Although targeting BRAF mutants with RAF inhibitors has achieved promising outcomes in cancer therapy, drug resistance remains a remarkable challenge, and underlying molecular mechanisms are not fully understood. Here, we characterized a previously unknown group of oncogenic BRAF mutants with in-frame insertions (LLRins506 or VLRins506) of αC-β4 loop. Using structure modeling and molecular dynamics simulation, we found that these insertions formed a large hydrophobic network that stabilizes R-spine and thus triggers the catalytic activity of BRAF. Furthermore, these insertions disrupted BRAF dimer interface and impaired dimerization. Unlike BRAF(V600E), these BRAF mutants with low dimer affinity were strongly resistant to all RAF inhibitors in clinic or clinical trials, which arises from their stabilized R-spines. As predicted by molecular docking, the stabilized R-spines in other BRAF mutants also conferred drug resistance. Together, our data indicated that the stability of R-spine but not dimer affinity determines the RAF inhibitor resistance of oncogenic BRAF mutants.
Introduction: Central venous occlusive disease (CVOD) is a complication that can occur in patients with end-stage renal disease who are receiving hemodialysis. When CVOD develops, patients often require multiple re-interventions to maintain their dialysis access. CVOD can be treated by various strategies such as balloon angioplasty, stenting, lower limb or extra-anatomical grafts, hybrid grafts or surgical bypasses such as right atrial (RA). In this systematic review, we aim to evaluate the indications, technical aspects, and outcomes after RA bypass grafting for the treatment of CVOD in hemodialysis patients. Methods: A systematic and comprehensive literature search was conducted using various electronic databases. We included articles that reported described and reported outcomes of RA bypass grafting for the treatment of CVOD in hemodialysis patients. A narrative review of the indications and technical aspects of RA bypass grafting was performed. We also pooled and reported the primary patency, secondary patency, postoperative complications, and 30-day mortality of RA bypass grafting. Results: A total of 21 studies with 55 patients who underwent RA bypass grafting were included in our systematic review. Follow-up period ranged from 0.5 to 84 months. The mean pooled primary patency and secondary patency of RA bypass grafting were 8.1 ± 4.9 and 21.7 ± 20.1 months, respectively. The incidence of early postoperative complications such as surgical site infection, bleeding, and access thrombosis was 0%, 4%, and 4%, respectively. The overall 30-day mortality was 4%. Conclusions: This systematic review summarizes the patient characteristics, technical features and outcomes of RA bypass grafting in the treatment of hemodialysis-related CVOD. RA bypass grafting may be a viable last-resort option when less invasive or conventional treatment options have been exhausted.
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