Front Pediatr

BACKGROUND: Nutritional status is a major prognostic factor for breathing and the survival of patients with cystic fibrosis (CF). Since 2012, the development of CFTR modulators has considerably transformed the outcome of this disease. Indeed, both lung function and body mass index are improved by CFTR modulators, such as Lumacaftor/Ivacaftor. However, few data exist regarding the outcome of nutritional intakes under Lumacaftor/Ivacaftor. METHODS: We conducted a prospective single-center study in children with CF treated with Lumacaftor/Ivacaftor to evaluate their nutritional intake before and after treatment. RESULTS: Thirty-four children were included in this study, with a median age of 12.4 years [11.9; 14.7]. There was no significant improvement in weight, height or BMI. Patients' total energy intake was not significantly changed with Lumacaftor/Ivacaftor, while carbohydrate intakes decreased significantly. We found that blood levels of vitamin E and Selenium were significantly increased under Lumacaftor/Ivacaftor, without a significant increase in supplementation. In patients with a BMI Z-score < 0 at treatment initiation, there was a significant improvement in weight and BMI Z-score, while TEI and carbohydrate intakes were significantly lower. CONCLUSION: We showed that treatment with Lumacaftor/Ivacaftor improved the nutritional status of patients without necessarily being associated with an increase in nutritional intake. Although these data need to be confirmed in larger cohorts, they support the hypothesis that weight gain under modulators is multifactorial, and may be related to a decrease in energy expenditure or an improvement in absorption

Dietary intake assessment in children with cystic fibrosis using 3-day food diaries: a single-centre study

BACKGROUND: Malnutrition is both a feature and major cause of morbidity in cystic fibrosis (CF). Therefore, nutritional management is an essential element of patient care. In 2016, an international guideline for nutritional management in patients with CF was published. In light of these recommendations, the aim of this study was to investigate the dietary intake of children with CF at the University Hospital of Bordeaux. METHODS: We conducted a retrospective study at the Paediatric CF Centre of the University Hospital of Bordeaux. Patients aged 2-18 years with CF who completed a 3-day food diary at home between January 2015 and December 2020 were included. RESULTS: A total of 130 patients, with a median age of 11.8 [interquartile range (IQR): 8.3; 13.4] years, were included. The median Z-score for BMI was -0.35 (IQR: -0.9; 0.2) and 20% of the patients had a Z-score for BMI < -1. Recommended total energy intakes were achieved in 53% of the patients, particularly those with nutritional support. Recommended protein intake was met in 28% of the cases, while fat and carbohydrate intakes were met in 54%. Vitamin and micronutrient levels were normal in 80% of the patients, with the exception of vitamin K, which was within the therapeutic range in only 42% of the cases. CONCLUSION: Recommended nutritional targets are difficult to achieve in patients with CF, and providing nutritional support during follow-up remains a challenge

A quantitative imaging-based screen reveals the exocyst as a network hub connecting endocytosis and exocytosis

The coupling of endocytosis and exocytosis underlies fundamental biological processes ranging from fertilization to neuronal activity and cellular polarity. However, the mechanisms governing the spatial organization of endocytosis and exocytosis require clarification. Using a quantitative imaging-based screen in budding yeast, we identified 89 mutants displaying defects in the localization of either one or both pathways. High-resolution single-vesicle tracking revealed that the endocytic and exocytic mutants she4 Delta and bud6 Delta alter post-Golgi vesicle dynamics in opposite ways. The endocytic and exocytic pathways display strong interdependence during polarity establishment while being more independent during polarity maintenance. Systems analysis identified the exocyst complex as a key network hub, rich in genetic interactions with endocytic and exocytic components. Exocyst mutants displayed altered endocytic and post-Golgi vesicle dynamics and interspersed endocytic and exocytic domains compared with control cells. These data are consistent with an important role for the exocyst in coordinating endocytosis and exocytosis

Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant

International audienceGastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present