Angew Chem Int Ed Engl. 2025 Apr 3:e202505714. doi: 10.1002/anie.202505714. Online ahead of print.

ABSTRACT

Antibiotic-resistant bacteria of the genus Pandoraea, frequently acquired from the environment, are an emerging cause of opportunistic respiratory infections, especially in cystic fibrosis (CF) patients. However, their specialized metabolites, including niche and virulence factors, remained unknown. Through genome mining of environmental and clinical isolates of diverse Pandoraea species, we identified a highly conserved biosynthesis gene cluster (pan) that codes for a non-ribosomal peptide synthetase (NRPS) assembling a new siderophore. Using bioinformatics-guided metabolic profiling of wild type and a targeted null mutant, we discovered the corresponding metabolites, pandorabactin A and B. Their structures and chelate (gallium) complexes were elucidated by a combination of chemical degradation, derivatization, NMR, and MS analysis. Metagenomics and bioinformatics of sputum samples of CF patients indicated that the presence of the pan gene locus correlates with the prevalence of specific bacteria in the lung microbiome. Bioassays and mass spectrometry imaging showed that pandorabactins have antibacterial activities against various lung pathogens (Pseudomonas, Mycobacterium, and Stenotrophomonas) through depleting iron in the competitors. Taken together, these findings offer first insight into niche factors of Pandoraea and indicate that pandorabactins shape the diseased lung microbiota through the competition for iron.

PMID:40178319 | DOI:10.1002/anie.202505714

J Antimicrob Chemother. 2025 Apr 3:dkaf101. doi: 10.1093/jac/dkaf101. Online ahead of print.

ABSTRACT

OBJECTIVES: Mycobacterium abscessus is the most frequent of the rapidly growing mycobacteria responsible for lung infections in patients suffering from cystic fibrosis and COPD. Imipenem is currently recommended in the treatment of these infections in spite of β-lactamase production. Since the targets of β-lactams include transpeptidases of both the l,d and d,d specificities, we tested, in vitro, intracellularly and in vivo, a combination of two β-lactams active on these enzymes, amoxicillin and imipenem, alone or in combination with the β-lactamase inhibitor relebactam.

METHODS: Drug combinations were evaluated against M. abscessus CIP 104536T and clinical isolates (n = 35) by determining MICs, FIC indices and time-killing. Drug combinations were also evaluated in macrophages and in mice.

RESULTS: In the presence of relebactam, synergy between amoxicillin and imipenem was observed against both M. abscessus CIP 104536T and the clinical isolates. Against M. abscessus CIP 104536T, the addition of 1 mg/L imipenem and 4 mg/L relebactam led to a decrease in the MIC of amoxicillin from 64 to 1 mg/L. The triple combination was active in vitro and intracellularly (a 4.30 decrease in the log10 cfu/mL and 82% killing, respectively). The triple combination was effective in reducing log10 cfu in mouse organs and mouse spleen weights, and in preventing losses in mouse weights.

CONCLUSIONS: The amoxicillin/imipenem/relebactam combination was synergistic in vitro and effective in vivo against M. abscessus. Since these drugs are clinically available, the triple combination should be considered by clinicians and further evaluated based on the reporting of the patient outcomes.

PMID:40177837 | DOI:10.1093/jac/dkaf101

JAC Antimicrob Resist. 2025 Apr 2;7(2):dlaf047. doi: 10.1093/jacamr/dlaf047. eCollection 2025 Apr.

ABSTRACT

Mycobacterium abscessus (MAB) is a rapidly growing, non-tuberculous mycobacterium that has emerged as a significant pathogen in both pulmonary and extrapulmonary infections. It is rising in prevalence, especially among individuals with underlying lung conditions such as cystic fibrosis and chronic obstructive pulmonary disease, highlighting its growing clinical importance. The treatment of MAB infections is notoriously challenging due to intrinsic resistance to many antibiotics and low cure rates, typically <50%. Macrolides are a cornerstone in the treatment of MAB infections because regimens that include effective macrolide therapy are associated with higher cure rates. However, MAB possesses intrinsic and acquired drug resistance mechanisms against macrolides, complicating drug susceptibility testing and selection of highly effective treatment regimens. This review aims to provide a summary of the current understanding of macrolide resistance mechanisms in MAB. We explored the epidemiology of resistance in different countries and the molecular mechanisms involved. We have highlighted the variability in sensitivity of existing markers to predict phenotypic macrolide drug resistance across different countries, suggesting the involvement of unknown resistance mechanisms. By synthesizing current knowledge and identifying gaps in the literature, this review seeks to inform clinical practice and guide future research efforts in the fight against MAB drug resistance.

PMID:40177306 | PMC:PMC11961302 | DOI:10.1093/jacamr/dlaf047

Pharmacol Res Perspect. 2025 Apr;13(2):e70083. doi: 10.1002/prp2.70083.

ABSTRACT

The combination of Elexacaftor/Tezacaftor/Ivacaftor (ETI) has resulted in a significant improvement in lung function and global clinical parameters, which have not been previously achieved with other CFTR modulators. However, there is a paucity of evidence in the literature on the long-term use of ETI in adolescents and patients with severe pulmonary impairment. Furthermore, the response to ETI may differ between homozygotes and heterozygotes, as well as between naïve patients and those previously treated with other CFTR modulators. A retrospective study was conducted to examine changes in percent predicted forced expiratory volume in 1 s (ppFEV1), body-mass index (BMI), and sweat chloride concentration (SwCl) at baseline and at 6, 12 and 24 months after the initiation of ETI. Secondary outcomes included the number of pulmonary exacerbations, Cystic Fibrosis Questionnaire-Revised (CFQ-R) score, adverse events, mortality and transplantation rates. 139 subjects were included and followed up for up to 2 years after starting ETI. The results demonstrated a significant improvement in ppFEV1 and BMI after 12 months of therapy (respectively, 16%, p < 0.001; +1.5 kg/m2, p = 0.005), with a slight decline in the values after 24 months. This effect was independent of genotype and showed a different degree of response in naïve subjects compared to patients previously treated with other CFTR modulators. SwCl decreased from 84 to 37 mmol/L over 24 months (p < 0.001). 58.3% reduction of PEx rate was observed compared to the number of exacerbations prior to ETI. Overall, lung function, SwCl, PEx rate, CFQ-R scores and BMI improved after 24 months of ETI treatment. ETI was well tolerated, and none of the patients interrupted the treatment due to toxicity.

PMID:40176392 | DOI:10.1002/prp2.70083

Int J Biol Macromol. 2025 Mar 31:142627. doi: 10.1016/j.ijbiomac.2025.142627. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa (P. aeruginosa) is a multidrug-resistant opportunistic pathogen responsible for chronic obstructive pulmonary disease (COPD), cystic fibrosis, and ventilator-associated pneumonia (VAP), leading to cancer. Developing an efficacious vaccine remains the most promising strategy for combating P. aeruginosa infections. In this study, we employed an advanced in silico strategy to design a highly efficient and stable mRNA vaccine using immunoinformatics tools. Whole proteome data were utilized to identify highly immunogenic vaccine candidates using subtractive proteomics. Three extracellular proteins were prioritized for T- and linear B-cell epitope prediction. Beta-definsin protein sequence was incorporated as an adjuvant at the N-terminus of the construct. A total of 3 CTL, 3 HTL, and 3 linear B cell highly immunogenic epitopes were combined using specific linkers to design this multi-peptide construct. The 5' and 3' UTR sequences, Kozak sequence with a stop codon, and signal peptides followed by a poly-A tail were incorporated into the above vaccine construct to create our final mRNA vaccine. The vaccines exhibited antigenicity scores >0.88, ensuring high antigenicity with no allergenic or toxic. Physiochemical properties analysis revealed high solubility and thermostability. Three-dimensional structural analysis determined high-quality structures. Vaccine-receptor docking and molecular dynamic simulations demonstrated strong molecular interactions, stable binding affinities, dynamic nature, and structural stability of this vaccine, with significant immunogenic responses of the immune system against the vaccine. The immunological simulation indicates successful cellular and humoral immune responses to defend against P. aeruginosa infection. Validation of the study outcomes necessitates both experimental and clinical testing.

PMID:40174835 | DOI:10.1016/j.ijbiomac.2025.142627

EBioMedicine. 2025 Apr 1;114:105670. doi: 10.1016/j.ebiom.2025.105670. Online ahead of print.

ABSTRACT

BACKGROUND: Small airways (<2 mm diameter) are major sites of airflow obstruction in chronic obstructive pulmonary disease (COPD). This study aimed to quantify the impact of small airway disease, characterized by narrowing, occlusion, and obliteration, on airflow parameters in smokers and end-stage patients with COPDs.

METHODS: We performed computational fluid dynamics (CFD) simulations of inspiratory airflow in three lung groups: control non-used donor lungs (no smoking/emphysema history), non-used donor lungs with a smoking history and emphysema, and explanted end-stage COPD lungs. Each group included four lungs, with two tissue cylinders. Micro-CT-scanned small airways were segmented into 3D models for CFD simulations to quantify pressure, resistance, and shear stress. CFD results were benchmarked against simplified linear and Weibel models.

FINDINGS: CFD simulations showed higher pressures in COPD vs. controls (p = 0.0091) and smokers (p = 0.015), along with increased resistance (p = 0.0057 vs. controls; p = 0.0083 vs. smokers) and up to a tenfold rise in shear stress (p = 0.010 vs. controls). Narrowing and occlusion were shown to independently increase pressure, resistance, and shear stress, which were validated through segmentation corrections. Pressures and resistance assessed with simplified models were up to seven-fold higher for smokers and even 72 higher for COPD compared with CFD values.

INTERPRETATION: These findings show that increased airflow parameters can explain the association between small airway disease and airflow limitation in COPD, underscoring small airway vulnerability. Additionally, they highlight the limitations of theoretical models in accurately capturing small airway disease.

FUNDING: Supported by the KU Leuven (C16/19/005).

PMID:40174553 | DOI:10.1016/j.ebiom.2025.105670

PLoS Pathog. 2025 Apr 2;21(4):e1013021. doi: 10.1371/journal.ppat.1013021. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen responsible for airway infections in immunocompromised individuals, including those with cystic fibrosis (CF). P. aeruginosa has a type III secretion system (T3SS) that translocates effectors into host cells. ExoS is a T3SS effector with ADP ribosyltransferase (ADPRT) activity. ExoS ADPRT activity promotes P. aeruginosa virulence by inhibiting phagocytosis and limiting oxidative burst in neutrophils. The P. aeruginosa T3SS also translocates flagellin, which can activate the NLRC4 inflammasome, resulting in: 1) gasdermin-D pores, release of IL-1β and pyroptosis; and 2) histone 3 citrullination (CitH3), nuclear DNA decondensation and expansion into the neutrophil cytosol with incomplete NET extrusion. However, studies with P. aeruginosa PAO1 indicate that ExoS ADPRT activity inhibits the NLRC4 inflammasome in neutrophils. Here, we identified an ExoS+ CF clinical isolate of P. aeruginosa with a hyperactive T3SS. Variants of the hyperactive T3SS mutant or PAO1 were used to infect neutrophils from C57BL/6 mice that were wildtype or engineered to have a CF genotype or defects in inflammasome assembly. Responses to NLRC4 inflammasome assembly or ExoS ADPRT activity were assayed and found to be similar for C57BL/6 or CF neutrophils. ExoS ADPRT activity in the hyperactive T3SS mutant regulated inflammasome, nuclear DNA decondensation and incomplete NET extrusion responses, like PAO1, but promoted enhanced CitH3 and plasma membrane rupture (PMR). Glycine supplementation inhibited PMR by the hyperactive T3SS mutant, suggesting ninjurin-1 is required for this process. These results identify enhanced neutrophil PMR as a pathogenic activity of ExoS ADPRT in hypervirulent P. aeruginosa.

PMID:40173191 | DOI:10.1371/journal.ppat.1013021

Am J Health Syst Pharm. 2025 Apr 2:zxaf071. doi: 10.1093/ajhp/zxaf071. Online ahead of print.

ABSTRACT

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

PURPOSE: A customized Epic scoring tool for monitoring medications requiring renal dose adjustment utilizing Epic Bugsy and a custom renal function trend scoring column was developed and implemented in June 2023 at UT Southwestern Medical Center (UTSW) to replace the manual review and intervention (i-Vent) documentation process.

METHODS: This retrospective, observational cohort study evaluated pharmacist interventions and antimicrobial dosing before and after implementation of the UTSW renal clinical pharmacist responsibility (CPR) dose adjustment tool. Adult patients (aged 18 years or older) requiring renal dose adjustment were included. The preintervention group included patients admitted between July 1 and August 31, 2022, whereas the postintervention group included patients admitted from July 1 through August 31, 2023. Patients exempt from the institutional automatic adult renal dosing guideline (ie, those with cystic fibrosis, solid organ transplantation, or bone marrow transplantation) or actively receiving renal replacement therapy during the index encounter were excluded.

RESULTS: In a comparable 2-month timespan, implementation of the renal CPR dose adjustment tool resulted in a 68.2% increase in the number of renal dosing interventions completed (P < 0.0001), a 47.2% reduction in the number of unique alerts requiring pharmacist review (P < 0.0001), and an increase in the proportion of actionable interventions per alert requiring review from 11.1% before implementation to 39.4% after implementation (P < 0.0001). Pharmacist satisfaction with the renal monitoring workflow also improved with implementation.

CONCLUSION: In a comparable 2-month timespan, implementation of the renal CPR dose adjustment tool at UTSW resulted iin improvements in interventions completed, a reduction in alerts requiring review, an increased total duration that selected antimicrobials were dosed appropriately, and improved pharmacist satisfaction.

PMID:40172577 | DOI:10.1093/ajhp/zxaf071

Curr Opin Pediatr. 2025 Mar 27. doi: 10.1097/MOP.0000000000001458. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: The field of cystic fibrosis is experiencing dramatic changes, as the translation of a massive body of scientific knowledge accumulated from the day of the cloning of the CFTR gene has led to the identification of effective therapies to correct the basic defect. This has also allowed care providers and people with cystic fibrosis in low-income and middle-income countries (LMICs) to become more knowledgeable and proficient in cystic fibrosis cares.

RECENT FINDINGS: This review focuses on two main aspects highly relevant to understand the current status of cystic fibrosis in LMICs: The recognition of the universal occurrence of cystic fibrosis, as well as the varying incidence in different regions of the world, and the collaborative international efforts for dissemination of best care practices as an attempt to close gaps in care.

SUMMARY: As the field continues to change rapidly, multiple international efforts are attempting to close gaps and disparities clearly apparent between affluent countries and LMICs. However, these efforts are seriously hampered by limited access to effective therapies and most dramatically to CFTR modulator drugs.

PMID:40172290 | DOI:10.1097/MOP.0000000000001458

mBio. 2025 Apr 2:e0037425. doi: 10.1128/mbio.00374-25. Online ahead of print.

ABSTRACT

Staphylococcus aureus is one of the most common pathogens isolated from the lungs of people with cystic fibrosis (CF), but little is known about its ability to colonize this niche. We performed a transposon-sequencing (Tn-seq) screen to identify genes necessary for S. aureus growth in media prepared from ex vivo CF sputum. We identified 19 genes that were required for growth in all sputum media tested and dozens more that were required for growth in at least one sputum medium. Depleted mutants of interest included insertions in many genes important for surviving metal starvation, as well as the primary regulator of cysteine metabolism, cymR. To investigate the mechanisms by which these genes contribute to S. aureus growth in sputum, we quantified low-molecular-weight thiols, nutrient transition metals, and the host metal-sequestration protein calprotectin in sputum from 11 individuals with CF. In all samples, the abundance of calprotectin exceeded nutrient metal concentration, explaining the S. aureus requirement for metal-starvation genes. Furthermore, all samples contain potentially toxic quantities of cysteine and sufficient glutathione to satisfy the organic sulfur requirements of S. aureus. Deletion of the cysteine importer genes tcyA and tcyP in the ∆cymR background restored growth to wild-type levels in CF sputum, suggesting that the mechanism by which cymR is required for growth in sputum is to prevent uncontrolled import of cysteine or cystine from this environment. Overall, this work demonstrates that calprotectin and cysteine limit S. aureus growth in CF sputum.IMPORTANCEStaphylococcus aureus is a major cause of lung infections in people with cystic fibrosis (CF). This work identifies genes required for S. aureus growth in this niche, which represent potential targets for anti-Staphylococcal treatments. We show that genes involved in surviving metal starvation are required for growth in CF sputum. We also found that the primary regulator of cysteine metabolism, CymR, plays a critical role in preventing cysteine intoxication during growth in CF sputum. To support these models, we analyzed sputum from 11 individuals with CF to determine concentrations of calprotectin, nutrient metals, and low-molecular-weight thiols, which have not previously been quantified together in the same samples.

PMID:40172197 | DOI:10.1128/mbio.00374-25

Front Med (Lausanne). 2025 Mar 18;12:1527843. doi: 10.3389/fmed.2025.1527843. eCollection 2025.

ABSTRACT

BACKGROUND: Established morpho-functional chest magnetic resonance imaging (MRI) detects abnormalities in lung morphology and perfusion in people with cystic fibrosis (pwCF) using a dedicated scoring system. Functional assessment is performed using contrast-enhanced (CE) perfusion MRI. Novel matrix pencil decomposition MRI (MP-MRI) is a contrast agent-free alternative, but further validation of this technique is needed.

OBJECTIVES: The aim of this study was to evaluate the applicability of the validated morpho-functional chest MRI score for CE perfusion and MP perfusion MRI in a multireader approach.

METHODS: Twenty-seven pwCF (mean age 20.8 years, range 8.4-45.7 years) underwent morpho-functional MRI including CE perfusion and MP perfusion MRI in the same examination. Nine blinded chest radiologists of different experience levels assessed lung perfusion and applied the validated chest MRI score to CE- and MP-MRI. Inter-reader agreement of perfusion scores in CE- and MP-MRI were compared with each other and with the MRI morphology score. Differences according to the readers' experience were also analyzed.

RESULTS: The CE perfusion scores were overall lower than the MP perfusion scores (6.2 ± 3.3 vs. 6.9 ± 2.0; p < 0.05) with a strong correlation between both perfusion scores (r = 0.74; p < 0.01). The intraclass correlation coefficient (ICC) as measure for inter-reader agreement was good and significant for both perfusion scores, but higher for the CE perfusion score (0.75, p < 0.001) than for MP perfusion scores (0.61, p < 0.001). The Bland-Altman analysis revealed a difference in CE and MP perfusion scores with more extreme values in CE perfusion scores compared to MP perfusion scores (r = 0.62, p < 0.001). The morphology score showed a moderate to good correlation with the CE perfusion score (r = 0.73, p < 0.01) and the MP perfusion score (r = 0.55, p < 0.01). We did not find a difference in scoring according to the radiological experience level.

CONCLUSION: The established chest MRI score can be applied both to validated CE and novel MP perfusion MRI with a good interreader reliability. The remaining difference between CE and MP-MRI scores may be explained by a lack of routine in visual analysis of MP-MRI and may favor an automated analysis for use of MP-MRI as a noninvasive outcome measure.

PMID:40171501 | PMC:PMC11958188 | DOI:10.3389/fmed.2025.1527843

NEJM Catal Innov Care Deliv. 2025 Feb;6(2). doi: 10.1056/CAT.24.0095. Epub 2025 Jan 15.

ABSTRACT

Cystic fibrosis (CF) affects more than 160,000 individuals globally and has seen improved survival rates due to multidisciplinary care models and pharmacotherapy innovations. However, the associated costs remain substantial, prompting the authors to study and evaluate the expense of CF ambulatory care to understand how care structure influences costs. People with CF (PwCF) at large pediatric CF centers in both the United States and Ireland were recruited for parallel observational, prospective studies. Based upon the process of care, the lead clinicians at both sites identified and agreed on three strata of patients (0-11 months, 1-5 years, and 6-17 years of age). Process maps were developed for each of the age cohorts at each site, and the costs of ambulatory care - with emphasis on routine CF clinic visits - were measured utilizing time-driven activity-based costing (TDABC). A dollar-per-minute capacity cost rate (CCR) was calculated for all resources used in the care cycle. The total direct cost was obtained by multiplying the CCR for each resource by the time the resource was used during the patient's care cycle. The cost was summed across all resource types to obtain the cost over the entire care cycle for each site. Service operations were benchmarked to one site and variance analysis was performed. In total, 58 PwCF were included in the analysis (49 in the United States and 9 in Ireland); 4 were 0-11 months, 17 were 1-5 years, and 37 were 6-17 years of age. Physicians (United States) and respiratory consultants (Ireland) had the highest CCRs. Physicians and registered dietitians spent the most time with patients in the United States, compared with the clinical nurse specialists and dietitians in Ireland. The total variance in cost for clinical visits was largest in the 6- to 17-year-old group (28% variance, with 100% in the United States vs. 128% in Ireland). In the 6- to 17-year-old group, the largest drivers in total variance were quantity variance (variance in duration of time spent with patients), which was 108% greater in Ireland); the skill mix variance (variance in clinician type performing service for a given time), which was 49% greater in the United States; and the rate variance (variance in compensation levels across sites), which was 31% greater in the United States. The authors' use of TDABC to characterize the cost of multidisciplinary care during ambulatory clinic visits for PwCF, in combination with variance analysis (the quantitative investigation of the difference between actual and expected costs), provides new and innovative ways to compare costs across similar health care service delivery sites, providing insights into the distinctive features of each. A granular understanding of cost and comparison of resource utilization between centers provides valuable, organizationally relevant insights.

PMID:40171477 | PMC:PMC11960789 | DOI:10.1056/CAT.24.0095

Front Pediatr. 2025 Mar 18;13:1564156. doi: 10.3389/fped.2025.1564156. eCollection 2025.

ABSTRACT

INTRODUCTION: Primary Ciliary Dyskinesia (PCD) is a rare genetic disorder affecting motile cilia, leading to impaired mucociliary clearance and increased susceptibility to respiratory infections. These infections contribute to long-term complications such as bronchiectasis and lung function decline.

OBJECTIVES: This review explores both the acute and long-term impact of respiratory infections in children with PCD, while highlighting the multiple contributors to infection susceptibility. The review also evaluates emerging personalized approaches such as gene and mRNA therapy that hold promise for restoring ciliary function and reducing the burden of acute infections in pediatric PCD.

KEY FINDINGS AND CONCLUSIONS: Acute respiratory infections have a significant impact on morbidity in pediatric PCD, driving progressive airway remodeling. While current treatment strategies focus on managing infections directly, emerging therapies targeting inflammation and genetic causes hold promise for reducing infection burden and improving long-term outcomes. Future advances in personalized medicine could further enhance therapeutic approaches in this population.

PMID:40171169 | PMC:PMC11958984 | DOI:10.3389/fped.2025.1564156

Front Cell Infect Microbiol. 2025 Mar 18;15:1445660. doi: 10.3389/fcimb.2025.1445660. eCollection 2025.

ABSTRACT

Mycobacterium abscessus is a nontuberculous mycobacterium emerging as a significant pathogen in individuals with chronic lung diseases, including cystic fibrosis and chronic obstructive pulmonary disease. Current therapeutics have poor efficacy. Strategies of bacterial control based on host defenses are appealing; however, antimycobacterial immunity remains poorly understood and is further complicated by the appearance of smooth and rough morphotypes, which elicit distinct host responses. We investigated the role of serum components in neutrophil-mediated clearance of M. abscessus morphotypes. M. abscessus opsonization with complement enhanced bacterial killing compared to complement-deficient opsonization. Killing of rough isolates was less reliant on complement. Complement C3 and mannose-binding lectin 2 (MBL2) were deposited on M. abscessus morphotypes in distinct patterns, with a greater association of MBL2 on rough M. abscessus. Killing was dependent on C3; however, depletion and competition experiments indicate that canonical complement activation pathways are not involved. Complement-mediated killing relied on natural IgG and IgM for smooth morphotypes and on IgG for rough morphotypes. Both morphotypes were recognized by complement receptor 3 in a carbohydrate- and calcium-dependent manner. These findings indicate a role for noncanonical C3 activation pathways for M. abscessus clearance by neutrophils and link smooth-to-rough adaptation to complement activation.

PMID:40171164 | PMC:PMC11959001 | DOI:10.3389/fcimb.2025.1445660

Pediatr Pulmonol. 2025 Apr;60(4):e71078. doi: 10.1002/ppul.71078.

ABSTRACT

BACKGROUND: As the life expectancy of people with cystic fibrosis (PwCF) increases, understanding long-term complications, including CF-related bone disease (CFBD), is crucial.

OBJECTIVE: This study aimed to longitudinally characterize CFBD and to compare the bone status of pancreatic sufficient (PS) and pancreatic insufficient (PI) PwCF.

METHODS: This longitudinal analysis included PwCF older than 8 years of age who had at least one dual-energy X-ray absorptiometry test between 2008 and 2021. Data were collected on serum parameters of bone metabolism, nutritional history, habitual activity, and fractures in addition to other demographic and clinical characteristics.

RESULTS: The study included 80 PwCF: 32 (40%) were PS and 48 (60%) PI. Normal dual-energy X-ray absorptiometry results were found in 42 (53%) patients: 16 (50%) in the PS group and 26 (54%) in the PI group (p = 0.72). Three (9%) of the PS group and seven (15%) of the PI group had at least one Z-score below -2 (p = 0.49). The longitudinal bone density decline over a mean of 4.8 years was similar in the two groups. In a logistic regression analysis, pancreatic insufficiency was not found to be a risk factor for CFBD. Female sex was the only significant risk factor for a pathological Z-score.

CONCLUSIONS: The prevalence and severity of CFBD were not found to correlate with pancreatic sufficiency. The similar prevalence of CFBD between patients with PS and PI suggests that screening, and eventually treatment, should be offered to all PwCF, irrespective of pancreatic status.

PMID:40170622 | DOI:10.1002/ppul.71078

Br J Clin Pharmacol. 2025 Apr 2. doi: 10.1002/bcp.70027. Online ahead of print.

ABSTRACT

AIM: Dipeptidyl peptidase-1 (DPP-1) inhibitors have been studied for the treatment of neutrophil-mediated inflammatory diseases including bronchiectasis, bronchial asthma and cystic fibrosis. This study evaluated the pharmacokinetics, pharmacodynamics, safety and tolerability of DPP-1 inhibitor HSK31858 in healthy Chinese volunteers.

METHODS: Volunteers in Part A randomly received single doses of HSK31858 (15, 40, 60 and 80 mg) or placebo in fasted states. The 40-mg cohort also received HSK31858 40 mg or placebo in fed states. In Part B, volunteers randomly received HSK31858 10, 20 and 40 mg or placebo once daily for 28 days in fasted states. The primary endpoints were safety and tolerability of HSK31858.

RESULTS: Among 38 volunteers in Part A and 36 in Part B, HSK31858 was well tolerated; no deaths, serious adverse events, or discontinuations due to adverse events occurred. The median Tmax was 0.75 to 1.0 h and the mean terminal t1/2 was 16.5 to 21.0 h in the fasted state with single doses of HSK31858. Both Cmax and AUC0-t exhibited a dose-dependent rise. Food had no effect on AUC. Multiple doses of HSK31858 demonstrated a similar pharmacokinetics profile, with about 2-fold accumulation in AUC. HSK31858 dose-dependently inhibited neutrophil count-normalized neutrophil elastase (NEnorm) activity. The maximal percentage decrease in NEnorm activity relative to baseline during 28 days of HSK31858 treatments was 13.6% and 76.4% with HSK31858 10 and 40 mg once-daily, respectively.

CONCLUSION: HSK31858 was safe and well tolerated. The pharmacokinetics and pharmacodynamics profile of HSK31858 supports further clinical development for the treatment of neutrophil-mediated inflammatory diseases.

TRIAL REGISTRATION: NCT05663593.

PMID:40170587 | DOI:10.1002/bcp.70027

Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666251329792. doi: 10.1177/17534666251329792. Epub 2025 Apr 1.

NO ABSTRACT

PMID:40170358 | DOI:10.1177/17534666251329792

Commun Biol. 2025 Apr 2;8(1):540. doi: 10.1038/s42003-025-07944-w.

ABSTRACT

Preterm birth disrupts intestinal epithelial maturation, impairing digestive and absorptive functions. This study integrates analysis of single-cell RNA sequencing datasets, spanning fetal to adult stages, with human preterm intestinal models derived from the ileal tissue of preterm infants. We investigate the potential of extracellular vesicles (EVs) derived from human Wharton's jelly mesenchymal stem cells to promote intestinal maturation. Distinct enterocyte differentiation trajectories are identified during the transition from immature to mature stages of human intestinal development. EV treatment, particularly with the EV39 line, significantly upregulates maturation-specific gene expression related to enterocyte function. Gene set enrichment analysis reveals an enrichment of TGFβ1 signaling pathways, and proteomic analysis identifies TGFβ1 and FGF2 as key mediators of EV39's effects. These treatments enhance cell proliferation, epithelial barrier integrity, and fatty acid uptake, primarily through CFTR-dependent mechanisms-unique to human preterm models, not observed in mouse intestinal organoids. This highlights the translational potential of EV39 and CFTR activation in promoting the functional maturation of the premature human intestine.

PMID:40169914 | DOI:10.1038/s42003-025-07944-w

Basic Clin Androl. 2025 Apr 1;35(1):13. doi: 10.1186/s12610-025-00260-7.

ABSTRACT

BACKGROUND: Azoospermia, the most severe form of male infertility, is categorized into two types: non-obstructive azoospermia (NOA) and obstructive azoospermia (OA), which exhibit significant genetic heterogeneity. Azoospermia factor (AZF) deletion is a common cause of NOA, whereas congenital bilateral absence of the vas deferens (CBAVD), a severe subtype of OA, is frequently linked to cystic fibrosis transmembrane conductance regulator (CFTR) gene variants. This case report is the first to document the coexistence of a partial AZFa microdeletion and a homozygous CFTR variant in a CBAVD-affected azoospermic patient with intact spermatogenesis.

CASE PRESENTATION: A 32-year-old man presented with primary infertility and azoospermia. Clinical evaluation revealed CBAVD (normal hormone levels, low semen volume, pH 6.0, and absence of the vas deferens). Genetic analysis accidentally revealed a 384.9 kb AZFa deletion (sY84 and sY86, but not sY1064, 1182) that removed USP9Y but retained DDX3Y in the proband, his fertile brother, and his father. A homozygous CFTR variant (TG12-5T) was also detected in the proband and his brother and was inherited from heterozygous parental carriers. Microdissection testicular sperm extraction (micro-TESE) revealed intact spermatogenesis, confirmed by histology and immunofluorescence, indicating normal germ cell development.

CONCLUSION: This case expands the intricate genetic spectrum of azoospermia by illustrating the critical role of DDX3Y in the AZFa region in spermatogenesis and the variable penetrance of CFTR variant (TG12-5T) in CBAVD. These insights may refine diagnostic strategies and underscore the necessity for tailored fertility management in individuals with multifactorial genetic anomalies.

PMID:40169970 | DOI:10.1186/s12610-025-00260-7

Biomed Pharmacother. 2025 Mar 31;186:117957. doi: 10.1016/j.biopha.2025.117957. Online ahead of print.

ABSTRACT

BACKGROUND: Overactive neutrophilic inflammation causes damage to the airways and death in people with cystic fibrosis (CF), a genetic disorder resulting from mutations in the CFTR gene. Reducing the impact of inflammation is therefore a major concern in CF. Evidence indicates that dysfunctional NRF2 signaling in CF individuals may impair their ability to regulate their oxidative and inflammatory responses, although the role of NRF2 in neutrophil-dominated inflammation and tissue damage associated with CF has not been determined. Therefore, we examined whether curcumin, an activator of NRF2, might provide a beneficial effect in the context of CF.

METHODS: Combining Cftr-depleted zebrafish as an innovative biomedical model with CF patient-derived airway organoids (AOs), we aimed to understand how NRF2 dysfunction leads to abnormal inflammatory status and tissue remodeling and determine the effects of curcumin in reducing inflammation and tissue damage in CF.

RESULTS: We demonstrate that NFR2 is instrumental in regulating neutrophilic inflammation and repair processes in vivo, thereby preventing inflammatory damage. Importantly, curcumin treatment restores NRF2 activity in both CF zebrafish and AOs. Curcumin reduces neutrophilic inflammation in CF context, by rebalancing the production of epithelial ROS and pro-inflammatory cytokines. Furthermore, curcumin improves tissue repair by reducing CF-associated fibrosis. Our findings demonstrate that curcumin prevents CF-mediated inflammation via activating the NRF2 pathway.

CONCLUSIONS: This work highlights the protective role of NRF2 in limiting inflammation and injury and show that therapeutic strategies to normalize NRF2 activity, using curcumin or others NRF2 activators, might simultaneously reduce airway inflammation and damage in CF.

PMID:40168724 | DOI:10.1016/j.biopha.2025.117957