Turk J Pediatr. 2025 Feb 20;67(1):22-30. doi: 10.24953/turkjpediatr.2025.4680.

ABSTRACT

BACKGROUND: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) variants are essential for determining eligibility for CFTR modulator drugs (CFTRms). In contrast to Europe and the USA, the treatment eligibility profile of cystic fibrosis (CF) patients in Türkiye is not known. In this study we aimed to determine the eligibility of CF patients in Türkiye for the CFTRms.

METHODS: The Cystic Fibrosis Registry of Türkiye (CFrT) data was used to determine the age of patients in the year 2021 and the genetic variants they were carrying. Age- and CFTR-variant appropriate modulator therapies were determined using the Vertex® algorithm.

RESULTS: Among a total of 1930 registered patients, CTFR gene analysis was performed on a total of 1841 (95.4%) patients. Mutations were detected in one allele in 10.7% (198 patients), and in both alleles in 79% (1455 patients) of patients. A total of 855 patients (51.7% for whom at least 1 mutation was detected) were eligible for the drugs. The most appropriate drug among genotyped patients was found to be elexacaftor/tezacaftor/ivacaftor for 486 patients (26.4%), followed by ivacaftor for 327 patients (17.7%) and lumacaftor/ivacaftor for 42 patients (2%).

CONCLUSIONS: Only half of patients registered in CFrT were eligible for CFTRms, which is a significant difference from the CFTR variant profile seen in USA and Europe. However, access to treatment is hampered for some patients whose genes are not analysed. Further studies in CF populations, where rare mutations are relatively more common, will contribute to the field of CFTR modulator treatments for such rare mutations.

PMID:40084730 | DOI:10.24953/turkjpediatr.2025.4680

Exp Ther Med. 2025 Feb 25;29(4):85. doi: 10.3892/etm.2025.12835. eCollection 2025 Apr.

ABSTRACT

The coronavirus disease-19 (COVID-19) pandemic has been a very significant health issue in the period between 2020 and 2023, forcing research to characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequences and to develop novel therapeutic approaches. Interleukin-6 (IL-6) and IL-8 are considered significant therapeutic targets for COVID-19 and emerging evidence has suggested that microRNAs (miRNAs/miRs) serve a key role in regulating these genes. MiRNAs are short, 19-25 nucleotides in length, non-coding RNAs that regulate gene expression at the post-transcriptional level through the sequence-selective recognition of the 3'-untranslated region (3'-UTR) of the regulated mRNAs, eventually repressing translation, commonly, via mRNA degradation. For example, among several miRNAs involved in the regulation of the COVID-19 'cytokine storm', miR-93-5p can inhibit IL-8 gene expression by directly targeting the 3'-UTR of IL-8 mRNA. In addition, miR-93-5p can regulate Toll-like receptor-4 (TLR4) and interleukin-1 receptor-associated kinase 4 (IRAK4) expression, thus affecting the nuclear factor-κB (NF-κB) pathway and the expression of NF-κB-regulated genes, such as IL-6, IL-1β and other hyper-expressed genes during the COVID-19 'cytokine storm'. In the present study, the results provided preliminary evidence suggesting that the miR-93-5p-based miRNA therapeutics could be combined with the anti-inflammatory aged garlic extract (AGE) to more effectively inhibit IL-8 gene expression. The human bronchial epithelial IB3-1 cell line was employed as experimental model system. IB3-1 cells were stimulated with the BNT162b2 COVID-19 vaccine and transfected with pre-miR-93-5p in the absence or in the presence of AGE, to verify the inhibitory effects on the BNT162b2-induced expression of the IL-8 gene. The accumulation of IL-8 mRNA was assessed by RT-qPCR; the release of IL-8 protein was determined by Bio-Plex assay. In addition, the possible applications of TLR4/NF-κB inhibitory agents (such as miR-93-5p and AGE) for treating human pathologies at a hyperinflammatory state, such as COVID-19, cystic fibrosis and other respiratory diseases, were summarized.

PMID:40084194 | PMC:PMC11904878 | DOI:10.3892/etm.2025.12835

BMC Infect Dis. 2025 Mar 13;25(1):358. doi: 10.1186/s12879-025-10736-6.

ABSTRACT

This systematic review evaluates the efficacy and safety of COVID-19 vaccines in individuals with cystic fibrosis (CF). A systematic search of major databases conducted between December 2019 and January 2024 identified eight cohort studies comprising 1,361 CF patients. Studies without subgroup analyses specific to CF patients were excluded, which may have limited the generalizability of findings, particularly for CF lung transplant recipients. COVID-19 vaccines generally induced robust serological responses following the second and third doses, although reduced antibody levels were observed in lung transplant recipients. Factors influencing humoral response included prior SARS-CoV-2 infection, age, inhaled corticosteroid use, and immunosuppressive therapy. Vaccination-related adverse events were predominantly mild. Although breakthrough infections were reported, severe COVID-19 outcomes were infrequent among vaccinated CF patients. The evidence supports the immunogenicity and safety of COVID-19 vaccines in the CF patients. However, individualized vaccination strategies may be necessary for CF lung transplant recipients and those on immunosuppressive therapies. Further research is essential to optimize vaccination strategies and to identify risk factors associated with breakthrough infections in this high-risk population.

PMID:40082759 | DOI:10.1186/s12879-025-10736-6

Cell Death Differ. 2025 Mar 13. doi: 10.1038/s41418-025-01474-y. Online ahead of print.

ABSTRACT

The plasma concentrations of acyl CoA binding protein (ACBP) encoded by the gene diazepam binding inhibitor (DBI) are increased in patients with severe osteoarthritis (OA). Here, we show that knee OA induces a surge in plasma ACBP/DBI in mice subjected to surgical destabilization of one hind limb. Knockout of the Dbi gene or intraperitoneal (i.p.) injection of a monoclonal antibody (mAb) neutralizing ACBP/DBI attenuates OA progression in this model, supporting a pathogenic role for ACBP/DBI in OA. Furthermore, anti-ACBP/DBI mAb was also effective against OA after its intraarticular (i.a.) injection, as monitored by sonography, revealing the capacity of ACBP/DBI to locally reduce knee inflammation over time. In addition, i.a. anti-ACBP/DBI mAb improved functional outcomes, as indicated by the reduced weight imbalance caused by OA. At the anatomopathological level, i.a. anti-ACBP/DBI mAb mitigated histological signs of joint destruction and synovial inflammation. Of note, i.a. anti-ACBP/DBI mAb blunted the OA-induced surge of plasma ACBP/DBI, as well as that of other inflammatory factors including interleukin-1α, interleukin-33, and tumor necrosis factor. These findings are potentially translatable to OA patients because joints from OA patients express both ACBP/DBI and its receptor GABAARγ2. Moreover, a novel mAb against ACBP/DBI recognizing an epitope conserved between human and mouse ACBP/DBI demonstrated similar efficacy in mitigating OA as an anti-mouse ACBP/DBI-only mAb. In conclusion, ACBP/DBI might constitute a promising therapeutic target for the treatment of OA.

PMID:40082721 | DOI:10.1038/s41418-025-01474-y

JAMA Netw Open. 2025 Mar 3;8(3):e250572. doi: 10.1001/jamanetworkopen.2025.0572.

ABSTRACT

IMPORTANCE: Inequitable access to transplant in the US is well recognized, yet the nature and extent of upstream disparities in care prior to transplant are unknown.

OBJECTIVE: To understand patterns of referral for lung transplant by race, ethnicity, and neighborhood-level socioeconomic status.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included adults aged 18 to 80 years with obstructive and restrictive lung disease from a single large-volume transplant center in Cleveland, Ohio, who were diagnosed between January 1, 2006, and May 11, 2023.

EXPOSURES: Neighborhood resources.

MAIN OUTCOMES AND MEASURES: The main outcome was the transition to the next stage of the transplant care continuum, death, or a lapse in care. Cause-specific Cox proportional hazards regression models were used to account for death as a competing risk, adjusting for age at index encounter (respective to each cohort), diagnosis, and sex as covariates.

RESULTS: This study included 30 050 patients with obstructive and restrictive lung disease with primary care encounters (mean [SD] age, 65 [13] years; 56.1% female), 73 817 with a pulmonary medicine encounter, 4198 undergoing lung transplant evaluation, and 1378 on the lung transplant waiting list. In a multivariable model including age, diagnosis, sex, area deprivation index, and race and ethnicity (including 3.3% Hispanic, 15.2% non-Hispanic Black, and 81.5% non-Hispanic White individuals), patients residing in the least-resourced neighborhoods were 97% more likely to die without transitioning to pulmonary medicine (hazard ratio [HR], 1.97 [95% CI, 1.78-2.17]), 90% more likely to die prior to lung transplant evaluation (HR, 1.90 [95% CI, 1.77-2.04]), 40% more likely to die prior to placement on the waiting list (HR, 1.40 [95% CI, 1.11-1.76]), and 97% more likely to die prior to transplant (HR, 1.97 [95% CI, 1.18-3.29]) compared with patients residing in the most-resourced neighborhoods. These patients were also 13% less likely to transition to pulmonary medicine (HR, 0.87 [95% CI, 0.82-0.92]) and 45% less likely to be placed on the waiting list (HR, 0.55 [95% CI, 0.44-0.68]) despite a 69% increased likelihood of transplant evaluation (HR, 1.69 [95% CI, 1.36-2.09]). While non-Hispanic Black patients had lower risks of death across all stages of care, they experienced a 39% lower likelihood of proceeding to lung transplant evaluation (HR, 0.61 [95% CI, 0.51-0.74]). Racial differences in the cumulative incidence of waiting list placement were found, but differences were not consistent across levels of neighborhood resources.

CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of patients diagnosed with restrictive and obstructive pulmonary disease, increased mortality risks and decreased likelihood of care escalations for patients who were socioeconomically disadvantaged and for racial and ethnic minority patients were found. These results suggest potential interventions for advancing equitable access to lung transplant.

PMID:40080022 | PMC:PMC11907320 | DOI:10.1001/jamanetworkopen.2025.0572

Microb Pathog. 2025 Mar 11:107473. doi: 10.1016/j.micpath.2025.107473. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a prominent bacterial pathogen that causes several nosocomial infections and is notorious for its environmental resilience and rapid development of resistance to frontline antibiotics. A major cause of mortality and morbidity among cystic fibrosis patients, multidrug-resistant P. aeruginosa is often targeted with the antibiotic colistin as a last option. However, increasing reports of colistin resistance among P. aeruginosa is a significant concern. Though the molecular mechanisms responsible for the development of colistin resistance are well known, the evolutionary trajectory to colistin resistance is an important area of investigation. In this work, using the adaptive laboratory evolution (ALE) approach we have evolved a colistin-sensitive P. aeruginosa ancestral strain to a resistant one. During the process of laboratory evolution in 106 generations, colistin MIC was increased 32-fold. The evolved strain had lower fitness than the ancestral strain, as evidenced by a lower growth rate. Moreover, the evolved strain produced more biofilm and less pyocyanin pigment. Interestingly, the evolved strain showed collateral sensitivity to several antibiotics, including ampicillin, tetracycline, streptomycin, gentamycin, nalidixic acid, trimethoprim, rifampicin, and chloramphenicol. On analysing various TCS modules involved in the development of colistin resistance, a novel missense mutation (V136G) was detected in the PmrB sensor kinase. In silico analysis indicated that the V136G substitution would destabilize the PmrB kinase structure, making the mutation deleterious. However, the functionality of the PmrB mutant remains to be validated experimentally.

PMID:40081679 | DOI:10.1016/j.micpath.2025.107473

Respir Med. 2025 Mar 11:108036. doi: 10.1016/j.rmed.2025.108036. Online ahead of print.

ABSTRACT

BACKGROUND: Lung ultrasound is becoming increasingly important in the diagnosis of acute and chronic lung disease, especially in children and adolescents. In children with cystic fibrosis (CF), conventional radiography or computed tomography (CT) has been the main modality used to evaluate acute pneumonia or the progression of chronic lung disease. This Study aimed to evaluate Lung-Ultrasound as a diagnostic tool for children and adolescents with CF.

METHODS: We examined 30 CF patients with lung ultrasound before and after spirometry and compared them with lung ultrasounds of 15 lung-healthy children. We used a comprehensive and complete examination procedure with 12 probe positions to determine the best examination procedure in retrospect. In addition, an acceptance survey was conducted among the children and adolescents after the examination.

RESULTS: There was a significant difference in pleural irregularities, B-lines, consolidations and the adapted Peixoto et al. score between CF patients and healthy children before spirometry. We found excellent discrimination between patients and lung-healthy subjects using the Peixoto-score (AUC 0.968), pleural irregularities (AUC 0.890. CF patients had more B-lines, more consolidations, and a higher Peixoto score (mean difference 7.7 points).There was no significant difference in lung ultrasound results in children with CF before and after spirometry. Shortening our extended examination procedure would minimally compromise diagnostic accuracy. The lung ultrasound examination was well accepted by the children.

CONCLUSION: We could demonstrate that lung ultrasound is a sensitive and reliable method for assessing pulmonary changes in cystic fibrosis.

PMID:40081670 | DOI:10.1016/j.rmed.2025.108036

JBRA Assist Reprod. 2025 Mar 13. doi: 10.5935/1518-0557.20240102. Online ahead of print.

ABSTRACT

OBJECTIVE: To determine the carrier frequency of X-linked and autosomal recessive diseases in patients attending a human fertility institute in Colombia.

METHODS: This retrospective observational study included patients and gamete donors attending a Human Fertility Institute in Colombia between January 2017 and June 2023. Sociodemographic data and results of Next Generation Sequencing laboratory panels for screening of recessive disease-causing mutations were collected and analyzed.

RESULTS: Data from 746 samples were analyzed; 599 (80.3%) were Colombian origin individuals and 147 (19.7%) were foreigners. At least one mutation was detected in 526 (70.5%) individuals. Of note, 893 pathogenic genetic variants were identified.The genetic variants most frequently observed in all the individuals studied were associated with the following diseases (carrier frequency): alpha thalassemia (10.5%), alpha-1 antitrypsin deficiency (10%), congenital adrenal hyperplasia due to 21-hydroxylase deficiency (9.4%), cystic fibrosis (7.3%), spinal muscular atrophy type 1 (5.6%) and Stargardt disease type 1 (5.0%). The most frequent genetic variant observed in the subgroup of Colombian origin individuals was associated with alpha-1 antitrypsin deficiency (11.3%).

CONCLUSIONS: Information on the frequency of recessive diseases in Colombia is limited. This pioneering carrier genetic screening identified a high percentage of carriers for at least one recessive autosomal or X-linked in the population evaluated. Screening for recessive mutations could lead to an evolution in family planning programs and a decrease in the number of patients affected by recessive disorders. Furthermore, it could become a routine test not only in cases of assisted reproduction but also in cases of natural gestation.

PMID:40080775 | DOI:10.5935/1518-0557.20240102

J Exp Med. 2025 Jun 2;222(6):e20230803. doi: 10.1084/jem.20230803. Epub 2025 Mar 13.

ABSTRACT

To distinguish pathogens from commensals, the intestinal epithelium employs cytosolic innate immune sensors. Activation of the NAIP-NLRC4 inflammasome initiates extrusion of infected intestinal epithelial cells (IEC) upon cytosolic bacterial sensing. We previously reported that activation of the inflammasome in tuft cells, which are primarily known for their role in parasitic infections, leads to the release of prostaglandin D2 (PGD2). We observe that NAIP-NLRC4 inflammasome activation in tuft cells leads to an antibacterial response with increased IL-22 and antimicrobial protein levels within the small intestine, which is dependent on PGD2 signaling. A NKp46+ subset of ILC3 expresses the PGD2 receptor CRTH2 and is the source of the increased IL-22. Inflammasome activation in tuft cells also leads to better control of Salmonella Typhimurium in the distal small intestine. However, tuft cells in the cecum and colon are dispensable for antibacterial immunity. These data support that intestinal tuft cells can also induce antibacterial responses, possibly in a tissue-specific manner.

PMID:40079814 | DOI:10.1084/jem.20230803

J Antimicrob Chemother. 2025 Mar 13:dkaf073. doi: 10.1093/jac/dkaf073. Online ahead of print.

ABSTRACT

BACKGROUND: Mycobacterium abscessus is an important cause of pulmonary infections, particularly among people with cystic fibrosis. Current treatment options for M. abscessus are suboptimal. Apramycin is a promising alternative aminoglycoside for M. abscessus, in part due to its ability to avoid intrinsic aminoglycoside-modifying enzymes in this pathogen.

OBJECTIVES: Define the pharmacodynamic activity of apramycin doses against M. abscessus.

METHODS: Apramycin and amikacin pharmacodynamics were assessed against two amikacin-susceptible M. abscessus subsp. abscessus isolates (ATCC 19977 and NR-44261) using a 14-day hollow fibre infection model (HFIM). Viable bacterial counts were determined during exposure to amikacin (15-20 mg/kg q24h) and 3 fractionated doses of apramycin (15 mg/kg q12h, 30 mg/kg q24h, 60 mg/kg q48h) using pharmacokinetic profiles predicted in epithelial lining fluid.

RESULTS: Against ATCC 19977, apramycin activity exceeded that of amikacin, with maximum bacterial reductions between 1.51 and 2.18 log10 cfu/mL for the different doses. Apramycin 15 mg/kg q12h displayed slightly better killing compared with the other apramycin dosing regimens between 96 and 144h before regrowth occurred. NR-44261 was not inhibited by amikacin and the activity of apramycin against this isolate was similar between the three doses (∼0.5 log10 cfu/mL reductions). After 14 days of exposure to apramycin monotherapy, ATCC 19977 and NR-44261 became apramycin resistant with MICs of >32 mg/L.

CONCLUSIONS: Apramycin exhibited greater pharmacodynamic activity than amikacin against amikacin-susceptible M. abscessus isolates and may be a promising therapy for this pathogen. However, antibiotic combination strategies to minimize apramycin resistance from emerging may be necessary.

PMID:40079270 | DOI:10.1093/jac/dkaf073

Can J Respir Ther. 2025 Mar 3;61:20-32. doi: 10.29390/001c.129988. eCollection 2025.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This condition disrupts chloride channels and leads to the production of thick, sticky mucus, affecting the respiratory and gastrointestinal systems. CF's prevalence is particularly high in Saudi Arabia, where the incidence has increased from 1 in 2,000 to 1 in 1,000 births. Effective management of CF is essential for improving patient outcomes, yet there is a notable lack of understanding regarding respiratory therapists' (RTs) adherence to established CF management protocols.

METHODS: This descriptive quantitative study aimed to assess RTs' adherence to the Cystic Fibrosis Foundation's guidelines. Using a convenience sampling technique, a self-report survey was distributed to 750 members of the Saudi Society for Respiratory Care (SSRC), resulting in 351 responses, of which 166 were fully completed and met the inclusion criteria. The survey focused on RTs' knowledge and management practices related to CF. Data analysis was conducted using SPSS version 25, with descriptive statistics (mean, standard deviation, frequency, percentage, and mode) and non-parametric tests. The Kruskal-Wallis Test was employed to evaluate differences in adherence scores across demographic groups (e.g., education level, years of experience). Chi-square analysis was applied to examine relationships between categorical demographic variables (e.g., region of practice) and adherence to guidelines.

RESULTS: The analysis revealed significant gaps in RTs' adherence to CF guidelines, with only 42.8% accurately identifying the sweat chloride threshold for CF diagnosis and a limited 36.1% recognizing Pseudomonas aeruginosa as a common CF pathogen. Additionally, just 56.6% correctly identified the gold-standard airway clearance therapy. The Wilcoxon signed-ranks test further highlighted a statistically significant disparity (p = 0.00) between RTs' theoretical knowledge and practical application of CF management techniques, emphasizing the need for improved training.

DISCUSSION: The findings suggest a need for enhanced training and resources to bridge the gap between theoretical knowledge and practical management of CF. The lack of adherence to clinical guidelines could impact patient outcomes and survival rates.

CONCLUSION: Improving RTs' adherence to CF management guidelines through ongoing education and updated clinical standards is essential. Addressing these gaps could elevate the standard of care and contribute to better patient outcomes and survival rates in Saudi Arabia.

PMID:40078596 | PMC:PMC11901341 | DOI:10.29390/001c.129988

Front Med (Lausanne). 2025 Feb 26;12:1479638. doi: 10.3389/fmed.2025.1479638. eCollection 2025.

ABSTRACT

BACKGROUND: Little information is available regarding whether active physical activity lowers mortality risk in individuals with bronchiectasis.

METHODS: We used the Korean National Health Insurance Service database from 2010 to 2016 to evaluate the association between changes in physical activity and mortality risk in individuals with bronchiectasis. Of 552,510 individuals with newly diagnosed bronchiectasis, we enrolled 165,842 individuals who had two consecutive health examinations before and after bronchiectasis diagnosis, within two years, as the study aimed to measure changes in exercise habits between the two time points. Active physical activity was defined as engaging in moderate- or vigorous-intensity physical activity at least once a week, either before or after bronchiectasis diagnosis. The outcome measure was all-cause mortality.

RESULTS: During a mean follow-up of 6.2 ± 2.1 years, 10,535 (6.4%) individuals with bronchiectasis died. Individuals with bronchiectasis who were physically active exhibited a lower mortality rate than those who were physically inactive. Mortality reduction was particularly evident in the exercise maintainers group (aHR [adjusted hazard ratio] = 0.69, 95% confidence interval [CI] = 0.64-0.74) and individuals with physical activity ≥1,000 metabolic equivalent of task-min per week (aHR = 0.73, 95% CI = 0.70-0.77) compared to those who were physically inactive.

CONCLUSION: Engaging in active physical activity is associated with a decreased risk of mortality in individuals with bronchiectasis.

PMID:40078390 | PMC:PMC11896819 | DOI:10.3389/fmed.2025.1479638

Nutrients. 2025 Feb 28;17(5):868. doi: 10.3390/nu17050868.

ABSTRACT

BACKGROUND: Exocrine pancreatic insufficiency in cystic fibrosis (CF) increases fecal choline losses, but the postnatal course of plasma choline and its metabolites in these patients is unknown. While choline homeostasis is crucial for cellular, bile, and lipoprotein metabolism, via phosphatidylcholine (PC) and via betaine as a methyl donor, choline deficiency is associated with impaired lung and liver function, including hepatic steatosis.

OBJECTIVE: The goal of our study was to evaluate the plasma levels of choline, betaine, trimethylamine oxide (TMAO), PC, and PC subclasses in CF patients from infancy to adulthood and compare those with exocrine pancreatic insufficiency (EPI) to those with pancreatic sufficiency (EPS).

METHODS: Retrospective analysis of target parameters in plasma samples (July 2015-November 2023) of CF patients (0.64-24.6 years) with tandem mass spectrometry.

RESULTS: A total of 477 samples from 162 CF patients were analyzed. In CF patients with EPI (N = 148), plasma choline and betaine concentrations were lower and decreased with age compared to EPS patients showing normal values. TMAO concentrations, indicating intestinal choline degradation by bacterial colonization, were frequently elevated in EPI from infancy onwards, and inversely related to plasma choline and betaine levels. PC-containing linoleic acid levels were lower in EPI, but arachidonic and docosahexaenoic acid content was similar in both patient groups.

CONCLUSION: CF patients with EPI are at risk of choline and betaine deficiency compared to exocrine pancreas-sufficient CF patients. Elevated TMAO concentrations in EPI patients indicate increased bacterial colonization leading to choline degradation before absorption. These findings indicate that laboratory testing of choline, betaine, and TMAO as well as clinical trials on choline supplementation are warranted in CF patients.

PMID:40077735 | DOI:10.3390/nu17050868

Int J Mol Sci. 2025 Mar 6;26(5):2336. doi: 10.3390/ijms26052336.

ABSTRACT

Atherosclerosis (AS) is a disease characterised by the accumulation of atherosclerotic plaques on the inner walls of blood vessels, resulting in their narrowing. In its early stages, atherosclerosis remains asymptomatic and undetectable by conventional pathological methods. However, as the disease progresses, it can lead to a series of cardiovascular diseases, which are a leading cause of mortality among middle-aged and elderly populations worldwide. Neutrophil extracellular traps (NETs) are composed of chromatin and granular proteins released by neutrophils. Upon activation by external stimuli, neutrophils undergo a series of reactions, resulting in the release of NETs and subsequent cell death, a process termed NETosis. Research has demonstrated that NETosis is a means by which neutrophils contribute to immune responses. However, studies on neutrophil extracellular traps have identified NETs as the primary cause of various inflammation-induced diseases, including cystic fibrosis, systemic lupus erythematosus, and rheumatoid arthritis. Consequently, the present review will concentrate on the impact of neutrophil extracellular traps on atherosclerosis formation, analysing it from a molecular biology perspective. This will involve a systematic dissection of their proteomic components and signal pathways.

PMID:40076955 | DOI:10.3390/ijms26052336

Int J Mol Sci. 2025 Feb 27;26(5):2066. doi: 10.3390/ijms26052066.

ABSTRACT

The introduction of CFTR modulators in the clinics has improved body mass index in cystic fibrosis (CF) individuals. Leptin is a major regulator of appetite and energy expenditure but is also involved in bone metabolism. Whether circulating leptin levels are associated with low bone mineral density (BMD) and fracture risk in CF remains unknown. Therefore, the present study aims to analyze and integrate the current evidence linking leptin and bone loss in CF. As no scientific evidence was found, we focused on secondary dysregulations of bone loss in CF that may be linked to pathologies that are similar to the various dysregulations and multisystemic manifestations in CF. Studies published from 2001 to 2022 were identified through the PubMed, Scopus, and Web of Science databases, and screening was performed following the PRISMA guidelines. The included studies were assessed using a quality checklist. From the 774 records identified, 28 studies met the inclusion criteria. Although no evidence has been found directly related to bone loss in CF individuals, some studies revealed a positive association between leptin levels and BMD, while others found an inverse association. Current evidence suggests that for circulating leptin levels to be a predictive biomarker of bone health, further research will be needed to reveal the direct and indirect mechanisms behind leptin and bone loss and to understand whether changes in leptin levels correlate with changes in BMD. Of note, studies with CF people would be of high importance to understand the role of leptin in CF-related bone disease.

PMID:40076690 | DOI:10.3390/ijms26052066

Int J Mol Sci. 2025 Feb 25;26(5):2012. doi: 10.3390/ijms26052012.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen with a multidrug-resistant profile that has become a critical threat to global public health. It is one of the main causes of severe nosocomial infections, including ventilator-associated pneumonia, chronic infections in patients with cystic fibrosis, and bloodstream infections in immunosuppressed individuals. Development of vaccines against P. aeruginosa is a major challenge owing to the high capacity of this bacterium to form biofilms, its wide arsenal of virulence factors (including secretion systems, lipopolysaccharides, and outer membrane proteins), and its ability to evade the host immune system. This review provides a comprehensive historical overview of vaccine development efforts targeting this pathogen, ranging from early attempts in the 1970s to recent advancements, including vaccines based on novel proteins and emerging technologies such as nanoparticles and synthetic conjugates. Despite numerous promising preclinical developments, very few candidates have progressed to clinical trials, and none have achieved final approval. This panorama highlights the significant scientific efforts undertaken and the inherent complexity of successfully developing an effective vaccine against P. aeruginosa.

PMID:40076637 | DOI:10.3390/ijms26052012

Int J Mol Sci. 2025 Feb 21;26(5):1871. doi: 10.3390/ijms26051871.

ABSTRACT

Cystic fibrosis (CF) is characterized by chronic respiratory infections and excessive inflammation, driven by both host- and pathogen-derived proteases. The dysregulated activity of proteolytic enzymes such as neutrophil elastase (NE), cathepsin G, and matrix metalloproteases (MMPs) degrades lung tissue, exacerbates airway remodeling, and perpetuates inflammatory cycles. Concurrently, bacterial proteases from pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus contribute to immune evasion and tissue destruction, compounding disease severity. Despite advances in antimicrobial and anti-inflammatory therapies, protease-driven lung damage remains a critical challenge. This review examines the dual role of host and bacterial proteases in CF pathophysiology, highlighting emerging protease-targeted therapies aimed at mitigating lung damage and inflammation. Strategies explored include the inhibition of NE, MMPs, and bacterial proteases, with a focus on innovative therapeutic approaches such as dual-function inhibitors, biologics, and advanced drug delivery systems. By restoring the protease-antiprotease balance, these interventions offer the potential to improve clinical outcomes and quality of life for CF patients.

PMID:40076497 | DOI:10.3390/ijms26051871

Hum Genomics. 2025 Mar 12;19(1):25. doi: 10.1186/s40246-025-00736-7.

ABSTRACT

BACKGROUND: Global fertility decline has led to increased use of assisted reproductive technology (ART), raising concerns about genetic risks to offspring. This study aimed to investigate cystic fibrosis transmembrane conductance regulator (CFTR) variants in Chinese families and assess their association with pregnancy complications and neonatal outcomes.

METHODS: This prospective cohort study included 446 Chinese families (148 natural conceptions, 298 ART conceptions) who underwent whole genome sequencing. We analyzed the frequency of pathogenic/likely pathogenic CFTR variants and their association with preterm birth (PTB), pregnancy complications, and neonatal outcomes.

RESULTS: Twelve pathogenic/likely pathogenic CFTR variants were identified, with K464N (c.1392G > T) being the most prevalent (2.9% of cohort). PTB incidence was significantly higher in pregnancies with fetal CFTR variants (43.1%, 22/51) compared to those without (17.5%, 69/395; p < 0.001). Fetuses carrying the CFTR K464N variant exhibited a 3.39-fold increased risk of PTB (95% confidence interval (CI): 1.39-8.23, p = 0.007) after adjusting for confounders. Neither fetal nor maternal CFTR variants were significantly associated with other neonatal outcomes, including neonatal weight, Apgar scores, respiratory distress, or hyperbilirubinemia (p > 0.050).

CONCLUSION: These findings suggest a potential association between fetal CFTR K464N variant and increased risk of preterm birth in Chinese families, highlighting the importance of considering CFTR genotyping in prenatal care.

PMID:40075526 | DOI:10.1186/s40246-025-00736-7

Cell Mol Life Sci. 2025 Mar 13;82(1):109. doi: 10.1007/s00018-025-05627-7.

ABSTRACT

Cystic fibrosis (CF) is a life-shortening genetic disorder, caused by mutations in the CF transmembrane conductance regulator (CFTR) protein that regulates ion and fluid transport in epithelial tissue. Female CF patients face considerable fertility challenges, with higher prevalence of deficient fertility compared to healthy women. Not much is known about the underlying causes. In particular, the pathobiology of the endometrium, the uterus' inner lining essential for pregnancy and expressing fluctuating CFTR levels during the menstrual cycle, is unexplored in CF. To address this gap, we developed organoid models from CF patient endometrium. The organoids recapitulated CF characteristics and revealed molecular and pathway differences in cycle-recapitulating hormone responses compared to healthy endometrial organoids. Furthermore, specific functional aberrations were restored by CFTR modulator treatment. To further complement human organoid models for unraveling endometrial pathobiology in CF, we also developed organoids from a genetic CF mouse model that were also found to recapitulate CF characteristics. Moreover, single-cell RNA-sequencing analysis of the CF mouse uterus revealed molecular traits in the endometrium similar to the human CF endometrium (as evidenced by its organoid model). Our study provides new endometrium models to advance our understanding of CF-associated endometrial pathobiology, particularly regarding menstrual cycle aberrations that impact fertility. This research is timely since improved CF therapeutics result in increased life expectancy, allowing more CF patients to consider starting a family.

PMID:40074868 | DOI:10.1007/s00018-025-05627-7

J Cyst Fibros. 2025 Mar 11:S1569-1993(25)00073-6. doi: 10.1016/j.jcf.2025.03.004. Online ahead of print.

ABSTRACT

Fatigue is common among adults with cystic fibrosis (awCF) and may be associated with systemic inflammation. This study examines systemic inflammation, measured by C-reactive protein (CRP), and fatigue, assessed using the Cystic Fibrosis Questionnaire-Revised (CFQ-R) vitality domain, in individuals initiating elexacaftor/tezacaftor/ivacaftor (ETI) therapy. In a cohort of 61 awCF from St. Paul's Hospital, Vancouver, CRP and vitality were measured at baseline and at 1, 3, 6, and 12 months post-ETI initiation. We observed reductions in CRP and increases in vitality over the 12-month period. Linear mixed-effects models were used to examine the relationship between CRP and vitality adjusted for age, sex, BMI, and lung function. Our findings demonstrated a significant, independent inverse association between CRP and vitality. These results highlight the potential role of systemic inflammation in influencing vitality in awCF undergoing ETI therapy. Further research incorporating additional inflammatory markers and psychosocial variables is warranted to deepen our understanding of fatigue mechanisms in this population.

PMID:40074570 | DOI:10.1016/j.jcf.2025.03.004