Targeted Delivery of Abaloparatide to Spinal Fusion Site Accelerates Fusion Process in Rats.

Spinal fusions are performed to treat congenital skeletal malformations, spondylosis, degenerative disk diseases, and other pathologies of the vertebrae that can be resolved by reducing motion between neighboring vertebrae. Unfortunately, up to 100,000 fusion procedures fail per year in the United States, suggesting that efforts to develop new approaches to improve spinal fusions are justified. We have explored whether the use of an osteotropic oligopeptide to target an attached bone anabolic agent to the fusion site might be exploited to both accelerate the mineralization process and improve the overall success rate of spinal fusions. The data presented below demonstrate that subcutaneous administration of a modified abaloparatide conjugated to 20 mer of D-glutamic acid not only localizes at the spinal fusion site but also outperforms the standard of care (topically applied BMP2) in both speed of mineralization (p < 0.05) and overall fusion success rate (p < 0.05) in a posterior lateral spinal fusion model in male and female rats, with no accompanying ectopic mineralization. Because the bone-localizing conjugate can be administered ad libitum post-surgery, and since the procedure appears to improve on standard of care, we conclude that administration of a bone-homing anabolic agent for improvement of spinal fusion surgeries warrants further exploration.

H3K27ac acts as a molecular switch for doxorubicin-induced activation of cardiotoxic genes.

BACKGROUND: Doxorubicin (Dox) is an effective chemotherapeutic drug for various cancers, but its clinical application is limited by severe cardiotoxicity. Dox treatment can transcriptionally activate multiple cardiotoxicity-associated genes in cardiomyocytes, the mechanisms underlying this global gene activation remain poorly understood. METHODS AND RESULTS: Herein, we integrated data from animal models, CUT&Tag and RNA-seq after Dox treatment, and discovered that the level of H3K27ac (a histone modification associated with gene activation) significantly increased in cardiomyocytes following Dox treatment. C646, an inhibitor of histone acetyltransferase, reversed Dox-induced H3K27ac accumulation in cardiomyocytes, which subsequently prevented the increase of Dox-induced DNA damage and apoptosis. Furthermore, C646 alleviated cardiac dysfunction in Dox-treated mice by restoring ejection fraction and reversing fractional shortening percentages. Additionally, Dox treatment increased H3K27ac deposition at the promoters of multiple cardiotoxic genes including Bax, Fas and Bnip3, resulting in their up-regulation. Moreover, the deposition of H3K27ac at cardiotoxicity-related genes exhibited a broad feature across the genome. Based on the deposition of H3K27ac and mRNA expression levels, several potential genes that might contribute to Dox-induced cardiotoxicity were predicted. Finally, the up-regulation of H3K27ac-regulated cardiotoxic genes upon Dox treatment is conservative across species. CONCLUSIONS: Taken together, Dox-induced epigenetic modification, specifically H3K27ac, acts as a molecular switch for the activation of robust cardiotoxicity-related genes, leading to cardiomyocyte death and cardiac dysfunction. These findings provide new insights into the relationship between Dox-induced cardiotoxicity and epigenetic regulation, and identify H3K27ac as a potential target for the prevention and treatment of Dox-induced cardiotoxicity.

Hi-C, a chromatin 3D structure technique advancing the functional genomics of immune cells.

The functional performance of immune cells relies on a complex transcriptional regulatory network. The three-dimensional structure of chromatin can affect chromatin status and gene expression patterns, and plays an important regulatory role in gene transcription. Currently available techniques for studying chromatin spatial structure include chromatin conformation capture techniques and their derivatives, chromatin accessibility sequencing techniques, and others. Additionally, the recently emerged deep learning technology can be utilized as a tool to enhance the analysis of data. In this review, we elucidate the definition and significance of the three-dimensional chromatin structure, summarize the technologies available for studying it, and describe the research progress on the chromatin spatial structure of dendritic cells, macrophages, T cells, B cells, and neutrophils.