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Abstract The nasal and bronchial epithelium are unified parts of the respiratory tract that are affected in the monogenic disorder cystic fibrosis (CF). Recent studies have uncovered that nasal and bronchial tissues exhibit intrinsic variability, including differences in mucociliary cell composition and expression of unique transcriptional regulatory proteins which relate to germ layer origin. In the present study, we explored whether intrinsic differences between nasal and bronchial epithelial cells persist in cell cultures and affect epithelial cell functioning in CF. Comparison of air–liquid interface (ALI) differentiated epithelial cells from subjects with CF revealed distinct mucociliary differentiation states of nasal and bronchial cultures. Moreover, using RNA sequencing we identified cell type-specific signature transcription factors in differentiated nasal and bronchial epithelial cells, some of which were already poised for expression in basal progenitor cells as evidenced by ATAC sequencing. Analysis of differentiated nasal and bronchial epithelial 3D organoids revealed distinct capacities for fluid secretion, which was linked to differences in ciliated cell differentiation. In conclusion, we show that unique phenotypical and functional features of nasal and bronchial epithelial cells persist in cell culture models, which can be further used to investigate the effects of tissue-specific features on upper and lower respiratory disease development in CF.

Abstract Background Cystic fibrosis is a rare recessive monogenic disease caused by loss-of-function mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Recently developed CFTR-modulators (i.e. drugs that rescue CFTR-function) have improved the prognosis of the disease, but are only available for certain, relatively common mutations. More than 2000 genetic variants in CFTR have been described, many of which are uncharacterized, while efficacy of CFTR-modulators can differ depending on genotype. Personalized models that can predict drug efficacy in patients with rare mutations could help to provide access to effective CFTR-modulator treatment. The forskolin induced swelling (FIS) assay in rectal organoids can robustly measure CFTR-function and CFTR-modulator efficacy, and pilot studies indicate that FIS accurately predicts treatment efficacy in individual patients. In the HIT-CF Organoid Study, rectal organoids from patients with rare CFTR-mutations are screened for CFTR-modulator efficacy to identify patients that could clinically benefit from these drugs. Methods In this EU-H2020 funded multi-centre study, rectal biopsies are obtained from approximately 500 subjects with rare CFTR-mutations from 17 different EU countries and sent to central laboratories. Organoids are generated, on which several novel CFTR-modulating drugs are screened for efficacy. In the process, a biobank is generated which could be used for future research. Subjects whose organoids show a response to treatment will be asked to participate in subsequent clinical trials evaluating the clinical efficacy of tested drugs. Discussion The HIT-CF Organoid Study applies the intestinal organoid model for personalized medicine in patients with rare variant cystic fibrosis, who are currently excluded from classical CFTR-modulator trials. Together with the subsequent clinical trials in high responders, this study aims to create a new pathway for access to CFTR-modulating drugs for patients with ultra-rare CFTR variants. Trial registration This trial has been registered in the Netherlands Trial Registry (NTR7520, https://www.trialregister.nl/trial/7304 ), a primary registry approved and recognized by WMO and ICMJE, on 2018-10-02.

This article focuses on a specific aspect of the leaders of the four main British parties’ image-building strategies in the 2015 campaign—the stage-management of their private lives. Indeed, family life is used as a key instrument in the construction of a particular dimension of the leaders’ public personality theorised by Ana Inés Langer as the “private persona.” Based primarily on a televised corpus, it seeks to analyse the political messages that were conveyed through public fatherhood. In addition, attention is devoted to the involvement of the leaders’ wives.