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Journal articleShort C, Semple T, Abkir M, et al., 2026, , Thorax
INTRODUCTION: The current cystic fibrosis (CF) care era, while hugely welcome, raises new challenges, particularly the need for more sensitive pulmonary outcome measures. Seeking further optimisation, we previously developed a Short extension to multiple breath washout measure (MBWShX) which captures previously overlooked, under-ventilated lung units but lacks regional information. Functional lung MRI addresses this limitation. We hypothesised these measures would be more sensitive to change in tracking CF lung disease than usual clinical respiratory function tests. METHODS: Forty-six people with (pw)CF, median age 15 (range 6-55) years were recruited to a single-centre study. While clinically stable, pwCF performed OE-MRI, MBW+/-ShX and spirometry at baseline and at 6 monthly intervals over 18 months of follow-up. A subgroup of pwCF (n=20) and age-matched healthy controls (HC, n=20) performed two repeatability visits within 6 weeks. RESULTS: OE-MRI/MBWShX were well tolerated, differentiated HC and CF groups, and were repeatable with negligible differences between two visits <6 weeks apart. OE-MRI/MBWShX parameters worsened at 12 months (p<0.05) and 18 months (p<0.01). In contrast, conventional measures of pulmonary function (FEV1+ LCI2.5) did not change significantly. CONCLUSIONS: OE-MRI/MBWShX are novel, sensitive tools to track progression of abnormalities in lung structure/function. Such progression may not be detected by conventional outcome measures. CF transmembrane conductance regulator (CFTR) modulators have been transformative for many pwCF and generally lead to substantial improvements in lung health. Stable FEV1 over longer time periods and, during mucoactive treatment withdrawal, may give false reassurance. OE-MRI/MBWShX reveal the likely less welcome reality that lung-disease progresses despite CFTR modulators. These measures could be considered in future studies when enhanced sensitivity is required.
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Journal articleDavies JC, Wilson G, Hughes D, 2026, , Thorax, Vol: 81, Pages: 511-513
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Journal articleDe Boeck K, Burgel P-R, Bierlaagh M, et al., 2026, , J Cyst Fibros
Genotype-based drug development has yielded highly effective therapies, notably the triple combinations elexacaftor/tezacaftor/ivacaftor (ETI) and vanzacaftor/tezacaftor/deutivacaftor (VTD), now approved in Europe for people with CF having at least one non-class I variant. However not all these people with CF will respond to ETI or VTD, and a few not under the label may respond. Facilitating opportunities to access for patients with rare variants has required a shift in paradigm toward functional testing-based access. This approach assesses the potential benefit of modulator therapy using in vitro functional assays, either in engineered systems expressing defined CFTR variants (theratyping) or in patient-derived tissues (theranostics). We review theranostics as a critical tool for personalized medicine in CF, highlighting its validation in in vitro models derived from patients' own cells such as human intestinal organoids and human nasal epithelial cells. We discuss the current regulatory landscape regarding modulator approval and propose strategies for improving equitable access to effective treatments for all people with CF. Importantly, we advocate for functional assays to be accepted as standalone evidence of drug efficacy for patients with rare variants. Theranostic approaches remain critical when theratyping has not been achieved, and genetic data is not available or clearly interpretable. Indeed, theranostics has emerged as an essential pillar of CF drug access, complementing genotype-driven strategies. As the field advances, continued validation, standardization, and regulatory integration of in vitro functional assays will be key to ensuring that every person with CF-regardless of their genotype-has the opportunity to benefit from precision therapies.
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Journal articleFarias A, Bridgeman VL, Rodrigues FS, et al., 2026, , Proc Natl Acad Sci U S A, Vol: 123
Metastatic breast cancer accounts for 7% of cancer-related deaths, with the lungs being a common site of cancer spread. In parallel, lower respiratory tract infections, including those caused by respiratory syncytial virus (RSV), remain a common cause of morbidity and mortality worldwide. Acute viral respiratory infections induce marked changes in the lung. However, how these changes influence metastasis initiation and cancer progression remains unclear. Using breast cancer and other cancer cell types in an experimental lung metastasis model, we show that RSV infection impairs tumor cell seeding and early growth in the lung, resulting in fewer metastatic nodules. We demonstrate that restriction of metastatic spread is due to alterations in the lung environment mediated by RSV-induced type I interferons (IFNs). Consistent with this idea, intranasal administration of recombinant IFN-α is sufficient to recapitulate the anti-metastatic effect of RSV infection. Using single cell RNA sequencing supported by in vivo and ex vivo validation, we show that IFN-α influences interactions between epithelial/endothelial cells and cancer cells. Furthermore, both RSV infection and IFN-α administration trigger marked local and systemic upregulation of Galectin-9, an IFN-inducible protein associated with acute respiratory infection in humans. Treatment of cancer cells with Galectin-9 alone is sufficient to restrict metastatic seeding. Altogether, our results suggest that type I IFNs induced by respiratory virus infection render the lungs less permissive to cancer cell seeding and consequently interfere with the ability of tumor cells to successfully initiate metastatic colonization.
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Journal articleSinadinos A, Bell R, Juarez-Molina CI, et al., 2026, , Molecular Therapy Advances, ISSN: 3117-387X
Targeting of the nasal epithelium for sustained therapeutic protein secretion represents a potential non-invasive lentiviral vector application strategy. Using reporter imaging, molecular, and radiopharmaceutical tracing methods in mice, we have developed an intranasal (nose-only) dosing strategy with a Sendai-virus envelope glycoprotein pseudotyped lentiviral vector (rSIV.F/HN). Using multiple (up to 10) small volume (5 μL) intranasal bolus applications, technetium radiotracer showed >90% liquid retention in the murine head and <1% in the lung. Following vector administration, transgene expression was dose-related in the nose with minimal lung expression. No acute nasal toxicity was associated with nose-only delivery. Next, we compared levels of a secreted protein, Gaussia luciferase (Gluc), in the airways and serum after nose-only and intravenous administration of rSIV.F/HN-Gluc (2e8 TU/mouse). Gluc expression in the nose and lungs was higher following nose-only versus intravenous administration. Serum levels were similar after either route of administration. Finally, nose-only delivery of rSIV.F/HN encoding GM-CSF, led to sufficient lung levels of this therapeutic protein to correct disease biomarkers in a mouse model of pulmonary alveolar proteinosis. We conclude that non-invasive administration of a lentiviral vector to the nasal epithelium provides a safe and convenient route for secreted protein production and is readily translatable into humans.
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Journal articleJackson R, Bentley S, Davies JC, et al., 2026, , Paediatr Respir Rev
The availability of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators has transformed outcomes for people with cystic fibrosis (pwCF). Eligibility, conferred initially by clinical trial data, has evolved through advances in in vitro 'theratyping' and use of real‑world evidence. Since ivacaftor's approval for a single gating variant in 2012, eligibility has broadened to over 180 variants with the highly effective therapies elexacaftor/tezacaftor/ivacaftor and recently launched vanzacaftor/tezacaftor/deutivacaftor. Regulatory authorities have increasingly accepted non‑traditional evidence, notably the FDA's 2017 ivacaftor extension based on cell‑based assays and, in 2025, the EMA's decision to extend elexacaftor/tezacaftor/ivacaftor to people ≥2 years with at least one non class I variant. However, clinical response remains variable, influenced in part by baseline characteristics, pharmacokinetics, pharmacogenetics, and environmental exposures. We outline evolving approaches to determining eligibility and strategies to improve methods to predict, verify, and monitor clinical response in an era of personalised medicine.
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Journal articleBokobza I, Wilson G, Downes A, et al., 2026, , Am J Respir Crit Care Med
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Journal articleGriesenbach U, McLachlan G, Sinadinos A, et al., 2026, , Molecular Therapy Advances, Vol: 34, Pages: 201655-201655, ISSN: 3117-387X
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Journal articleBarnes M, Stretch S, Swieboda D, et al., 2026, , Mucosal Immunology, ISSN: 1933-0219
RationaleBronchiolitis is the commonest cause of hospital admission in children under the age of 1 year, most cases being due to respiratory syncytial virus (RSV) infection. The mechanisms causing infantile bronchiolitis are incompletely understood but include a deficient mucosal interferon response, neutrophilic inflammation and enhanced mucosal Type-2 responses.ObjectivesWe sought to determine the mucosal immune processes associated with severe paediatric bronchiolitis.MethodsWe performed transcriptomic analyses on mucosal samples from infants hospitalized with Moderate (n = 48) and Severe (n = 40) bronchiolitis. Differential expression and regression analyses determined genes associated with different severity categories. Responses were modelled in vitro using air–liquid interface human nasal epithelial cell culture models.Measurements and main resultsWe confirmed weakened interferon-associated signalling in severe RSV and non-RSV bronchiolitis but unexpectedly found elevated IL-36α (an IL-1 family cytokine implicated in chronic inflammatory diseases) early in infection. Conversely, IL36A was decreased in whole blood during severe RSV, suggesting that this association is unique to the mucosa. In human nasal epithelial cells grown in vitro under air–liquid interface we found IL-36α to be produced by epithelial cells during RSV infection and that its secretion is enhanced by neutrophils.ConclusionsThese findings implicate mucosal IL-36α as a dominant feature of severe paediatric bronchiolitis.
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Journal articleSanchez-Garcia MA, Sadiku P, Ortmann BM, et al., 2026, , Nature Immunology, Vol: 27, ISSN: 1529-2908
Correction to: Nature Immunology https://doi.org/10.1038/s41590-025-02301-9, published online 28 October 2025.In the version of this article initially published, the surname of Musa M. Mhlanga was misspelled (Mhalanga) and is now amended in the HTML and PDF versions of the article.
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