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Background: m6A-methyltransferaseMETTL3 anddemethylaseFTO regulate gene expressionby dynamically modifying RNAmethylation. However, theirclinical relevancein renal Clear Cell Carcinoma (CCRCC) hasnotbeenwell elucidated. Objective: This study aimsto investigate prognostic values of FTO and METTL3mRNA and DNA methylation, their differential expression andassociations with chemokines and inflammation-related genes in CCRCC. Method: Kaplan-Meier survival curves and multivariate cox regression were performed for survival analyses, and random-effects meta-analysis was for differential expression of FTO and METTL3 in CCRCC. Results: A significantly negative correlation existed between mRNA and DNA methylation for bothFTOandMETTL3.Survival analysis showed a superior survival in patients with either high FTOmRNA or low DNA methylation,or low METTL3mRNA or high DNA methylation. The adjusted hazard ratios were 0.67 (95% CI: 0.49-0.91, p=0.01) for high vs. low FTOmRNA, 2.17 (1.38-3.42, p=0.0008) for high vs. low FTODNA methylation, 1.97 (1.45-2.68, p<0.0001) for high vs. low METTL3mRNA, and 0.49 (0.31-0.79, p=0.003) for high vs. low METTL3DNA methylation, respectively. There was a significant interaction between FTO and METTL3mRNA levels (p =0.024). Upregulation of FTO and METTL3 with 1.64 folds (95% CI: 1.43-1.89) and 1.17 folds (1.02-1.35), respectively, was observed in CCRCCvs. normal kidney tissues.FTO and METTL3mRNA had opposite direction in association with the expression of CD8+ T cell migration-relatedchemokines. Conclusion: Dysregulated FTO and METTL3may beinvolved in the disease development and progression,and affect immune response in CCRCC.FTO and METTL3 expression and DNA methylation are potential prognostic markers of CCRCC.

Background. LHON is a progressive disease with early disease onset and male predominance, usually causing devastating visual loss to patients. These systematic review and meta-analysis are aimed at summarizing epidemiology, disease onset and progression, visual recovery, risk factors, and treatment options of Leber’s hereditary optic neuropathy (LHON) with mitochondrial DNA mutation G11778A from current evidence. Methods. The PubMed database was examined from its inception date to November 2021. Data from included studies were pooled with either a fixed-effects model or a random-effects model, depending on the results of heterogeneity tests. Sensitivity analysis was conducted to test the robustness of results. Results. A total of 41 articles were included in the systematic review for qualitative analysis, and 34 articles were included for quantitative meta-analysis. The pooled estimate of proportion of G11778A mutation among the three primary mutations of mitochondrial DNA (G11778A, G3460A, and T14484C) for LHON was 73% (95% CI: 67% and 79%), and the LHON patients with G11778A mutation included the pooled male ratio estimate of 77% (76% and 79%), the pooled age estimate of 35.3 years (33.2 years and 37.3 years), the pooled onset age estimate of 22.1 years (19.7 years and 24.6 years), the pooled visual acuity estimate of 1.4 LogMAR (1.2 LogMAR and 1.6 LogMAR), and the pooled estimate of spontaneous visual recovery rate (in either 1 eye) of 20% (15% and 27%). Conclusions. The G11778A mutation is a prevalent mitochondrial DNA mutation accounting for over half of LHON cases with three primary mutations. Spontaneous visual recovery is rare, and no effective treatment is currently available.