Background: Oral cavity cancer (OCC) is one of the most common carcinoma diseases. Recent genome-wide association studies (GWAS) have reported numerous genetic variants associated with OCC susceptibility. However, the regulatory mechanisms of these genetic variants underlying OCC remain largely unclear. Objective: This study aimed to identify OCC-related genetics risk genes contributing to the prognosis of OCC. Methods: By combining GWAS summary statistics (N = 4,151) with expression quantitative trait loci (eQTL) across 49 different tissues from the GTEx database, we performed an integrative genomics analysis to uncover novel risk genes associated with OCC. By leveraging various computational methods based on multi-omics data, we prioritized some of these risk genes as promising candidate genes for drug repurposing in OCC. Results: Using two independent computational algorithms, we found that 14 risk genes whose genetics-modulated expressions showed a notable association with OCC. Among them, nine genes were newly identified, such as IRF4 (P = 2.5×10-9 and P = 1.06×10-4), TNS3 (P = 1.44×10-6 and P = 4.45×10-3), ZFP90 (P = 2.37×10-6 and P = 2.93×10-4), and DRD2 (P = 2.0×10-5 and P = 6.12×10-3), by using MAGMA and S-MultiXcan methods. These 14 genes were significantly overrepresented in several cancer-related terms (FDR < 0.05), and 10 of 14 genes were enriched in 10 potential druggable gene categories. Based on differential gene expression analysis, the majority of these genes (71.43%) showed remarkable differential expressions between OCC patients and paracancerous controls. Integration of multi-omics-based evidence from genetics, eQTL, and gene expression, we identified that the novel risk gene of IRF4 exhibited the highest ranked risk score for OCC (score = 4). Survival analysis showed that dysregulation of IRF4 expression was significantly associated with cancer patients outcomes (P = 8.1×10-5). Conclusions: Based on multiple omics data, we constructed a computational framework to pinpoint risk genes for OCC, and we prioritized 14 risk genes associated with OCC. There were nine novel risk genes, including IRF4 gene, which is significantly associated with the prognosis of OCC. These identified genes provide a drug repurposing resource to develop therapeutic drugs for treating patients, thereby contributing to the personalized prognostic management of OCC patients.
Recently, mounting evidence indicates that N6‐methyladenosine (m6A) modification functions as a pivotal posttranscriptional modification that regulates noncoding RNA biogenesis to influence the progression of multiple diseases. However, whether m6A modification is involved in aortic dissection (AD) development has never been reported. Meanwhile, numerous studies have shown that AngII‐induced inflammatory damage and excessive apoptosis of human aortic smooth muscle cells (HASMCs) are the crucial pathological features of AD development. Therefore, in this study, we intended to explore whether m6A modification can regulate AD progression by influencing the damage effects of AngII on HASMCs and elucidate the underlying mechanisms. Firstly, we screened and confirmed the high expression of alkylation repair homolog protein 5 (ALKBH5), a key m6A demethylase, in aortic tissues from AD patients, indicating that m6A modification may indeed be involved in AD progression. Subsequently, we demonstrated that ALKBH5 can exacerbate the AngII‐induced HASMC inflammatory injury as well as apoptosis and shorten the survival time of AngII‐infused mice. Mechanistically, we revealed that lncRNA TMPO‐AS1 is a downstream target for ALKBH5 to affect AD progression in vitro and vivo. Meanwhile, we confirmed that ALKBH5‐mediated m6A demethylation downregulates lnc‐TMPO‐AS1 by decreasing the stability of its nascent. Further, we demonstrated that lnc‐TMPO‐AS1 exhibits its functions in HASMCs, at least partly, through downregulating IRAK4 at the epigenetic level by combining with EZH2. Finally, the direct positive correlation between ALKBH5 and IRAK4 in terms of the expression level and biological function was confirmed, which further enforced the preciseness and correctness of our findings. In conclusion, our study demonstrated that ALKBH5 aggravates AD by promoting inflammatory response and apoptosis of HASMCs via regulating lnc‐TMPO‐AS1/EZH2/IRAK4 signals in an m6A modification manner and may provide a novel molecular basis for subsequent researchers to searching for novel therapeutic approaches to improve the health of patients fighting AD and other cardiovascular diseases.
Background Exercise rehabilitation is conducive to increasing functional ability and improving health outcomes, but its effectiveness in patients with acute heart failure (AHF) is still controversial. Purpose In this study, our aim was to systematically examine the efficacy of exercise rehabilitation in people with AHF. Methods A search was conducted for randomized controlled trial studies on exercise rehabilitation in patients with AHF up to November 2021. Two investigators conducted literature selection, quality assessments, and data extractions independently. The primary outcome was 6-minute walk distance, and the secondary outcomes were left ventricular ejection fraction, quality of life, Short Physical Performance Battery, readmission, and mortality. RevMan (version 5.3) software was used for the meta-analysis. Results Twelve studies with 1215 participants were included. Exercise rehabilitation significantly improved the 6-minute walk distance (mean difference [MD], 33.04; 95% confidence interval [CI], 31.37–34.70; P < .001; I 2 = 0%), quality of life (MD, −11.57; 95% CI, −19.25 to −3.89; P = .003; I 2 = 98%), Short Physical Performance Battery (MD, 1.40; 95% CI, 1.36–1.44; P < .001; I 2 = 0%), and rate of readmission for any cause (risk ratio, 0.48; 95% CI, 0.26–0.88; P = .02; I 2 = 7%), compared with routine care. However, no statistically significant effects on left ventricular ejection fraction (MD, 0.94; 95% CI, −1.62 to 3.51; P = .47; I 2 = 0%) and mortality (risk ratio, 1.07; 95% CI, 0.64–1.80; P = .79; I 2 = 0%) were observed. Conclusions Compared with routine care, exercise rehabilitation improved functional ability and quality of life, reducing readmission in patients with AHF.
Abstract There is growing evidence that microRNAs play important roles in cellular responses to hypoxia and in pulmonary hypertensive vascular remodeling, but the exact molecular mechanisms involved are not fully elucidated. In this study, we identified miR-322 as one of the microRNAs induced in lungs of chronically hypoxic mice and rats. The expression of miR-322 was also upregulated in primary cultured rat pulmonary arterial smooth muscle cells (PASMC) in response to hypoxia. We demonstrated that HIF-1α, but not HIF-2α, transcriptionally upregulates the expression of miR-322 in hypoxia. Furthermore, miR-322 facilitated the accumulation of HIF-1α in the nucleus and promoted hypoxia-induced cell proliferation and migration. Direct targeting BMPR1a and smad5 by miR-322 was demonstrated in PASMCs suggesting that downregulation of BMP -S mad signaling pathway may be mediating the hypoxia-induced PASMC proliferation and migration. Our study implicates miR-322 in the hypoxic proliferative response of PASMCs suggesting that it may be playing a role in pulmonary vascular remodeling associated with pulmonary hypertension.
Background: Former studies have revealed that fluoroquinolone (FQ) can induce aortic expansion and rupture. While FQ is widely used in perioperative anti-infection therapy, its impact on graft patency and patient survival is unknown. Methods: Coronary artery bypass grafting (CABG) data were extracted from the MIMIC-III database. Chi-square tests, Fisher’s exact tests, t-tests, or ANOVAs were used to compare baseline data between groups determined by FQ therapy status, depending on the data type. Propensity score matching was used to establish a balanced cohort. Cox regression was used to investigate the impact of FQ on CABG patient survival, whereas paired t-tests were used to analyze secondary results. Results: Of the 5030 patients who underwent CABG, 937 (18.6%) received oral or intravenous FQ therapy. Using propensity score matching, these 819 patients were successfully matched with 819 controls in a 1:1 ratio. Cox regression showed that FQ significantly decreased survival among CABG patients (HR: 1.62, 95% CI: 1.21−2.15, p = 0.001). Furthermore, FQ usage was associated with longer hospitalization (<0.0001), ICU duration (<0.0001), ventilation period (<0.0001), and duration of vasopressor administration (<0.0001). Conclusions: Perioperative FQ therapy was associated with worse prognosis and a more difficult recovery among patients with CABG.
Iron deficiency (ID) is a global nutritional deficiency that was shown to be involved in the pathogenesis of aortic aneurysm and dissection (AAD) in our previous studies. Some studies suggested that mitochondrial dynamics was involved in the apoptosis and phenotypic transformation of vascular smooth muscle cells (VSMCs). However, little is known about the role of mitochondrial dynamics in aortic medial degeneration (AMD) promoted by an iron deficient diet. The present study investigated the effect of ID on the phenotypic transformation of VSMCs, the progression of AMD, and the underlying mechanism. The expression of p-Drp1 (Ser616) and Fis1 was markedly upregulated in the aortic media of AAD patients and ApoE-/- mice with subcutaneous AngII osmotic pumps. ID facilitated the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs), which triggered excessive mitochondrial fission, induced the phenotypic transformation of VSMCs, and ultimately accelerated the progression of AMD. Furthermore, the present study indicated that an inhibitor of Drp1 could partially reverse this process. Maintaining iron balance in the human body may prevent the development of AAD.
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