Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers

Transcatheter Aortic Valve Replacement for Failed Surgical or Transcatheter Bioprosthetic Valves: A Comprehensive Review

Transcatheter aortic valve replacement (TAVR) has proven to be a safe, effective, and less invasive approach to aortic valve replacement in patients with aortic stenosis. In patients who underwent prior aortic valve replacement, transcatheter and surgical bioprosthetic valve dysfunction may occur as a result of structural deterioration or nonstructural causes such as prosthesis–patient mismatch (PPM) and paravalvular regurgitation. Valve-in-Valve (ViV) TAVR is a procedure that is being increasingly utilized for the replacement of failed transcatheter or surgical bioprosthetic aortic valves. Data regarding long-term outcomes are limited due to the recency of the procedure’s approval, but available data regarding the short- and long-term outcomes of ViV TAVR are promising. Studies have shown a reduction in perioperative and 30-day mortality with ViV TAVR procedures compared to redo surgical repair of failed bioprosthetic aortic valves, but 1-year and 5-year mortality rates are more controversial and lack sufficient data. Despite the reduction in 30-day mortality, PPM and rates of coronary obstruction are higher in ViV TAVR as compared to both redo surgical valve repair and native TAVR procedures. New transcatheter heart valve designs and new procedural techniques have been developed to reduce the risk of PPM and coronary obstruction. Newer generation valves, new procedural techniques, and increased operator experience with ViV TAVR may improve patient outcomes; however, further studies are needed to better understand the safety, efficacy, and durability of ViV TAVR