Non-Coding Ribonucleic Acids as Diagnostic and Therapeutic Targets in Cardiac Fibrosis.

PURPOSE OF REVIEW: Cardiac fibrosis is a crucial juncture following cardiac injury and a precursor for many clinical heart disease manifestations. Epigenetic modulators, particularly non-coding RNAs (ncRNAs), are gaining prominence as diagnostic and therapeutic tools. RECENT FINDINGS: miRNAs are short linear RNA molecules involved in post-transcriptional regulation; lncRNAs and circRNAs are RNA sequences greater than 200 nucleotides that also play roles in regulating gene expression through a variety of mechanisms including miRNA sponging, direct interaction with mRNA, providing protein scaffolding, and encoding their own products. NcRNAs have the capacity to regulate one another and form sophisticated regulatory networks. The individual roles and disease relevance of miRNAs, lncRNAs, and circRNAs to cardiac fibrosis have been increasingly well described, though the complexity of their interrelationships, regulatory dynamics, and context-specific roles needs further elucidation. This review provides an overview of select ncRNAs relevant in cardiac fibrosis as a surrogate for many cardiac disease states with a focus on crosstalk and regulatory networks, variable actions among different disease states, and the clinical implications thereof. Further, the clinical feasibility of diagnostic and therapeutic applications as well as the strategies underway to advance ncRNA theranostics is explored.

Ranking United States University-Based General Surgery Programs on the Academic Achievement of Surgery Department Faculty.

OBJECTIVE: Rankings of residency programs are highly influential and utilized by residency applicants. Existing ranking resources often use opaque criteria that may include bias or do not accurately represent the academic achievement of current faculty. This study aims to create an updated general surgery residency ranking list based on the academic achievements of their respective surgery department faculty members. DESIGN: One hundred and six general surgery residency programs were selected from the American Medical Association Residency & Fellowship Programs Database. The names of faculty members affiliated with the departments of surgery were manually obtained. Lifetime and five-year h-indexes, a sum of grant awards from the National Institute of Health and Veterans Affairs, and a tally of journal editorial board positions were collected for the faculty. Metrics were compared among surgical departments, and the corresponding residency programs were ranked accordingly. SETTING: The study evaluated university-based general surgery residency programs in the United States from 2017 to 2019 via assessing their respective institutions' departments of surgery. PARTICIPANTS: A total of 7568 faculty members were evaluated. Faculty were required to be full-time, clinical surgeons to meet inclusion criteria. RESULTS: Based on a composite of all measured criteria, the top overall surgery department was at the University of Michigan. Massachusetts General Hospital had the highest lifetime and five-year h-indexes. Brigham and Women's Hospital had the most National Institute of Health funding, and the University of Pittsburgh Medical Center had the most Veterans Affairs funding. Washington University in St. Louis/Barnes Jewish Hospital had the most editorial board positions in their department. CONCLUSIONS: The academic success of departments of surgery was evaluated to develop a ranking list of general surgery residency programs. Through utilizing standardized methods and several measures of academic achievement, this comprehensive general surgery residency classification system will allow residency applicants to make more informed decisions.

Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma.

We recently reported the development of a novel inhibitor of Rho-mediated gene transcription (1, CCG-203971) that is efficacious in multiple animal models of acute fibrosis, including scleroderma, when given intraperitoneally. The modest in vivo potency and poor pharmacokinetics (PK) of this lead, however, make it unsuitable for long term efficacy studies. We therefore undertook a systematic medicinal chemistry effort to improve both the metabolic stability and the solubility of 1, resulting in the identification of two analogs achieving over 10-fold increases in plasma exposures in mice. We subsequently showed that one of these analogs (8f, CCG-232601) could inhibit the development of bleomycin-induced dermal fibrosis in mice when administered orally at 50mg/kg, an effect that was comparable to what we had observed earlier with 1 at a 4-fold higher IP dose.