Journal of Cystic Fibrosis最新文献

{"title":"WS04.02Gut microbiota-metabolome relationships across CFTR modulator usage: preliminary findings from the GRAMPUS-CF study","authors":"R. Marsh ,&nbsp;W. Cheung ,&nbsp;D. Arends ,&nbsp;D. Sills ,&nbsp;D.W. Rivett ,&nbsp;A.R. Smyth ,&nbsp;C. van der Gast","doi":"10.1016/j.jcf.2025.03.511","DOIUrl":"10.1016/j.jcf.2025.03.511","url":null,"abstract":"<div><h3>Objectives</h3><div>Despite shifts to highly effective CFTR modulators, some people with cystic fibrosis (pwCF) continue to experience intestinal abnormalities, associated symptoms, and gut microbiota dysbiosis. Baseline faecal samples across children and adults in the Gut Research Advancing a Mechanistic and Personalised Understanding of Symptoms in Cystic Fibrosis (GRAMPUS-CF) study were used to investigate relationships between gut microbiota composition and the intestinal metabolome under elexacaftor/tezacaftor/ivacaftor (ETI) treatment.</div></div><div><h3>Methods</h3><div>Gut microbiota profile was determined using PacBio full-length 16S HiFi sequencing (<em>n</em>=70). Untargeted metabolomics, including additional lipidomics, were performed with ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) (<em>n</em>=64). Correlation-based approaches were used to construct networks highlighting relationships between taxa and metabolites across paired samples. Participant clinical data was integrated to investigate associations with microbiota structure and function.</div></div><div><h3>Results</h3><div>A wide array of unique metabolites from the metabolomic (<em>n</em>=660) and lipidomic approaches (<em>n</em>=527) were identified from participant faecal samples. Network analyses highlighted both positive and negative associations across beneficial and potentially pathogenic taxa, extending to relationships with metabolites and lipids of physiological interest in the CF intestine. Clinical demographics also explained the variance observed across microbiota structure, alongside metabolomic and lipidomic profiles.</div></div><div><h3>Conclusions</h3><div>Faecal multi-omics indicate important relationships with gut microbiota structure across pwCF undertaking CFTR modulator therapy. Temporal dynamics of the gut microbiome across these participants will be investigated across ETI therapy in the GRAMPUS-CF study. Further clinical data, participant symptomatic data, and intestinal physiology metrics will support our future analyses.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S8"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS05.02CFTR mRNA delivery with a revolutionary non-LNP nanoemulsion formulation to differentiated primary human airway epithelium and airway organoid","authors":"K. Ito ,&nbsp;S. Hassibi ,&nbsp;Y. Yamamoto ,&nbsp;J. Shur ,&nbsp;G. Rapeport ,&nbsp;S. Sobolov","doi":"10.1016/j.jcf.2025.03.517","DOIUrl":"10.1016/j.jcf.2025.03.517","url":null,"abstract":"<div><h3>Objectives</h3><div>Cystic fibrosis (CF) is a progressive genetic disorder with impaired normal clearance of mucus due to the defect of a chloride channel, cystic fibrosis transmembrane regulator (CFTR). Currently approved CFTR modulators are applicable to limited genotypes and the universally applicable therapy would be functional CFTR protein expression by <em>CFTR</em> gene delivery. To address this challenge, RIGImmune has developed a non-LNP formulation delivery system, Nano-Emulsion Enhanced Delivery (NEED^TM) platform to deliver optimised CFTR encoded mRNA therapeutics.</div></div><div><h3>Methods</h3><div>Optimised <em>CFTR</em> mRNAs (Northern RNA, Canada) formulated with NEED^TM nanoemulsion system (RIG-301) were apically applied for up to 4 hrs to air-liquid interface (ALI) cultured differentiated human alveolar or bronchial epithelium (hAE or hBE, Epithelix) obtained from healthy subjects. Cells were collected at different timepoints up to 72hrs post-delivery, and CFTR protein was detected by western blotting. RIG-301 was also applied to human induced pluripotent stem cell (iPSC) derived CF ΔF508- airway organoids, and effects of forskolin-induced swelling were evaluated (HiLung Inc. Japan).</div></div><div><h3>Results</h3><div>RIG-301 nanoemulsion system (z-average particle size 176.9 nm) showed higher and long-lasting CFTR protein expression than naked CFTR mRNA delivery or delivered with jetPrime transfection reagent in hAE and hBE. In addition, RIG-301 showed an increased forskolin-induced swelling of CF-airway organoid, and the effects were comparable to or better than that of a triple combinations of CFTR modulators (VX-661/VX-445/VX-770: 3, 3 and 1 µM, respectively).</div></div><div><h3>Conclusion</h3><div>Our results demonstrate the capability of the NEED^TM platform to deliver optimised CFTR mRNA in ALI hAE and hBE cultures, as well as CF organoid. These preclinical data warrant further investigation of CFTR delivery and functional rescue in cells derived from CF patients.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S10"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS05.03Single administration of a lipid nanoparticle encapsulating HA-tagged CFTR mRNA to non-human primate lung results in expression of mRNA and protein in airway epithelium","authors":"J. Chen,&nbsp;M. El Khatib,&nbsp;G. Venkataraman,&nbsp;K. Srinivasan,&nbsp;J. Cefalu,&nbsp;S. Sherman,&nbsp;S. Katikaneni,&nbsp;S. Mohapatra,&nbsp;E. Hoxha,&nbsp;V. Kharitonov,&nbsp;B. Wustman,&nbsp;D. Ishimaru,&nbsp;J.A. Couch,&nbsp;D.J. Lockhart,&nbsp;M. Weinberg,&nbsp;H. Clark","doi":"10.1016/j.jcf.2025.03.518","DOIUrl":"10.1016/j.jcf.2025.03.518","url":null,"abstract":"<div><h3>Objectives</h3><div>Airway epithelial cells represent a key therapeutic target for the treatment of cystic fibrosis (CF), as abnormal CF <em>t</em>ransmembrane conductance regulator (CFTR) function in these cells drives the progression of lung disease in patients. The aim of the current study was to evaluate the cell-specific biodistribution and expression of a <em>CFTR</em> mRNA encapsulated in lipid nanoparticles (LNPs) upon delivery to the lungs of non-human primates.</div></div><div><h3>Methods</h3><div>Cynomolgus macaques (N=2 + 1 control) were anesthetized and delivered a HA-tagged human <em>CFTR</em> mRNA encapsulated in a ReCode Therapeutics LNP via intratracheal intubation in a nebulized aerosol. Lung tissues were harvested at 24h, digested and FAC-sorted in preparation for 10X single-cell RNA sequencing and transcriptomic analysis. Utilizing a custom bioinformatics and machine learning workflow, sorted cells with specific transcriptomic cell lineage signatures were evaluated for the presence of <em>HA-CFTR</em> mRNA. An immunohistochemistry (IHC) assay targeting the HA tag was developed to confirm the translational fidelity of the mRNA cargo.</div></div><div><h3>Results</h3><div>RNA isolated from EPCAM+ lung cells were analyzed using a UMAP dimensionality reduction on 10X Genomics scRNAseq sequencing data in the form of a cell-gene matrix to visualize the co-localization of <em>HA-CFTR</em> and various epithelial airway marker genes. A confirmatory machine learning model, trained on the Human Lung Atlas, was used to classify cell type and verify cell tropism. Data indicate presence of <em>HA-CFTR</em> mRNA in multiple sub-types of airway epithelial cells, including <em>SFTPB</em>+ ionocytes, <em>SCGB1A1</em>+ secretory cells, <em>AGER</em>+ AT Type 1 cells, and <em>SFTPC</em>+ AT Type 2 cells. IHC confirmed localization of the translated HA-tagged protein in secretory and basal airway cells.</div></div><div><h3>Conclusions</h3><div>Using a combinatory bioinformatic and spatial workflow, we show that dosing with LNP-<em>HA-CFTR</em> mRNA results in the delivery of nascent and translated cargo to key airway populations associated with CF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S10"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS05.04Comparison of preclinical and preliminary clinical safety profile of SPL84, an ASO for treatment of CF patients carrying the 3849 +10 Kb C -> T mutation, supporting an ongoing Phase 2 study","authors":"L. Friedman ,&nbsp;E. Ozeri-Galai ,&nbsp;A. Cohen ,&nbsp;G. Hart ,&nbsp;Y. Caraco ,&nbsp;M. Wanounou ,&nbsp;E. Kerem","doi":"10.1016/j.jcf.2025.03.519","DOIUrl":"10.1016/j.jcf.2025.03.519","url":null,"abstract":"<div><h3>Background</h3><div>SpliSense is developing SPL84, an inhaled ASO for the treatment of pwCF carrying the 3849 +10kb C-&gt;T (3849) mutation. SPL84 fully restored CFTR function in patient-derived HNEs and HBEs. Preclinical toxicology studies in mice and monkeys and a Phase 1 study in healthy volunteers (HVs) were conducted to support the ongoing Phase 2 study in 3849 pwCF.</div></div><div><h3>Methods</h3><div>In the preclinical toxicology studies, SPL84 was given via inhalation once a week for 9 weeks to mice and monkeys at dose levels of up to 54.4 mg/kg/week and 20.8 mg/kg/week, respectively. In the Phase 1 study, 32 subjects received a single inhaled dose of SPL84 at either 20, 40, 80, 160 mg or placebo (n=8 per cohort; 3:1 active:placebo). The primary objective was to evaluate the safety and tolerability of SPL84, and the secondary objective was to characterize the pharmacokinetics of SPL84.</div></div><div><h3>Results</h3><div>No SPL84-related clinical signs were observed in the preclinical toxicology studies. All of the microscopic changes in the lungs were regarded as non-adverse and reflected a normal clearance process for inhaled material. Systemic exposure in both species was low and the no observed adverse effect level for mice and monkeys was 54.4 and 20.8 mg/kg/week, respectively, which provided sufficient safety margins for the Phase 1 clinical doses.</div><div>SPL84 was well tolerated in the Phase 1 HV study, with no significant SPL84-related adverse events, and no significant effect on vital signs, clinical laboratory values, electrocardiogram, physical examination, or pulmonary function. Systemic exposure of SPL84 was low, as expected for an inhaled product, and tended to be dose dependent.</div></div><div><h3>Conclusions</h3><div>The safety and systemic exposure profile of SPL84 is similar across species (mice, monkeys, and humans). The preclinical and clinical safety profile of SPL84 is promising, with no clinical signs as well as low systemic exposure. This supported the initiation of an ongoing global Phase 2 study for the treatment of 3849 pwCF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S10"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS09.03SLC26A9-mediated chloride transport is important for mucociliary clearance by healthy and cystic fibrosis airway epithelium","authors":"A. Balazs ,&nbsp;T. Rubil ,&nbsp;G.L. Harnisch ,&nbsp;C.K. Wong ,&nbsp;W. Namkung ,&nbsp;M. Drescher ,&nbsp;K. Seidel ,&nbsp;S.Y. Graeber ,&nbsp;M.A. Mall","doi":"10.1016/j.jcf.2025.03.542","DOIUrl":"10.1016/j.jcf.2025.03.542","url":null,"abstract":"<div><div>Genetic studies identified the solute carrier family 26 member 9 (<em>SLC26A9</em>) chloride transporter as a modifier of lung function in health and in cystic fibrosis (CF). Further, genetic deletion of <em>SLC26A9</em> in mice showed that SLC26A9–mediated chloride secretion is required to prevent mucus obstruction in type 2 airway inflammation. These data suggest that SLC26A9 is a promising therapeutic target in CF and potentially in other muco-obstructive lung diseases, however, its role in coordinated ion transport and mucociliary clearance in the human airways is not well understood. We generated human nasal epithelial (HNE) cultures from healthy donors and from patients with CF homozygous for either F508del or class I CFTR mutations to assess SLC26A9-mediated chloride secretion by short-circuit current measurements and to study the effect of pharmacological inhibition of SLC26A9 on mucociliary transport (MCT) velocity via time-lapse video microscopy. Inhibition with either S9-A13 or CFTRinh172 showed that SLC26A9 and CFTR contributed to basal (∆Isc=-0.55 µA/cm²; -1.74 µA/cm²) and cAMP-stimulated (∆Isc=-2.53 µA/cm²; -6.08 µA/cm²) chloride secretion in healthy HNE, whereas inhibition of both SLC26A9 and CFTR abolished transepithelial chloride secretion. Inhibition of SLC26A9 decreased MCT velocity (2.6 µm/s vs. 22.71 µm/s; p&lt;0.001) in healthy HNE. In CF cultures homozygous for F508del or class I mutations, residual chloride transport was predominantly mediated by SLC26A9. SLC26A9 inhibition decreased MCT velocity (1.85 µm/s vs. 14.87µm/s; p&lt;0.0001) in CF cultures. SLC26A9 and CFTR synergistically regulate transepithelial chloride secretion in healthy airway epithelia. In the CF airway epithelium SLC26A9 is important for residual chloride secretion and mucociliary transport, independent of the CFTR genotype. These findings support that SLC26A9 represents a promising therapeutic target to promote mucociliary clearance in CF and potentially in other muco-obstructive lung diseases.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S18"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS03.05What factors influence heart rate reserve in evaluating and prescribing exercise intensity for children and young people with CF?","authors":"E. Main ,&nbsp;W. Shirras ,&nbsp;N. Filipow ,&nbsp;H. Douglas ,&nbsp;E. Raywood ,&nbsp;S. Stanojevic","doi":"10.1016/j.jcf.2025.03.508","DOIUrl":"10.1016/j.jcf.2025.03.508","url":null,"abstract":"<div><h3>Objectives</h3><div>Heart rate reserve (HRR), the difference between resting heart rate (RHR) and peak heart rate (PHR), is commonly used to evaluate and prescribe exercise intensity in adults <span><span>(ACSM, 2021)</span><svg><path></path></svg></span>. HRR is less commonly used in children and young people (CYP), who are physiologically and metabolically different to adults. They have higher PHR and RHR during rest and exercise and both typically decline with age and fluctuate with changes in physical fitness. This study aimed to investigate the influence of age, fitness and illness on RHR, PHR and HRR in CYP with Cystic Fibrosis (CF).</div></div><div><h3>Methods</h3><div>Data from CYP with CF participating in <span><span>Project Fizzyo (UK)</span><svg><path></path></svg></span> were used. RHR was the average of <span><span>5 lowest HR values</span><svg><path></path></svg></span> from daily Fitbit monitoring. PHR came from a Polar H10 ECG chest strap worn during a 25-level 10-metre modified shuttle test (MST‐25). Fitness was defined by distance achieved in the MST‐25, <span><span>normalised for age</span><svg><path></path></svg></span>. Severity of illness was represented by FEV₁ % predicted. Linear regression was used to investigate associations between HRR and age, RHR, PHR, illness and fitness.</div></div><div><h3>Results</h3><div>134 participants (48.5% male, average age 10.1 years, average FEV₁ 90% predicted) performed the MST‐25 at baseline. Significant associations: Age and fitness explained 41% and 5% of the variability in RHR respectively, with RHR decreasing in older CYP. Fitness and illness explained 14% and 8% of the variability in PHR respectively. The HRR interval ranged between 110 bpm at age 6 to 123 bpm at age 16, increasing by 1.27 bpm (95% CI 0.13 - 2.4) per year, as children got older. PHR explained 46% of the variability in HRR, and PHR, age, fitness and illness combined explained 73% of the variability in HRR.</div></div><div><h3>Conclusion</h3><div>HRR is strongly associated with age in CYP with CF, and to a lesser degree fitness and illness. While proportional contribution of these factors to HHR may differ in adults, the HRR approach remains appropriate for evaluating and prescribing exercise intensity in CYP with CF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S7"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS15.02Impact of one versus two responsive CFTR variants on sweat chloride and FEV1 responses to elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: a real-world study","authors":"P.-R. Burgel ,&nbsp;J. Da Silva ,&nbsp;C. Martin ,&nbsp;E. Girodon ,&nbsp;J.-L. Paillasseur ,&nbsp;French CF National Reference network study group","doi":"10.1016/j.jcf.2025.03.577","DOIUrl":"10.1016/j.jcf.2025.03.577","url":null,"abstract":"<div><h3>Objectives</h3><div>It remains unknown whether responses to elexacaftor-tezacaftor-ivacaftor (ETI) vary according to the number of ETI-responsive <em>CFTR</em> variants in people with cystic fibrosis (pwCF).</div></div><div><h3>Methods</h3><div>Data from pwCF treated with ETI were obtained using the French adult ETI-real world study and the French Compassionate program. <em>CFTR</em> variants were classified according to their ETI-responsiveness, as determined in the French Compassionate Program. Sweat chloride concentrations with ETI and absolute change in sweat chloride and in ppFEV₁ following ETI initiation were described, comparing pwCF with one vs. two ETI-responsive variants.</div></div><div><h3>Results</h3><div>Among 1266 participants, 834 had two ETI-responsive variants and 432 had only one. Median [IQR] sweat chloride concentrations were lower in participants with two vs. one ETI-responsive variants; 36 [24; 50] mmol/l and 53 [26; 72] mmol/l, respectively (<em>P</em>&lt;0.0001). The proportion of participants with sweat chloride concentration &lt;30 mmol/l was 35.7% vs. 15.0% in those with two vs. one ETI-responsive variants, respectively (Chi-square, <em>P</em>&lt;0.00001). In multivariable analyses, the number of ETI-responsive variants was a determinant of sweat chloride concentration with ETI (<em>P</em>&lt;0.0001) but not of absolute change in ppFEV₁ following ETI initiation (<em>P</em>=0.80).</div></div><div><h3>Conclusion</h3><div>PwCF with two responsive <em>CFTR</em> variants have better correction of CFTR function than those with one responsive <em>CFTR</em> variant when treated with ETI, but sweat chloride response is not predictive of the change in ppFEV₁. These data suggest that maximal improvement in lung function is already obtained with current CFTR modulators and that no further lung function improvement may be expected from newer modulators with more potent restoration of CFTR function.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S30"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS09.06Investigation of HE4 expression in relation to epithelial mesenchymal transition in cystic fibrosis epithelial cells","authors":"M. Pócsi ,&nbsp;G.J. Balla ,&nbsp;F. Fenyvesi ,&nbsp;Á. Rusznyák ,&nbsp;Z. Fejes ,&nbsp;I. Balogh ,&nbsp;M. Macek Jr. ,&nbsp;M.D. Amaral ,&nbsp;B. Nagy Jr.","doi":"10.1016/j.jcf.2025.03.545","DOIUrl":"10.1016/j.jcf.2025.03.545","url":null,"abstract":"<div><h3>Objective</h3><div>Elevated expression of human epididymis protein 4 (HE4) was described in cystic fibrosis (CF), which was directly influenced by impaired CFTR via NF-κB in p.Phe508del-CFTR CFBE 41o− cells <em>in vitro</em>. Dysfunctional CFTR was also associated with epithelial mesenchymal transition (EMT) in CF. However, no data is available if HE4 expression alters and is linked to CF-related EMT.</div></div><div><h3>Methods</h3><div>EMT characteristics were compared between CFBE 41o− cells expressing p.Phe508del-CFTR and wt-CFTR through the expression of epithelial and mesenchymal markers by RT-qPCR and fluorescence microscopy. EMT was further triggered in p.Phe508del-CFTR CFBE cells by TGF-β1 from 24-96h to investigate the relationship of EMT with HE4 and MMP9 expression. To restore CFTR dysfunction, VX-445/VX-661/VX-770 was applied to monitor EMT phenotype. The direct effect of abnormal HE4 expression on EMT and MMP9 was analyzed when: <em>i)</em> mutant CFBE cells were treated with recombinant HE4, and <em>ii)</em> HE4 expression was artificially reduced by transfection with HE4 specific siRNA.</div></div><div><h3>Results</h3><div>Untreated p.Phe508del-CFTR CFBE cells had a trend to be more mesenchymal than wt-CFTR CFBE cells and showed higher HE4 and MMP9 levels. However, in response to TGF-β1, E-cadherin levels were lower, while those of N-cadherin and MMP9 were higher in p.Phe508del-CFTR CFBE cells. In parallel, HE4 levels were decreased already after 48h and further reduced until 96h. The EMT phenotype could be reversed by CFTR modulators causing a decrease in both HE4 and MMP9 levels. Finally, both treatment with recombinant HE4 and downregulated HE4 levels promoted EMT with induced MMP9 in p.Phe508del-CFTR CFBE cells.</div></div><div><h3>Conclusion</h3><div>High baseline HE4 levels in CF may contribute to the development of EMT accompanied with decreasing intracellular HE4 and upregulated MMP9 expression in airway epithelial cells.</div><div><strong>Grants:</strong> This study is supported by FK-135327 grant (BN) and UID/04046/2025 centre grant in MDA lab (to BioISI) from FCT/MCTES Portugal.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Page S19"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144203907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS02.05The effect of sleep on the quality of life of children with cystic fibrosis","authors":"F.F. Karkın Gürel ,&nbsp;D. Ademhan Tural ,&nbsp;H. Yetisgin ,&nbsp;S.S. Akyan Soydas ,&nbsp;S. Ozkan Tabakci ,&nbsp;S. Eryilmaz Polat ,&nbsp;G.D. Tugcu ,&nbsp;G. Cinel","doi":"10.1016/j.jcf.2025.03.502","DOIUrl":"10.1016/j.jcf.2025.03.502","url":null,"abstract":"<div><h3>Objectives</h3><div>We aimed to evaluate the effects of sleep-disordered breathing, sleep quality, and sleepiness on the quality of life (QoL) of children with cystic fibrosis (cwCF).</div></div><div><h3>Method</h3><div>This cross-sectional observational study was conducted on cwCF and healthy children (control) aged 6-18 from July to November 2024. Aged-appropriate QoL, Pediatric Sleep Questionnaire (PSQ), Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) were applied to all participants. Demographics of all participants and clinical characteristics of cwCF were collected. Subgroup analyses were made between patients who used (n:17) modulators and those who did not (n:23).</div></div><div><h3>Results</h3><div>The study included 40 cwCF and 54 controls. There were no differences according to age and sex distribution between the groups. The QoL results are summarized in Table 1. PSQ, PSQI, and EUS scores were statistically significantly higher in cwCF than in the controls (p-values, respectively; &lt;0.001, &lt;0.001, 0.013). Table 2 summarizes the regression analysis results of sleep-disordered breathing, sleep quality, and sleepiness on QoL in cwCF aged 6-13. A statistically significant difference was found in the digestive subscale of QoL between patients receiving and not receiving modulators in cwCF aged 6-13 (p=0.036). The frequency of sleep-disordered breathing (p=0.047), poor sleep quality (p=0.030), and daytime sleepiness (p=0.248) was more common in patients who did not use modulators than those who did</div></div><div><h3>Conclusion</h3><div>Sleep-disordered breathing, daytime sleepiness, and sleep quality were found to have important roles in the quality of life of cwCF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S4-S5"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WS06.04Cystic fibrosis and pregnancy: the impact of modulator therapy","authors":"H. Boyd ,&nbsp;D. Wat ,&nbsp;D. Nazareth ,&nbsp;F. Frost ,&nbsp;J. Daniels ,&nbsp;R. Ashworth ,&nbsp;D. Dickins","doi":"10.1016/j.jcf.2025.03.525","DOIUrl":"10.1016/j.jcf.2025.03.525","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;With the increased number of pregnacies seen in Patients With Cystic Fibrosis (pwCF) following the introduciton of Highly Effective Modulator Therapy (HEMT) the aim of our study was to look at outcomes at a single, large tertiary CF centre for women going through pregnancy with CF, to identify whether there were significant differences following the introduction of HEMT with a particular note looking at pregnancies defined as high risk (with an FEV1 &lt;60%).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Retrospective non-controlled study looking at pwCF who had a pregnancy between 2010 and 2023.&lt;/div&gt;&lt;div&gt;We reviewed electronic notes for patients at Liverpool Heart and Chest (LHCH) for miscarriage being recorded in notes. We reviewed notes from LHCH and Liverpool Women's Hospital (LWH) for demographic information and respiratory, obstetric and neonatal outcomes for pwCF who had a livebirth outcome.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;We identified a total of 66 pregnancies over the period 2010 to 2023 for analysis; nineteen miscarriages and forty-seven livebirths.&lt;span&gt;&lt;div&gt;&lt;div&gt;&lt;table&gt;&lt;thead&gt;&lt;tr&gt;&lt;th&gt;Outcome&lt;/th&gt;&lt;th&gt;Non-HEMT (n= 27)&lt;/th&gt;&lt;th&gt;HEMT (n=39)&lt;/th&gt;&lt;/tr&gt;&lt;/thead&gt;&lt;tbody&gt;&lt;tr&gt;&lt;td&gt;Miscarriage Rate&lt;/td&gt;&lt;td&gt;33% (9/27)&lt;/td&gt;&lt;td&gt;25% (10/39)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;In Vitro Fertilisation&lt;/td&gt;&lt;td&gt;39% (7)&lt;/td&gt;&lt;td&gt;7% (2)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Pre-Pregnancy FEV1&lt;/td&gt;&lt;td&gt;78% (range 45-97%)&lt;/td&gt;&lt;td&gt;73% (range 31-105%)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Pregnancy FEV1&lt;/td&gt;&lt;td&gt;78% (range 36-97%)&lt;/td&gt;&lt;td&gt;72% (range 39-117%)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Post Pregnancy FEV1&lt;/td&gt;&lt;td&gt;77% (range 36-99%)&lt;/td&gt;&lt;td&gt;74% (range 36-122%)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Average change in FEV1 %&lt;/td&gt;&lt;td&gt;+0.4% (range –12% to +13%)&lt;/td&gt;&lt;td&gt;-0.9% (range –23 to +12)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Change FEV1% post pregnancy&lt;/td&gt;&lt;td&gt;-1.5% (range –23 to +11%)&lt;/td&gt;&lt;td&gt;+0.8% (range –18 to +14)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;High Risk Pregnancies (FEV1 &lt;60%)&lt;/td&gt;&lt;td&gt;13% (2)&lt;/td&gt;&lt;td&gt;25% (8)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Average Gestation at Delivery&lt;/td&gt;&lt;td&gt;37.51 weeks&lt;/td&gt;&lt;td&gt;36.89 weeks&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Number of Preterm Deliveries&lt;/td&gt;&lt;td&gt;28% (5)&lt;/td&gt;&lt;td&gt;40% (10)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;C-Sections&lt;/td&gt;&lt;td&gt;34% (6)&lt;/td&gt;&lt;td&gt;68% (17)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;-Elective&lt;/td&gt;&lt;td&gt;17% (3)&lt;/td&gt;&lt;td&gt;48% (12)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;-Emergency&lt;/td&gt;&lt;td&gt;17% (3)&lt;/td&gt;&lt;td&gt;20% (5)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Vaginal Deliveries&lt;/td&gt;&lt;td&gt;67% (12)&lt;/td&gt;&lt;td&gt;32% (8)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;SCBU Admission&lt;/td&gt;&lt;td&gt;41% (7)&lt;/td&gt;&lt;td&gt;34% (8)&lt;/td&gt;&lt;/tr&gt;&lt;tr&gt;&lt;td&gt;Birthweight&lt;/td&gt;&lt;td&gt;2966g (1620-3850g)&lt;/td&gt;&lt;td&gt;2851g (1155-3880g)&lt;/td&gt;&lt;/tr&gt;&lt;/tbody&gt;&lt;/table&gt;&lt;/div&gt;&lt;/div&gt;&lt;/span&gt;&lt;/div&gt;&lt;div&gt;While the number of women experiencing exacerbations in pregnancy was similar between groups, women in the HEMT group had fewer exacerbations and required fewer weeks of antibiotic treatment. The most common indications for C-section or induction was cystic fibrosis and respiratory decline/ chest infection.&lt;span&gt;&lt;div&gt;&lt;div&gt;&lt;table&gt;&lt;thead&gt;&lt;tr&gt;&lt;th&gt;Outcome&lt;/th&gt;&lt;th&gt;Non-high-risk Pregnancy on HEMT (FEV1% &gt;60%) (n=21)&lt;/th&gt;&lt;th&gt;High-risk Pregnancy on HEMT","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"24 ","pages":"Pages S12-S13"},"PeriodicalIF":5.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144204935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}