N-methyladenosine (mA) modification of mRNA is emerging as an important regulator of gene expression that affects different developmental and biological processes, and altered mA homeostasis is linked to cancer. mA modification is catalysed by METTL3 and enriched in the 3' untranslated region of a large subset of mRNAs at sites close to the stop codon. METTL3 can promote translation but the mechanism and relevance of this process remain unknown. Here we show that METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon, supporting a mechanism of mRNA looping for ribosome recycling and translational control. Electron microscopy reveals the topology of individual polyribosomes with single METTL3 foci in close proximity to 5' cap-binding proteins. We identify a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). METTL3 promotes translation of a large subset of oncogenic mRNAs-including bromodomain-containing protein 4-that is also mA-modified in human primary lung tumours. The METTL3-eIF3h interaction is required for enhanced translation, formation of densely packed polyribosomes and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. These findings uncover a mechanism of translation control that is based on mRNA looping and identify METTL3-eIF3h as a potential therapeutic target for patients with cancer.

No adequate randomized trials have been reported for a comparison between hepatic resection (HR) versus radiofrequency ablation (RFA) for the treatment of patients with very early stage hepatocellular carcinoma (HCC), defined as an asymptomatic solitary HCC <2 cm. For compensated cirrhotic patients with very early stage HCC, a Markov model was created to simulate a randomized trial between HR (group I) versus primary percutaneous RFA followed by HR for cases of initial local failure (group II) versus percutaneous RFA monotherapy (group III); each arm was allocated with a hypothetical cohort of 10,000 patients. The primary endpoint was overall survival. The estimates of the variables were extracted from published articles after a systematic review. In the parameter estimations, we assumed the best scenario for HR and the worst scenario for RFA. The mean expected survival was 7.577 years, 7.564 years, and 7.356 years for group I, group II, and group III, respectively. One-way sensitivity analysis demonstrated that group II was the preferred strategy if the perioperative mortality rate was greater than 1.0%, if the probability of local recurrence following an initial complete ablation was <1.9% or if the positive microscopic resection margin rate was >0.3%. The 95% confidence intervals for the difference in overall survival were ؊0.18-0. Although several observational studies and suboptimal randomized controlled trials have demonstrated that radiofrequency ablation (RFA) was comparable to HR with regard to the overall survival of patients with early stage HCC, 3-9 few comparative studies have been reported for very early stage HCC between HR and RFA. To obtain a definitive conclusion, it would be mandatory to perform a well-designed randomized trial concerning overall survival. However, an adequate randomized controlled trial would require enrollment of an enormous sample size of several thousands of patients.In this study, instead of performing a real randomized controlled trial, a simulated randomized trial was performed to compare the overall survival of compensated cirrhotic patients with very early stage HCC treated with HR, RFA, or the combined approach of primary RFA followed by HR for cases of initial local failure. Patients and MethodsStudy Purpose. We tried to compare HR and percutaneous RFA for the treatment of compensated cirrhotic patients with very early stage HCC by using a Markov model wherein the primary endpoint was overall survival.

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