Lancet Respir Med. 2025 Jul 30:S2213-2600(25)00206-1. doi: 10.1016/S2213-2600(25)00206-1. Online ahead of print.

ABSTRACT

Identifying safe and effective therapies that target the underlying cause of cystic fibrosis remains a key priority for the cystic fibrosis community. CFTR modulators are first-in-class, regulatory-approved therapies that improve the function of the protein encoded by the CFTR gene and are associated with dramatic and sustained clinical benefits. Although approximately 90% of the population with cystic fibrosis could benefit from these therapies based on genetic eligibility, a crucial unmet need remains: developing CFTR-directed therapies for the ultra-rare population with cystic fibrosis who are not candidates for CFTR modulators due to either ineligibility or intolerance. Addressing this unmet need will depend on the clinical advancement of nucleic acid-based therapies (NABTs), a term that includes variant-specific antisense oligonucleotide therapies and variant-agnostic mRNA and DNA-based gene therapies. The clinical development of NABTs for those who are not candidates for or unable to take CFTR modulators is challenged not only by the relatively small target population, which affects feasible trial sizes, but also by unique regulatory requirements for long-term safety follow-up and the potential yet unknown short-term and long-term risks with genetic therapy cross-exposure or re-exposure. This Personal View addresses the proactive planning needed to maximise trial opportunities for the population who are not candidates for CFTR modulators, including considerations for subsequent NABT trial participation following previous NABT exposure.

PMID:40752498 | DOI:10.1016/S2213-2600(25)00206-1

Respir Investig. 2025 Aug 1;63(5):964-966. doi: 10.1016/j.resinv.2025.07.019. Online ahead of print.

ABSTRACT

Dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential but undercharacterized risk factor for nontuberculous mycobacterial pulmonary disease (NTM-PD). We reviewed health records to identify clinical features of NTM-PD patients who exhibited CFTR dysfunction, defined by sweat chloride concentration (SCC) ≥30 mmol/L. CFTR genotyping was performed in those with elevated SCC. Among 40 patients, 77.5 % were female, and the median age was 70 years (IQR 54.3-73). M. avium complex was most frequently isolated (87.5 %). Median SCC was 31 mmol/L (IQR 22.3-51.8), with 23 patients (57.5 %) showing elevated levels. Patients with elevated SCC were often female, with low BMI, history of tobacco use, bronchiectasis, and small airway disease, and were likely to initiate antimycobacterial therapy. Clinically relevant CFTR variants were found in 5 (29 %) patients. These findings suggest CFTR dysfunction may contribute to NTM-PD pathogenesis. Comprehensive molecular and functional studies are warranted to elucidate underlying mechanisms.

PMID:40752189 | DOI:10.1016/j.resinv.2025.07.019

Oncoimmunology. 2025 Dec;14(1):2542334. doi: 10.1080/2162402X.2025.2542334. Epub 2025 Aug 1.

ABSTRACT

The α2-adrenergic receptor agonist dexmedetomidine (DEX) exerts context-dependent antitumor effects, with its efficacy influenced by dose, immune cell involvement and combination with immune checkpoint inhibitors. It will be important to understand to which extent DEX and other α2-adrenergic agonists act on α2-adrenergic receptors from cancer and immune cells.

PMID:40748168 | PMC:PMC12320808 | DOI:10.1080/2162402X.2025.2542334

Nat Commun. 2025 Aug 1;16(1):7059. doi: 10.1038/s41467-025-62199-7.

ABSTRACT

Hyperactivation of the cystic fibrosis transmembrane conductance regulator (CFTR) contributes to secretory diarrhea, a major cause of pediatric mortality worldwide, and autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of end-stage renal disease. Selective CFTR inhibition is a potential therapeutic strategy, with (R)-BPO-27 emerging as a promising candidate. Here, we present a cryo-EM structure of CFTR bound to (R)-BPO-27 at an overall resolution of 2.1 Å. Contrary to the previous hypothesis that it inhibits CFTR current by competition with ATP, we demonstrate that (R)-BPO-27 instead directly occludes the chloride-conducting pore while permitting ATP hydrolysis, thus uncoupling the two activities. Furthermore, we find that inhibitor binding requires some degree of NBD separation, as the inhibition rate inversely correlates with the probability NBD dimerization. These findings clarify the compound's mechanism and provide a molecular basis for optimizing its clinical potential.

PMID:40750590 | DOI:10.1038/s41467-025-62199-7

J Cyst Fibros. 2025 Jul 31:S1569-1993(25)01529-2. doi: 10.1016/j.jcf.2025.07.008. Online ahead of print.

ABSTRACT

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) prevents malnutrition in people with exocrine pancreatic insufficiency, including those with cystic fibrosis (CF). We developed a lipase that is stable against proteolysis and at the pH of the fed stomach, so it can be taken during a meal to promote mixing of enzyme and substrate. We designed a dose-ranging study of ANG003, a microbial PERT combining this lipase with low pH-stable protease and amylase, also of microbial origin.

METHODS: This was a multicenter, randomized evaluation of ANG003 in subjects with CF, studied once without PERT and again after randomization to a single dose level of four possible combinations of lipase, protease, and amylase. We developed blood-based substrate absorption challenge tests employing DHA+EPA, whey and potato starch to determine dose-response to each of these enzymes, respectively.

RESULTS: ANG003 improved DHA+EPA absorption with a statistically significant increase with 80 mg and 120 mg lipase doses compared to 20 mg (p = 0.03; p = 0.004). The absorption of total fats followed a similar pattern to DHA+EPA. There was a significant increase in absorbed amino acid equivalents, reflecting proteolysis, over no PERT in the highest (75 mg) dose of protease (p = 0.03). In subjects without diabetes, glucose was slightly lower while c-peptide levels remained unchanged with all amylase doses. Adverse events were mild and transient. No serious adverse events occurred.

CONCLUSIONS: ANG003 lipase significantly improves DHA+EPA and total fat absorption in a dose dependent manner. Results for ANG003 protease and amylase activity suggest that doses lower than those in current porcine-derived PERTs may be efficacious.

PMID:40750484 | DOI:10.1016/j.jcf.2025.07.008

Clin Ther. 2025 Jul 31:S0149-2918(25)00245-0. doi: 10.1016/j.clinthera.2025.07.007. Online ahead of print.

NO ABSTRACT

PMID:40750460 | DOI:10.1016/j.clinthera.2025.07.007

Protein Expr Purif. 2025 Jul 30:106786. doi: 10.1016/j.pep.2025.106786. Online ahead of print.

ABSTRACT

Human plasma gelsolin (pGSN) is an 83 kDa actin-binding protein involved in cytoskeletal remodeling, inflammation, and host defense. Its clinical relevance as a biomarker and potential therapeutic agent, particularly in conditions like sepsis, acute respiratory distress syndrome (ARDS), and cystic fibrosis, has driven interest in scalable recombinant expression. However, high-yield production of functionally active gelsolin is hindered by its complex structure and folding requirements. To address this, we developed a scalable, high-yield bacterial expression system that achieves among the highest reported levels of functional recombinant human gelsolin (rGelsolin) using a GST-fusion strategy incorporating a tobacco etch virus (TEV) protease cleavage site, optimized for solubility and downstream processing. High-density fed-batch fermentation in E. coli yielded 5.0 g/L of soluble protein. Following a three-step purification process with removal of the GST tag, 2.1 g/L of tag-free, high-purity rGelsolin with >95% purity was obtained. Structural characterization by circular dichroism spectroscopy confirmed that rGelsolin adopted a native-like secondary structure and exhibited thermal stability (Tm ∼59 °C). Correct processing of the recombinant protein was verified by N- and C-terminal sequencing. Functional assays demonstrated that rGelsolin bound to and severed actin filaments in a calcium-dependent manner, similar to native plasma gelsolin. These findings demonstrate a scalable, cost-effective platform for producing bioactive rGelsolin in E. coli, with structural and functional features comparable to native pGSN, supporting its potential utility in diagnostic, therapeutic, and structural applications in the context of acute and chronic inflammatory diseases.

PMID:40750002 | DOI:10.1016/j.pep.2025.106786

Life Sci. 2025 Jul 30:123888. doi: 10.1016/j.lfs.2025.123888. Online ahead of print.

ABSTRACT

Dopamine is a neuromodulator molecule that is involved in several systems in the human body. As a neurotransmitter, it plays a role in regulating reward, pleasure, and motor control in the brain. Beyond its well-known central nervous system functions it significantly influences peripheral systems including kidneys, circulatory system, and notably, immune system. It increases glomerular filtration rate and renal blood flow in the kidneys, while it increases aortic pressure and cardiac output in the circulatory system. Crucially, dopamine and its receptors have been identified on various immune cells, playing a significant immunomodulatory role that contributes to balanced immune responses and has implications in autoimmune diseases and conditions like sepsis. Moreover, in the respiratory system, dopamine plays a significant role in the pathophysiology of major respiratory disorders such as asthma, cystic fibrosis, chronic obstructive pulmonary disease, and lung cancer. Depending on the type of receptor, dopaminergic receptors contribute to the pathophysiology of lung disease. As part of the narrative review, we have identified dopaminergic receptors in the respiratory system, their anatomic locations, and their specific mechanisms of action in the pathophysiology of major respiratory disorders. We have also identified and summarized molecular therapy protocols that can be used in the treatment of these disorders, considering the evolving understanding of dopamine's broad systemic effects.

PMID:40749823 | DOI:10.1016/j.lfs.2025.123888

J Am Acad Orthop Surg Glob Res Rev. 2025 Jul 29;9(8). doi: 10.5435/JAAOSGlobal-D-24-00304. eCollection 2025 Aug 1.

ABSTRACT

INTRODUCTION: Perioperative outcomes for patients with cystic fibrosis (CF) have not been previously described following spine surgery. This study used PearlDiver to examine the 90-day postoperative outcomes and 4-year revision rates after posterior lumbar fusion (PLF) for patients with CF compared with matched controls.

METHODS: This study examined a cohort of PLF patients with versus without CF. Patients were matched 1:10 for age, sex, Elixhauser Comorbidity Index, and the number of levels. Ninety-day postoperative outcomes and 4-year revision rates were compared.

RESULTS: One hundred twenty-seven patients with CF were matched with 1263 controls without CF. On multivariable logistic regression, those with CF had statistically significantly increased 90-day odds of the following: venous thromboembolism (odds ratio [OR], 4.2), pleural effusion (OR, 3.4), dyspnea (OR, 3.2), respiratory failure (OR, 2.8), pneumonia (OR, 2.6), acute kidney injury (OR, 2.4), hospital readmissions, (OR, 2.2), and emergency department visits (OR, 2.1). Notably, patients with CF were not at increased odds of 4-year subsequent lumbar surgery.

DISCUSSION: Patients with CF were at significantly increased odds of pulmonary and other defined adverse events. These findings are pertinent in the perioperative risk assessment, patient/family recommendations, and surgical preparations for patients with CF being considered for PLF.

PMID:40749196 | DOI:10.5435/JAAOSGlobal-D-24-00304

J Med Microbiol. 2025 Aug;74(8). doi: 10.1099/jmm.0.002051.

ABSTRACT

Background. Achromobacter xylosoxidans and Pseudomonas aeruginosa are two pathogens that cause persistent airway infections in individuals with cystic fibrosis (CF). The persistence of P. aeruginosa is partly due to a high capacity to form biofilms and the ability to exert antagonism against other bacteria. Loss of microbial diversity in conjunction with chronic P. aeruginosa colonization is strongly correlated with low lung function in CF. A. xylosoxidans and P. aeruginosa are frequently co-isolated in CF airway cultures. This study aims to investigate the reciprocal effects on growth inhibition and biofilm formation between P. aeruginosa and A. xylosoxidans in vitro.Method. Six isolates of A. xylosoxidans, isolated from three CF patients in early and late stages of a chronic infection, were cultured together with a CF isolate of P. aeruginosa. Biofilm formation was assessed using a microtiter assay and crystal violet staining. Quantitative PCR was used to quantify species proportions in biofilms. Growth curves were performed to compare planktonic growth rates.Results. Three A. xylosoxidans isolates, all of which were from early-stage infections, inhibited biofilm formation of P. aeruginosa. The inhibition was concentration-dependent and required the interaction of live bacteria during the early stages of biofilm development. The inhibitory effect was not caused by nutrient depletion of the planktonic cells. The selected A. xylosoxidans isolate had a stronger capacity to adhere to plastic surfaces compared to the P. aeruginosa isolate.Conclusions . A. xylosoxidans can inhibit P. aeruginosa biofilm formation in vitro. The observed effect requires active interactions between live cells during the attachment stage of biofilm formation, possibly due to differences in adhesion capacity.

PMID:40748998 | DOI:10.1099/jmm.0.002051

J Pediatr Surg Case Rep. 2020 Feb;53:101381. doi: 10.1016/j.epsc.2019.101381. Epub 2019 Dec 28.

ABSTRACT

Individuals with cystic fibrosis (CF) who possess milder and less common mutations can have preservation of exocrine pancreatic function (EPF) but are at risk for recurrent pancreatitis, chronic pancreatic damage, and loss of EPF. They may develop sequelae secondary to pancreatic disease including malabsorption, chronic pain, and disordered eating. In severe cases, endoscopic and surgical intervention is necessary. With advancement of CFTR modulators, individuals with more unique mutations are eligible for modulator therapy, leading to preservation of pancreatic function and elimination of further pancreatitis and co-morbidities. Our case illustrates an adolescent female with CF and chronic pancreatitis with associated malabsorption, loss of EPF, chronic pain and nausea. She underwent a Puestow procedure and subsequent initiation of ivacaftor/tezacaftor, which dramatically improved her medical course and quality of life. With earlier intervention, including modulator therapy, patients with CF and pancreatic disease can potentially preserve EPF and obtain an improved quality of life.

PMID:40746763 | PMC:PMC12312001 | DOI:10.1016/j.epsc.2019.101381

Microbiol Spectr. 2025 Jul 31:e0038225. doi: 10.1128/spectrum.00382-25. Online ahead of print.

ABSTRACT

Nontuberculous mycobacterial (NTM) infections in people with cystic fibrosis (pwCF) can have detrimental effects on prognosis and pose significant challenges to treatment. However, there are still questions regarding the contribution and influence of NTMs on the respiratory microbiome and the mechanisms by which NTMs cause infections. Here, we investigate the impact of NTM infection on microbiome composition and lung function (percent predicted forced expiratory volume in 1 second). Primary comparisons were between culture-positive cohorts for Mycobacterium avium complex and Mycobacterium abscessus complex and those who were culture-negative for NTMs and attending outpatient clinics. Additionally, the consequence of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy status and positive NTM culture was assessed in terms of microbiome change. Our data suggest that the presence of NTM significantly alters the diversity and the composition of the lung microbiota in pwCF, including those receiving CFTR modulator therapies. Importantly, significant associations were detected between NTM presence and changes in abundance of Pseudomonas aeruginosa and Burkholderia cepacia complex members, inferring modulatory effects of NTMs on respiratory microbiomes. This study contributes to the understanding of NTM infection and these organisms' interaction with the respiratory microbiome and CFTR modulator therapy, highlighting the need for further research in this area.IMPORTANCEThe influence of NTM infection in pwCF is still debated, and the extent of their contribution to mortality and morbidity is still questioned. Findings in this study highlight a link between the presence of NTMs and significant alterations in the composition of the respiratory microbiome, particularly with respect to some of the canonical CF pathogens, especially Pseudomonas aeruginosa and members of the Burkholderia cepacia complex. This indicates that complex relationships are occurring within the microbiome. This study further contributes to the understanding of NTM infection in pwCF, with and without CFTR modulator therapy, and highlights the need for further research in this area. The knowledge gained from this study has implications for treatment strategies and management, ultimately aiming to improve and prolong the lives of pwCF.

PMID:40744839 | DOI:10.1128/spectrum.00382-25

Otolaryngol Head Neck Surg. 2025 Aug;173 Suppl 1:S1-S56. doi: 10.1002/ohn.1344.

ABSTRACT

The American Academy of Otolaryngology-Head and Neck Surgery Foundation has published a supplement to this issue of Otolaryngology-Head and Neck Surgery featuring the updated "Clinical Practice Guideline: Adult Sinusitis". To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 developed recommendations address diagnostic accuracy for adult rhinosinusitis, the appropriate use of ancillary tests to confirm diagnosis and guide management (including radiography, nasal endoscopy, computed tomography, and testing for allergy and immune function), and the judicious use of systemic and topical therapy. Emphasis was also placed on identifying multiple chronic conditions that would modify management of rhinosinusitis, including asthma, cystic fibrosis, an immunocompromised state, and ciliary dyskinesia. An updated guideline is needed as a result of new clinical trials, new systematic reviews, and the lack of consumer participation in the initial guideline development group.

PMID:40742114 | DOI:10.1002/ohn.1344

Otolaryngol Head Neck Surg. 2025 Aug;173(2):299-316. doi: 10.1002/ohn.1342.

ABSTRACT

The American Academy of Otolaryngology-Head and Neck Surgery Foundation has published the updated "Clinical Practice Guideline: Adult Sinusitis" as a supplement to this issue of Otolaryngology-Head and Neck Surgery. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 developed recommendations address diagnostic accuracy for adult rhinosinusitis, the appropriate use of ancillary tests to confirm diagnosis and guide management (including radiography, nasal endoscopy, computed tomography, and testing for allergy and immune function), and the judicious use of systemic and topical therapy. Emphasis was also placed on identifying multiple chronic conditions that would modify management of rhinosinusitis, including asthma, cystic fibrosis, immunocompromised state, and ciliary dyskinesia. An updated guideline is needed as a result of new clinical trials, new systematic reviews, and the lack of consumer participation in the initial guideline development group. METHODS: This executive summary describes the guideline developed using the 55-page protocol published as the American Academy of Otolaryngology-Head and Neck Surgery Foundation's Clinical Practice Guideline Development Manual (3rd edition), which summarizes the methodology for assessments of current data, topic prioritization, development of key action statements, application of value judgements, and related procedures. The guideline update group represented the disciplines of otolaryngology-head and neck surgery, infectious disease, family medicine, allergy and immunology, advanced practice nursing, and a consumer advocate. DIFFERENCES FROM PRIOR GUIDELINE: This clinical practice guideline is as an update, and replacement, for an earlier guideline published in 2015 by the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF).1 An update was planned for 5 years after the initial publication date and was further necessitated by new primary studies and systematic reviews that might suggest a need for modifying clinically important recommendations.2 Changes in content and methodology from the prior guideline include the following: New evidence from 14 guidelines, 194 systematic reviews, and 133 RCTs. Emphasis on patient education and counseling with new explanatory tables. Expanded action statement profiles to explicitly state quality improvement opportunities, confidence in the evidence, intentional vagueness, and differences of opinion. Enhanced external review process to include public comment and journal peer review. New algorithm to clarify decision making, watchful waiting, action statement relationships. Extension of watchful waiting (without antibiotic therapy) as an initial management strategy to all patients with uncomplicated acute bacterial rhinosinusitis (ABRS) regardless of severity, not just patients with "mild" illness (prior guideline). Clarified the recommended timeline for the diagnosis, conservative management and antibiotic treatment of ABRS. Change in recommendation to first-line antibiotic therapy for ABRS amoxicillin, with or without clavulanate, from amoxicillin alone (prior guideline). Addition of aspirin exacerbated respiratory disease (AERD) as a chronic condition that modifies management of chronic rhinosinusitis (CRS). Three new key action statements on managing CRS that focus on the use of biologics (recommend against when patients do not have polyps and educate patients about them when they do) and a recommendation against the empiric use of antibiotics for CRS solely as a third-party requirement for surgery or imaging.

PMID:40741969 | DOI:10.1002/ohn.1342

Bio Protoc. 2025 Jul 20;15(14):e5399. doi: 10.21769/BioProtoc.5399. eCollection 2025 Jul 20.

ABSTRACT

Well-differentiated airway epithelial cultures are commonly used to study airway stem cell lineages, ion and fluid transport, respiratory virus infection and replication, and disease mechanisms in vitro. This culture model involves the isolation and expansion of airway stem cells followed by their differentiation at an air-liquid interface (ALI), a process that has been previously documented in humans and mice. Domestic ferrets (Mustela putorius furo) have gained considerable importance in respiratory disease research due to their notable susceptibility to these conditions and their anatomical similarities to humans. Here, we present a comprehensive description of the isolation and culture of stem/progenitor cells from the ferret airway, along with a protocol for their differentiation at the ALI. Our findings have demonstrated that this ferret culture system not only supports the differentiation of the predominant airway epithelial cell types but also facilitates the generation of rare airway epithelial subpopulations, including pulmonary ionocytes, tuft cells, and pulmonary neuroendocrine cells. Additionally, we provide a detailed procedure for measuring transepithelial ion transport relevant to airway diseases, particularly cystic fibrosis. The ability to isolate and culture ferret airway stem cells, combined with ALI differentiation and functional assessment of transepithelial ion transport, offers a powerful platform for evaluating genetic and pharmacologic interventions related to cystic fibrosis. Key features • A protocol for isolating ferret airway basal cells and generating air-liquid interface (ALI) cultures for electrophysiologic research. • Detailed procedures for propagating ferret airway basal cells and culturing in vitro well-differentiated airway epithelium. • A protocol for measuring ion transport, conductance, and immunofluorescence to identify airway cell types.

PMID:40741390 | PMC:PMC12304463 | DOI:10.21769/BioProtoc.5399

Front Pharmacol. 2025 Jul 16;16:1632924. doi: 10.3389/fphar.2025.1632924. eCollection 2025.

ABSTRACT

Cystic Fibrosis (CF), a multi-organ disease stemming from CFTR gene mutations, is characterized by progressive pulmonary disease, chronic inflammation, and a pro-oxidative environment. The intricate relationship between CFTR dysfunction, oxidative stress, and inflammation underscores the need to accurately characterize oxidative stress markers to identify therapeutic targets. This review compiles and analyzes methodologies employed in the CF field for this purpose, presenting selected applications and outcomes while highlighting potential inconsistencies due to experimental variations. The review encompasses a wide array of analytical techniques. These include methods for direct reactive oxygen species (ROS) detection (e.g., superoxide, hydrogen peroxide), characterization of oxidative damage to lipids (e.g., TBARS, F2-isoprostanes; lipidomics), proteins (e.g., carbonylation, S-nitrosylation, S-glutathionylation; proteomics), and DNA (e.g., 8-OHdG). Assays for major non-enzymatic antioxidants (glutathione, vitamins), enzymatic antioxidant systems (superoxide dismutase, catalase, glutathione peroxidase), and total antioxidant capacity (TAC) are detailed. Furthermore, methods to assess mitochondrial function for studying oxidative stress in CF are discussed. The critical choice of experimental models (in vitro, in vivo) and biological samples (e.g., blood, sputum, BALF, EBC, cells), along with their specific considerations, are also integral to the review. Application of these diverse methodologies frequently reveals heightened oxidative stress and perturbed antioxidant defenses across various CF-relevant compartments, although results can be influenced by the specific model or technique utilized. Ultimately, this comprehensive analysis underscores the complexity of assessing oxidative stress in CF and strongly advocates for the implementation of integrated, multiparametric strategies. Such synergistic approaches, combining complementary methodologies, are crucial for a holistic understanding of redox dysregulation, facilitating the identification of reliable biomarkers, and guiding the development of more effective, targeted antioxidant therapies to improve clinical outcomes in CF.

PMID:40740993 | PMC:PMC12307221 | DOI:10.3389/fphar.2025.1632924

Front Med (Lausanne). 2025 Jul 16;12:1611304. doi: 10.3389/fmed.2025.1611304. eCollection 2025.

ABSTRACT

BACKGROUND: Lung organoids have emerged as a promising tool for studying lung development, function, and disease pathology. The present study aimed to analyze the current status and development trends of lung organoid research over the past years, present visual representations, and provide references for future research directions using bibliometric analysis.

METHODS: Information on articles on lung organoids extracted from the Web of Science Core Collection, such as year of publication, journal, country, institution, author, and keywords, was analyzed. R, VOSviewer, and SCImago Graphica were used to visualize publication trends, co-authorship analysis, co-occurrence analysis, and hotspot evolution.

RESULTS: The number of global publications has increased from 1 in 2011 to 929 in 2024. The Nature produced the highest number of citations (2,675 citations). The United States (8,155 citations and 281 publications), University Medical Center Utrecht (2083 citations and 11 publications), and Clevers H (2,711 citations and 21 publications) were the most influential countries, institutions, and authors, respectively. Co-occurrence cluster analysis of the top 54 keywords formed four clusters: (1) idiopathic pulmonary fibrosis, (2) lung cancer, (3) cystic fibrosis, (4) COVID-19.

CONCLUSION: Overall, research on lung organoids continues to increase. The United States of America and the Netherlands dominated global studies. The analysis of pulmonary fibrosis, lung cancer and COVID-19 occupied a prominent position of research in this area. The research hotspots for lung organoids are disease model and microphysiological systems. Standardization, accurate disease modeling, and ethics and safety remain pressing challenges that need to be addressed in this field.

PMID:40740941 | PMC:PMC12307212 | DOI:10.3389/fmed.2025.1611304

J Cyst Fibros. 2025 Jul 30:S1569-1993(25)01533-4. doi: 10.1016/j.jcf.2025.07.011. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic infection and inflammation of the lungs contribute significantly to disease progression in persons with cystic fibrosis (pwCF). Treatment regimens are largely based on isolating the putative causative pathogen(s) from respiratory samples using basic culturing methods. While this strategy has shown to be highly valuable in the management of CF, the approach is time-consuming and often misses detection of pathogenic microbes that are more difficult to culture, including Mycobacterium spp.

METHODS: In our proof-of-concept study, we evaluated shallow metagenomic shotgun sequencing to detect potential infection-causing pathogens at species level in sputum, oropharyngeal and salivary samples of pwCF (n = 13), and compared it to culture results from the clinic and standard 16S rRNA V4 amplicon sequencing.

RESULTS: Shallow shotgun sequencing improved the detection of pathogenic species in respiratory samples compared to culture methods. In particular, shallow shotgun sequencing could detect pathogenic species associated with CF, specifically Staphylococcus aureus, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Haemophilus influenzae and Mycobacterium spp. in sputum, oropharyngeal and/or salivary samples. Notably, Mycobacterium spp. was not detected based on 16S rRNA amplicon sequencing. Moreover, our approach was able to distinguish S. aureus from S. epidermidis and H. influenzae from H. parainfluenzae. This is not possible with 16S amplicon sequencing, but highly valuable in a clinical setting.

CONCLUSIONS: The improved detection of CF pathogens and other critical microbiome members as well as insights into their relative abundance within the community, could provide more knowledge on patient's disease status leading to more personalized medicine and ultimately benefit patient care.

PMID:40738767 | DOI:10.1016/j.jcf.2025.07.011

BMJ Open. 2025 Jul 30;15(7):e097071. doi: 10.1136/bmjopen-2024-097071.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a genetic condition of impaired membrane electrolyte transport and is characterised by defects in the production and function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Ground-breaking CFTR modulator therapy has resulted in a notable shift in the clinical presentation and progressive nature of CF, across both pulmonary and extrapulmonary systems. Access to CFTR modulator therapies in people with CF is occurring in a staged, descending age process, with clinical trials focusing primarily on safety and efficacy. There is a lack of robust, real-world longitudinal data on CFTR modulator therapy in infants and young children where extrapulmonary outcomes such as growth, micronutrient status and pancreatic function are the key focus.

METHODS AND ANALYSIS: Pancreatic, nutritional and clinical outcomes in children 0-5 years with CF during the first 2 years of CFTR modulator therapy (PaNC) is a prospective cohort study involving all eight tertiary paediatric CF centres in Australia. Infants and children 4 months to 5 years of age who are eligible for elexacaftor/tezacaftor/ivacaftor (ETI) or ivacaftor (IVA) meet the inclusion criteria for PaNC, with a total eligible cohort of 303 children at the commencement of recruitment. The primary outcomes are change in weight-for-length/body mass index z score and change in serum micronutrient status, at 6-12 monthly intervals, during the first 2 years of treatment with ETI or IVA. Secondary outcomes include change in exocrine pancreatic function, measured by faecal elastase-1, change in the use and dose of pancreatic enzyme replacement therapy, nutritional and gastrointestinal therapies and change in sweat chloride levels. Linear mixed modelling will be used to analyse primary and secondary endpoints. This protocol is reported in accordance with 'The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement' reporting guidelines.

ETHICS AND DISSEMINATION: Overarching governance and ethics approval has been granted by Monash Health Human Research Ethics Committee, in addition to all eight sites receiving site-specific authorisation approvals prior to the commencement of recruitment. Opportunities for CF consumers to be involved in targeted dissemination plans will be initiated via CF Australia at the completion of the study period. Additionally, a summary of non-identifiable results will be provided to CF consumers and CF healthcare providers via scientific and lay conferences and via peer-reviewed journals.

TRIAL REGISTRATION NUMBER: ACTRN12624001185550; Pre-results.

PMID:40738633 | DOI:10.1136/bmjopen-2024-097071

Respir Med. 2025 Jul 28:108274. doi: 10.1016/j.rmed.2025.108274. Online ahead of print.

ABSTRACT

BACKGROUND: The impact of previous exposure to CFTR therapies on efficacy of Elexacaftor-tezacaftor-ivacaftor (ETI) therapy is unclear.

OBJECTIVE: Objective of this study was to quantify differences in clinical parameters and chronic sinus disease with ETI therapy among those naive and previously exposed to CFTR modulator therapies.

METHODS: Our cohort included 115 pwCF, median (IQR) age of 23 (17, 32) years. Clinical data was collected at initiation of ETI therapy and at three-month intervals for one year. Twenty-one pwCF with sinus CT scan performed within three-months of initiation of ETI therapy (baseline) and after one-year on ETI therapy were included in this study, and changes were compared using both Lund-Mackay (LM) and Sheikh-Lind (SL) sinus CT scoring systems.

RESULTS: Among the total cohort of 115 pwCF, 49 (42.6%) were naive to CFTR modulators and the remaining 66 (57.4%) were previously exposed to CFTR modulators before switching to ETI. With one-year of ETI therapy, significant increases in ppFEV1 and BMI were observed (p<0.001), and change was independent of previous CFTR modulator exposure (p=0.5 and 0.4 respectively). Similarly, significant reduction in median sinus CT scores were noted, median total score of LM sinus CT scoring system decreased from 5.5 to 2.8 (p<0.001) and SL score decreased from 3.8 to 2.2 (p<0.001) and changes were independent of previous CFTR exposure.

CONCLUSION: ETI therapy was associated with improved clinical outcomes and improvement in sinus CT scans in pwCF and changes were independent of previous CFTR modulator therapies.

PMID:40738373 | DOI:10.1016/j.rmed.2025.108274