Xiamen Chang Gung Hospital

Colorectal cancer (CRC) represents a major cause of cancer-related mortality worldwide. Exosomes derived from cancer-associated fibroblasts (CAFs-Exo) transfer oncogenic signals to cancer cells, promoting tumor growth, metastasis, and glutamine metabolism. However, the specific contribution of CAFs-Exo to the pathogenesis of CRC is still largely unexplored. The conditioned medium of CAFs (CAF-CM) and CAFs-Exo were used to treat CRC cells. The effects on cell behaviors were evaluated by measuring cell viability, proliferation, migration, invasion, and sphere formation. The influence on glutamine metabolism was assessed by detecting glutamine consumption and glutamine and α-ketoglutarate production. MeRIP, RIP, RNA pull-down, and mRNA stability assays were used to assess the METTL1/SLC1A5 mRNA interaction. Animal experiments were used to evaluate the function of CAFs-Exo invivo. CAF-CM promoted CRC cell proliferation, migration, invasion, sphere formation, and glutamine metabolism invitro. CAF-CM increased METTL1 expression and m7G modification levels in CRC cells. Si-METTL1-CAF-CM exerted inhibitory effects on CRC cell malignant behaviors and glutamine metabolism. Mechanistically, METTL1 stabilized SLC1A5 mRNA by mediating its m7G modification. SLC1A5 overexpression reversed the inhibitory effects of si-METTL1-CAF-CM on CRC cell malignant behaviors and glutamine metabolism. Furthermore, CAFs-Exo increased METTL1 protein levels in CRC cells. Sh-METTL1-CAFs-Exo suppressed tumor growth and lung metastasis invivo. Our findings identify a novel CAFs-Exo/METTL1/SLC1A5 axis that drives CRC progression partially by reprogramming glutamine metabolism, revealing new potential therapeutic targets for CRC treatment.

The genome-wide association study (GWAS) summary data utilized in this study are publicly available from the IEU OpenGWAS project, UK Biobank (UKB), FinnGen and Blood Cell Consortium. We acknowledge all the consortiums, investigators, and participants for making these resources available. Table S1: The IVs for downregulated IL-13 signaling proxied by decreased circulating eosinophil counts. Table S2: Overview of outcome GWAS datasets and sample overlap bias estimates. Table S3: Results of Mendelian randomization. Table S4: Heterogeneity test of Mendelian randomization. Table S5: Pleiotropy test of Mendelian randomization. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Mavacamten is a novel selective cardiac myosin inhibitor indicated for patients with obstructive hypertrophic cardiomyopathy (oHCM). Given its negative inotropic properties, which theoretically reduce myocardial contractility and affect left atrial systolic function, concerns have arisen about its potential association with an increased incidence of atrial fibrillation (AF). The study aims to assess this potential association. We employed a dual approach combining real-world data analysis and evidence synthesis. First, disproportionality and time-to-onset analyses were performed using the FDA Adverse Event Reporting System (FAERS) across two models: the general population (Model 1) and an HCM-specific cohort (Model 2). Independent risk factors for AF were identified using logistic regression. Second, a meta-analysis of placebo-controlled trials was conducted to evaluate the safety profile of mavacamten, with pooled risk ratios (RRs) and 95% confidence intervals (CIs) . In the disproportionality analysis, Model 1 revealed a signal for AF with mavacamten (adjusted ROR 18.54, 95% CI 11.53–29.80, P < 0.05; EB05 11.55). In contrast, no significant disproportionality signal was observed in Model 2 (aROR 4.28, 95% CI 1.30–14.07, P = 0.017; EB05 0.74). The time-to-onset analysis indicated a random failure type for AF occurrence in mavacamten-treated patients. The meta-analysis included five RCTs and one retrospective cohort study. Compared with placebo, mavacamten was not associated with an increased risk of AF (RR = 0.92, 95% CI 0.80–1.06, P = 0.12). Our findings did not identify a significant association between mavacamten and AF in patients with HCM. These results should be interpreted with caution due to the limited number of studies and small sample sizes.

MicroRNAs are promising liquid biopsy biomarkers, but their clinical translation is hindered by detection challenges, including low abundance, high sequence similarity, and background interference. Here we present SE-SPTM-PCR, a detection platform integrating selective miRNA enrichment using locked nucleic acid probes with specific probe terminal mediated RT-qPCR. We show that SE-SPTM-PCR eliminates nonspecific amplification and achieves 100-fold higher sensitivity than conventional stem-loop RT-qPCR. In clinical studies, SE-SPTM-PCR significantly improves hsa-miR-92a-3p performance for colorectal cancer detection, increasing its AUC from 0.72 to 0.85 in 48 patients versus 48 controls. Additionally, SE-SPTM-PCR also restores utility to two abandoned biomarkers: For HCMV reactivation monitoring in 32 DNA positive and 32 DNA negative hematopoietic stem cell transplant recipients, hcmv-miR-UL22A-5p achieves an AUC of 0.95. For nasopharyngeal carcinoma, ebv-miR-BART3-3p reaches a perfect AUC of 1.0 in 40 patients and 40 controls. This platform provides a robust tool for miRNA-based liquid biopsy, offering enhanced diagnostic accuracy to support early disease detection and personalized treatment strategies.

Non-obese non-alcoholic fatty liver disease (NAFLD), or “lean NAFLD”, challenges the assumption that fatty liver predominantly affects obese individuals. In elderly populations, age-related changes in body composition further limit the utility of body mass index (BMI) for metabolic risk stratification. We aimed to characterise the metabolic profile of lean NAFLD and quantify dose–response relationships between key biochemical markers and NAFLD risk in elderly Chinese adults. We analysed health-examination data from community-dwelling adults aged $$\ge$$65 years attending a primary care centre in Xiamen, China (2022–2024). After excluding individuals with excessive alcohol intake, viral hepatitis markers, or missing ultrasound records, 10,586 participants were included. NAFLD was diagnosed ultrasonographically. Participants were classified as lean (BMI <24 kg/m$$^2$$) or overweight/obese (BMI $$\ge$$24 kg/m$$^2$$) per Chinese criteria. We compared metabolic profiles across four BMI–NAFLD phenotypes and performed stratified analyses by triglyceride-to-HDL cholesterol (TG/HDL-C) ratio and serum uric acid categories. NAFLD prevalence was 30.8% (3,258/10,586), with 35.8% (1,167/3,258) occurring in lean individuals. Lean NAFLD participants exhibited higher TG/HDL-C ratios, fasting glucose, glycated haemoglobin, and uric acid levels than Lean Healthy participants, alongside greater prevalence of hypertension (40.3% vs. 25.0%) and diabetes (23.1% vs. 8.9%). NAFLD prevalence increased from 14.2% (TG/HDL-C <1.0) to 59.4% (TG/HDL-C $$\ge$$2.0) among lean participants, and from 15.6% (normal uric acid) to 47.4% (hyperuricaemia). In multivariable models, the highest TG/HDL-C stratum (TG/HDL-C $$\ge$$2.0) conferred 2.26-fold increased odds of NAFLD (95% CI 1.98–2.57) versus the lowest stratum. A composite model combining TG/HDL-C, uric acid, waist circumference, and fasting glucose achieved an AUC of 0.706 (95% CI 0.688–0.724), substantially exceeding TG/HDL-C alone (AUC 0.615). Over one-third of NAFLD cases in this elderly cohort occurred in lean individuals with substantial metabolic disturbances, and 91.4% simultaneously met MASLD cardiometabolic criteria. TG/HDL-C $$\ge$$2.0 functions primarily as a high-specificity rule-in marker (specificity 97.9%, PPV 59.4%) rather than a screening tool; a composite model incorporating TG/HDL-C ratio, uric acid, waist circumference, and fasting glucose provides improved discrimination (AUC 0.706) for identifying lean individuals with hepatic steatosis in primary care settings where BMI-based screening alone is insufficient.

Inositol (ISL) refers to a group of simple carbohydrates known for their insulin-sensitizing effects, with Myo-inositol (MYO) and d-chiro-inositol (DCI) being the most prevalent isoforms. This umbrella meta-analysis aimed to evaluate the impact of inositol supplementation on gestational diabetes (GDM) as well as maternal and neonatal outcomes in women with GDM. We performed a systematic search of the literature in the PubMed and Scopus databases up until September 2024 to identify relevant studies. Publications with the following criteria were eligible: (i) the study design was a meta-analysis of RCTs, (ii) the population consisted of pregnant women with GDM, (iii) the intervention involved ISL supplementation, compared to a placebo, and (iv) the primary outcome was the incidence of GDM. The secondary outcomes included glycemic indices, preterm birth, pregnancy-induced hypertension, birth weight, neonatal hypoglycemia, gestational age at birth, cesarean delivery, shoulder dystocia, macrosomia, and neonatal intensive care unit admission. The pooled results were presented as standardized mean differences for continuous outcomes and relative risks (RR) with 95% confidence intervals (CI) for dichotomous outcomes, using a random effects model. A total of 19 studies involving 17 932 participants were included in the analysis. ISL supplementation was linked to a lower risk of GDM (RR: 0.42; 95% CI = 0.37-0.49), reduced need for insulin therapy (RR: 0.33; 95% CI = 0.19-0.58), decreased incidence of pregnancy-induced hypertension (RR: 0.34; 95% CI = 0.27-0.44), lower rates of preterm birth (RR: 0.38; 95% CI = 0.31-0.47), and a reduced rate of neonatal hypoglycemia. Additionally, ISL significantly lowered oral glucose tolerance test results, fasting blood sugar levels, and birth weight, while increasing fasting serum insulin levels and gestational age at birth. Subgroup analyses indicated that the effects varied based on the type of intervention and dosage of ISL used. Administering ISL during pregnancy might offer a promising approach to the prevention and management of GDM and its related health outcomes.