Elucidating thoracic aortic dissection pathogenesis: The interplay of m1A-related gene expressions and miR-16-5p/YTHDC1 Axis in NLRP3-dependent pyroptosis.

The underlying molecular mechanisms of thoracic aortic dissection (TAD) remain incompletely understood. Recent insights into RNA methylation and microRNA-mediated gene regulation offer new avenues for exploring how these processes contribute to the pathophysiology of TAD, particularly through the modulation of pyroptosis and smooth muscle cell viability. This research aimed to elucidate the interplay of m1A-related gene expressions and miR-16-5p/YTHDC1 Axis in NLRP3-dependent pyroptosis, a mechanism implicated in the pathogenesis of TAD. We collected tissue samples from 28 human TAD patients and 8 healthy aortic group, as well as utilized a mouse model to replicate the disease. A combination of computational, in vitro, and in vivo methods was applied, including CIBERSORTx analysis, Pearson correlation, gene transfection using antagomiR-16-5p, siRNA, and several staining as well as cell culture techniques. Our analysis indicated two differentially expressed genes, ALKBH2 and YTHDC1. We found significant upregulation of has-miR-16-5p and downregulation of YTHDC1 at mRNA level in AD samples. Immune cell infiltration in TAD samples was examined using the CIBERSORTx database. We confirmed that YTHDC1 was a target of miR-16-5p, as evidenced by an inhibitory effect on luciferase activity. Inhibition of miR-16-5p enhanced SMC proliferation and promoted cell viability whilst downregulating NLRP3-pyroptosis. YTHDC1 expression was increased, and NLRP3-pyroptosis expressions were inhibited, suggesting miR-16-5p/YTHDC1 axis may involve the NLRP3-pyroptosis of the SMC. In vivo analyses confirmed the prevention of NLRP3-pyroptosis in middle layer of the thoracic aorta, implying that the miR-16-5p/YTHDC1 axis regulated SMC proliferation via NLRP3-pyroptosis signaling. Our findings underscored the anti-pyroptotic role of miR-16-5p/YTHDC1 axis in the pathogenesis of TAD, suggesting a potential therapeutic strategy via targeting YTHDC1 and suppressing miR-16-5p to inhibit NLRP3-dependent pyroptosis. Although further investigation is needed, these results relating to SMC proliferation are a significant step forward in understanding TAD.

Body mass index and the risk of abdominal aortic aneurysm presence and postoperative mortality: a systematic review and dose-response meta-analysis.

BACKGROUND: The clinical data regarding the relationships between BMI and abdominal aortic aneurysm (AAA) are inconsistent, especially for the obese and overweight patients. The aims of this study were to determine whether obesity is associated with the presence of AAA and to investigate the quantitative relationship between BMI and the risk of AAA presence and postoperative mortality. MATERIALS AND METHODS: PubMed, Web of Science, and Embase databases were used to search for pertinent studies updated to December 2023. The pooled relative risk (RR) with 95% CI was estimated by conventional meta-analysis based on random effects model. Dose-response meta-analyses using robust-error meta-regression (REMR) model were conducted to quantify the associations between BMI and AAA outcome variables. Subgroup analysis, sensitivity analysis, and publication bias analysis were performed according to the characteristics of participants. RESULTS: Eighteen studies were included in our study. The meta-analysis showed a higher prevalence of AAA with a RR of 1.07 in patients with obesity. The dose-response meta-analysis revealed a nonlinear relationship between BMI and the risk of AAA presence. A 'U' shape curve reflecting the correlation between BMI and the risk of postoperative mortality in AAA patients was also uncovered, suggesting the 'safest' BMI interval (28.55, 31.05) with the minimal RR. CONCLUSIONS: Obesity is positively but nonlinearly correlated with the increased risk of AAA presence. BMI is related to AAA postoperative mortality in a 'U' shaped curve, with the lowest RR observed among patients suffering from overweight and obesity. These findings offer a preventive strategy for AAA morbidity and provide guidance for improving the prognosis in patients undergone AAA surgical repair.

Investigating hybrid nanoparticles for drug delivery in multi-stenosed catheterized arteries under magnetic field effects.

This groundbreaking study pioneers the exploration of the therapeutic implications of a constant magnetic field simultaneously with hybrid nanoparticles on blood flow within a tapered artery, characterized by multiple stenosis along its exterior walls and a central thrombus, employing three-dimensional bio-fluid simulations. In addition, a magnetized catheter is inserted into the thrombus to increase the therapeutic potential of this novel method. The flow condition under consideration has applications in targeted medication distribution, improved medical device design, and improved diagnostics, as well as in advancing healthcare and biomedical engineering. Our investigation primarily aims to optimize blood flow efficiency, encompassing key parameters like pressure, velocity, and heat fluctuations influenced by diverse geometric constraints within the stenotic artery. Precise solutions are obtained through the finite element method (FEM) coupled with advanced bio-fluid dynamics (BFD) software. Hybrid nanoparticles and magnetic fields impacted pressure and velocity, notably reducing pressure within the stenosis. Convective heat flux remained uniform, while temperature profiles showed consistent inlet rise and gradual decline with transient variations. This approach promotes fluid flow, and convection within stenosed arteries, enhances heat transport, evacuates heat from stenotic regions, and improves heat dispersion to surrounding tissues. These findings hold promise for targeted therapies, benefiting patients with vascular disorders, and advancing our understanding of complex bio-fluid dynamics.

Exploring the therapeutic potential of Sirt6-enriched adipose stem cell-derived exosomes in myocardial ischemia-reperfusion injury: unfolding new epigenetic frontiers.

BACKGROUND: The management of myocardial ischemia-reperfusion injury (MIRI) presents continuous therapeutic challenges. NAD-dependent deacetylase Sirtuin 6 (Sirt6) plays distinct roles in various disease contexts and is hence investigated for potential therapeutic applications for MIRI. This study aimed to examine the impact of Sirt6-overexpressing exosomes derived from adipose stem cells (S-ASC-Exo) on MIRI, focusing on their influence on AIM2-pyroptosis and mitophagy processes. The sirtuin family of proteins, particularly Sirtuin 6 (Sirt6), play a pivotal role in these processes. This study aimed to explore the potential therapeutic effects of Sirt6-enriched exosomes derived from adipose stem cells (S-ASC-Exo) on regulating MIRI. RESULTS: Bioinformatic analysis revealed a significant downregulation of Sirt6 in MIRI subjected to control group, causing a consequential increase in mitophagy and pyroptosis regulator expressions. Therefore, our study revealed that Sirt6-enriched exosomes influenced the progression of MIRI through the regulation of target proteins AIM2 and GSDMD, associated with pyroptosis, and p62 and Beclin-1, related to mitophagy. The introduction of S-ASC-Exo inhibited AIM2-pyroptosis while enhancing mitophagy. Consequently, this led to a significant reduction of GSDMD cleavage and pyroptosis in endothelial cells, catalyzing a deceleration in the progression of atherosclerosis. Extensive in vivo and in vitro assays were performed to validate the expressions of these specific genes and proteins, which affirmed the dynamic modulation by Sirt6-enriched exosomes. Furthermore, treatment with S-ASC-Exo drastically ameliorated cardiac functions and limited infarct size, underlining their cardioprotective attributes. CONCLUSIONS: Our study underscores the potential therapeutic role of Sirt6-enriched exosomes in managing MIRI. We demonstrated their profound cardioprotective effect, evident in the enhanced cardiac function and attenuated tissue damage, through the strategic modulation of AIM2-pyroptosis and mitophagy. Given the intricate interplay between Sirt6 and the aforementioned processes, a comprehensive understanding of these pathways is essential to fully exploit the therapeutic potential of Sirt6. Altogether, our findings indicate the promise of Sirt6-enriched exosomes as a novel therapeutic strategy in treating ischemia-reperfusion injuries and cardiovascular diseases at large. Future research needs to underscore optimizing the balance of mitophagy during myocardial ischemia to avoid potential loss of normal myocytes.

Clinical symbiosis of hybrid nanoparticles and induced magnetic field on heat and mass transfer in multiple stenosed artery with erratic thrombosis.

This article scrutinizes blood circulation through an artery having magnetized hybrid nanoparticles (silver and gold) with multiple stenoses at the outer walls and erratic thrombus of different radii at the center. In the realm of biomedical innovation, magnetized hybrid nanoparticles emerge as a captivating frontier. These nanoparticles, amalgamating diverse materials, exhibit magnetic properties that engender novel prospects for targeted drug delivery, medical imaging enhancement, and therapeutic interventions. The study was carried out employing modern bio-fluid dynamics (BFD) software. In this iterative procedure, a second-order finite difference approach is used to solve the governing equations with 0.005 tolerance. The experiment is performed on a blood conduit with mild stenosis assumptions, and expressions of temperature, resistance impedance to flow, velocity, wall shear stress, and pressure gradient are generated by employing related boundary conditions. No one has ever attempted to acquire the remedial impact of an induced magnetic field and hybrid nanoparticles on the bloodstream in a tapering artery containing multiple stenoses on the outside walls and multi-thrombus at the center using 3-D bio-fluid simulation. Furthermore, the study's findings are unique, and these computational discoveries were not previously published by any researcher. The findings suggest that hybrid nanoparticles can be used as medication carriers to reduce the impact of thrombosis and stenosis-induced resistance to blood flow or coagulation-related factors.

Efficacy and Safety of Five Broad-Spectrum Antiseizure Medications for Adjunctive Treatment of Refractory Epilepsy: A Systematic Review and Network Meta-analysis.

BACKGROUND: Overall, up to one-third of epilepsy patients have drug-resistant epilepsy. However, there was previously no meta-analysis to support the guidelines for broad-spectrum antiseizure medication selection for the adjunctive treatment of refractory epilepsy. In the present meta-analysis, we assessed the efficacy and safety of three second-generation broad-spectrum antiseizure medications, lamotrigine (LTG), levetiracetam (LEV), and topiramate (TPM), and two third-generation broad-spectrum antiseizure medications, perampanel (PER) and lacosamide (LCM), for the adjunctive treatment of refractory epilepsy. METHODS: We systematically searched PubMed, Embase, and CENTRAL from inception to July 15, 2022. The studies included in the meta-analysis were required to meet the following criteria: (1) be randomized, double-blind clinical trials; (2) include patients aged >2 years with a clinical diagnosis of drug-resistant epilepsy; (3) have at least 8 weeks for the treatment period excluding the titration phase; and (4) report the outcomes of seizure response, seizure freedom and the withdrawal rate due to treatment-emergent adverse effects. Data were extracted, and the risk of bias for each study was assessed by two authors independently using RoB2 tools. We performed the network meta-analysis for each outcome through a group of programs in the mvmeta and network packages in Stata. Relative odds ratios with 95% confidence intervals were calculated as the result of the analyses. The surface under the cumulative ranking curve (SUCRA) and mean ranks were used to rank these treatments. RESULTS: Forty-two randomized controlled trials (RCTs) (LTG-placebo: n = 6, LEV-placebo: n = 13, TPM-placebo: n = 9, PER-placebo: n = 6, LCM-placebo: n = 7, LEV-TPM: n = 1) with 10257 participants (LTG = 569, LEV = 1626, TPM = 701, PER = 1734, LCM = 1908, placebo = 3719) were included. Levetiracetam had subequal efficacy in 50 % seizure frequency reduction to TPM [odds ratio (OR) 1.00, 95% confidence interval (CI) 0.73-1.38], and LEV had a higher rate of ≥ 50% seizure frequency reduction than LCM (OR 1.49, 95% CI 1.11-2.01) and PER (OR 1.68, 95% CI 1.24-2.29). Levetiracetam was also related to a higher proportion of seizure freedom participants than TPM (OR 1.87, 95% CI 1.20-2.89), PER (OR 2.23, 95% CI 1.12-4.43), and LCM (OR 2.97, 95% CI 1.46-6.05). In addition, LEV was associated with a lower risk of experiencing at least one treatment-emergent adverse event (TEAE) than PER (OR 0.63, 95% CI 0.46-0.85) and TPM (OR 0.51, 95 % CI 0.36-0.72) and a lower proportion of patients experiencing TEAEs leading to discontinuation than PER (OR 0.51, 95% CI 0.27-0.97) and TPM (OR 0.50, 95 % CI 0.27-0.93). CONCLUSIONS: Third-generation drugs (PER and LCM) had no advantages in terms of efficacy and safety for adjunctive treatment of refractory epilepsy compared with several second-generation drugs (LEV and LTG). Levetiracetam was the priority choice for adjunctive treatment of refractory epilepsy. Perampanel and LCM had no advantages in terms of efficacy and safety among the five drugs. REGISTRATION: PROSPERO registration number, CRD42022344153; last edited on December 23, 2022.

Chemokines in patients with Alzheimer's disease: A meta-analysis.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease in elderly people. Many researches have reported that neuroinflammation is related to AD. Chemokines are a class of small cytokines that play important roles in cell migration and cell communication, which involved in neuroinflammation. Up to now there is no meta-analysis to explore the difference of chemokines between AD patients and healthy elderly individuals. Method: We searched PubMed, Web of science, Cochrane library, EMBASE and Scopus databases from inception to January 2022. Data were extracted by two independent reviewers, and the Review Manager 5.3 was used for the meta-analysis. Result: Thirty-two articles were included and analyzed. The total number of participants in the included study was 3,331. We found that the levels of CCL5 (SMD = 2.56, 95% CI: 1.91-3.21), CCL15 (SMD = 3.30, 95% CI: 1.48-5.13) and IP-10 (SMD = 3.88, 95% CI: 1.84-5.91) in the plasma of AD patients were higher than healthy people. MCP-1 protein (SMD = 0.67, 95% CI: 0.29-1.05) in the AD patients' CSF was higher than healthy controls. Conclusion: These results suggested that chemokines may play an important role in AD. These findings could provide evidences for the diagnosis and treatment of AD. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021278736, identifier: CRD42021278736.

The Effect of N6-Methyladenosine Regulators and m6A Reader YTHDC1-Mediated N6-Methyladenosine Modification Is Involved in Oxidative Stress in Human Aortic Dissection.

Aortic dissection (AD) develops pathological changes in the separation of the true and false aortic lumen, with high lethality. m6A methylation and oxidative stress have also been shown to be involved in the onset of AD. Through bioinformatics methods, three differentially expressed m6A regulators (YTHDC1, YTHDC2, and RBM15) were excavated from the GSE52093 dataset in the Gene Expression Omnibus (GEO) database, and functional enrichment analysis of the differentially expressed genes (DEGs) regulated by m6A regulators was performed. Then, the genes with oxidative stress-related functions among these genes were found. The protein interaction network of the oxidative stress-related genes and the competing endogenous RNA- (ceRNA-) miRNA-mRNA network were constructed. Among them, DHCR24, P4HB, and PDGFRA, which have m6A differences in AD samples, were selected as key genes. We also performed immune infiltration analysis, as well as cell-gene correlation analysis, on samples from the dataset. The results showed that YTHDC1 was positively correlated with macrophage M1 and negatively correlated with macrophage M2. Finally, we extracted AD and healthy aorta RNA and protein from human tissues that were taken from AD patients and patients who received heart transplants, performed quantitative real-time PCR (qRT-PCR) on YTHDC2 and RBM15, and performed qRT-PCR and western blot (WB) detection on YTHDC1 to verify their differences in AD. The mRNA and protein levels of YTHDC1 were consistent with the results of bioinformatics analysis and were downregulated in AD. Immunofluorescence (IF) was used to colocalize YTHDC1 and endothelial cell marker CD31. After knocking down YTHDC1 in human umbilical vein endothelial cells (HUVECs), reactive oxygen species (ROS) levels had a tendency to increase and the expression of peroxide dismutase SOD2 was decreased. This study provides assistance in discovering the role of m6A regulator YTHDC1 in AD. In particular, m6A modification participates in oxidative stress and jointly affects AD.

Identifying the Role of Oxidative Stress-Related Genes as Prognostic Biomarkers and Predicting the Response of Immunotherapy and Chemotherapy in Ovarian Cancer.

Background: Ovarian cancer (OC) is one of the most frequently seen and fatal gynecological malignancies, and oxidative stress (OS) plays a critical role in the development and chemoresistance of OC. Materials and Methods: OS-related genes (OSRGs) were obtained from the Molecular Signatures Database. Besides, gene expression profiles and clinical information from The Cancer Genome Atlas (TCGA) were selected to identify the prognostic OSRGs. Moreover, univariate Cox regression, LASSO, and multivariate Cox regression analyses were conducted sequentially to establish a prognostic signature, which was later validated in three independent Gene Expression Omnibus (GEO) datasets. Next, gene set enrichment analysis (GSEA) and tumor mutation burden (TMB) analysis were performed. Afterwards, immune checkpoint genes (ICGs) and the tumor immune dysfunction and exclusion (TIDE) algorithm, together with IMvigor210 and GSE78220 cohorts, were applied to comprehensively explore the role of OSRG signature in immunotherapy. Further, the CellMiner and Genomics of Drug Sensitivity in Cancer (GDSC) databases were also applied in investigating the significance of OSRG signature in chemotherapy. Results: Altogether, 34 prognostic OSRGs were identified, among which 14 were chosen to establish the most valuable prognostic signature. The Kaplan-Meier (KM) analysis suggested that patients with lower OS-related risk score had better prognosis. The area under the curve (AUC) values were 0.71, 0.76, and 0.85 in 3, 5, and 7 years separately, and the stability of this prognostic signature was confirmed in three GEO datasets. As revealed by GSEA and TMB analysis results, OC patients in low-risk group might have better immunotherapeutic response, which was consistent with ICG expression and TIDE analyses. Moreover, both IMvigor210 and GSE78220 cohorts demonstrated that patients with lower OS-related risk score were more likely to benefit from anti-PD-1/L1 immunotherapy. In addition, the association between prognostic signature and drug sensitivity was explored. Conclusion: According to our results in this work, OSRG signature can act as a powerful prognostic predictor for OC, which contributes to generating more individualized therapeutic strategies for OC patients.

CircRNA-Based Cervical Cancer Prognosis Model, Immunological Validation and Drug Prediction.

BACKGROUND: Cervical cancer (CC) is a common cancer in female, which is associated with problems like poor prognosis. Circular RNA (circRNA) is a kind of competing endogenous RNA (ceRNA) that has an important role in regulating microRNA (miRNA) in many cancers. The regulatory mechanisms of CC immune microenvironment and the transcriptome level remain to be fully explored. METHODS: In this study, we constructed the ceRNA network through the interaction data and expression matrix of circRNA, miRNA and mRNA. Meanwhile, based on the gene expression matrix, CIBERSORT algorithm was used to reveal contents of tumor-infiltrating immune cells (TIICs). Then, we screened prognostic markers based on ceRNA network and immune infiltration and constructed two nomograms. In order to find immunological differences between the high- and low-risk CC samples, we examined multiple immune checkpoints and predicted the effect of PD-L1 ICI immunotherapy. In addition, the sensitive therapeutics for high-risk patients were screened, and the potential agents with anti-CC activity were predicted by Connective Map (CMap). RESULTS: We mapped a ceRNA network including 5 circRNAs, 17 miRNAs and 129 mRNAs. From the mRNA nodes of the network six genes and two kind of cells were identified as prognostic makers for CC. Among them, there was a significant positive correlation between CD8+ T cells and SNX10 gene. The results of TIDE and single sample GSEA (ssGSEA) showed that T cells CD8 do play a key role in inhibiting tumor progression. Further, our study screened 24 drugs that were more sensitive to high-risk CC patients and several potential therapeutic agents for reference. CONCLUSIONS: Our study identified several circRNA-miRNA-mRNA regulatory axes and six prognostic genes based on the ceRNA network. In addition, through TIIC, survival analysis and a series of immunological analyses, T cells were proved to be good prognostic markers, besides play an important role in the immune process. Finally, we screened 24 potentially more effective drugs and multiple potential drug compounds for high- and low-risk patients.

Relationship between serum homocysteine, fibrinogen, lipoprotein-a level, and peripheral arterial disease: a dose-response meta-analysis.

AIM: At present, the relationship between serum homocysteine (Hcy), fibrinogen (FIB), lipoprotein-a (LPa), and PAD is uncertain, and there has been no meta-analysis to establish the dose-response relationship between their exposure levels and PAD. METHODS AND RESULTS: Relevant literature published in PubMed, Embase, and Web of Science was retrieved. The robust error meta-regression method was used to assess the linear and non-linear dose-response relationship between exposure level and PAD risk. A total of 68 articles, involving 565,209 participants, were included. Combined with continuous variables, the serum Hcy, FIB, and LPa levels of PAD patients were significantly higher than those of healthy individuals. The odds ratios (ORs) of PAD for individuals with high Hcy, FIB, and LPa levels compared with those with low levels were 1.47, 1.14, and 1.76, respectively. The study also showed that circulating Hcy, FIB, and LPa were significantly elevated in patients with PAD compared with controls. The level of Hcy and the risk of PAD presented a U-shaped distribution. The nonlinear dose-response model showed that each 1 µmol/L increase in serum Hcy increased the risk of PAD by 7%. Similarly, for each 10 mg/dL FIB and 10 mg/dL LPa increases, the risk of PAD increased by 3% and 6%, respectively. CONCLUSIONS: This meta-analysis provided evidence that elevated Hcy, PIB, and LPa levels may increase the risk of PAD, and the risk of PAD increases with the increase in serum exposure within a certain range. By controlling Hcy level, the incidence of PAD may be reduced to control the PAD growing epidemic. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42021250501), https://www.crd.york.ac.uk/prospero/.

Establishment, immunological analysis, and drug prediction of a prognostic signature of ovarian cancer related to histone acetylation.

In recent years, epigenetic modifications have been increasingly regarded as an important hallmark of cancer. Histone acetylation, as an important part of epigenetic modification, plays a key role in the progress, treatment, and prognosis of many cancers. In this study, based on the TCGA database, we performed LASSO regression and the Cox algorithm to establish a prognostic signature of ovarian cancer associated with histone acetylation modulator genes and verified it externally in the GEO database. Subsequently, we performed an immunological bioinformatics analysis of the model from multiple perspectives using the CIBERSORT algorithm, ESTIMATE algorithm, and TIDE algorithm to verify the accuracy of the model. Based on the prognostic model, we divided ovarian cancer patients into high-risk and low-risk groups, and assessed survival and the efficacy of accepting immunosuppressive therapy. In addition, based on the analysis of characteristics of the model, we also screened targeted drugs for high-risk patients and predicted potential drugs that inhibit platinum resistance through the connectivity map method. We ultimately constructed a histone acetylation modulator-related signature containing 10 histone acetylation modulators, among which HDAC1, HDAC10, and KAT7 can act as independent prognostic factors for ovarian cancer and are related to poor prognosis. In the analysis of the tumor microenvironment, the proportion of the B-infiltrating cells and the macrophages was significantly different between the high- and low-risk groups. Also, the samples with high-risk scores had higher tumor purity and lower immune scores. In terms of treatment, patients in the high-risk group who received immunotherapy had a higher likelihood of immune escape or rejection and were less likely to respond to platinum/paclitaxel therapy. Finally, we screened 20 potential drugs that could target the model for reference.

N1-Methyladenosine (m1A) Regulation Associated With the Pathogenesis of Abdominal Aortic Aneurysm Through YTHDF3 Modulating Macrophage Polarization.

Objectives: This study aimed to identify key AAA-related m1A RNA methylation regulators and their association with immune infiltration in AAA. Furthermore, we aimed to explore the mechanism that m1A regulators modulate the functions of certain immune cells as well as the downstream target genes, participating in the progression of AAA. Methods: Based on the gene expression profiles of the GSE47472 and GSE98278 datasets, differential expression analysis focusing on m1A regulators was performed on the combined dataset to identify differentially expressed m1A regulatory genes (DEMRGs). Additionally, CIBERSORT tool was utilized in the analysis of the immune infiltration landscape and its correlation with DEMRGs. Moreover, we validated the expression levels of DEMRGs in human AAA tissues by real-time quantitative PCR (RT-qPCR). Immunofluorescence (IF) staining was also applied in the validation of cellular localization of YTHDF3 in AAA tissues. Furthermore, we established LPS/IFN-γ induced M1 macrophages and ythdf3 knockdown macrophages in vitro, to explore the relationship between YTHDF3 and macrophage polarization. At last, RNA immunoprecipitation-sequencing (RIP-Seq) combined with PPI network analysis was used to predict the target genes of YTHDF3 in AAA progression. Results: Eight DEMRGs were identified in our study, including YTHDC1, YTHDF1-3, RRP8, TRMT61A as up-regulated genes and FTO, ALKBH1 as down-regulated genes. The immune infiltration analysis showed these DEMRGs were positively correlated with activated mast cells, plasma cells and M1 macrophages in AAA. RT-qPCR analysis also verified the up-regulated expression levels of YTHDC1, YTHDF1, and YTHDF3 in human AAA tissues. Besides, IF staining result in AAA adventitia indicated the localization of YTHDF3 in macrophages. Moreover, our in-vitro experiments found that the knockdown of ythdf3 in M0 macrophages inhibits macrophage M1 polarization but promotes macrophage M2 polarization. Eventually, 30 key AAA-related target genes of YTHDF3 were predicted, including CD44, mTOR, ITGB1, STAT3, etc. Conclusion: Our study reveals that m1A regulation is significantly associated with the pathogenesis of human AAA. The m1A "reader," YTHDF3, may participate in the modulating of macrophage polarization that promotes aortic inflammation, and influence AAA progression by regulating the expression of its target genes.

Comprehensive Analysis of Key m6A Modification Related Genes and Immune Infiltrates in Human Aortic Dissection.

Objective: To identify the feature of N6-methyladenosine (m6A) methylation modification genes in acute aortic dissection (AAD) and explore their relationships with immune infiltration. Methods: The GSE52093 dataset including gene expression data from patients with AAD and healthy controls was downloaded from Gene Expression Omnibus (GEO) database in order to obtain the differentially expressed genes (DEGs). The differentially methylated m6A genes were obtained from the GSE147027 dataset. The differentially expressed m6A-related genes were obtained based on the intersection results. Meanwhile, the protein-protein interaction (PPI) network of differentially expressed m6A-related genes was constructed, and hub genes with close relationships in the network were selected. Later, hub genes were verified by using the GSE153434 dataset. Thereafter, the relationships between these genes and immune cells infiltration were analyzed. Results: A total of 279 differentially expressed m6A-related genes were identified in the GSE52093 and GSE147027 datasets. Among them, 94 genes were up-regulated in aortic dissection (AD), while the remaining 185 were down-regulated. As indicated by Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, these genes were mainly associated with extracellular matrix (ECM) and smooth muscle cells (SMCs). The seven hub genes, namely, DDX17, CTGF, FLNA, SPP1, MYH11, ITGA5 and CACNA1C, were all confirmed as the potential biomarkers for AD. According to immune infiltration analysis, it was found that hub genes were related to some immune cells. For instance, DDX17, FLNA and MYH11 were correlated with Macrophages M2. Conclusion: Our study identifies hub genes of AD that may serve as the potential biomarkers, illustrates of the molecular mechanism of AD, and provides support for subsequent research and treatment development.

Systemic characterization of alternative splicing related to prognosis, immune infiltration, and drug sensitivity analysis in ovarian cancer.

Background: Alternative splicing (AS) plays an essential role in tumorigenesis and progression. This study intended to construct an innovative prognostic model based on AS events to gain more precise survival prediction and search for potential therapeutic targets in ovarian cancer. Methods: Seven types of AS events in ovarian serous cystadenocarcinoma (OV) patients with RNA-seq were obtained using The Cancer Genome Atlas (TCGA) SpliceSeq tool and database. Cox and Kaplan-Meier curve analyses were employed to establish the prognostic models. Relying on drug sensitivity data from the CellMiner database, Genomics of Drug Sensitivity (GDS) was adopted to estimate the platinum-sensitive analysis. Furthermore, a prognostic splicing factor (SF)-AS network was constructed using Cytoscape. Finally, in order to explore the influence of the tumor microenvironment on the prognosis of OV patients, we first combined a similar network fusion and consensus clustering (SNF-CC) algorithm to identify three OV subtypes based on survival-related AS events and then utilized single-sample Gene Set Enrichment Analysis (ssGSEA) method to perform immune cell infiltration analysis. Results: A total of 48,049 AS events and 21,841 related genes were selected from 318 OV samples, and 2,206 AS events associated with disease-free survival (DFS) were identified. Multivariate Cox and Kaplan-Meier curve analyses were then employed to establish the prognostic models. Receiver operating characteristic (ROC) analysis from 0.59 to 0.75 showed that these models were highly efficient in distinguishing patient survival. GDS was adopted with the CellMiner database to provide some insights for platinum-sensitive analysis of OV. Furthermore, a prognostic SF-AS network, which discovered a significant connection between SFs and prognostic AS genes, was constructed using Cytoscape. The combined SNF-CC algorithm revealed three distinct OV subtypes based on the prognostic AS events, and the associations between this novel molecular classification and immune cell infiltration were further explored. Conclusions: We developed a powerful prognostic AS signature for OV and provided a deeper understanding of SF-AS network regulatory mechanisms, as well as platinum-sensitive and cancer immune microenvironments. These results revealed various candidate biomarkers and potential targets for OV treatment strategies.

Ferroptosis-related genes identify tumor immune microenvironment characterization for the prediction of prognosis in cervical cancer.

Background: Cervical cancer (CC) is a disease that affects female health; therefore, timely prevention and diagnosis of CC are crucial to decrease its mortality. Ferroptosis, an iron-dependent form of non-apoptotic cell death, is involved in tumor progression. However, the role of ferroptosis-related genes (FRGs) in the immune microenvironment of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) remains unclear. Methods: The data sets of CESC patients, including RNA sequencing (RNA-seq) data and clinical information, were obtained from The Cancer Genome Atlas (TCGA). The ESTIMATE algorithm was used to determine the stromal score, immune score, estimate score, and tumor purity in the CESC patients' data. Additionally, FRGs were identified and used to construct a signature marker for the diagnosis and prognosis of CESC. Patients were assigned to a high- or low-risk group based on their median risk score. The tumor microenvironment (TME), immune infiltration, and functional enrichment were compared between the low- and high-risk groups. Functional analyses, including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and single-sample Gene Set Enrichment Analysis (ssGSEA), were conducted to explore the underlying mechanisms in the development and prognosis of CESC. Results: The results showed that the estimate score was suitable for predicting the prognosis of CESC patients. Additionally, a prediction model involving four FRGs [phosphatidylethanolamine-binding protein 1 (PEBP1), dual oxidase 1 (DUOX1), iron-sulfur cluster assembly enzyme (ISCU), and cytochrome b (-245) beta subunit (CYBB)] was constructed. The performance of the prognostic model and significant clinical characteristics in predicting CESC prognosis was subsequently validated. Our results showed that the expression of CYBB affected immune cells. Gene functional enrichment analyses showed that these differentially expressed FRGs were mainly enriched in the immunity-related signaling pathways, which indicated that FRGs might affect the development and prognosis of CC by regulating the immune microenvironment. Conclusions: The expression profiles of FRGs are closely related to the TME and the prognostic survival of CESC patients. The interaction between ferroptosis and immunity in the development of CC provides new insight into the molecular mechanisms of CC.

Compared of efficacy and safety of high-dose donepezil vs standard-dose donepezil among elderly patients with Alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: Donepezil is a first-line drug for the treatment of Alzheimer's disease (AD). However, there are no meta-analyses on efficacy and safety of high-dose versus standard-dose donepezil in the treatment of moderate-to-severe AD. RESEARCH DESIGN AND METHODS: We searched for randomized controlled trials (RCTs) from 1993 to May 2021 PubMed, Cochrane Library, EMBASE, Web of Science, and Scopus databases. The outcomes of the meta-analysis included cognitive function, global assessment, and the incidence of adverse events and serious adverse events. RESULTS: Five RCTs (2974 people) were included in this meta-analysis. The improvement of cognitive function was significant among the patients with the treatment of high-dose donepezil [SMD = 0.12, 95% CI: 0.03 ~ 0.22; p = 0.01]. Between the two groups, there was no significant difference in global assessment. Compared with standard-dose donepezil, there was no difference in the incidence of adverse events when high-dose donepezil was used. However, it was found that high-dose donepezil administration increased the risk of heart problems through subgroup analysis of the two serious adverse events. CONCLUSION: High-dose donepezil is more effective than standard-dose donepezil in improving cognitive function of the elderly with moderate-to-severe AD. However, more attention should be paid to patients with heart problems when high-dose donepezil was used.

Novel insights into the role of 5-Methylcytosine RNA methylation in human abdominal aortic aneurysm.

Background: It remains largely unclear about the function of 5-methylcytosine (m5C) RNA modification in the context of abdominal aortic aneurysm (AAA). In this regard, the present work focused on investigating m5C RNA methylation and related modulator expression levels in AAA. Materials and methods: To this end, we quantified the m5C methylation levels in AAA tissues (n = 32) and normal aortic tissues (n = 12) to examine the mRNA m5C status and m5C modulator expression at mRNA and protein levels. Meanwhile, modulator localization within AAA tissue samples was detected by immunohistochemistry (IHC). Moreover, RNA immunoprecipitation-sequencing (RIP-seq) was also used to analyze the lncRNAs and mRNA binding to Aly/REF, as an m5C reader. Results: m5C expression markedly elevated in AAA in comparison with normal aortic samples in the AAA cases. The major 5-methylcytosine modulators, including NSUN2, NSUN5, and Aly/REF, which represented the major parameters related to the abnormal m5C modification level, were observed up-regulating in AAA tissues at both protein and mRNA levels. In addition, NSUN2 mRNA level remarkably related to Aly/REF expression, and they were co-expressed in the same cells in AAA group. Regarding the cellular location, Aly/REF was associated with inflammatory (CD45+, CD3+) infiltrates. Simultaneously, after screening for reads in AAA tissue compare with anti-Aly/REF group relative to IgG as control, we obtained totally 477 differentially expressed Aly/REF-binding lncRNAs and 369 differentially expressed Aly/REF-binding mRNAs in AAA tissue. The functions of Aly/REF-interacting lncRNA were involved in immune system process and macrophages infiltration. Through regulatory network (lncRNA-mRNA) analysis, our findings predicted the potential mechanism of Aly/REF-induced lncBCL2L1 and Aly/REF-lncFHL1 axis in AAA and inspire the understanding of m5C and lncRNA in AAA. Conclusions: This study is the first to examine m5A modification within human AAA samples. Our results indicate that m5C modulators, namely, Aly/REF and NUSN2, play vital parts in the human AAA pathogenic mechanism, which shed new lights on the function of m5C modification within AAA. Taken together, findings in this work offer a possible RNA methylation modification mechanism within clinical AAA.

Systemic Inflammatory Markers for Predicting Overall Survival in Patients with Osteosarcoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Inflammatory markers are associated with tumor genesis and progression, but their prognostic significance in osteosarcoma remains unclear. Therefore, we discussed the prognostic value of related inflammatory markers in osteosarcoma through a meta-analysis and systematic review. These inflammatory markers include C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR), and Glasgow prognostic score (GPS). METHODS: The Chinese National Knowledge Infrastructure (CNKI), Wanfang, Chinese Scientific Journals (VIP), PubMed, Embase, and Cochrane libraries were searched. The design of meta-analysis was made based on the PICOS (population, intervention/exposure, control, outcomes, and study design) principles, and STATA 15.1 was used to analyze the data. The Newcastle-Ottawa scale (NOS) was used to assess the quality of included studies. Hazard ratios (HRs) for overall survival (OS) and disease-specific survival (DPS) were extracted for the investigation of the prognostic value of inflammatory markers. RESULTS: Twelve researches with 2162 osteosarcoma patients were included in total. The pooled results showed that elevated NLR, CRP, and GPS are all greatly related to shortening of OS among patients with osteosarcoma (HR = 1.68, P = 0.007, 95% CI: 1.15-2.45; HR = 1.96, P = 0.002, 95% CI: 1.28-3.00; HR = 2.54, P < 0.0001, 95% CI: 1.95-3.31, respectively), and CRP level is significantly associated with shortening of DPS among patients with osteosarcoma (HR = 2.76, 95% CI:2.01-3.80, P < 0.0001), additionally. However, the correlation between LMR or PLR and the prognosis of osteosarcoma is not statistically significant (HR = 0.60, 95% CI: 0.30-1.18, P = 0.138; HR = 1.13, 95% CI: 0.85-1.49, P = 0.405, respectively). The outcomes of subgroup analysis to NLR and CRP suggested that histology, ethnicity, metastasis, and sample size all have an impact on its prognosis of patients with osteosarcoma. CONCLUSION: Worsened prognosis may be related to high levels of NLR, CRP, and GPS before treatment rather than LMR or PLR, which can provide the basis for clinicians to judge the outcomes of prognosis. Trial Registration. PROSPERO (CRD42021249954), https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=249954.