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

J Obstet Gynaecol Can. 2025 Mar 10:102811. doi: 10.1016/j.jogc.2025.102811. Online ahead of print.

ABSTRACT

COVID-19 outcomes are worse in non-pregnant patients that are cystic fibrosis carriers; however, no studies have examined COVID-19 outcomes in pregnant patients that are cystic fibrosis carriers. We evaluated the cystic fibrosis carrier status of pregnant patients with COVID-19 in three geographical regions in the United States and compared outcomes between non-carriers and carriers. Out of 2430 pregnant patients with COVID-19, 229 had a cystic fibrosis screen. Pregnant cystic fibrosis carriers were associated with 47.90 times greater odds of hospitalization with COVID-19 than non-carriers. A larger cohort will be needed to draw strong conclusions.

PMID:40074033 | DOI:10.1016/j.jogc.2025.102811

Am J Respir Crit Care Med. 2025 Mar 12. doi: 10.1164/rccm.202409-1824OC. Online ahead of print.

ABSTRACT

RATIONALE: Mycobacterium abscessus group bacteria (MABS) cause lethal infections in people with chronic lung diseases. Transmission mechanisms remain poorly understood; the detection of dominant circulating clones (DCCs) has suggested potential for person-to-person transmission.

OBJECTIVES: This study aimed to determine the role of drinking water in the transmission of MABS.

METHODS: A total of 289 isolates were cultured from respiratory samples (231) and drinking water sources (58) across Queensland, Australia.

MEASUREMENTS AND MAIN RESULTS: Whole genome sequences were analysed to identify DCCs and determine relatedness. Half of the isolates (144, 49·8%) clustered with previously described DCCs, of which 30 formed a clade within DCC5. Pangenomic analysis of the water-associated DCC5 clade revealed an enrichment of genes associated with copper resistance. Four instances of plausible epidemiological links were identified between genomically-related clinical and water isolates.

CONCLUSIONS: We provide evidence that drinking water is a reservoir for MABS and may be a vector in the chain of MABS infection.

PMID:40072241 | DOI:10.1164/rccm.202409-1824OC

Pediatr Pulmonol. 2025 Mar;60(3):e71044. doi: 10.1002/ppul.71044.

ABSTRACT

BACKGROUND: People with cystic fibrosis (pwCF) often have multifactorial peripheral muscle abnormalities attributed to, for example, malnutrition, steroid use, altered redox balance and, potentially, CF-specific intrinsic alterations. Malnutrition in CF now includes an increasing prevalence of overweight and obesity, particularly in those receiving CF transmembrane conductance regulator (CFTR) modulator therapy (CFTRm). We aimed to characterise peripheral muscle function and body composition in pwCF on Elexacaftor/Tezacaftor/Ivacaftor (ETI) CFTRm, compared to healthy controls.

METHODS: Fifteen pwCF on ETI, and 15 healthy age- and sex-matched controls (CON), underwent whole-body dual-energy X-ray absorptiometry scans, and a comprehensive evaluation of peripheral muscle function. Tests included quadriceps maximal isometric force measurement, an intermittent isometric quadriceps fatiguing protocol, handgrip strength dynamometry, squat jump height assessment, and 1-min sit-to-stand testing.

RESULTS: No significant differences in quadriceps maximal isometric force (CON: 181.60 ± 92.90 Nm vs. CF: 146.15 ± 52.48 Nm, p = 0.21, d = 0.47), handgrip strength (CON: 34 ± 15 kg vs. CF: 31 ± 11 kg, p = 0.62, d = 0.18), peripheral muscle endurance, fatigue, or power were observed between the groups. Moreover, no significant differences in whole-body, trunk or limb lean mass, fat-free mass, fat mass, or whole-body bone mineral density were evident.

CONCLUSION: Comparable peripheral muscle mass and function has been demonstrated in pwCF on ETI, albeit a group with good lung function. Research is needed to confirm these findings longitudinally in pwCF, including those with more severe lung disease, who are less physically active, and have less optimal nutrition and exercise support.

PMID:40071679 | DOI:10.1002/ppul.71044

Pediatr Pulmonol. 2025 Mar;60(3):e71042. doi: 10.1002/ppul.71042.

ABSTRACT

BACKGROUND: Genetic modifiers have been identified that increase the risks of lung disease and other complications, such as diabetes in people with cystic fibrosis (CF). Variants in the hemochromatosis gene (HFE) were reported in a study of adults to be associated with worse lung disease.

OBJECTIVES: To ascertain the frequency of HFE variants, particularly C282Y (c.845G > A) and H63D (c.187C > G) and to determine if they are associated with variations in the onset and early severity of CF lung disease as well as abnormalities in iron status.

DESIGN: We studied with whole genome sequencing and clinical outcome measures in a cohort of 104 children with CF at 5-6 years old who were previously found to show an association between aggregated genetic modifiers and an earlier onset and a more severe lung disease phenotype.

RESULTS: In our cohort, 23% have H63D and 11% have C282Y. Lung function at age 6 years and Pseudomonas aeruginosa infections did not differ by HFE variants, but having C282Y was associated with more pulmonary exacerbations in the first 6 years of life. Three patients have H63D/C282Y genotype, and all showed phenotypic expression of hemochromatosis with abnormal iron indices.

CONCLUSION: Our study revealed that the presence of HFE variant C282Y in people with CF may lead to more severe lung disease manifestations beginning in early childhood. There is a risk of hemochromatosis in CF patients with two HFE variants, and thus they should be followed for evidence of iron overload.

PMID:40071665 | DOI:10.1002/ppul.71042

Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666251323181. doi: 10.1177/17534666251323181. Epub 2025 Mar 12.

ABSTRACT

Nontuberculous mycobacteria (NTM) are ubiquitous, opportunistic pathogens that can cause lung disease in people with non-cystic fibrosis bronchiectasis (NCFB) and cystic fibrosis (CF). The incidence of NTM pulmonary infections and lung disease has continued to increase worldwide over the last decade among both groups. Notably, women with NCFB NTM pulmonary disease (NTM-PD) bear a disproportionate burden with NTM rates increasing in this population as well as having consistently higher incidence of NTM-PD compared to men. In contrast, among people with CF, an overall increased risk among women has not been observed. In the United States, the majority of people with CF are taking highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators, and these numbers are increasing worldwide. The long-term impact of CFTR modulator medications on NTM infections is not entirely understood. Guidelines for the screening, diagnosis, and management of NTM-PD exist for people with NCFB and CF, but do not consider unique implications relevant to women. This review highlights aspects of NTM-PD among women with NCFB and CF, including the epidemiology of NTM infection, special considerations for treatment, and unmet research needs relevant to women with NTM-PD.

PMID:40071337 | DOI:10.1177/17534666251323181

Ital J Pediatr. 2025 Mar 11;51(1):71. doi: 10.1186/s13052-025-01918-8.

ABSTRACT

INTRODUCTION: Children with congenital lung disease (CLD) may suffer from long-term complications, such as impairments in lung growth, decreased total lung volume, recurrent lower respiratory tract infections and, in some cases, malignant transformation.

OBJECTIVE AND METHODS: we described retrospective data on diagnostic process, clinical and functional data regarding a cohort of symptomatic and asymptomatic children with CLD followed in a single third level center in the last twenty years.

RESULTS: 91 children were included in the study. Five classes of disease were examined. Bronchial tree and pulmonary abnormalities represent the most common anomalies. Despite the improved resolution of prenatal diagnosis, most of patients underwent chest CT scan to confirm the initial diagnostic suspicion. The most reported symptoms were wheezing, recurrent respiratory infections and acute respiratory failure. According to malformation type, patients underwent to surgery, endoscopic and/or medical treatment. Improvement of symptoms occurred faster in patients surgically and endoscopically treated. No statistical difference in the number of exacerbations before and after treatment was recorded, as well as no differences in spirometry values were observed among surgically and non-surgically treated children. No malignant transformation was observed in two patients with intra-lobar sequestration and hybrid lesion during the follow up period.

CONCLUSION: the clinical presentation of congenital airway and lung disorders varies significantly depending on the type of malformation, making it challenging to standardize treatment strategies and follow-up programs. Based on our experience, prompt surgical or endoscopic intervention in early symptomatic children leads to faster symptom improvement and normal lung function in the follow-up period. However, further prospective studies are needed to better define optimal treatment strategies for these rare conditions, particularly for asymptomatic patients, for whom management approaches remain poorly established.

PMID:40069796 | DOI:10.1186/s13052-025-01918-8

Orphanet J Rare Dis. 2025 Mar 11;20(1):117. doi: 10.1186/s13023-025-03618-2.

ABSTRACT

BACKGROUND: The current development of gynecology services for children and adolescents seeks to meet needs both in the overall population and in patients with rare diseases. In France, the referral center for rare gynecological diseases specializes in four major types of conditions, namely, uterovaginal malformations, hereditary hemorrhagic diseases, rare benign breast diseases, and gynecological repercussions of rare chronic diseases.

OBJECTIVE: To describe consecutive patients who had a first visit in 2018-2023 at the referral center for rare gynecological diseases at the Necker Pediatric University Hospital in Paris, France, and who were diagnosed with a condition in any of the four categories listed above.

MATERIAL AND METHODS: For this single-center retrospective observational cohort study, data from the referral-center database were collected and reviewed. These data included year of birth, age at and reason for first gynecology visit, and rare chronic disease and referring rare-disease center for patients seen for gynecological repercussions of rare chronic diseases.

RESULTS: The 704 included patients had a median age of 15.2 years (interquartile range 3.8) at the first visit. Among them, 100 (14.2%) had uterovaginal malformations, 32 (4.6%) hereditary hemorrhagic diseases, 17 (2.4%) rare benign breast diseases, and 555 (78.8%) gynecological repercussions of rare chronic diseases. The leading reasons for the visit were dysmenorrhea (15.6%), menorrhagia (15.5%), uterovaginal malformations (15.2%), and irregular periods (14.9%).

CONCLUSION: Repercussions of rare chronic diseases managed at rare-disease referral centers were by far the leading reason for seeking gynecological expertise in rare diseases. In this complex situation, the underlying disease and its treatments interact with the gynecological manifestations and their treatment, requiring close collaboration among all specialists caring for each patient.

PMID:40069734 | DOI:10.1186/s13023-025-03618-2

J Cyst Fibros. 2025 Mar 10:S1569-1993(25)00065-7. doi: 10.1016/j.jcf.2025.02.015. Online ahead of print.

ABSTRACT

INTRODUCTION: Functional magnetic resonance imaging (MRI) of the lung usually assesses lung impairment as ventilation defect percentage (VDP). However, VDP only reflects the overall burden of disease and does not characterize the regional distribution (i.e. pattern) of defects. The defect distribution index (DDI) is a metric which shows quantitatively how clustered versus scattered defects are with a higher DDI indicating more clustered defects.

AIM: To assess the applicability and validity of the DDI to 129Xe-MRI and PREFUL-MRI of CF lung disease.

METHODS: The DDI algorithm was applied to fractional ventilation maps previously acquired with 129Xe-MRI and PREFUL-MRI of 37 children with CF and 13 healthy controls.

RESULTS: The calculation of DDI was feasible for all MRI data. DDI was significantly higher in patients with CF compared to healthy controls (mean difference [95 % CI] 129Xe-MRI DDI60 %mean -1.94 [-2.86 - -1.02], p=0.0001), strongly correlated with other functional outcomes such as VDP and the lung clearance index, and decreased significantly in CF patients with pulmonary exacerbations after antibiotic treatment (e.g. 129Xe-MRI DDI60 % mean -1.03 [-0.44 - -1.63], p=0.002).

CONCLUSION: The DDI is applicable to functional 129Xe-MRI and PREFUL-MRI data providing complementary information to VDP by assessing defect distribution rather than defect size. It shows meaningful clinimetric properties and improves with treatment. The DDI shows potential as a parameter for comprehensive monitoring of CF lung disease and treatment.

PMID:40069051 | DOI:10.1016/j.jcf.2025.02.015

J Cyst Fibros. 2025 Mar 10:S1569-1993(25)00061-X. doi: 10.1016/j.jcf.2025.02.013. Online ahead of print.

ABSTRACT

BACKGROUND: Recent studies revealed that some people with cystic fibrosis (pwCF) receiving the full dose of Elexacaftor/Tezacaftor/Ivacaftor (ETI) experience adverse events (AEs), leading to discontinuation or dose adjustments of their modulator treatment. We aimed to investigate if pwCF who experienced AEs had high exposure to ETI, and to what extent dose reduction resulted in changes in exposure, side effects and efficacy.

METHOD: This retrospective case series presents ETI exposure in pwCF who required ETI dose reduction due to AEs. ETI exposure was measured by minimal concentration (Cmin) levels, while sweat chloride concentration (SCC) was used to assess efficacy. AEs were graded using the common terminology criteria for AEs. Ten pwCF who experienced AEs during ETI treatment were included in the study.

RESULTS: The mean Cmin levels at the full ETI dose were 10.1 mg/L for elexacaftor, 4.2 mg/L for tezacaftor, and 1.2 mg/L for ivacaftor. These values exceed the mean Cmin values from the registration studies, which are 5.5 mg/L for elexacaftor, 2.1 mg/L for tezacaftor, and 0.8 mg/L for ivacaftor. The most frequently reported AEs were psychiatric and nervous system disorders. In all ten pwCF, an improvement of AEs was noted after dose reduction. The mean SCC measured on the full ETI dose was 38 mmol/L. Post dose reduction, the mean SCC was 44 mmol/L.

CONCLUSION: This study suggest that AEs of ETI in most cases could be related to elevated exposure levels. Dose reduction decreases ETI exposure and AEs while maintaining efficacy as determined with sweat chloride levels.

PMID:40069050 | DOI:10.1016/j.jcf.2025.02.013

Neonatal Netw. 2025 Mar 1;44(1):20-32. doi: 10.1891/NN-2024-0033.

ABSTRACT

Meconium ileus (MI) is the result of the accumulation of thick, dry, inspissated meconium that creates a bowel blockage, most commonly in the terminal ileum. These pockets of meconium prevent passage of stool beyond the point of obstruction, which leads to distention of the proximal bowel, bowel wall thickening, and distal microcolon. Occurring most commonly (90%) in conjunction with cystic fibrosis (CF), the occurrence of MI without CF is rare. The literature describes the incidence of MI associated with CF occurring in as many as 24.9% of those who have a pair (homozygous) of the most common CF gene mutation, Delta F508. The incidence of MI decreases with other CF mutations, of which there are over 2,000. The morbidity and mortality risks are related to whether the MI is simple or complex. Simple MI can be managed clinically with contrast enemas to relieve the obstruction and restore bowel function, while complex MI requires surgical intervention for possible bowel necrosis, perforation, peritonitis, strictures, and/or volvulus that can occur in utero or after birth. This article presents a case report of a 32-week-gestation female infant with gross abdominal distention beginning on day of life 1. The differential diagnosis, necessary testing, and required treatment that led to the final diagnosis will be presented. Additionally, radiographic modalities used to confirm the diagnosis are discussed. Finally, nursing management of the infant with simple or complex MI and short- and long-term challenges for infants and their families will be addressed.

PMID:40068907 | DOI:10.1891/NN-2024-0033

Cancer Cell. 2025 Mar 10;43(3):361-379.e10. doi: 10.1016/j.ccell.2025.02.010.

ABSTRACT

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.

PMID:40068595 | DOI:10.1016/j.ccell.2025.02.010

Pediatr Pulmonol. 2025 Mar;60(3):e71038. doi: 10.1002/ppul.71038.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a multisystem disease characterized by persistent lung infection. Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) improves respiratory-related quality of life and reduces rates of infection and antibiotic treatments. Reduced antibiotic use may alter bacterial drug resistance patterns.

METHODS: This was a single center, retrospective, observational study analyzing respiratory cultures obtained from people with CF (pwCF) before and after starting ETI therapy. Antibiotic courses and culture data, including susceptibilities, were obtained from the electronic medical record.

RESULTS: There were 312 pwCF on ETI included, with an average age at ETI initiation of 20.9 ± 12.0 years and an average length of time on ETI 2.48 ± 0.69 years. Compared to the pre-ETI period, pwCF post-ETI had reductions in the number of antibiotic courses per year (2.5 to 0.7, p < 0.001), antibiotics utilized per course (1.4 to 1.0, p < 0.001), and percentage of courses including intravenous antibiotics (59% to 38%, p < 0.001). The fraction of pwCF with at least one culture positive for Pseudomonas aeruginosa, Burkholderia species, or Stenotrophomonas maltophilia decreased after ETI initiation, though changes were not significant for Staphylococcus aureus. Antibacterial resistance patterns were similar for most antibiotics in pre- and post-ETI periods, with P. aeruginosa exhibiting more resistance to fluoroquinolones post-ETI. Individuals with resistant organisms pre-ETI were less likely to clear the pathogen post-ETI.

CONCLUSION: Treatment with ETI significantly decreased antibiotic utilization and the prevalence of gram-negative organisms. Although fewer antibiotics were used, antibiotic resistance remained unchanged or even increased post-ETI due largely to the greater persistence of resistant organisms.

PMID:40067072 | DOI:10.1002/ppul.71038

Front Pharmacol. 2025 Feb 24;16:1537095. doi: 10.3389/fphar.2025.1537095. eCollection 2025.

ABSTRACT

OBJECTIVE: Intestinal current measurement (ICM) provides a sensitive bioassay for assessment of cystic fibrosis transmembrane conductance regulator (CFTR) function in rectal biopsies ex vivo and is used as a diagnostic tool for cystic fibrosis (CF). Furthermore, ICM was shown to be sensitive to detect pharmacological rescue of CFTR function by CFTR modulators in people with CF carrying responsive CFTR mutations. Results from clinical trials of CFTR modulators across age groups indicate that CFTR function in the sweat duct may be age-dependent with children reaching higher levels than adults. However, little is known about age dependency of CFTR function in the intestinal epithelium.

METHODS: We investigated CFTR-mediated chloride secretion in rectal biopsies from 258 people without CF and 72 people with pancreatic-insufficient CF from 1 month to 68 years of age. Change in transepithelial short-circuit current in response to cyclic adenosine monophosphate (cAMP)-mediated (100 μM IBMX, 1 µM forskolin, basolateral) and cholinergic (100 μM carbachol, basolateral) stimulation was assessed as a readout for CFTR function using perfused micro-Ussing chambers. Furthermore, quantitative real-time PCR of CFTR and morphometric analysis of epithelial cells lining the crypts and surface of the rectal mucosa were performed to assess regulation at the levels of gene expression and epithelial cell densities.

RESULTS: We found that CFTR-mediated chloride secretion across rectal tissues, as determined from cAMP-mediated as well as cholinergic chloride-secretory responses was highest during infancy and early childhood and declined with age in people without CF (both P < 0.001). Although, there was no difference in cAMP-mediated currents in people with CF, potassium-secretory responses induced by cholinergic stimulation were also reduced with increasing age. Transcript analyses showed that CFTR mRNA expression was slightly increased with increasing age in people without CF (P < 0.05). Morphometric analyses demonstrated that CFTR expressing colonocytes at the crypt base were decreased with age (P < 0.05). A secondary analysis of the ICM data of our previous studies on the effects of lumacaftor/ivacaftor on CFTR function in F508del -homozygous people with CF aged 12 years and older and 2-11 year old children showed correlations of the change in cAMP-mediated and cholinergic chloride secretory response with the age of people with CF (P < 0.01 and P < 0.05, respectively).

CONCLUSION: These results demonstrate that CFTR function in the rectal epithelium is reduced with increasing age and indicate that this change is likely due to a decline in the number of secretory colonocytes at the crypt base. These findings suggest that differences in CFTR expressing cells may explain increased functional responses to CFTR modulator therapies in children compared to adult people with CF.

PMID:40066329 | PMC:PMC11891205 | DOI:10.3389/fphar.2025.1537095