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Background: It is difficult to distinguish between arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM) because of their similar clinical manifestations. This study aimed to develop a novel diagnostic algorithm for distinguishing ACM from DCM. Methods: Two public datasets containing human ACM and DCM myocardial samples were used. Consensus clustering, non‐negative matrix factorization and principal component analysis were applied. Weighted gene co‐expression network analysis and machine learning methods, including random forest and the least absolute shrinkage and selection operator, were used to identify candidate genes. Receiver operating characteristic curves and nomograms were performed to estimate diagnostic efficacy, and Spearman's correlation analysis was used to assess the correlation between candidate genes and cardiac function indices. Results: Both ACM and DCM showed highly similar gene expression patterns in the clustering analyses. Hub gene modules associated with cardiomyopathy were obtained using weighted gene co‐expression network analysis. Thirteen candidate genes were selected using machine learning algorithms, and their combination showed a high diagnostic value (area under the ROC curve = 0.86) for distinguishing ACM from DCM. In addition, TATA‐box binding protein associated factor 15 showed a negative correlation with cardiac index (R = −0.54, p = 0.0054) and left ventricular ejection fraction (R = −0.48, p = 0.0015). Conclusions: Our study revealed an effective diagnostic model with key gene signatures, which indicates a potential tool to differentiate between ACM and DCM in clinical practice. In addition, we identified several genes that are highly related to cardiac function, which may contribute to our understanding of ACM and DCM. [ABSTRACT FROM AUTHOR]

There is growing interest in studying the genetic contributions to longevity, but limited relevant genes have been identified. In this study, we performed a genetic association study of longevity in a total of 15,651 Chinese individuals. Novel longevity loci, BMPER (rs17169634; p = 7.91 × 10−15) and TMEM43/XPC (rs1043943; p = 3.59 × 10−8), were identified in a case–control analysis of 11,045 individuals. BRAF (rs1267601; p = 8.33 × 10−15) and BMPER (rs17169634; p = 1.45 × 10−10) were significantly associated with life expectancy in 12,664 individuals who had survival status records. Additional sex‐stratified analyses identified sex‐specific longevity genes. Notably, sex‐differential associations were identified in two linkage disequilibrium blocks in the TOMM40/APOE region, indicating potential differences during meiosis between males and females. Moreover, polygenic risk scores and Mendelian randomization analyses revealed that longevity was genetically causally correlated with reduced risks of multiple diseases, such as type 2 diabetes, cardiovascular diseases, and arthritis. Finally, we incorporated genetic markers, disease status, and lifestyles to classify longevity or not‐longevity groups and predict life span. Our predictive models showed good performance (AUC = 0.86 for longevity classification and explained 19.8% variance of life span) and presented a greater predictive efficiency in females than in males. Taken together, our findings not only shed light on the genetic contributions to longevity but also elucidate correlations between diseases and longevity. [ABSTRACT FROM AUTHOR]

Therapeutically intervening the function of RNA in vivo remains a big challenge. We here developed an exosome-based strategy to deliver engineered RNA-binding protein for the purpose of recruiting specific RNA to the lysosomes for degradation. As a proof-of-principle study, RNA-binding protein HuR was fused to the C-terminus of Lamp2b, a membrane protein localized in both exosome and lysosome. The fusion protein was able to be incorporated into the exosomes. Moreover, exosomes engineered with Lamp2b-HuR successfully decreased the abundance of RNA targets possibly via lysosome-mediated degradation, especially when the exosomes were acidified. The system was specifically effective in macrophages, which are lysosome enriched and resistant to routine transfection mediated RNAi strategy. In the CCl4-induced liver injury mouse model, we found that delivery of acidified exosomes engineered with Lamp2b-HuR significantly reduced liver fibrosis, together with decreased miR-155 and other inflammatory genes. In summary, the established exosome-based RNA-binding protein delivery strategy, namely "exosome-mediated lysosomal clearance", takes the advantage of exosome in targeted delivery and holds great promise in regulating a set of genes in vivo. [ABSTRACT FROM AUTHOR]

Exosomes, which are small lipid bilayer vesicles that can be released by multiple cell types, mediate communication between cells by transporting nucleic acids, proteins, and other bioactive molecules. Pioneering studies have revealed that exosomes can exert multiple functions in shaping tumor immune responses in the crosstalk between tumor cells and surrounding immune cells. Emerging studies have also demonstrated the powerful function of engineered exosomes in cancer immunotherapy. Here, the recent progress in this field and focus on exosomes as mediators, drug carriers, and prognostic biomarkers in tumor immunotherapy is summarized. This review not only summarizes the progress of this field, but also provides insights and perspectives on exosome‐based strategies in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Cancer‐associated cachexia (CAC) has tremendous effects on the patient's tolerance to chemotherapy and the quality of life, especially in the advanced stages, such as the acute and terminal stages of chronic myeloid leukemia (CML). However, the underlying mechanisms and mediators remain unclear. Here, we showed that mice injected with CML‐derived exosomes had significant weight loss and great drop of body fat rate. In the meanwhile, we found that CML‐derived exosomes could be taken up by adipose tissue, and, in turn, suppressed the adipogenic ability of adipose‐derived mesenchymal stem cells (ADSCs). By RNA sequencing, miR‐92a‐3p was found highly expressed in both CML cells and the derivative exosomes. Mechanistically, miR‐92a‐3p inhibited adipogenesis of ADSCs via posttranscriptionally decreasing C/EBPα expression when transferred into the ADSCs with the exosomes, and encapsulating miR‐92a‐3p inhibitor into CML exosomes blocked the antiadipogenic effects of CML exosomes. In addition, we also found that miR‐92a‐3p was highly expressed in exosomes from some other types of cancers that cause cachexia. These results demonstrate that adipogenesis inhibition by tumor‐derived exosomes, mainly exosomal microRNAs like miR‐92a‐3p, are the main mediators for CAC. [ABSTRACT FROM AUTHOR]