Pub Date : 2026-01-01DOI: 10.1016/j.jcf.2025.07.007
Nicolas Henao-Romero , Lingxiu Susan Liu , Amirala O.M. Nazari , Dain Kim , Xiaojie Luan , Kash Desai , Julian S. Tam , Juan P. Ianowski , Verónica A. Campanucci
Background
Gastrointestinal (GI) complications are a common source of morbidity for people with cystic fibrosis (pwCF). The pathobiology of these clinical presentations is not fully understood, but there is evidence that gut dysmotility may be a primary contributor.
Methods
We studied gut motility in ileum samples from CF (CFTR-/-) and wild-type (WT) swine at birth (P0) and one week of post-natal life (P7) using organ bath assays.
Results
Ileal samples from both WT and CF swine displayed spontaneous peristalsis. CF swine presented with reduced basal amplitude of the peristaltic waves compared to WT swine. Stimulating the ileal samples with increasing concentrations of acetylcholine (ACh) resulted in four main findings: 1) ACh increased the amplitude of smooth muscle contraction in all ileal samples in a dose-dependent manner. 2) At P7, ACh stimulation caused a significant increase in the maximum smooth muscle contraction in the WT but not in the CF samples. 3) Increasing doses of ACh caused fatigue-like contracting decline in smooth muscle from WT samples at both ages, but not in samples from CF swine. 4) ACh stimulation had no effect on the frequency of smooth muscle contraction in either genotype.
Conclusions
Our results show ileal dysmotility in the CF swine characterized by a decrease in basal peristalsis and weaker smooth muscle contraction. Our data suggest that GI dysmotility would impact chyme transit through the GI tract, which may predispose pwCF to intestinal manifestations associated with the disease.
{"title":"Dysmotility in the ileum of CFTR null swine","authors":"Nicolas Henao-Romero , Lingxiu Susan Liu , Amirala O.M. Nazari , Dain Kim , Xiaojie Luan , Kash Desai , Julian S. Tam , Juan P. Ianowski , Verónica A. Campanucci","doi":"10.1016/j.jcf.2025.07.007","DOIUrl":"10.1016/j.jcf.2025.07.007","url":null,"abstract":"<div><h3>Background</h3><div>Gastrointestinal (GI) complications are a common source of morbidity for people with cystic fibrosis (pwCF). The pathobiology of these clinical presentations is not fully understood, but there is evidence that gut dysmotility may be a primary contributor.</div></div><div><h3>Methods</h3><div>We studied gut motility in ileum samples from CF (CFTR-/-) and wild-type (WT) swine at birth (P0) and one week of post-natal life (P7) using organ bath assays.</div></div><div><h3>Results</h3><div>Ileal samples from both WT and CF swine displayed spontaneous peristalsis. CF swine presented with reduced basal amplitude of the peristaltic waves compared to WT swine. Stimulating the ileal samples with increasing concentrations of acetylcholine (ACh) resulted in four main findings: 1) ACh increased the amplitude of smooth muscle contraction in all ileal samples in a dose-dependent manner. 2) At P7, ACh stimulation caused a significant increase in the maximum smooth muscle contraction in the WT but not in the CF samples. 3) Increasing doses of ACh caused fatigue-like contracting decline in smooth muscle from WT samples at both ages, but not in samples from CF swine. 4) ACh stimulation had no effect on the frequency of smooth muscle contraction in either genotype.</div></div><div><h3>Conclusions</h3><div>Our results show ileal dysmotility in the CF swine characterized by a decrease in basal peristalsis and weaker smooth muscle contraction. Our data suggest that GI dysmotility would impact chyme transit through the GI tract, which may predispose pwCF to intestinal manifestations associated with the disease.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 146-150"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682670","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}
Pub Date : 2026-01-01DOI: 10.1016/j.jcf.2025.08.007
Qiwei Xiao , Goutham Mylavarapu , James F. Chmiel , Robert Fleck , Jean-Pierre Amoakon , Md Monir Hossain , Aisaku Nakamura , Mark DiFrancesco , Andrew Paisley , Christine L. Schuler , Alister Bates , Matthew Willmering , Anjaparavanda P Naren , Raúl San José Estépar , Raouf Amin
Background
Morphological changes of the pulmonary vasculature in cystic fibrosis (CF) with advancing age, disease progression and modulator therapy are not fully understood.
Methods
Sixty-five subjects with CF and baseline pulmonary function underwent a high-resolution CT scan, exercise testing, diffusion capacity and lung clearance index. The ratio of small blood vessel volume (vessels< 5mm2 or “BV5”) to total blood vessel volume (TBV) was estimated from CT scans (BV5/TBV%). The findings were validated in a second CF cohort with concurrent CT and pulmonary function at baseline. Modulator effects were determined by comparing the changes in BV5/TBV% with age and FEV1 % across groups (subjects who were naïve to modulators, those that received 1st generation modulators and those that received Trikafta). The relationship between BV5/TBV% and age in healthy controls was examined.
Results
BV5/TBV% began to decline in the first decade of life and below FEV1 % of 113; this decline was associated with a decrease in diffusion and exercise parameters. The decline of BV5/TBV% with age was independent from the decline in FEV1 %. There was no significant decline in BV5/TBV% with advancing age in healthy controls or in those who received Trikafta. Early in CF, there was a relative hypervascularity of the small fraction of the pulmonary circulation which reversed to relative hypovascularity with the steady decline of BV5/TBV%.
Conclusions
The attrition of small blood vessels measured by BV5/TBV% in CF starts during the first decade of life, when lung function is normal, even with 1st generation modulator use, but not with Trikafta.
{"title":"Pulmonary vascular morphology in cystic fibrosis","authors":"Qiwei Xiao , Goutham Mylavarapu , James F. Chmiel , Robert Fleck , Jean-Pierre Amoakon , Md Monir Hossain , Aisaku Nakamura , Mark DiFrancesco , Andrew Paisley , Christine L. Schuler , Alister Bates , Matthew Willmering , Anjaparavanda P Naren , Raúl San José Estépar , Raouf Amin","doi":"10.1016/j.jcf.2025.08.007","DOIUrl":"10.1016/j.jcf.2025.08.007","url":null,"abstract":"<div><h3>Background</h3><div>Morphological changes of the pulmonary vasculature in cystic fibrosis (CF) with advancing age, disease progression and modulator therapy are not fully understood.</div></div><div><h3>Methods</h3><div>Sixty-five subjects with CF and baseline pulmonary function underwent a high-resolution CT scan, exercise testing, diffusion capacity and lung clearance index. The ratio of small blood vessel volume (vessels< 5mm<sup>2</sup> or <sup>“</sup>BV5”) to total blood vessel volume (TBV) was estimated from CT scans (BV5/TBV%). The findings were validated in a second CF cohort with concurrent CT and pulmonary function at baseline. Modulator effects were determined by comparing the changes in BV5/TBV% with age and FEV1 % across groups (subjects who were naïve to modulators, those that received 1<sup>st</sup> generation modulators and those that received Trikafta). The relationship between BV5/TBV% and age in healthy controls was examined.</div></div><div><h3>Results</h3><div>BV5/TBV% began to decline in the first decade of life and below FEV1 % of 113; this decline was associated with a decrease in diffusion and exercise parameters. The decline of BV5/TBV% with age was independent from the decline in FEV1 %. There was no significant decline in BV5/TBV% with advancing age in healthy controls or in those who received Trikafta. Early in CF, there was a relative hypervascularity of the small fraction of the pulmonary circulation which reversed to relative hypovascularity with the steady decline of BV5/TBV%.</div></div><div><h3>Conclusions</h3><div>The attrition of small blood vessels measured by BV5/TBV% in CF starts during the first decade of life, when lung function is normal, even with 1<sup>st</sup> generation modulator use, but not with Trikafta.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 158-165"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955875","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}
People with cystic fibrosis (pwCF) are at increased risk for fluid and electrolyte imbalances due to continuous salt loss. Congruently, guidelines advocate increased salt intake. However, pwCF are also at increased risk for developing cardiovascular disease. Understanding how CFTR modulators affect fluid and electrolyte homeostasis is important to provide evidence-based guidance for pwCF treated with CFTR modulators.
Methods
We quantified the effect of Elexacaftor/tezacaftor/ivacaftor (ETI) treatment on blood pressure, electrolyte- and acid-base balance, aldosterone levels, and the diuretic and natriuretic response to an oral NaHCO3 and volume loading test in 50 pwCF initiating ETI treatment.
Results
In pwCF, ETI treatment increased blood pressure, plasma Na+, and the diuretic response to oral NaHCO3 and volume loading. Congruently, ETI markedly decreased heart rate, aldosterone levels, venous total CO2 and the proportion of pwCF with low plasma Na+.
Conclusions
In pwCF, ETI treatment improves NaCl and fluid conservation. Future guidelines should consider an increased risk for cardiovascular disease in pwCF after initiation of CFTR modulator treatment. Salt repletion appears unnecessary in ETI-treated pwCF.
{"title":"Elexacaftor/tezacaftor/ivacaftor corrects salt-wasting in cystic fibrosis","authors":"Peder Berg , Amalie Quist Rousing , Søren Jensen-Fangel , Sascha Bandulik , Richard Warth , Mads Vaarby Sørensen , Majbritt Jeppesen , Jens Leipziger","doi":"10.1016/j.jcf.2025.12.006","DOIUrl":"10.1016/j.jcf.2025.12.006","url":null,"abstract":"<div><h3>Background</h3><div>People with cystic fibrosis (pwCF) are at increased risk for fluid and electrolyte imbalances due to continuous salt loss. Congruently, guidelines advocate increased salt intake. However, pwCF are also at increased risk for developing cardiovascular disease. Understanding how CFTR modulators affect fluid and electrolyte homeostasis is important to provide evidence-based guidance for pwCF treated with CFTR modulators.</div></div><div><h3>Methods</h3><div>We quantified the effect of Elexacaftor/tezacaftor/ivacaftor (ETI) treatment on blood pressure, electrolyte- and acid-base balance, aldosterone levels, and the diuretic and natriuretic response to an oral NaHCO<sub>3</sub> and volume loading test in 50 pwCF initiating ETI treatment.</div></div><div><h3>Results</h3><div>In pwCF, ETI treatment increased blood pressure, plasma Na<sup>+</sup>, and the diuretic response to oral NaHCO<sub>3</sub> and volume loading. Congruently, ETI markedly decreased heart rate, aldosterone levels, venous total CO<sub>2</sub> and the proportion of pwCF with low plasma Na<sup>+</sup>.</div></div><div><h3>Conclusions</h3><div>In pwCF, ETI treatment improves NaCl and fluid conservation. Future guidelines should consider an increased risk for cardiovascular disease in pwCF after initiation of CFTR modulator treatment. Salt repletion appears unnecessary in ETI-treated pwCF.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 32-37"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145714694","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}
Pub Date : 2026-01-01DOI: 10.1016/j.jcf.2025.12.002
Marco Salvatore , Giuseppe Campagna , Annalisa Amato , Daniela Pierannunzio , Pietro Ripani , Giovanni Taccetti , Benedetta Fabrizzi , Fabio Majo , Rita Padoan
Background
The prognosis for people with Cystic Fibrosis (CF) has significantly improved due to the introduction of CF Transmembrane Regulator (CFTR) modulators. This study aims to analyze pregnancies and related outcomes in Italian women with CF while also identifying current and potential future challenges.
Methods
This retrospective study utilized data from the Italian cystic fibrosis Registry (ICFR), focusing on pregnancies occurring between 2016 and 2023. Key clinical variables assessed included genotype, age at conception, body mass index, percent predicted forced respiratory volume (ppFEV₁), presence of CF-related diabetes (CFRD), and CFTR modulator therapy. The outcomes analyzed were pulmonary function and BMI as a surrogate of nutritional status before and after pregnancy, as well as preterm birth rate, birthweight, and mode of delivery.
Results
Between 2016 and 2023, the ICFR reported 172 pregnancies, of which 148 (86.0 %) were carried to term. The median age at conception was 31.8 years (range: 17.0–43.9), median BMI 21.6 kg/m² (range: 16.5–38.9), and median ppFEV₁ 79.7 (range: 29.0–120.4). CFRD was present in 32 women (21.6 %), and 55 (37.2 %) were receiving CFTR modulator therapy. Better clinical status at the beginning of pregnancy was observed in 2016-23 period, with a higher mean ppFEV1, in the mean age at conception and in the mean BMI value. In the present study, only a limited number of women were in severe clinical condition (<5 % had a severe ppFEV1 value or a BMI showing a malnutrition status).
The overall preterm birth (<37 weeks gestation) was 24.1 % (34 cases), higher in women with CFRD (40.6 %) and lowest in those receiving CFTRm (22.7 %). Median birthweight was 2,990 g (range: 800–4,155 g). The overall cesarean section rate was 54.9 %, peaking at 81.2 % in women with CFRD.
Conclusion
Understanding national pregnancy trends and outcomes is essential for informing effective public health strategies and improving maternal–infant wellbeing. An increasing number of women with CF are achieving successful pregnancies and delivering healthy babies. It is essential to provide women treated with CFTR modulators with up-to-date information regarding the safety of these therapies during pregnancy and breastfeeding.
{"title":"Pregnancies in women with cystic fibrosis in the era of CFTR modulators: Current challenges and future perspectives. Insights from the Italian cystic fibrosis registry","authors":"Marco Salvatore , Giuseppe Campagna , Annalisa Amato , Daniela Pierannunzio , Pietro Ripani , Giovanni Taccetti , Benedetta Fabrizzi , Fabio Majo , Rita Padoan","doi":"10.1016/j.jcf.2025.12.002","DOIUrl":"10.1016/j.jcf.2025.12.002","url":null,"abstract":"<div><h3>Background</h3><div>The prognosis for people with Cystic Fibrosis (CF) has significantly improved due to the introduction of CF Transmembrane Regulator (CFTR) modulators<em>.</em> This study aims to analyze pregnancies and related outcomes in Italian women with CF while also identifying current and potential future challenges<em>.</em></div></div><div><h3>Methods</h3><div>This retrospective study utilized data from the Italian cystic fibrosis Registry (ICFR), focusing on pregnancies occurring between 2016 and 2023. Key clinical variables assessed included genotype, age at conception, body mass index, percent predicted forced respiratory volume (ppFEV₁), presence of CF-related diabetes (CFRD), and CFTR modulator therapy. The outcomes analyzed were pulmonary function and BMI as a surrogate of nutritional status before and after pregnancy, as well as preterm birth rate, birthweight, and mode of delivery.</div></div><div><h3>Results</h3><div>Between 2016 and 2023, the ICFR reported 172 pregnancies, of which 148 (86.0 %) were carried to term. The median age at conception was 31.8 years (range: 17.0–43.9), median BMI 21.6 kg/m² (range: 16.5–38.9), and median ppFEV₁ 79.7 (range: 29.0–120.4). CFRD was present in 32 women (21.6 %), and 55 (37.2 %) were receiving CFTR modulator therapy. Better clinical status at the beginning of pregnancy was observed in 2016-23 period, with a higher mean ppFEV<sub>1</sub>, in the mean age at conception and in the mean BMI value. In the present study, only a limited number of women were in severe clinical condition (<5 % had a severe ppFEV<sub>1</sub> value or a BMI showing a malnutrition status).</div><div>The overall preterm birth (<37 weeks gestation) was 24.1 % (34 cases), higher in women with CFRD (40.6 %) and lowest in those receiving CFTRm (22.7 %). Median birthweight was 2,990 g (range: 800–4,155 g). The overall cesarean section rate was 54.9 %, peaking at 81.2 % in women with CFRD.</div></div><div><h3>Conclusion</h3><div>Understanding national pregnancy trends and outcomes is essential for informing effective public health strategies and improving maternal–infant wellbeing. An increasing number of women with CF are achieving successful pregnancies and delivering healthy babies. It is essential to provide women treated with CFTR modulators with up-to-date information regarding the safety of these therapies during pregnancy and breastfeeding<em>.</em></div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 86-91"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145768176","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}
Pub Date : 2026-01-01DOI: 10.1016/j.jcf.2025.08.010
HL Chandler , M Germuska , TM Lancaster , C Xanthe , C O’leary , S Stirk , H Lu , K Murphy , C Metzler-Baddeley , RG Wise , J Duckers
Background
Cystic fibrosis (CF) is a progressive inherited disorder that primarily affects the lungs. With recent breakthroughs in effective treatments for CF that increase life-expectancy, a higher prevalence of age-related comorbidities has been reported including cardiovascular disease, stroke and cognitive decline. Despite the known relationship between cardiovascular health and cerebrovascular function, very little is known about brain blood flow and oxygen metabolism in people with CF (PwCF).
Methods
In 14 PwCF and 56 healthy age / sex matched controls, we used pseudo-continuous arterial spin labelling (pCASL) to quantify cerebral perfusion in grey-matter and T2-Relaxation-Under-Spin-Tagging (TRUST) to estimate global oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO2).
Results
Compared to healthy controls, PwCF showed elevated CMRO2 (p = 0.015). There were no significant between-group differences in grey-matter CBF (p = 0.342), or whole brain OEF (p = 0.091). However, regional analysis showed certain areas with higher CBF in PwCF (p < .05, FDR).
Conclusions
Our results show increased CMRO2 and regional CBF in PwCF, which could be explained by potential differences in PaO2/PaCO2 and/or endothelial cell function. Our findings highlight the need for further investment in brain research in PwCF to reduce the risk of early cerebrovascular breakdown that leads to premature cognitive decline.
{"title":"Imaging brain vascular function in Cystic Fibrosis: an MRI study of cerebral blood flow and brain oxygenation","authors":"HL Chandler , M Germuska , TM Lancaster , C Xanthe , C O’leary , S Stirk , H Lu , K Murphy , C Metzler-Baddeley , RG Wise , J Duckers","doi":"10.1016/j.jcf.2025.08.010","DOIUrl":"10.1016/j.jcf.2025.08.010","url":null,"abstract":"<div><h3>Background</h3><div>Cystic fibrosis (CF) is a progressive inherited disorder that primarily affects the lungs. With recent breakthroughs in effective treatments for CF that increase life-expectancy, a higher prevalence of age-related comorbidities has been reported including cardiovascular disease, stroke and cognitive decline. Despite the known relationship between cardiovascular health and cerebrovascular function, very little is known about brain blood flow and oxygen metabolism in people with CF (PwCF).</div></div><div><h3>Methods</h3><div>In 14 PwCF and 56 healthy age / sex matched controls, we used pseudo-continuous arterial spin labelling (pCASL) to quantify cerebral perfusion in grey-matter and T<sub>2</sub>-Relaxation-Under-Spin-Tagging (TRUST) to estimate global oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO<sub>2</sub>).</div></div><div><h3>Results</h3><div>Compared to healthy controls, PwCF showed elevated CMRO<sub>2</sub> (<em>p =<!--> </em>0.015). There were no significant between-group differences in grey-matter CBF (<em>p =<!--> </em>0.342), or whole brain OEF (<em>p =<!--> </em>0.091). However, regional analysis showed certain areas with higher CBF in PwCF (<em>p</em> < .05, FDR).</div></div><div><h3>Conclusions</h3><div>Our results show increased CMRO<sub>2</sub> and regional CBF in PwCF, which could be explained by potential differences in PaO<sub>2</sub>/PaCO<sub>2</sub> and/or endothelial cell function. Our findings highlight the need for further investment in brain research in PwCF to reduce the risk of early cerebrovascular breakdown that leads to premature cognitive decline.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 166-171"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955807","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}
Pub Date : 2026-01-01DOI: 10.1016/j.jcf.2025.12.010
Chiara Tupini , Valeria Capurro , Nicoletta Pedemonte , Caterina Allegretta , Onofrio Laselva , Anna Tamanini , Giovanni Marzaro , Adriana Chilin , Paola Patrignani , Stefania Tacconelli , Alessandra De Michele , Marco Cafora , Anna Pistocchi , Giulio Cabrini , Ilaria Lampronti
Background
There is a prominent need for anti-inflammatory agents for people with Cystic Fibrosis (pwCF), even in the era of CFTR modulators. ETI (Elexacaftor/Tezacaftor/Ivacaftor) reduces but does not eliminate pulmonary inflammation, that chronically damages CF pulmonary tissues and favors recurrent pulmonary exacerbations. Furthermore, although known anti-inflammatory drugs are beneficial to pwCF, their side effects are limiting the clinical use. To address this issue, we developed a new synthetic furocoumarin molecule named GY971, able to reduce the excessive accumulation of neutrophils in the bronchial lumen, by targeting the NF-κB transcription factor (TF).
Methods
To assess its efficacy, GY971 was tested in human primary bronchial and nasal epithelial cells obtained ex vivo from different pwCF carrying the F508del mutation and infected with Pseudomonas aeruginosa. Moreover, GY971 was also administered in a zebrafish model infected with P. aeruginosa in vivo.
Results
GY971 reduced neutrophil chemotaxis mediators both in CF bronchial epithelial cell lines and in CF primary bronchial and nasal epithelial cells ex vivo. The expression of key inflammatory proteins involved in CF lung disease, including IL-8, IL-1β, TNF-α and IL-6, was significantly reduced using nanomolar concentrations of GY971. Importantly, GY971 does not interfere with the ETI-mediated rescue of CFTR protein and showed no cytotoxic effects. Lastly, in vivo testing with a zebrafish model confirmed its effectiveness: GY971 decreased neutrophil recruitment in treated larvae across different concentrations, supporting earlier results from murine studies.
Conclusions
GY971 appears to be a promising molecule for the future development of combinatorial anti-inflammatory treatments together with ETI.
{"title":"GY971 mitigates inflammation by reducing neutrophil recruitment in cystic fibrosis Ex Vivo and In Vivo models","authors":"Chiara Tupini , Valeria Capurro , Nicoletta Pedemonte , Caterina Allegretta , Onofrio Laselva , Anna Tamanini , Giovanni Marzaro , Adriana Chilin , Paola Patrignani , Stefania Tacconelli , Alessandra De Michele , Marco Cafora , Anna Pistocchi , Giulio Cabrini , Ilaria Lampronti","doi":"10.1016/j.jcf.2025.12.010","DOIUrl":"10.1016/j.jcf.2025.12.010","url":null,"abstract":"<div><h3>Background</h3><div>There is a prominent need for anti-inflammatory agents for people with Cystic Fibrosis (pwCF), even in the era of CFTR modulators. ETI (Elexacaftor/Tezacaftor/Ivacaftor) reduces but does not eliminate pulmonary inflammation, that chronically damages CF pulmonary tissues and favors recurrent pulmonary exacerbations. Furthermore, although known anti-inflammatory drugs are beneficial to pwCF, their side effects are limiting the clinical use. To address this issue, we developed a new synthetic furocoumarin molecule named GY971, able to reduce the excessive accumulation of neutrophils in the bronchial lumen, by targeting the NF-κB transcription factor (TF).</div></div><div><h3>Methods</h3><div>To assess its efficacy, GY971 was tested in human primary bronchial and nasal epithelial cells obtained <em>ex vivo</em> from different pwCF carrying the <em>F508del</em> mutation and infected with <em>Pseudomonas aeruginosa</em>. Moreover, GY971 was also administered in a zebrafish model infected with <em>P. aeruginosa in vivo</em>.</div></div><div><h3>Results</h3><div>GY971 reduced neutrophil chemotaxis mediators both in CF bronchial epithelial cell lines and in CF primary bronchial and nasal epithelial cells <em>ex vivo</em>. The expression of key inflammatory proteins involved in CF lung disease, including IL-8, IL-1β, TNF-α and IL-6, was significantly reduced using nanomolar concentrations of GY971. Importantly, GY971 does not interfere with the ETI-mediated rescue of CFTR protein and showed no cytotoxic effects. Lastly, <em>in vivo</em> testing with a zebrafish model confirmed its effectiveness: GY971 decreased neutrophil recruitment in treated larvae across different concentrations, supporting earlier results from murine studies.</div></div><div><h3>Conclusions</h3><div>GY971 appears to be a promising molecule for the future development of combinatorial anti-inflammatory treatments together with ETI.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 135-145"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827265","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}
Pub Date : 2026-01-01DOI: 10.1016/j.jcf.2025.12.013
Miguel Angel Martinez Garcia , Patrick A Flume
{"title":"Real-life use of bronchodilators and inhaled corticosteroids in cystic fibrosis and non-CF bronchiectasis, Do guidelines matter?","authors":"Miguel Angel Martinez Garcia , Patrick A Flume","doi":"10.1016/j.jcf.2025.12.013","DOIUrl":"10.1016/j.jcf.2025.12.013","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 9-12"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834067","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}
Pub Date : 2026-01-01DOI: 10.1016/j.jcf.2025.09.006
Kari Thrasher , Jianguo Chen , Lianwu Fu , Dominique Benson , Jenna Ekstrom , Audra A. Hargett , Matthew B. Renfrow , Steven M. Rowe , Kim M. Keeling , David M. Bedwell
Background
Cystic fibrosis patients who carry a CFTR nonsense allele often express negligible CFTR protein, and thus, are unresponsive to CFTR modulators. Nonsense suppression (also called readthrough) is an emerging therapeutic approach for this patient subgroup that uses small molecules to suppress translation termination at in-frame premature termination codons (PTCs) and rescue full-length, functional CFTR protein. This study examines mechanistic aspects of readthrough at six CFTR PTCs commonly found in CF patients.
Methods
CFTR expression and chloride conductance were used to assess the responsiveness of six different CFTR PTCs to G418-mediated readthrough. LC-MS/MS was used to identify the CFTR variant proteins generated by readthrough of PTCs in their native, local CFTR mRNA sequence context. For each CFTR variant protein identified, the abundance, processing, activity, and responsiveness to CFTR modulators were characterized.
Results
CFTR expression and function varied widely among PTCs, with UGA generally being the most responsive to G418-mediated readthrough. The amino acids incorporated at PTCs during G418-induced readthrough also varied, depending on the PTC and its surrounding local mRNA context. Modulators stabilized and enhanced the abundance and activity of most CFTR variant proteins generated by PTC readthrough, with many variant proteins reaching WT CFTR activity.
Conclusions
Nonsense suppression therapy shows promise as a treatment for CF patients who carry a PTC, especially when combined with current CFTR modulators. Mechanistic insights of readthrough gleaned from this study can be used to develop better therapeutic strategies for treating CF patients who carry a nonsense mutation.
{"title":"Identity, functional consequences, and context effects of amino acids inserted during suppression of CFTR nonsense mutations","authors":"Kari Thrasher , Jianguo Chen , Lianwu Fu , Dominique Benson , Jenna Ekstrom , Audra A. Hargett , Matthew B. Renfrow , Steven M. Rowe , Kim M. Keeling , David M. Bedwell","doi":"10.1016/j.jcf.2025.09.006","DOIUrl":"10.1016/j.jcf.2025.09.006","url":null,"abstract":"<div><h3>Background</h3><div>Cystic fibrosis patients who carry a <em>CFTR</em> nonsense allele often express negligible CFTR protein, and thus, are unresponsive to CFTR modulators. Nonsense suppression (also called readthrough) is an emerging therapeutic approach for this patient subgroup that uses small molecules to suppress translation termination at in-frame premature termination codons (PTCs) and rescue full-length, functional CFTR protein. This study examines mechanistic aspects of readthrough at six <em>CFTR</em> PTCs commonly found in CF patients.</div></div><div><h3>Methods</h3><div>CFTR expression and chloride conductance were used to assess the responsiveness of six different <em>CFTR</em> PTCs to G418-mediated readthrough. LC-MS/MS was used to identify the CFTR variant proteins generated by readthrough of PTCs in their native, local <em>CFTR</em> mRNA sequence context. For each CFTR variant protein identified, the abundance, processing, activity, and responsiveness to CFTR modulators were characterized.</div></div><div><h3>Results</h3><div>CFTR expression and function varied widely among PTCs, with UGA generally being the most responsive to G418-mediated readthrough. The amino acids incorporated at PTCs during G418-induced readthrough also varied, depending on the PTC and its surrounding local mRNA context. Modulators stabilized and enhanced the abundance and activity of most CFTR variant proteins generated by PTC readthrough, with many variant proteins reaching WT CFTR activity.</div></div><div><h3>Conclusions</h3><div>Nonsense suppression therapy shows promise as a treatment for CF patients who carry a PTC, especially when combined with current CFTR modulators. Mechanistic insights of readthrough gleaned from this study can be used to develop better therapeutic strategies for treating CF patients who carry a nonsense mutation.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 106-117"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182107","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}
Pub Date : 2026-01-01DOI: 10.1016/j.jcf.2025.12.004
Julia Wynn, Andrew Haddad, Jennifer Hoskovec, Haywood L. Brown
{"title":"Response to Zemanick et al., “false reassurance following single gene non-invasive prenatal testing for cystic fibrosis”","authors":"Julia Wynn, Andrew Haddad, Jennifer Hoskovec, Haywood L. Brown","doi":"10.1016/j.jcf.2025.12.004","DOIUrl":"10.1016/j.jcf.2025.12.004","url":null,"abstract":"","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 181-182"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145714771","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}
The long-term clinical consequences of COVID-19 in cystic fibrosis (CF) remain largely unexplored. This study aimed to assess the incidence of long COVID in a large population of people with CF.
Methods
This prospective, multicentre study enrolled individuals with confirmed SARS-CoV-2 infection between July 2021 and October 2022. Data collected included clinical features prior to infection, symptoms during the acute phase, hospitalization and symptom persistence after 1 and 6 months. Long COVID was defined according to CDC criteria as persistence of at least one COVID-related symptom for one or more months after diagnosis. The mean variation of FEV1 recorded 6 months after acute infection was also evaluated.
Results
A total of 1102 people with CF were recruited (median age: 18 years, 520 younger than 18). The infection was symptomatic in 90.1 % of cases. During the acute phase, 8 subjects required oxygen support; 31 were hospitalized, one patient required intensive care. Complications included one thromboembolic event and two episodes of myocarditis, but no patient died. Mean variation of FEV1 after 6 months from the infection was +1.8 % (95 % CI: 1.0-2.7). Long COVID was documented in 64 subjects (5.8 %, 95 % CI: 4.5-7.4) with a variety of symptoms which were still present in 12 cases 6 months after infection (1.1 %, 95 % CI: 0.6-1.9).
Conclusions
In the omicron phase of the pandemic, COVID-19 was relatively mild and did not negatively impact pulmonary function after 6 months. Long COVID was observed at all ages, but extrapulmonary symptoms were more frequent and persistent in adults.
{"title":"COVID-19 in people with Cystic Fibrosis beyond the pre-omicron era: a prospective study with a specific focus on long COVID","authors":"Carla Colombo , Paola Medino , Marco Cipolli , Francesca Lucca , Giulia Cucchetto , Federico Alghisi , Fabiana Ciciriello , Angela Sepe , Camilla Romano , Giovanni Taccetti , Michela Francalanci , Maura Ambroni , Valentina Donati , Giovanna Pizzamiglio , Maura Spotti , Novella Rotolo , Maria Cristina Lucanto , Simona Cristadoro , Francesca Ficili , Giuseppina Leonetti , Francesco Blasi","doi":"10.1016/j.jcf.2025.08.015","DOIUrl":"10.1016/j.jcf.2025.08.015","url":null,"abstract":"<div><h3>Background</h3><div>The long-term clinical consequences of COVID-19 in cystic fibrosis (CF) remain largely unexplored. This study aimed to assess the incidence of long COVID in a large population of people with CF.</div></div><div><h3>Methods</h3><div>This prospective, multicentre study enrolled individuals with confirmed SARS-CoV-2 infection between July 2021 and October 2022. Data collected included clinical features prior to infection, symptoms during the acute phase, hospitalization and symptom persistence after 1 and 6 months. Long COVID was defined according to CDC criteria as persistence of at least one COVID-related symptom for one or more months after diagnosis. The mean variation of FEV<sub>1</sub> recorded 6 months after acute infection was also evaluated.</div></div><div><h3>Results</h3><div>A total of 1102 people with CF were recruited (median age: 18 years, 520 younger than 18). The infection was symptomatic in 90.1 % of cases. During the acute phase, 8 subjects required oxygen support; 31 were hospitalized, one patient required intensive care. Complications included one thromboembolic event and two episodes of myocarditis, but no patient died. Mean variation of FEV<sub>1</sub> after 6 months from the infection was +1.8 % (95 % CI: 1.0-2.7). Long COVID was documented in 64 subjects (5.8 %, 95 % CI: 4.5-7.4) with a variety of symptoms which were still present in 12 cases 6 months after infection (1.1 %, 95 % CI: 0.6-1.9).</div></div><div><h3>Conclusions</h3><div>In the omicron phase of the pandemic, COVID-19 was relatively mild and did not negatively impact pulmonary function after 6 months. Long COVID was observed at all ages, but extrapulmonary symptoms were more frequent and persistent in adults.</div></div>","PeriodicalId":15452,"journal":{"name":"Journal of Cystic Fibrosis","volume":"25 1","pages":"Pages 172-178"},"PeriodicalIF":6.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000625","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}
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