Front Pediatr. 2025 May 13;13:1574919. doi: 10.3389/fped.2025.1574919. eCollection 2025.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is caused by CFTR gene mutations. Its diagnosis mainly depends on genetic and sweat chloride tests, but the complexity of these mutations challenges diagnosis.

METHODS: This paper reports a new case of a Chinese child with cough and wheezing, suspected of having CF. Trio whole-exome sequencing for the pedigree was carried out to detect CFTR gene mutations. Five tools, namely Mutation Taster, PolyPhen-2, SIFT, FATHMM, and PROVEAN, were used to predict the impacts of mutations on protein function. AlphaFold was employed to predict protein structures, and GROMACS software was used to conduct stability analysis through molecular dynamics simulations.

RESULTS: The child was diagnosed with severe pneumonia, plastic bronchitis, and acute asthmatic bronchitis, with a high suspicion of CF. Whole-exome sequencing revealed compound missense mutations in the CFTR gene: c.1408 (exon 11) G>A (p.V470M) and c.650 (exon 6) A>G (p.E217G), both of which were homozygous mutations. Parental genetic tests showed that the father was heterozygous for the mutations, and the mother was heterozygous at the c.650 (exon 6) A>G locus and homozygous at the c.1408 (exon 11) G>A locus. The results obtained by different prediction tools varied, and molecular dynamics simulations indicated that these mutations significantly affected the stability of the CFTR protein.

CONCLUSION: Analysis of this new case using multiple tools and computational chemistry simulations helps to further understand the impacts of mutations on CFTR protein function and the disease, offering novel insights into the diagnosis, treatment, and genetic counseling of CF caused by the complex and diverse mutations of the CFTR gene.

PMID:40433478 | PMC:PMC12106003 | DOI:10.3389/fped.2025.1574919

Exp Ther Med. 2025 May 13;30(1):134. doi: 10.3892/etm.2025.12884. eCollection 2025 Jul.

ABSTRACT

In the present review, simple approaches for the screening and characterization of natural compound agents that alter pro-inflammatory gene expression are described, with a particular focus on aged garlic extract (AGE), which has been the subject of several investigations that have supported its potential application as an anti-inflammatory agent. Additionally, evidence regarding the possible effects and mechanisms of action of two major AGE components, S-allyl cysteine (SAC) and S-1-propenyl-l-cysteine (S1PC), is reviewed. The proposed molecular targets of SAC and S1PC are IKKβ kinase, the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 complex, peroxisome proliferator-activated receptor-γ, histone deacetylase and toll-like receptor 4 (TLR4). Targeting these molecules causes a marked reduction in NF-κB activity accompanied by a notable decrease in the transcription of NF-κB-regulated genes. Another main objective of the present review was to discuss the possibility that AGE and its bioactive components could be employed in the treatment of several human pathologies that are characterized by a hyperinflammatory state resulting from dysregulation of the TLR4 and NF-κB pathways. SAC is of interest in the treatment of lung pathologies, neurological diseases, osteoarthritis, muscular atrophy, cardiovascular diseases, diabetes and cancer. Additionally, the anti-oxidative activities of AGE, SAC and S1PC are compatible with their employment in the treatment of diseases characterized by oxidative stress, such as sickle cell disease and β-thalassemia.

PMID:40432842 | PMC:PMC12107228 | DOI:10.3892/etm.2025.12884

ERJ Open Res. 2025 May 27;11(3):00970-2024. doi: 10.1183/23120541.00970-2024. eCollection 2025 May.

ABSTRACT

BACKGROUND: The triple cystic fibrosis transmembrane conductance regulator (CFTR) modulators combination elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with cystic fibrosis (pwCF) bearing at least one F508del allele. Despite the development of CFTR modulators having dramatically improved respiratory outcomes in pwCF, clinical studies have showed variable responses to this drug formulation. Of note, airway inflammation and bacterial colonisation persist in the upper and lower respiratory tract even in ETI-treated patients.

METHODS: We first tested the clinical exoproducts (EXO) of Pseudomonas aeruginosa isolated from 15 CF patients in wild-type (WT) and F508del-CFTR CF bronchial epithelial (CFBE) cells. We were then prompted to evaluate the effects of EXO in ex-vivo patient-derived tissues. Therefore, we cultured primary nasal epithelial cells (HNECs) with EXO isolated from the corresponding pwCF to mimic the native status of CF airway.

RESULTS: We found that EXO variably decreased WT-, F508del- and ETI-dependent F508del-CFTR function and increased proinflammatory cytokines and reactive oxygen species (ROS) levels in a clinical strain-specific manner. Similarly, we observed a variable reduction of F508del-CFTR function in presence or absence of ETI and upregulation of proinflammatory cytokines and ROS levels. Interestingly, HNECs treated with EXO isolated from the corresponding donor and three different pwCF showed a variable reduction of ETI-dependent F508del-CFTR function mainly due to clinical strains with limited effect of patient background. Furthermore, we demonstrated that ETI pretreatment decreased the cytokines and ROS levels down to the levels of uninfected cells.

CONCLUSION: These preclinical studies suggest that in vitro screening of patient-specific response to CFTR modulators under infection/inflammation conditions could prove to be a valuable tool to enhance the prediction of clinical response.

PMID:40432819 | PMC:PMC12107384 | DOI:10.1183/23120541.00970-2024

Cureus. 2025 Apr 26;17(4):e83047. doi: 10.7759/cureus.83047. eCollection 2025 Apr.

ABSTRACT

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by impaired mucociliary clearance, leading to recurrent respiratory tract infections, chronic rhinosinusitis, and progressive bronchiectasis. Pseudomonas aeruginosa is a common pathogen associated with poorer clinical outcomes in patients with PCD. While environmental sources of P. aeruginosa are well-documented in cystic fibrosis (CF) patients, to our knowledge, this is the first reported case implicating toothbrush colonization as a likely source of recurrent P. aeruginosa infections in a patient with PCD. We present a case of a 53-year-old Puerto Rican male with a history of sinusitis, bronchiectasis, hearing loss, and chronic cough, diagnosed with PCD, having a positive genetic testing for RSPH4A (c.921+3_921+6del (intronic)) founder mutation. Despite aggressive treatment, the patient continued to experience recurrent P. aeruginosa infections. Investigation into potential environmental sources revealed that the patient's toothbrush was colonized with P. aeruginosa, making it a likely source of reinfection. After modifying his oral hygiene practices, the patient showed significant clinical improvement with no subsequent hospitalizations. This case highlights the novel identification of a toothbrush as a source of recurrent P. aeruginosa infections in a patient with PCD. It underscores the importance of considering environmental factors in the management of chronic respiratory infections in patients with PCD. These findings suggest that routine evaluation and disinfection of hygiene tools, such as toothbrushes, may be critical in preventing recurrent infections and their long-term consequences in patients with PCD. Future research should aim to establish clinical guidelines for preventing bacterial transmission from the built environment in this vulnerable population.

PMID:40432624 | PMC:PMC12106793 | DOI:10.7759/cureus.83047

Nutrients. 2025 May 9;17(10):1632. doi: 10.3390/nu17101632.

ABSTRACT

Background: Sufficient choline supply is essential for tissue functions via phosphatidylcholine and sphingomyelin within membranes and secretions like bile, lipoproteins and surfactant, and in one-carbon metabolism via betaine. Choline requirements are linked to age and genetics, folate and cobalamin via betaine, and arachidonic (ARA) and docosahexaenoic (DHA) acid transport via the phosphatidylcholine moiety of lipoproteins. Groups at risk of choline deficiency include preterm infants, children with cystic fibrosis (CF) and patients dependent on parenteral nutrition. Fortifiers, formula and supplements may differently impact their choline supply. Objective: To evaluate added amounts of choline, folate, cobalamin, ARA and DHA in fortifiers, supplements and formula used in pediatric care from product files. Methods: Nutrient contents from commonly used products, categorized by age and patient groups, were obtained from public sources. Data are shown as medians and interquartile ranges. Results: 105 nutritional products including fortifiers, formula and products for special indications were analyzed. Choline concentrations were comparable in preterm and term infant formulas (≤6 months) (31.9 [27.6-33.3] vs. 33.3 [30.8-35.2] mg/100 kcal). Products for toddlers, and patients with CF, kidney or Crohn's disease showed Choline levels from 0 to 39 mg/100 kcal. Several products contain milk components and lecithin-based emulsifiers potentially increasing choline content beyond indicated amounts. Conclusions: Choline addition is standardized in formula for term and preterm infants up to 6 months, but not in other products. Choline content may be higher in several products due to non-declared sources. The potential impact of insufficient choline supply in patients at risk for choline deficiency suggests the need for biochemical analysis of products.

PMID:40431372 | DOI:10.3390/nu17101632

Pharmaceuticals (Basel). 2025 May 15;18(5):729. doi: 10.3390/ph18050729.

ABSTRACT

This article profiles 27 innovative advancements in small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) in 2024. These drugs target various therapeutic areas including non-small cell lung cancer, advanced or metastatic breast cancer, glioma, relapsed or refractory acute leukemia, urinary tract infection, Staphylococcus aureus bloodstream infections, nonalcoholic steatohepatitis, primary biliary cholangitis, Duchenne muscular dystrophy, hypertension, anemia due to chronic kidney disease, extravascular hemolysis, primary axillary hyperhidrosis, chronic obstructive pulmonary disease, severe alopecia areata, WHIM syndrome, Niemann-Pick disease type C, schizophrenia, supraventricular tachycardia, congenital adrenal hyperplasia, and cystic fibrosis. Among these approved small-molecule drugs, those with unique mechanisms of action and designated as breakthrough therapies by the FDA represent a significant proportion, highlighting ongoing innovation. Notably, eight of these drugs (including Rezdiffra®, Voydeya®, Iqirvo®, Voranigo®, Livdelzi®, Miplyffa®, Revuforj®, and Crenessity®) are classified as "first-in-class" and have received breakthrough therapy designation. These agents not only exhibit distinct mechanisms of action but also offer substantial improvements in efficacy for patients compared to prior therapeutic options. This article offers a comprehensive analysis of the mechanisms of action, clinical trials, drug design, and synthetic methodologies related to representative drugs, aiming to provide crucial insights for future pharmaceutical development.

PMID:40430547 | DOI:10.3390/ph18050729

Life (Basel). 2025 May 20;15(5):815. doi: 10.3390/life15050815.

ABSTRACT

This study investigated the prevalence of cystic fibrosis-related diabetes (CFRD) in the Croatian cystic fibrosis (CF) population, the age at diagnosis, insulin requirements, and the relationship between age at diagnosis and other clinical parameters. Medical records from 152 patients with genetically and laboratory-confirmed CF were reviewed through to 2025. The American Diabetes Association criteria were used to diagnose CFRD. Anthropometric and clinical data were collected from the latest medical records. A total of 17 out of 152 patients had CFRD, with a prevalence of 4.8% in the paediatric population (4/84) and 19.1% in adults (13/68). The median age of CFRD diagnosis was 14 years (range 9-22 years, SD = 3.95). Thirteen patients used insulin: one used bolus only, seven used basal-bolus multiple daily injections, and five used insulin pumps. The average total daily insulin (TDI) per kilogram (kg) body weight was 0.447 U/kg (SD = 0.429). The age at CFRD diagnosis was positively correlated with the body mass index (BMI) (p = 0.029). Patients requiring insulin by age 15 had higher TDI and were more likely to have CF liver disease (p = 0.027, p = 0.037, respectively). The prevalence of CFRD and age at diagnosis aligned with previous studies. Patients diagnosed at a younger age and requiring insulin earlier had lower BMIs, likely due to a faster decline in beta cell function and earlier onset of insulinopenia.

PMID:40430241 | DOI:10.3390/life15050815

Int J Mol Sci. 2025 May 8;26(10):4487. doi: 10.3390/ijms26104487.

ABSTRACT

Accurate genetic diagnosis is essential for appropriate treatment in cystic fibrosis (CF). Large copy number variants like duplications in the CFTR gene are rare and often classified as variants of uncertain significance (VUSs) due to unknown characteristics of the inserted material, complicating diagnosis and treatment decisions. We identified a previously uncharacterized exon 22 duplication (CFTRdup22) in the CFTR gene in two anamnestically unrelated people with CF, both exhibiting a mild phenotype. Initial classification as a VUS was based on standard genetic testing. We employed a custom next-generation sequencing (NGS) panel to determine the exact breakpoints of the duplication and conducted mRNA sequencing to confirm its effect on splicing. DNA and RNA analyses allowed for precise breakpoint determination, confirming that the duplication was in tandem and the reading frame remained intact. This, as well as a residual CFTRdup22 function of ~30% as measured via intestinal current measurement, is consistent with a clinically milder CF phenotype. Collectively, the precise characterization of the variants' breakpoints, localization and orientation enabled us to reclassify the variant as likely pathogenic. This study highlights the importance of advanced genetic techniques, such as NGS and breakpoint analysis, in accurately identifying CF-causing variants. It underscores the importance of a comprehensive approach and persistence when suspecting a specific genetic condition. This can aid in reclassifying VUSs, providing a definitive diagnosis for the affected family and enabling appropriate therapeutic interventions, including the use of CFTR modulators.

PMID:40429633 | DOI:10.3390/ijms26104487

J Clin Med. 2025 May 16;14(10):3492. doi: 10.3390/jcm14103492.

ABSTRACT

People with CF (pwCF) have a significant risk for pulmonary infections with non-tuberculous mycobacteria (NTM), particularly Mycobacterium abscessus (Mab). Mab is an emerging pathogen, which causes pulmonary infections in patients with chronic lung diseases, particularly CF; Mab pulmonary disease leads to progressive pulmonary dysfunction and increased morbidity and mortality. Despite advances in CF care, including CFTR modulators (CFTRm), Mab continues to pose a therapeutic challenge, with significant long-term medical burden. This review provides insights into the complex host-pathogen interplay of Mab infections in pwCF. It provides a detailed overview of Mab bacterial virulence factors, including biofilm formation, secretion systems, the virulence-associated rough morphotype, and antibiotic resistance mechanisms. This review also summarizes features conferring susceptibility of the CF host to Mab infections, alongside the contribution of the CF-host environment to the pathogenesis of Mab infection, such as antibiotic-derived microbial selection, within-host mycobacterial evolution, and interactions with co-pathogens such as Pseudomonas aeruginosa (PA). Finally, the therapeutic implications and novel treatments for Mab are discussed, considering the complex host-pathogen interplay.

PMID:40429486 | DOI:10.3390/jcm14103492

Medicina (Kaunas). 2025 Apr 26;61(5):808. doi: 10.3390/medicina61050808.

ABSTRACT

Background and Objective: This study's objective was to determine the impact of the percentage of lung tissue within the normal density range (PLND) on exacerbations and hospitalizations compared with the modified Bhalla and Reiff scores. We also investigated the effects of these measures on pulmonary function tests (PFTs). Materials and Methods: This retrospective analysis involved adult cystic fibrosis (CF) patients who had thoracic computed tomography (CT) while in a stable clinical condition. A dedicated radiologist analyzed CT images and conducted modified Bhalla, Reiff, and PLND assessments. We analyzed the exacerbations and hospitalizations in the year after the CT scan. We also examined PFTs at the time of the CT scan and one year later. Results: This study's population consisted of 63 subjects (33 men), with a median age of 23.2 years. The median modified Bhalla score was 9.0 (IQR: 7.0-12.0), the median Reiff score was 11.0 (IQR: 8.0-15.0), and the median PLND was 79.4% (IQR: 74.5-82.0). The Bhalla score had the strongest relationship with both the number of exacerbations (p < 0.001, r: -0.559) and hospitalizations the following year (p < 0.001, r: -0.636), followed by the PLND score and the Reiff score. Youden's index shows that the optimum cut-off values for hospitalization at ≤2 and >2 are 6.5 for the modified Bhalla score, 13.5 for the Reiff score, and 76.5% for the PLND. Conclusions: The measurement of PLND may serve as a predictor for exacerbation and hospitalization rates, aligning with the modified Bhalla and Reiff scores, and shows potential for application in follow-up assessments.

PMID:40428766 | DOI:10.3390/medicina61050808

Genes (Basel). 2025 May 20;16(5):603. doi: 10.3390/genes16050603.

ABSTRACT

BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) is a progressive inflammatory condition of the pancreas that leads to irreversible changes in pancreatic structure. The pancreatic α and β cells secrete hormones such as insulin and glucagon into the bloodstream. The pancreatic acinar cells secrete digestive enzymes that break down macromolecules. When these digestive enzymes do not function properly, maldigestion, malabsorption, and malnutrition may result. Presented here is a case study of an individual newly diagnosed with chronic pancreatitis, along with a genetic analysis of his son and an in-silico analysis of two of the variant proteins.

METHODS: This study was conducted using human subjects, namely, the proband (father) and his son. Medical genetic testing of the proband (father) identified the presence of two variants in the cystic fibrosis transmembrane receptor gene (CFTR): variant rs213950, resulting in a single amino acid change (p. Val470Met), and variant rs74767530, a nonsense variant (Arg1162Ter) with known pathogenicity for cystic fibrosis. Medical testing also revealed an additional missense variant, rs515726209 (Ala73Thr), in the CTRC gene. Cheek cell DNA was collected from both the proband and his son to determine the inheritance pattern and identify any additional variants. A variant in the human leukocyte antigen (rs7454108), which results in the HLA-DQ8 haplotype, was examined in both the proband and his son due to its known association with autoimmune disease, a condition also linked to chronic pancreatitis. In silico tools were subsequently used to examine the impact of the identified variants on protein function.

RESULTS: Heterozygosity for all variants originally identified through medical genetic testing was confirmed in the proband and was absent in the son. Both the proband and his son were found to have the DRB1*0301 (common) haplotype for the HLA locus. However, the proband was also found to carry a linked noncoding variant, rs2647088, which was absent in the son. In silico analysis of variant rs213950 (Val470Met) in CFTR and rs515726209 (Ala73Thr) in CTRC revealed distinct changes in predicted ligand binding for both proteins, which may affect protein function and contribute to the development of CP.

CONCLUSIONS: This case study of a proband and his son provides additional evidence for a polygenic inheritance pattern in CP. The results also highlight new information on the role of the variants on protein function, suggesting additional testing of ligand binding for these variants should be done to confirm the functional impairments.

PMID:40428425 | DOI:10.3390/genes16050603

Antibiotics (Basel). 2025 May 10;14(5):486. doi: 10.3390/antibiotics14050486.

ABSTRACT

BACKGROUND: Mycobacterium abscessus (MABS) is an opportunistic pathogen that causes chronic, difficult-to-treat pulmonary infections, particularly in people with cystic fibrosis (PwCF), leading to rapid lung function decline and increased morbidity and mortality. Treatment is particularly challenging due to the pathogen's resistance mechanisms and the need for prolonged multidrug therapy, which is characterized by poor clinical outcomes and highlights the urgent need for novel therapeutic strategies. Imipenem/relebactam, a novel β-lactam-β-lactamase inhibitor combination, demonstrates in vitro activity against resistant MABS strains and effective pulmonary penetration. Prior research indicates synergistic activity of imipenem with various antibiotics against M. abscessus.

OBJECTIVES: This study aims to evaluate the in vitro activity of imipenem/relebactam, alone and in combination with various antibiotics, against MABS clinical isolates from PwCF (n = 28).

METHODS: Susceptibility and synergy were assessed using broth microdilution and checkerboard assays. Extracellular time-kill assays were performed to evaluate the bactericidal activity of synergistic three-drug combinations containing imipenem/relebactam.

RESULTS: Imipenem/relebactam demonstrated potent in vitro activity against clinical MABS isolates, exhibiting substantial synergy with cefuroxime, cefdinir, amoxicillin, and cefoxitin. Rifabutin, azithromycin, moxifloxacin, clofazimine, and minocycline also demonstrated additive effects with imipenem/relebactam. Extracellular time-kill assays identified imipenem/relebactam + cefoxitin + rifabutin and imipenem/relebactam + cefoxitin + moxifloxacin as the most effective combinations.

CONCLUSIONS: These findings suggest that imipenem/relebactam may offer a significant advancement in the management of MABS infections in PwCF. The promising efficacy of multidrug regimens combining imipenem/relebactam with agents like cefoxitin, azithromycin, moxifloxacin, clofazimine, and rifabutin highlights potential therapeutic strategies.

PMID:40426552 | DOI:10.3390/antibiotics14050486

Antibiotics (Basel). 2025 Apr 23;14(5):427. doi: 10.3390/antibiotics14050427.

ABSTRACT

Pseudomonas aeruginosa, a multidrug-resistant pathogen, significantly impacts patients with chronic respiratory conditions like cystic fibrosis (CF) and non-CF chronic suppurative lung disease (CSLD), contributing to progressive lung damage and poor clinical outcomes. This bacterium thrives in the airway environments of individuals with impaired mucociliary clearance, leading to persistent infections and increased morbidity and mortality. Despite advancements in management of these conditions, treatment failure remains common, emphasising the need for alternative or adjunctive treatment strategies. Bacteriophage therapy, an emerging approach utilising viruses that specifically target bacteria, offers a potential solution to combat P. aeruginosa infections resistant to conventional antibiotics. This review examines the prevalence and disease burden of P. aeruginosa in CF and CSLD, explores the mechanisms behind antibiotic resistance, the promising role of bacteriophage therapy and clinical trials in this sphere.

PMID:40426494 | DOI:10.3390/antibiotics14050427

J Cyst Fibros. 2025 May 26:S1569-1993(25)00111-0. doi: 10.1016/j.jcf.2025.03.015. Online ahead of print.

ABSTRACT

BACKGROUND: Lenabasum is a cannabinoid receptor 2 (CB2) agonist under development for cystic fibrosis (CF), targeting inflammation. We evaluated the efficacy and safety of lenabasum in people with CF (pwCF).

METHODS: We conducted a global, 28-week, randomized, double-blind, placebo-controlled Phase 2b trial. PwCF were ≥12 years old with 2-3 pulmonary exacerbations (PEx) treated with intravenous (IV) antibiotics (or 1 PEx treated with IV and ≥1 PEx treated with oral antibiotics) in the past year. Subjects were randomized 2:1:2 to lenabasum 20 mg BID, lenabasum 5 mg BID, or placebo BID. Primary endpoint was rate of PEx, comparing lenabasum 20 mg BID to placebo.

RESULTS: Among 447 subjects from 21 countries, mean age was 26.9 (10.3 SD) years, 53.6% were female, 45.2% homozygous for F508del, and 24.9% received CFTR modulators. Highest ppFEV1 in the previous year was 69.2% with the majority having 1-2 PEx treated with IV antibiotics (2-7 PEx treated with either IV or oral antibiotics). PEx incidence over 28 weeks was 0.84 for placebo, 0.75 for lenabasum 5 mg BID, and 0.91 for lenabasum 20 mg BID; rates were not lower relative to placebo in the 5 mg (incidence rate ratio (IRR)=0.89, 95% CI 0.66 to 1.19, p = 0.44) or the 20 mg group (IRR 1.08, 95% CI 0.86 to 1.37, p = 0.51). PEx occurred less frequently in participants from Eastern Europe, but there was no evidence of regional variation in treatment efficacy. Lenabasum was well tolerated, without safety signals.

CONCLUSION: Lenabasum did not improve key clinical outcomes in this Phase 2b study in pwCF.

PMID:40425421 | DOI:10.1016/j.jcf.2025.03.015

Respir Med. 2025 May 25:108179. doi: 10.1016/j.rmed.2025.108179. Online ahead of print.

ABSTRACT

Bronchiectasis is a chronic inflammatory airway disease characterized by a self-perpetuating vortex of impaired mucociliary clearance, persistent infection, and progressive structural lung damage. While inflammation is central to disease activity and progression, targeted anti-inflammatory treatments have been limited. Understanding the different types of inflammation involved and their significant overlap is essential for effective management. This review explores key inflammation patterns, biomarkers, and available treatments across the spectrum of inflammation in bronchiectasis, with a particular focus on non-cystic fibrosis bronchiectasis in adults. Neutrophilic inflammation remains the hallmark of bronchiectasis, with promising reversible dipeptidyl peptidase-1 inhibitors reducing the activation of neutrophil serine proteases during neutrophil maturation. Eosinophilic inflammation has also gained attention, with evidence indicating that patients with this endotype may benefit from glucocorticoids and biologic therapies targeting type 2 inflammation. Additional inflammatory mechanisms discussed here include impaired epithelial function and mucociliary abnormalities, immune dysregulation, and airway inflammation triggered by infections, environmental irritants, and autoimmune conditions. Written for general clinicians, this review simplifies complex concepts, underscores key aspects of diagnostic evaluation, and discusses both conventional and emerging treatments for bronchiectasis, providing practical insights for improved personalized patient care.

PMID:40425105 | DOI:10.1016/j.rmed.2025.108179

Clin Transl Gastroenterol. 2025 May 27. doi: 10.14309/ctg.0000000000000857. Online ahead of print.

ABSTRACT

PURPOSE: Screening guidelines for pancreatic cancer (PC) based on genetic risk do not include patients with CF or CFTR gene variants. The objective of this study was to determine risk of PC in patients with CF or CFTR pathogenic/likely pathogenic (PLPV) gene variants.

METHODS: We conducted a retrospective cohort study of CF/CFTR PLPV patients in an integrated healthcare system from 2008-2023. Index date was the initial encounter within the health system, with censoring at loss of membership, death, or study completion. PC incidence rate (IR) was based on person-time at risk. Age- and sex-adjusted standardized incidence rate ratio (SIR) for PC was calculated for CF/CFTR compared to the non-CFTR reference population. We further stratified PC risk by age and family history of PC.

RESULTS: 12,682 patients with CF/CFTR were included with a median follow-up of 8.3 years (IQR 4.3-13.1). The cohort was 88% female, had median age at index of 25.8 (IQR 19.1-31.1) years, and was majority White and Hispanic. 8 total PC events occurred in the CF/CFTR group (IR 7.3 per 100,000 person-years). The adjusted SIR for PC was 2.3 (95% CL 1.2-4.7) for CF/CFTR variant patients. There was effect modification by age, with SIR (age≥50 years) of 2.87 (95% CL 1.37-6.01). Among CF/CFTR patients with family history of PC, 1 PC case was observed with SIR (age≥50 years) of 13.

CONCLUSION: Patients with CF or CFTR gene variants had an almost 3-fold higher adjusted risk of PC than the general population after age 50 years. The risk may be further increased with a family history of PC.

PMID:40423702 | DOI:10.14309/ctg.0000000000000857

mBio. 2025 May 27:e0077525. doi: 10.1128/mbio.00775-25. Online ahead of print.

ABSTRACT

Staphylococcus aureus infections remain an ongoing challenge for people with cystic fibrosis (PwCF), with the increased global prevalence of multidrug-resistant strains requiring new therapeutic approaches. Our previous studies demonstrated anti-inflammatory effects of several MEK1/2 inhibitor compounds, including PD0325901, CI-1040, and trametinib, in human phagocytes from PwCF and a murine S. aureus pulmonary infection model (M. De, G. Serpa, E. Zuiker, K. B. Hisert, et al., Front Cell Infect Microbiol 14:1275940, 2024, https://doi.org/10.3389/fcimb.2024.1275940). A recently developed MEK1/2 inhibitor compound, ATR-002, has been recognized for its ability to exert direct antibacterial effects on gram-positive bacterial species, including S. aureus (C. Bruchhagen, M. Jarick, C. Mewis, T. Hertlein, et al., Sci Rep 8:9114, 2018, https://doi.org/10.1038/s41598-018-27445-7). However, whether ATR-002 elicits antibacterial effects on clinically relevant strains of S. aureus or anti-inflammatory effects is unknown. In this study, the effects of ATR-002 on human CF macrophage TLR2-induced pro-inflammatory cytokine secretion were evaluated, demonstrating that ATR-002 reduced TNF-α and IL-8 secretion induced by the TLR2 agonists FSL-1 or Pam3CSK4. The antibacterial effects of ATR-002 were evaluated by minimum inhibitory concentration testing using S. aureus clinical isolates obtained from PwCF. Utilization of a murine methicillin-resistant S. aureus (MRSA) pulmonary infection model further confirmed the in vivo anti-inflammatory and antibacterial effects of ATR-002. Finally, infection of wild-type and Mek2KO mice revealed that loss of MEK2 was host-protective during MRSA pulmonary infection by reducing neutrophil-mediated inflammation without altering bacterial clearance. In summary, this study highlights the therapeutic potential of targeting the MEK1/2 pathway to combat MRSA pulmonary infections.IMPORTANCEStaphylococcus aureus infections pose a significant burden on global healthcare systems. Community-associated transmission of methicillin-resistant S. aureus (MRSA) and the increasing prevalence of other drug-resistant S. aureus isolates limit therapeutic options to combat this opportunistic pathogen. Infection-induced inflammation is a significant driver of tissue damage, especially in cystic fibrosis pulmonary infections. However, therapeutic strategies that can reduce inflammation without compromising host defense and bacterial clearance mechanisms are lacking. This study investigates the dual anti-inflammatory and antibacterial effects of a MEK1/2 inhibitor as a therapeutic strategy to target both host and pathogen with a single compound. This work also identifies host MEK2 as a specific target that can be modulated to reduce inflammation without impairing host defense against MRSA pulmonary infection. Results from this study can inform future human clinical trials to evaluate the ability of the MEK1/2 inhibitor compound ATR-002 to both combat S. aureus infections and reduce inflammation that accompanies these infections.

PMID:40422262 | DOI:10.1128/mbio.00775-25

IUBMB Life. 2025 May;77(5):e70027. doi: 10.1002/iub.70027.

ABSTRACT

Nonsense mutations in gene coding regions introduce an in-frame premature termination codon (PTC) in the mRNA transcript, resulting in the early termination of translation and the production of a truncated, nonfunctional protein. The absence of protein expression and the consequent loss of essential cellular functions are responsible for the severe phenotypes in the so-called genetic nonsense-related diseases (NRDs), such as cystic fibrosis, hemophilia, Duchenne muscular dystrophy, Fabry disease, Choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and even certain types of cancer. Nonsense mutations pose a significant challenge in the treatment of NRDs, as a specific approach directly addressing this genetic defect is currently unavailable. Developing new therapeutic strategies for nonsense suppression is a crucial goal of precision medicine. This review describes some of the most promising therapeutic approaches and emerging strategies for treating NRDs. It considered both the use of small molecules to interfere with molecular mechanisms related to nonsense mutations, such as translational readthrough-inducing drugs (TRIDs) or inhibitors of the nonsense-mediated decay (NMD) pathway, and also innovative approaches involving nucleic acids, such as gene editing, anticodon engineered-tRNA (ACE-tRNA), or mRNA-based therapy. Future research should focus on refining these approaches and exploring integrated and personalized treatments to enhance therapeutic outcomes and ensure continuous improvement in the quality of care.

PMID:40420818 | DOI:10.1002/iub.70027

Health Technol Assess. 2025 May;29(19):1-111. doi: 10.3310/CPLD8546.

ABSTRACT

BACKGROUND: Cystic fibrosis is a life-limiting genetic condition that affects over 9000 people in England. Cystic fibrosis is usually diagnosed through newborn screening and causes symptoms throughout the body, including the lungs and digestive system. Around 90% of individuals with cystic fibrosis have at least one copy of the F508del mutation on the cystic fibrosis transmembrane conductance regulator gene.

OBJECTIVES: To appraise the clinical effectiveness and cost-effectiveness of elexacaftor-tezacaftor-ivacaftor, tezacaftor-ivacaftor and lumacaftor-ivacaftor within their expected marketing authorisations for treating people with cystic fibrosis and at least one F508del mutation, compared with each other and with established clinical management before these treatments.

METHODS: A de novo systematic literature review (search date February 2023) was conducted searching electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), bibliographies of relevant systematic literature reviews, clinical trial registers, recent conferences and evidence provided by Vertex Pharmaceuticals (Boston, MA, USA). Data on the following outcomes were summarised: acute change in per cent predicted forced expiratory volume in 1 second (change in weight-for-age z-score; and change in pulmonary exacerbation frequency requiring intravenous antibiotics. Network meta-analyses were conducted where head-to-head data were not available. Data from clinical trials and real-world evidence were examined to assess long-term effectiveness. A patient-level simulation model was developed to assess the cost-effectiveness of the three modulator treatments. The model employed a lifetime horizon and was developed from the perspective of the National Health Service.

RESULTS: Data from 19 primary studies and 7 open-label extension studies were prioritised in the systematic literature review. Elexacaftor/tezacaftor/ivacaftor was associated with a statistically significant increase in predicted forced expiratory volume in 1 second and weight-for-age z-score and a reduction in pulmonary exacerbations compared with established clinical management, lumacaftor/ivacaftor and tezacaftor/ivacaftor, and also led to a reduction in the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management, although the magnitude of this decrease was uncertain. Lumacaftor/ivacaftor and tezacaftor/ivacaftor were also associated with a statistically significant increase in predicted forced expiratory volume in 1 second and reduction in pulmonary exacerbations relative to established clinical management, but with a smaller effect size than elexacaftor/tezacaftor/ivacaftor. There was some evidence that tezacaftor/ivacaftor reduced the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management, but little evidence that lumacaftor/ivacaftor reduced the rate of predicted forced expiratory volume in 1 second decline relative to established clinical management. The incremental cost-effectiveness ratios from the economic analysis were confidential. However, for all genotypes studied the incremental cost-effectiveness ratios were above what would be considered cost-effective based on the National Institute for Health and Care Excellence threshold of £20,000-30,000 per quality-adjusted life-year gained.

CONCLUSIONS: Despite the improved clinical benefits observed, none of the cystic fibrosis transmembrane conductance regulator gene modulators assessed would be considered cost-effective based on the National Institute for Health and Care Excellence threshold of £20,000-30,000 per quality-adjusted life-year gained. This is largely driven by the high acquisition costs of cystic fibrosis transmembrane conductance regulator gene modulator treatments.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42023399583.

FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135829) and is published in full in Health Technology Assessment; Vol. 29, No. 19. See the NIHR Funding and Awards website for further award information.

PMID:40418577 | DOI:10.3310/CPLD8546

Front Cell Infect Microbiol. 2025 May 9;15:1569331. doi: 10.3389/fcimb.2025.1569331. eCollection 2025.

ABSTRACT

INTRODUCTION: Chronic bacterial infections are responsible for significant morbidity and mortality in cystic fibrosis (CF) patients. Pseudomonas aeruginosa (Pa), the dominant CF pathogen, and Mycobacterium abscessus (Mab) can individually cause persistent, difficult to treat pulmonary infections. Co-infection by both pathogens leads to severe disease and poor clinical outcomes. Although interactions between Pa and other co-infecting pathogens in CF patients have been the focus of numerous studies, the dynamics of Pa-Mab interactions remain poorly understood.

METHODS: To address this knowledge gap, the study examined how Mab and Pa influenced each other through culture-based growth assays and molecular-based dual RNAseq analysis. Growth was measured by CFU determination and luminescence reporter -based readouts.

RESULTS: In initial studies, we noted that the growth of Pa continued unimpeded in a planktonic co-culture model, whereas Pa appeared to exert a bacteriostatic effect on Mab. Strikingly, exposure of Mab to cell-free spent supernatant of Pa resulted in a dramatic, dose-dependent bactericidal effect. Initial characterization indicated that this potent Pa-derived anti-Mab cidal activity was mediated by a heat-sensitive, protease-insensitive soluble factor of >3kDa size. Further analysis demonstrated that expression of this mycobactericidal factor requires LasR, a central regulator of Pa quorum sensing (QS). In contrast, ΔLasR Pa was still able to exert a bacteriostatic effect on Mab during co-culture, pointing to additional LasR-independent factors able to antagonize Mab growth. However, the ability of Mab to adapt during co-culture to counter the cidal effects of a LasR regulated factor suggested complex interspecies dynamics. Dual RNAseq analysis of Mab-Pa co-cultures revealed significant transcriptional remodeling of Mab, with differential expression of 68% of Mab genes compared to minimal transcriptional changes in Pa. Transcriptome analysis reflected slowed Mab growth and metabolic changes akin to a non-replicating persister phase. A tailored Mab response to Pa was evident by enhanced transcript levels of genes predicted to counteract alkylquinolone QS signals, respiratory toxins, and hydrogen cyanide.

DISCUSSION: The study showed Mab is capable of coexisting with Pa despite Pa's antagonistic effects, eliciting an adaptive molecular response in Mab. This study provides the first transcriptome-level insight into genetic interactions between the two CF pathogens offering potential strategies for disrupting their communities in a CF lung to improve patient clinical performance. Moreover, identification of a novel antimicrobial natural product with potent cidal activity against Mab could lead to new drug targets and therapies for Mab infections.

PMID:40415956 | PMC:PMC12098619 | DOI:10.3389/fcimb.2025.1569331