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PURPOSE: Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis-related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. METHODS: Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. RESULTS: The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. CONCLUSION: We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patientspecific CFRD risk to guide CFRD monitoring and treatment.

Immunotoxicity studies of nanoparticles on T cells addressed their effects on activation by T antigen receptor, but have neglected the regulation of proliferation by IL-2. In this study, the IL-2-dependent T lymphoblastoid WE17/10 cell line was used to compare silver (Ag-NPs) and fullerene (C60-NPs) nanoparticles' toxicity and evaluate whether these NPs could interfere with IL-2-dependent proliferation. Results have shown that Ag-NPs are more toxic, as they reduced cell viability at the highest concentration tested (100 μg/ml), while C60-NPs have shown good biocompatibility. Characterization of NP suspensions by dynamic light scattering measured large aggregates for C60-NPs, whereas Ag-NPs were relatively stable and well dispersed. This translated into a much larger uptake of Ag-NPs compared to C60-NPs, as measured by flow cytometry. Proliferation measurements by CFSE following 72 h incubation have shown that Ag-NPs decrease cell proliferation and C60-NPs slightly increase proliferation. CD25 expression was unchanged following exposure to C60-NPs, but was significantly increased by Ag-NPs' presence for short and long-term incubations. Analyses of three key signaling proteins activated by IL-2 receptor (Stat5, JNK and ERK1/2) by western immunoblotting have shown no effects from either NPs on Stat5 and JNK phosphorylation. ERK1/2 was slightly activated following a short exposure to Ag-NPs, while C60-NPs had no effect. Our results show that C60-NPs have good biocompatibility and do not interfere with IL-2-dependent proliferation. A deeper investigation would be needed for the case of Ag-NPs, since the mechanism of their action is still unclear.

Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10−44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

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