Background: Chemotherapy is an important strategy for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+HER2−) breast cancer (BC), but this subtype has a low response rate to chemotherapy. Growing evidence indicates that N⁶-methyladenosine (m⁶A) is the most common RNA modification in eukaryotic cells and that methyltransferase-like 3 (METTL3) participates in tumour progression in several cancer types. Therefore, exploring the function of METTL3 in HR+HER2− BC initiation and development is still important. Methods: mRNA and protein expression levels were analysed by quantitative real-time polymerase chain reaction and western blotting, respectively. Cell proliferation was detected by CCK-8 and colony formation assays. Cell cycle progression was assessed by flow cytometry. Cell migration and invasion were analysed by wound healing assays and transwell assays, respectively, and apoptosis was analysed by TUNEL assays. Finally, m⁶A modification was analysed by methylated RNA immunoprecipitation. Results: Chemotherapy-induced downregulation of the m⁶A modification is regulated by METTL3 depletion in HR+HER2− BC. METTL3 knockdown in MCF-7/T47D cells decreased the drug sensitivity of HR+HER2− BC cells by promoting tumour proliferation and migration and inhibiting apoptosis. Mechanistically, CDKN1A is a downstream target of METTL3 that activates the AKT pathway and promotes epithelial-mesenchymal transformation (EMT). Moreover, a decrease in BAX expression was observed when m⁶A modification was inhibited with METTL3 knockdown, and apoptosis was inhibited by the reduction of caspase-3/-9/-8. Conclusion: METTL3 depletion promotes the proliferation and migration and decreases the drug sensitivity of HR+HER2− BC via regulation of the CDKN1A/EMT and m⁶A-BAX/caspase-9/-3/-8 signalling pathways, which suggests METTL3 played a tumour-suppressor role and it could be a potential biomarker for predicting the prognosis of patients with HR+HER2− BC.

The incidence of gastric cardiac adenocarcinoma (GCA) has been increasing in the past two decades in China, but the molecular changes relating to carcinogenesis have not been well characterised.

BACKGROUND: Current methods for detecting esophageal cancer (EC) are generally invasive or exhibit limited sensitivity and specificity, especially for the identification of early-stage tumors. METHODS: We identified potential methylated DNA markers (MDMs) from multiple genomic regions in a discovery cohort, and a diagnostic model was developed and verified in a model-verification cohort of 297 participants. The accuracy of the MDM panel was validated in a multicenter, prospective cohort ( n = 1,429). The clinical performance of identified MDMs were compared with current tumor-associated protein markers. RESULTS: From 31 significant differentially methylated EC-associated regions identified in the marker discovery, we trained and validated a 3-MDM diagnostic model that could discriminate among patients with EC and volunteers without EC in a multicenter clinical prospective cohort with a sensitivity of 85.5% and a specificity of 95.3%. This panel showed higher sensitivity in diagnosing early-stage tumors, with sensitivities of 56% for stage 0 and 77% for stage I, compared with the performance of current biochemical markers. In population with high risk for EC, the sensitivity and specificity were 85.68% and 93.61%, respectively. CONCLUSION: The assessment of tumor-associated methylation status in blood samples can facilitate noninvasive and reliable diagnosis of early-stage EC, which warrants further development to expand screening and reduce mortality rates. TRIAL REGISTRATION: ChiCTR2400083525. FUNDING: Science and technology funds of Beijing Municipal Science & Technology Commission, Administrative Commission of Zhongguancun Science Park. Project number: Z201100005420007.

Background and Aim: The etiology and pathogenesis of Barrett’s esophagus (BE) have been widely studied during recent decades. However, the association between BE and possible risk factors, including abdominal obesity (AO), metabolic syndrome (MetS), insulin resistance (IR), and the microbiome has not reached a consensus and lacks a systematic assessment. The purpose of our study is to evaluate, quantify, and summarize the association between these factors and BE risk. Methods: A systematic search of Pubmed, Embase, and Cochrane Library databases was performed to identify relevant studies before September 2018. Studies were estimated with the OR, the weighted mean difference (WMD), and the 95% CI by using a random effects model. Subgroup analysis and publication bias were also performed. Results: A total of 46 citations were included in the analysis, and 119,273 subjects were analyzed (AO 13, MetS 15, IR 9, and microbiome: 9). The pooled results showed that AO (p < 0.01, OR 1.30, 95% CI 1.11–1.52, I² = 31.9%), MetS (p < 0.01, OR 1.68, 95% CI 1.40–2.01, I² = 87.6%), and IR (p < 0.01, WMD 0.23, 95% CI 0.11–0.35, I² = 55.8%) were all significantly associated with an increased risk of BE, but except for the microbiome (p > 0.05, OR 1.27, 95% CI 0.66–2.43, I² = 46.7%). In addition, subgroup analyses were stratified by waist-to-hip ratio, waist circumference, body mass index, diagnosis criteria, strain type, geographical region, and study design, respectively. Moreover, we observed no evidence of publication bias in Egger’s and Begg’s tests. Conclusions: Our study reveals that AO, MetS, and IR are significantly associated with BE risk, except for the microbiome. The mechanism of BE induced by 3 risk factors should be further explored.

Purpose: To determine the population attributable fraction (PAF) of fatty liver disease (FLD) for type 2 diabetes mellitus (T2DM) and compare it to the PAFs of other metabolic abnormalities. Methods: We conducted a 10-year retrospective cohort study of 33,346 individuals in Karamay Central Hospital of Xinjiang. Individuals were followed up for T2DM occurrence based on FBS. The PAFs of FLD were calculated generally and respectively in different sex and age groups. A comparison of the PAF of FLD and that of other metabolic abnormalities, as well as the PAFs of FLD in different groups classified based on age and sex, was performed using Cox regression. Results: During an average follow-up period of 3.71 years, 1486 T2DM were diagnosed. The incidence density of T2DM was 1.2/100 person-years, and cumulative incidence rate was 4456.31/100,000 person-years. Partial PAF (PAF_p) of FLD in the entire population was 23.11%. In the male population, PAF_p was higher at 30–40 years old. In the female population, it was higher when age ≥ 60 years old. In multivariable Cox regression model, FLD, male sex, age ≥ 45 years old, overweight, hypertriglyceridaemia, and systolic hypertension were independent risk factors for T2DM, with corresponding PAF_p of 25.00%, 24.99%, 36.47%, 24.96%, 5.71%, and 6.76%, respectively. Age ≥ 45 years old showed the highest PAFp and adjusted hazard ratio, followed by FLD. Conclusions: FLD contributes more to T2DM incidence than other metabolic disorders. Particular attention should be given to male populations of 30–40 and female populations above 60 for FLD prevention and treatment.