HSP90 in exosomes isolated from the RIPC was important in mediating the cardioprotective effects during I/R. CONCLUSION: Exosomal HSP90 induced by RIPC played a significant role in cardioprotection against I/R injury, and its function was in part linked to the inhibition of the complement system, JNK signalling and local and systemic inflammation, ultimately alleviating I/R-induced myocardial injury and apoptosis by the upregulation of Bcl-2 expression and the downregulation of proapoptotic Bax.

Microvesicles with mitochondrial content are increased in patients with sepsis and associated with inflammatory responses.

BACKGROUND: Endothelial activation plays an important role in sepsis-mediated inflammation, but the triggering factors have not been fully elucidated. Microvesicles carrying mitochondrial content (mitoMVs) have been implicated in several diseases and shown to induce endothelial activation. AIM: To explore whether mitoMVs constitute a subset of MVs isolated from plasma of patients with sepsis and contribute to endothelial activation. METHODS: MVs were isolated from human plasma and characterized by confocal microscopy and flow cytometry. Proinflammatory cytokines, including interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)-α, and soluble vascular cell adhesion molecule (sVCAM)-1 were detected by ELISA. Human umbilical vein endothelial cells (HUVECs) were stimulated with the circulating MVs to evaluate their effect on endothelial activation. RESULTS: MitoMVs were observed in plasma from patients with sepsis. Compared with those in healthy controls, expression of MVs, mitoMVs, proinflammatory cytokines and sVCAM-1 was increased. The number of mitoMVs was positively associated with TNF-α and sVCAM-1. In vitro, compared with MVs isolated from the plasma of healthy controls, MVs isolated from the plasma of patients with sepsis induced expression of OAS2, RSAD2, and CXCL10 in HUVECs. MitoMVs were taken up by HUVECs, and sonication of MVs significantly reduced the uptake of mitoMVs by HUVECs and expression of the above three type I IFN-dependent genes. CONCLUSION: MitoMVs are increased in the plasma of patients with sepsis, which induces elevated expression of type I IFN-dependent genes. This suggests that circulating mitoMVs activate the type I IFN signalling pathway in endothelial cells and lead to endothelial activation.

[Identify the characteristic genes of dilated cardiomyopathy and immune cell infiltration based on bioinformatics and machine learning].

Objective To identify the characteristic genes and immune infiltration in dilated cardiomyopathy (DCM) by bioinformatic analysis. Methods We identified differentially expressed genes (DEG) on two DCM gene expression data sets, and performed gene ontology (GO), disease ontology (DO), and gene set enrichment analysis (GSEA) functional enrichment to obtain potential pathways. Two machine learning algorithms including support vector machine recursive feature elimination (SVM-RFE) algorithm and Least Absolute Shrinkage and Selection Operator (LASSO) algorithm were used to determine diagnostic markers. Finally, we used the cell type analysis tool CIBERSORT for immune cell infiltration analysis. Results A total of 51 DEGs were finally identified. Thioredoxin interacting protein (TXNIP), crystallin Mu (CRYM), heat shock 70kDa protein 1-like (HSPA1L), and eukaryotic elongation factor 1A-1 (EEF1A1) were considered candidate diagnostic markers. Enrichment analysis focused on features including cardiac processes, outer membranes of mitochondria and organelles, ubiquitin-like protein ligase, natural killer cell-mediated cytotoxicity, Th1, and Th2 cell differentiation, T cell receptor signaling pathways, and Th17 cell differentiation. Immune cell infiltration found naive B cells, neutrophils, and γT cells may be involved in the pathogenesis of DCM. Besides, neutrophils, T follicular helper cells, and M1 macrophages were highly correlated with four characteristic genes. Conclusion The four characteristic genes identified by machine learning, TXNIP, CRYM, HSPA1L, and EEF1A1, show potentially close relation to DCM. At the same time, immune cell infiltration analysis can better showcase the pathophysiological process of DCM.