Personalized medicine in cystic fibrosis: genistein supplementation as a treatment option for patients with a rare S1045Y-CFTR mutation.

Cystic fibrosis (CF) is a life-shortening disease caused by the mutations that generate nonfunctional CF transmembrane conductance regulator (CFTR) protein. A rare serine-to-tyrosine (S1045Y) CFTR mutation was earlier reported to result in CF-associated fatality. We identified an African-American patient with the S1045Y mutation in CFTR, as well as a stop-codon mutation, who has a mild CF phenotype. The underlying mechanism of CF caused by S1045Y-CFTR has not been elucidated. In this study, we determined that S1045Y-CFTR exhibits twofold attenuated function compared with wild-type (WT)-CFTR. We report that serine-to-tyrosine mutation leads to increased tyrosine phosphorylation of S1045Y-CFTR, followed by recruitment and binding of E3-ubiquitin ligase c-cbl, resulting in enhanced ubiquitination and passage of S1045Y-CFTR in the endosome/lysosome degradative compartments. We demonstrate that inhibition of tyrosine phosphorylation partially rescues S1045Y-CFTR surface expression and function. Based on our findings, it could be suggested that consuming genistein (a tyrosine phosphorylation inhibitor) would likely ameliorate CF symptoms in individuals with S1045Y-CFTR, providing a unique personalized therapy for this rare CF mutation.

Cirrhosis-related sarcopenia may not resolve after liver transplantation.

Background & Aims: Sarcopenia has significant burden in cirrhosis and has been shown to worsen short-term post-liver transplantation (LT). This study aims to evaluate the long-term change in sarcopenia post-LT along with its associations and predictors. Methods: A retrospective study of adult patients who underwent LT at a tertiary centre between 1/1/2009 and 12/31/2018. Relevant demographic and clinical data were collected. Skeletal muscle index (SMI) was calculated using standard of care computerised tomography (CT) scans pre- and post-LT. Sarcopenia was defined using previously established cut-points. The primary outcome was SMI change post-LT and secondary outcome was post-LT mortality. Results: Out of 1165 patients, 401 met inclusion criteria (1,205 CT scans reviewed). The average age at transplant was 57 years; 63% were male. The average BMI was 28 kg/m2. Thirteen percent of females and 32% of males had sarcopenia pre-LT. Post-LT SMI declined by 4.7 cm2/m2 in the first year then by 0.39 cm2/m2 per year thereafter. Females had greater rate of decline in SMI after the first year compared with males (0.87 cm2/m2 per year vs. 0.17 cm2/m2 per year, respectively, p = 0.02). Post-LT physical rehabilitation, infection, and readmissions were not associated with SMI trajectory. At 3 years post-LT, 31% of females and 48% of males had sarcopenia. Baseline sarcopenia was the only predictor of long-term post-LT sarcopenia on multivariable analysis, but it was not associated with mortality. Conclusions: Sarcopenia does not appear to resolve post-LT and likely worsens leading to nearly doubling its prevalence in those with long-term follow-up. Immediate post-LT physical rehabilitation was not associated with SMI trajectory in our cohort. Impact and implications: The prevalence of sarcopenia is high among patients with cirrhosis; however, data are mixed on the impact of sarcopenia on post-liver transplant (LT) course and there have been no studies evaluating the long-term evolution of sarcopenia post-LT beyond 1 year. In this study, we analysed changes in muscle mass up to 3 years after transplant in 401 patients and found that sarcopenia did not resolve in most liver transplant recipients and skeletal muscle mass tended to worsen after transplant with the greatest decline in muscle mass in the first year post-LT. Interestingly, sarcopenia did not influence post-transplant outcomes. Future prospective studies are needed to further understand the natural course of sarcopenia post-LT to guide interventions aiming at reversing post-LT sarcopenia.