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Most known pathogenic point mutations in humans are C center dot G to T center dot A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle-based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases., Base editors are effective and safe for cholesterol reduction in non-human primates., Nature Biotechnology, 39 (8), ISSN:1546-1696, ISSN:1087-0156

The relevance of pancreatic texture for pancreatic fistula (POPF) formation after distal pancreatectomy (DP) remains ill defined. Recent POPF definition adjustments and common subjective pancreatic texture assessment are further drawbacks in the investigation of pancreatic texture as a factor for POPF development after DP. The predictive value of pancreatic texture by histologic assessment was investigated for POPF formation after DP, respecting the updated 2016 fistula definition. Histologic evaluation at the resection margin included amount of steatosis, degree of fibrosis, and pancreatic duct size. A total of 102 patients who underwent DP were included. Thirty-six patients developed POPF. There was no difference in histologic variables in patients with and without POPF. In the univariate analysis, none of the three histologic features showed significant correlation with POPF formation. The ROC (receiver operating characteristic) curve demonstrated poor utility for the grade of steatosis 0.481 ± 0.058 (p = 0.75) and grade of fibrosis 0.466 ± 0.058 (p = 0.57) as predictive factors for POPF formation. Results indicate that pancreatic texture does not predict POPF formation following DP. This is particularly relevant in the context of the increasing use of robotic and laparoscopic approaches for DPs with limited clinical pancreatic texture assessment by palpation.