The retinoic acid response is a minor component of the cardiac phenotype in H9c2 myoblast differentiation.

The H9c2 myoblast cell line, isolated from the left ventricular tissue of rat, is currently used in vitro as a mimetic for skeletal and cardiac muscle due to its biochemical, morphological, and electrical/hormonal signaling properties. During culture, H9c2 cells acquire a myotube phenotype, where a critical component is the inclusion of retinoic acid (RA). The results from some authors on H9c2 suggested that thousands of genes respond to RA stimuli, while others report hundreds of genes responding to RA over different cell types. In this article, using a more appropriate experimental design, we first confirm the H9c2 cardiac phenotype with and without RA and report transcriptomic and physiological changes regarding calcium handling, bioenergetics, and other biological concepts. Interestingly, of the 2360 genes showing a transcriptional change, 622 genes were statistically associated with the RA response. Of these genes, only 305 were RA-specific, and the rest also showed a culture-time component. Thus, the major expression changes (from 74 to 87%) were indeed due to culture conditions over time. Unexpectedly, only a few components of the retinol pathway in KEGG responded to RA. Our results show the role of RA in the H9c2 cultures impacting the interpretation using H9c2 as an in vitro model.

Molecular mechanisms of multi-omic regulation in breast cancer.

Breast cancer is a complex disease that is influenced by the concurrent influence of multiple genetic and environmental factors. Recent advances in genomics and other high throughput biomolecular techniques (-omics) have provided numerous insights into the molecular mechanisms underlying breast cancer development and progression. A number of these mechanisms involve multiple layers of regulation. In this review, we summarize the current knowledge on the role of multiple omics in the regulation of breast cancer, including the effects of DNA methylation, non-coding RNA, and other epigenomic changes. We comment on how integrating such diverse mechanisms is envisioned as key to a more comprehensive understanding of breast carcinogenesis and cancer biology with relevance to prognostics, diagnostics and therapeutics. We also discuss the potential clinical implications of these findings and highlight areas for future research. Overall, our understanding of the molecular mechanisms of multi-omic regulation in breast cancer is rapidly increasing and has the potential to inform the development of novel therapeutic approaches for this disease.

Epigenetics and Postsurgical Pain: A Scoping Review.

OBJECTIVE: Multiple factors are involved in the physiology and variability of postsurgical pain, a great part of which can be explained by genetic and environmental factors and their interaction. Epigenetics refers to the mechanism by which the environment alters the stability and expression of genes. We conducted a scoping review to examine the available evidence in both animal models and clinical studies on epigenetic mechanisms involved in the regulation of postsurgical and chronic postsurgical pain. METHODS: The Arksey and O'Malley framework and the PRISMA-ScR (Preferred Reporting Items for Systematic Review and Meta-Analysis, scoping reviews extension) guidelines were used. The PubMed, Web of Science, and Google Scholar databases were searched, and the original articles cited in reviews located through the search were also reviewed. English-language articles without time limits were retrieved. Articles were selected if the abstract addressed information on the epigenetic or epigenomic mechanisms, histone, or DNA methylation and microribonucleic acids involved in postsurgical and chronic postsurgical pain in animal models and clinical studies. RESULTS: The initial search provided 174 articles, and 95 were used. The available studies to date, mostly in animal models, have shown that epigenetics contributes to the regulation of gene expression in the pathways involved in postsurgical pain and in maintaining long-term pain. CONCLUSION: Research on possible epigenetic mechanisms involved in postsurgical pain and chronic postsurgical pain in humans is scarce. In view of the evidence available in animal models, there is a need to evaluate epigenetic pain mechanisms in the context of human and clinical studies.

Epigenetic Control of Hypertension by DNA Methylation: A Real Possibility.

Hypertension is a common chronic disease that particularly affects the elderly and can trigger several cardiovascular conditions. Although the treatment of hypertension has evolved in recent decades, many hypertensive patients still do not have properly controlled blood pressure. Accumulating evidence supports the hypothesis that DNA methylation plays an important role in regulating gene expression, altering the phenotype and function of the cardiovascular system. The present review highlights recent advances in research on DNA methylation in the development of hypertension. Several preclinical and clinical evidence show that methylation of different targets appears to be involved in hypertension. Studies of the involvement of DNA methylation have greatly improved our understanding of hypertension, but its use as a valid therapeutic target is still unknown. Further studies could help to bring to light the truth about gene therapy in hypertension.

Precision medicine in Ewing sarcoma: a translational point of view.

Ewing sarcoma is a rare tumor that arises in bones of children and teenagers but, in 15% of the patients it is presented as a primary soft tissue tumor. Balanced reciprocal chimeric translocation t(11;22)(q24;q12), which encodes an oncogenic protein fusion (EWSR1/FLI1), is the most generalized and characteristic molecular event. Using conventional treatments, (chemotherapy, surgery and radiotherapy) long-term overall survival rate is 30% for patients with disseminated disease and 65-75% for patients with localized tumors. Urgent new effective drug development is a challenge. This review summarizes the preclinical and clinical investigational knowledge about prognostic and targetable biomarkers in Ewing sarcoma, finally suggesting a workflow for precision medicine committees.

Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation.