Quant Imaging Med Surg. 2025 May 1;15(5):4431-4444. doi: 10.21037/qims-24-2205. Epub 2025 Apr 28.

ABSTRACT

BACKGROUND: Pulmonary magnetic resonance imaging (MRI) has the advantage of nonionizing radiation and multiparameter imaging of structure and function, facilitating its clinical use in a variety of pulmonary diseases. This study aimed to identify the research trends and emerging topics in pulmonary MRI by conducting a comprehensive bibliometric analysis of the field over the past decade.

METHODS: A search of the Web of Science Core Collection database was conducted with the words "lung" and "MRI" for literature published from 2014 to 2023. The data were further analyzed with R and CiteSpace software in terms of annual publications and citations, collaborative networks (countries, institutions, and authors), source's local impact, keyword clustering, and burst analysis.

RESULTS: A total of 1,839 publications related to pulmonary MRI have been published over the last decade, with a relatively slow growth trend. The top three journals in terms of total publications and citations were Magnetic Resonance in Medicine, Journal of Magnetic Resonance Imaging, and Radiology. The most productive country was the United States, and the countries with the strongest collaborative links were the United States and the United Kingdom. The most productive institutions and authors were Ruprecht Karls University Heidelberg (articles, n=309) and Wild JM (articles, n=86), respectively. Keyword cluster analysis identified five clusters: "lung cancer", "magnetic resonance imaging", "lung MRI", "cystic fibrosis", and "congenital diaphragmatic hernia". Keyword burst analysis showed that the keywords with the highest burst intensity in the first 5 years and the last 5 years were "mice" and "standardization", respectively.

CONCLUSIONS: Over the past decade, research trends in pulmonary MRI have focused on lung cancer and cystic fibrosis as the dominant clinical diseases. Research has been centered on standardizing pulmonary MRI to promote its clinical application.

PMID:40384665 | PMC:PMC12082580 | DOI:10.21037/qims-24-2205

J Cyst Fibros. 2025 May 16:S1569-1993(25)00771-4. doi: 10.1016/j.jcf.2025.04.005. Online ahead of print.

ABSTRACT

BACKGROUND: Advanced cystic fibrosis (CF) liver disease can necessitate liver transplantation. This study aims to investigate characteristics, waiting list dynamics, and waiting list mortality of people with CF (pwCF) registered for liver transplantation within Eurotransplant countries, to understand and improve transplant outcomes for this group.

METHODS: We analysed Eurotransplant liver transplantation registration data (January 2007-December 2022), comparing pwCF to people with no CF (pwnoCF) and non-CF age/liver disease severity score (Lab-MELD) matched controls, with subgroup comparisons between pwCF receiving isolated liver transplantation (LiverTx) and combined liver-lung transplantation (Liver+LungTx).

RESULTS: 215 out of 38,125 liver transplantation registrations were for pwCF. 65.1 % of the pwCF were listed for LiverTx and 34.9 % for Liver+LungTx. At registration, pwCF were younger (17.9 ± 0.8 vs. 55.0 ± 0.1; P < 0.05) and had lower Lab-MELD scores (10.0 ± 0.4 vs. 15.0 ± 0.0; P < 0.05) compared to pwnoCF. PwCF listed for LiverTx were younger (15.1 ± 0.9 vs. 26.0 ± 1.1; P < 0.05) and had higher Lab-MELD scores at transplantation (12.0 ± 1.0 vs. 9.0 ± 0.5; P < 0.05) compared to Liver+LungTx. PwCF had a higher 2-year waiting list mortality than non-CF matched controls (14.9 % vs. 0.0 %; P < 0.05). Within pwCF, mortality was higher for pwCF listed for Liver+LungTx than for LiverTx (30.7 % vs. 6.4 %; P < 0.05).

CONCLUSIONS: CF represents a distinct indication for liver transplantation, with increased varying waiting list mortality risks across the different CF-groups, not adequately captured by standard liver disease severity scores. PwCF considered for liver transplantation require close monitoring as their disease severity and mortality risk are not well represented in the current allocation algorithm, necessitating adaptations to the organ allocation rules.

PMID:40382307 | DOI:10.1016/j.jcf.2025.04.005

J Cyst Fibros. 2025 May 16:S1569-1993(25)01468-7. doi: 10.1016/j.jcf.2025.05.001. Online ahead of print.

ABSTRACT

Airway clearance to clear excessive sputum has long been a key part of cystic fibrosis care, however the introduction of highly effective modulator medications where many people with CF are experiencing reduced sputum loads, has raised a question about its necessity. Specifically, questions are being asked as to if exercise, historically an adjunct to airway clearance, could become a replacement. This short communication summarizes a debate that was held at the 2024 North American Cystic Fibrosis Conference, summarizing the key arguments for and against the replacement of traditional airway clearance with exercise.

PMID:40382306 | DOI:10.1016/j.jcf.2025.05.001

Drug Discov Today. 2025 May 15:104380. doi: 10.1016/j.drudis.2025.104380. Online ahead of print.

ABSTRACT

Inhaled antibiotics significantly impact respiratory-disorder management through targeted delivery with reduced systemic side effects. Advances in pharmaceutical formulations, particularly lipid-based nanomedicine, help improve biopharmaceutical performance and therapeutic efficacy. In addition, advancements in inhaler technologies ensure effective lung deposition and minimize systemic exposure. These innovations have further benefited chronic respiratory diseases like cystic fibrosis and COPD, where infections are frequent. For instance, the encapsulation of inhaled antibiotics, particularly the tobramycin liposomal system, has improved efficacy and reduced toxicity, whereas the nebulized colistin nanoformulation effectively targets multidrug-resistant pathogens, including the clinical efficacy of amikacin liposome inhalation in refractory pulmonary infections. Overall, advancements in lipid-based nanoformulation and delivery technologies have significantly enhanced the utility of inhaled antibiotics, providing safer and more-effective options for managing chronic and resistant infections.

PMID:40381726 | DOI:10.1016/j.drudis.2025.104380

Inflammopharmacology. 2025 May 17. doi: 10.1007/s10787-025-01771-5. Online ahead of print.

ABSTRACT

Respirable silica exposure adversely affects lung tissue immunopathology, triggering oxidative bursts in macrophages and neutrophils, releasing Damage-associated molecular patterns (DAMPs), including calprotectin proteins, S100A8, and S100A9. Calprotectin constitutes up to 45% of these innate immune cells, and serum levels of these alarmins correlate with inflammation, fibrosis, remodelling, and drug response in chronic diseases, including inflammatory bowel disease, asthma, and cystic fibrosis. The consequence of releasing calprotectin protein could trigger the pro-fibrotic effect of silicosis. This study aimed to investigate the role of calprotectin (S100A8/S100A9) as a pro-inflammatory and pro-fibrotic mediator in silica-induced lung fibrosis and evaluated the therapeutic potential of the calprotectin inhibitor, paquinimod. Using a mouse model of silicosis, silica exposure significantly elevated calprotectin expression, lung inflammation, and fibrosis, as evidenced by increased levels of epithelial-to-mesenchymal transition (EMT) markers, collagen deposition, and matrix metalloproteinases (MMPs). In vitro, stimulation of human bronchial fibroblasts with S100A8/S100A9 upregulated fibrotic markers (COL1A1 and α-SMA), which were reduced by inhibitors of TLR4 and RAGE receptors, as well as by paquinimod. Treatment with paquinimod effectively reduced these pathological changes, normalized calprotectin levels, decreased fibrosis scores, and attenuated NF-κB activation. These findings highlighted calprotectin's pivotal role in silica-induced lung fibrosis and inflammation, suggesting that its inhibition could be a promising therapeutic approach for silicosis and other fibro-inflammatory lung diseases. Further research is warranted to explore the precise mechanisms linking calprotectin to lung fibrosis and its potential as a biomarker and therapeutic target.

PMID:40381145 | DOI:10.1007/s10787-025-01771-5

Stem Cell Rev Rep. 2025 May 17. doi: 10.1007/s12015-025-10893-w. Online ahead of print.

ABSTRACT

The advent of intestinal organoids, three-dimensional structures derived from stem cells, has significantly advanced the field of biology by providing robust in vitro models that closely mimic the architecture and functionality of the human intestine. These organoids, generated from induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), or adult stem cells, possess remarkable capabilities for self-renewal, differentiation into diverse intestinal cell types, and functional recapitulation of physiological processes, including nutrient absorption, epithelial barrier integrity, and host-microbe interactions. The utility of intestinal organoids has been extensively demonstrated in disease modeling, drug screening, and personalized medicine. Notable examples include iPSC-derived organoids, which have been effectively employed to model enteric infections, and ESC-derived organoids, which have provided critical insights into fetal intestinal development. Patient-derived organoids have emerged as powerful tools for investigating personalized therapeutics and regenerative interventions for conditions such as inflammatory bowel disease (IBD), cystic fibrosis, and colorectal cancer. Preclinical studies involving transplantation of human intestinal organoids into murine models have shown promising outcomes, including functional integration, epithelial restoration, and immune system interactions. Despite these advancements, several challenges persist, particularly in achieving reproducibility, scalability, and maturation of organoids, which hinder their widespread clinical translation. Addressing these limitations requires the establishment of standardized protocols for organoid generation, culture, storage, and analysis to ensure reproducibility and comparability of findings across studies. Nevertheless, intestinal organoids hold immense promise for transforming our understanding of gastrointestinal pathophysiology, enhancing drug development pipelines, and advancing personalized medicine. By bridging the gap between preclinical research and clinical applications, these organoids represent a paradigm shift in the exploration of novel therapeutic strategies and the investigation of gut-associated diseases.

PMID:40380985 | DOI:10.1007/s12015-025-10893-w

AAPS PharmSciTech. 2025 May 16;26(5):135. doi: 10.1208/s12249-025-03131-6.

ABSTRACT

Cystic fibrosis is a serious life-threatening hereditary disease that occurs due to a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Ivacaftor (IVA) is a drug that targets the mutated CFTR protein. IVA is highly hydrophobic (log P = 5.6) with poor aqueous solubility (0.05 µg/mL) and is formulated as an amorphous solid dispersion tablet under the brand name Kalydeco®. The recommended daily dose of Kalydeco® is twice per day with a high fat meal to aid in IVA's absorption. In this research, we studied the application of cyclodextrins (CDs) to improve the dissolution of IVA. Phase solubility studies between IVA and four different CDs (α-, β-, γ-, and hydroxypropyl-β-CD [HP-β-CD]) were conducted and a significant improvement in IVA's aqueous solubility with HP-β-CD was observed. Solid state characterizations confirmed the formation of IVA/HP-β-CD inclusion complexes. In vitro dissolution studies were conducted at pH = 6.8 and showed improvement in IVA's rate and extent of dissolution with IVA/HP-β-CD (1:2) complexes in comparison to uncomplexed IVA. In vivo pharmacokinetics in mice showed a 2-fold increase in area under the curve (AUC) after the oral administration of the IVA/HP-β-CD complex in comparison to Kalydeco tablets. In addition, HP-β-CD extended the release of IVA from the IVA/HP-β-CD complexes with a longer Tmax of 7.05 h compared to 2.96 h with Kalydeco® tablets. These results demonstrate that CD inclusion complexes of IVA using HP-β-CD can be a successful alternative approach to improving the solubility of IVA while extending its release.

PMID:40379997 | DOI:10.1208/s12249-025-03131-6

J Cyst Fibros. 2025 May 15:S1569-1993(25)01467-5. doi: 10.1016/j.jcf.2025.04.012. Online ahead of print.

ABSTRACT

BACKGROUND: The cystic fibrosis (CF) transmembrane conductance regulator modulator (CFTRm) elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has demonstrated efficacy and safety in clinical trials and emerging observational studies in people with CF. This study evaluated the real-world impact of ELX/TEZ/IVA in a large cohort of people with CF in the UK.

METHODS: LONGITUDE is an observational, registry-based cohort study using data from the UK CF Registry to evaluate outcomes of ELX/TEZ/IVA in people aged ≥6 years who initiated ELX/TEZ/IVA from August 2019. Key outcomes included percent predicted forced expiratory volume in 1 s (ppFEV1), body mass index (BMI), pulmonary exacerbations (PEx), lung infections, transplants, deaths, and treatment discontinuation. We report results of people ≥12 years with data up to December 31, 2022.

RESULTS: A total of 5187 people were included (mean follow-up 19.1 months). ppFEV1 improvements were observed at 2 years (10.2; 95 % CI: 9.6, 10.8; n = 1448). A clinically meaningful difference in the annual change of ppFEV1 between ELX/TEZ/IVA-treated people and historical CFTRm-naïve controls was observed, with those treated with ELX/TEZ/IVA having less of a decline in lung function over time by 1.1 percentage points (95 % CI: 0.9, 1.4). A 64.7 % reduction in the rate of PEx, increase in BMI by 1.7 kg/m2 (SD: 2.3), reduced lung infections, and low number of lung transplants and deaths were also observed.

CONCLUSIONS: People with CF aged ≥12 years in the UK who initiated ELX/TEZ/IVA had sustained improvements in multiple CF-related health outcomes, consistent with results from clinical trials. These results support the positive impact of ELX/TEZ/IVA on the lives of people with CF.

PMID:40379539 | DOI:10.1016/j.jcf.2025.04.012

An Pediatr (Engl Ed). 2025 May 15:503836. doi: 10.1016/j.anpede.2025.503836. Online ahead of print.

ABSTRACT

INTRODUCTION: Treatments with CFTR protein modulators have improved respiratory and digestive health in patients with cystic fibrosis.

OBJECTIVE: To assess changes in intestinal inflammation through the analysis of fecal calprotectin in patients with cystic fibrosis during treatment with CFTR modulators.

MATERIAL AND METHODS: Prospective multicenter study of changes in fecal calprotectin in patients with cystic fibrosis treated with CFTR modulators, comparing double combinations (lumacaftor/ivacaftor or tezacaftor/ivacaftor) and triple combinations (elexacaftor/tezacaftor/ivacaftor). We collected aata before treatment initiation and at 6 and 12 months.

RESULTS: Analysis of 117 patients (69% with F508del/F508del). The median baseline fecal calprotectin level was 49 µg/g (IQR, 23-108); 48.7% had median levels greater than 50 µg/g and 11% levels greater than 250 µg/g. Fecal calprotectin decreased in both groups, with a greater decrease in patients treated with elexacaftor/tezacaftor/ivacaftor. We found a progressive decrease in abnormal values (>50 µg/g) at 6 months (48.7% vs 33.1%; P = .0067) and at 12 months (54% vs 33.5%; P = .0218). In the elexacaftor/tezacaftor/ivacaftor group, only two patients at 6 months and one patient at 12 months had levels greater than 250 µg/g. The estimated change at 12 months in the triple therapy group compared to the other group was -133 µg/g (95% CI, -254 to -13; P = .030); and, adjusting for sex, probiotics and Pseudomonas aeruginosa, -130 µg/g (-259 to -1; P = .049).

CONCLUSIONS: Treatment with CFTR modulators reduces intestinal inflammation in patients with cystic fibrosis, with a greater decrease in patients treated with triple therapy.

PMID:40379512 | DOI:10.1016/j.anpede.2025.503836

Lancet Child Adolesc Health. 2025 Jun;9(6):371-382. doi: 10.1016/S2352-4642(25)00099-9.

ABSTRACT

BACKGROUND: People with cystic fibrosis can have impaired insulin secretion and hyperglycaemia before meeting the diagnostic criteria for cystic fibrosis-related diabetes during an oral glucose tolerance test (OGTT). Insulin therapy given to such patients was associated with improved weight and lung function in several small, uncontrolled trials but might increase treatment burden and cause hypoglycaemia. We aimed to assess whether insulin treatment improves weight and lung function when given to patients with cystic fibrosis with early glycaemic abnormality.

METHODS: CF-IDEA was a multicentre, randomised controlled trial conducted at five children's hospitals in Australia and one in the USA. Eligible participants were children with cystic fibrosis aged 5-18 years without cystic fibrosis-related diabetes and with peak glucose concentration on a five-point OGTT of 8·2-11·0 mmol/L (cystic fibrosis insulin deficiency stage 1) or ≥11·1 mmol/L (cystic fibrosis insulin deficiency stage 2). Participants were randomly assigned (1:1) to insulin or observation. Randomisation was done using the biased coin method, followed by minimisation when the study groups became imbalanced by chance. Randomisation was stratified by glycaemic category (cystic fibrosis insulin deficiency stage 1 or 2), weight Z score (more than or equal to -0·61 or less than -0·61), and study centre. Participants in the insulin group received once-daily, long-acting insulin detemir by subcutaneous injection before breakfast, commencing at 0·1 units per kg per day, adjusted in 0·5-unit increments to achieve all fingerstick blood glucose concentrations between 4 mmol/L and 8 mmol/L. The primary outcomes were absolute changes in weight Z score, percentage predicted forced expiratory volume in 1 s (ppFEV1), and percentage predicted forced vital capacity (ppFVC), derived with generalised estimating equations and presented with two-sided 95% CIs. Severe hypoglycaemic events (defined as requiring outside assistance or causing reduced level of consciousness or seizure), insulin-related adverse events, and continuous glucose monitoring (CGM) percentage time with blood glucose below 3·9 mmol/L were recorded as safety outcomes. This study is registered with ClinicalTrials.gov, NCT01100892, and is completed.

FINDINGS: Between Dec 6, 2010, and Feb 25, 2022, 109 participants were randomly assigned to observation (n=54) or insulin (n=55). Five participants withdrew after the baseline visit, and the analysis therefore included 104 participants (53 observation and 51 insulin); 95 participants completed the 12-month protocol and nine completed only 6 months. Baseline characteristics were similar between the groups; however, the observation group included 30 (57%) boys and 23 (43%) girls, whereas the insulin group included 23 (45%) boys and 28 (55%) girls. The median daily insulin dose at 12 months was 0·12 units per kg per day (range 0·05-0·41). There were no statistically or clinically significant differences between the observation and insulin groups in change in weight Z score (difference insulin minus observation 0·07 [95% CI -0·04 to 0·18]; p=0·20), change in ppFEV1 (1·2 [-2·2 to 4·7]; p=0·48), or change in ppFVC (0·6 [-2·6 to 3·8]; p=0·72). Similarly, there were no significant differences in subgroup analyses by cystic fibrosis insulin deficiency stages 1 and 2. There were no episodes of severe hypoglycaemia or insulin-related adverse events, and we found no evidence of difference between the observation and insulin groups in CGM percentage time less than 3·9 mmol/L.

INTERPRETATION: Insulin treatment did not improve weight or lung function when given to children and adolescents with cystic fibrosis and early glycaemic abnormalities. Insulin treatment should not be given to those who do not meet OGTT criteria for cystic fibrosis-related diabetes.

FUNDING: National Health and Medical Research Council of Australia, Australian Cystic Fibrosis Research Trust, Pfizer Australasian Paediatric Endocrine Care Research Grant, Novo Nordisk Regional Diabetes Support Scheme, Sydney Children's Hospital Foundation.

PMID:40379429 | DOI:10.1016/S2352-4642(25)00099-9

Pharmacol Res. 2025 May 14:107775. doi: 10.1016/j.phrs.2025.107775. Online ahead of print.

ABSTRACT

The roles of gut microbiota and microbially modified bile acids in human health have become widely recognized. In the last five years, various microbially modified bile acids (e.g., proteinogenic amino-conjugated bile acids, polyamine-conjugated bile acids, neuroactive amine-conjugated bile acids, methylcysteamine-conjugated bile acid, acylated bile acids, dicarboxylic acid-conjugated bile acids, lithocholic acid (LCA) derivatives) were identified and evaluated, which greatly enriched the mammalian bile acid pool and the bioactivity of bile acids. The structure, enzyme, function, clinical reports of these bile acids, and the bacteria to produce these bile acids were summarized in this review. These novel bile acids had various functions including immunoregulation, receptor regulator, antimicrobial activity, and microbial communities regulating effect. 70, 4, 1, 11, 19, 41, 43, 9, 10 species were observed to produce proteinogenic amino-conjugated bile acids, neuroactive amine-conjugated bile acids, methylcysteamine-conjugated bile acid, acylated bile acids, dicarboxylic acid-conjugated bile acids, 3-oxoLCA, isoLCA, 3-oxoalloLCA, and isoalloLCA, respectively. The current review has shed new light on discovering new bile acid derivatives as drug candidates. These microbially modified bile acids may play important roles in disease such as sleeve gastrectomy, fatty acid, inflammatory bowel disease, cystic fibrosis, and type 2 diabetes, which may also participate in normal physiological processes such as growth of infants, longevity, and dietary habits.

PMID:40378940 | DOI:10.1016/j.phrs.2025.107775

Clin Nutr. 2025 Apr 30;50:76-82. doi: 10.1016/j.clnu.2025.04.027. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a genetic disorder involving multi-organ dysfunction, with nutritional status playing a crucial role in disease progression. Cystic Fibrosis Transmembrane conductance Regulator (CFTR) modulator therapy, particularly the combination Elexacaftor/Tezacaftor/Ivacaftor (ETI), has shown numerous clinical benefits, including significant improvements in nutritional status. However, the factors driving this nutritional improvement, especially the potential role of increased dietary intake, remain underexplored. This study aimed to assess changes in nutritional status and dietary intake in patients with CF (pwCF) treated with ETI.

METHODS: 62 pwCF (36 children, 26 adults) were analyzed in a prospective, realworld, multicenter study (https://clinicaltrials.gov/study/NCT06072365). Dietary intakes were assessed via 3-day food diaries collected at baseline (M0) and one year after ETI treatment initiation (M12).

RESULTS: Over the first year of ETI treatment, Body Mass Index (BMI) significantly increased with a median BMI Z-score gain of 0.2 (IQR: 0.7) for children and median BMI gain of 1.0 kg/m2 (IQR: 1.8) for adults. Notably, these gains occurred without a significant increase in median daily caloric intake (2216 kcal (IQR: 750) at M0 vs. 2266 (IQR: 733) kcal at M12). Pancreatic enzyme requirements and calprotectin decreased significantly with ETI (p < 0.001 and p < 0.01, respectively), indicating improved pancreatic function and intestinal inflammation in some patients. Seven patients became overweight after one year of ETI.

CONCLUSION: ETI therapy enhances nutritional status in pwCF, independently of increased caloric intake. Further research is essential to refine dietary recommendations under ETI treatment, aiming to prevent overweight and obesity while optimizing health outcomes.

PMID:40378731 | DOI:10.1016/j.clnu.2025.04.027

Stat Med. 2025 May;44(10-12):e70082. doi: 10.1002/sim.70082.

ABSTRACT

Group sequential designs in clinical trials allow for interim efficacy and futility monitoring. Adjustment for baseline covariates can increase power and precision of estimated effects. However, inconsistently applying covariate adjustment throughout the stages of a group sequential trial can result in inflation of type I error, biased point estimates, and anticonservative confidence intervals. We propose methods for performing correct interim monitoring, estimation, and inference in this setting that avoid these issues. We focus on two-arm trials with simple, balanced randomization and continuous outcomes. We study the performance of our boundary, estimation, and inference adjustments in simulation studies. We end with recommendations about the application of covariate adjustment in group sequential designs.

PMID:40377247 | DOI:10.1002/sim.70082

J Respir Biol Transl Med. 2025 Mar;2(1):10002. doi: 10.70322/jrbtm.2025.10002. Epub 2025 Mar 24.

ABSTRACT

Pulmonary arterial hypertension (PAH) is a progressive, lethal, and incurable disease of the pulmonary vasculature. A previous genome-wide association study (GWAS) with Affymetrix microarray analysis data exhibited elevated histidine triad nucleotide-binding protein 3 (HINT3) in the lung samples of PAH compared to control subjects (failed donors, FD) and the positive correlations of HINT3 with deubiquitinase USP11 and B-cell lymphoma 2 (BCL2). In this study, we aim to investigate the roles and interplay of USP11 and HINT3 in the apoptosis resistance of PAH. The levels of USP11 and HINT3 were increased in the lungs of idiopathic PAH (IPAH) patients and Hypoxia/Sugen-treated mice. USP11 and HINT3 interacted physically, as shown by co-immunoprecipitation (co-IP) assay in human pulmonary arterial endothelial cells (HPAECs). HINT3 was degraded by polyubiquitination, which was reversed by USP11. Furthermore, HINT3 interacted with the anti-apoptotic mediator, BCL2. Overexpression of USP11 increased BCL2 content, congruent to elevated lung tissue levels seen in IPAH patients and Hypoxia/Sugen-treated mice. Conversely, the knockdown of HINT3 function led to a depletion of BCL2. Thus, we conclude that USP11 stabilizes HINT3 activation, which contributes to endothelial apoptosis-resistance of pulmonary arterial endothelial cells in PAH. This can potentially be a novel therapeutic target for ubiquitination modulators for PAH.

PMID:40376595 | PMC:PMC12080269 | DOI:10.70322/jrbtm.2025.10002

Front Pharmacol. 2025 May 1;16:1559399. doi: 10.3389/fphar.2025.1559399. eCollection 2025.

ABSTRACT

BACKGROUND: Pharmacogenomic (PGx) variants can significantly impact drug response, but limited data exists on their prevalence in Middle Eastern populations. This study aimed to investigate the inheritance of certain markers in candidate pharmacogenes among healthy Saudis.

METHODS: DNA samples from 95 unrelated healthy Saudi participants were genotyped using the Affymetrix Axiom Precision Medicine Diversity Array. Thirty-eight variants in 15 pharmacogenes were analyzed based on their clinical relevance and lack of previous reporting in Saudi populations.

RESULTS: Twenty-six of the 37 tested markers were undetected in the cohort. The selected variants in six genes [DPYD (rs1801268), CACNA1S (rs772226819), EGFR (rs121434568), RYR1 (rs193922816), CYP2B6 (rs3826711), and MT-RNR1 (rs267606617, rs267606618, rs267606619)] were found to be non-existing among Saudis. In contrast, 11 variants and alleles in nine pharmacogenes were detected at varying frequencies. Notable findings included high frequencies of variants in ATIC [rs4673993, minor allele frequency (MAF) = 0.71)] and SLC19A1 (rs1051266, MAF = 0.48) affecting methotrexate efficacy. Three alleles were identified in CYP3A4, including a common (CYP3A4 rs2242480) and two rare alleles (*3 and *22). Another three markers [rs16969968 in CHRNA5, rs11881222 in IFNL3 (IL28B), and SLCO1B1*14] were found to be highly distributed among the participants (MAF = 0.35, 0.30, and 0.14, respectively). Conversely, three rare markers: CYP2A6*2, NAT2*14, and rs115545701 in CFTR, were identified at low-frequency levels (MAF = 0.021, 0.011, 0.005, respectively). Statistically significant differences in allele frequencies were observed for eight variants between Saudi and African populations, five variants compared to East Asians, and two variants compared to Europeans.

CONCLUSION: This study provides novel insights into the distribution of clinically relevant PGx variants in the Saudi population. The findings have implications for personalizing treatments for various conditions, including rheumatoid arthritis, cystic fibrosis, and hepatitis C. These data contribute to the development of population-specific PGx testing panels and treatment guidelines.

PMID:40376268 | PMC:PMC12078325 | DOI:10.3389/fphar.2025.1559399

Nat Nanotechnol. 2025 May 15. doi: 10.1038/s41565-025-01903-6. Online ahead of print.

ABSTRACT

Liver macrophages capture circulating nanoparticles and reduce their delivery to target organs. Serum proteins adsorb to the nanoparticle surface after administration. However, the adsorbed serum proteins and their cognate cell receptors for removing nanoparticles from the bloodstream have not been linked. Here we use a multi-omics strategy to identify the adsorbed serum proteins binding to specific liver macrophage receptors. We discovered six absorbed serum proteins that bind to two liver macrophage receptors. Nanoparticle physicochemical properties can affect the degree of the six serum proteins adsorbing to the surface, the probability of binding to cell receptors and whether the liver removes the nanoparticle from circulation. Identifying the six adsorbed proteins allowed us to engineer decoy nanoparticles that prime the liver to take up fewer therapeutic nanoparticles, enabling more nanoparticles for targeting extrahepatic tissues. Elucidating the molecular interactions governing the nanoparticle journey in vivo will enable us to control nanoparticle delivery to diseased tissues.

PMID:40374797 | DOI:10.1038/s41565-025-01903-6

An Pediatr (Engl Ed). 2025 May 14:503857. doi: 10.1016/j.anpede.2025.503857. Online ahead of print.

ABSTRACT

Cystic fibrosis is a severe genetic disease caused by variants in the CFTR gene. Although it is a multisystem disease, respiratory involvement is the main cause of morbidity and mortality. Cystic fibrosis transmembrane conductance regulator modulator (CFTRm) therapies have advanced the treatment of this disease by improving function of this protein. Ivacaftor, the first CFTRm, has been found to significantly improve lung function and quality of life in patients with certain gating variants. However, only a small percentage of patients in Spain are eligible for this treatment. Combinations of correctors and potentiators, such as lumacaftor-ivacaftor or tezacaftor-ivacaftor, have been developed for treatment of patients with the most frequent variant (F508del), although with limited benefits. Triple therapy with elexacaftor-tezacaftor-ivacaftor has been found to significantly improve respiratory, gastrointestinal and nutritional outcomes as well as quality of life, thus changing the management of CF in eligible patients. The impact of triple therapy is also reflected in an increase in life expectancy and a decrease in mortality and lung transplantation. As regards hepatic and pancreatic involvement, while CFTR modulators have exhibited promising effects, further research is required. The use of CFTR modulators has also shifted nutritional status trends in patients with CF, reducing the risk of undernutrition but increasing the risk of obesity. The use of these drugs for treatment of less frequent variants and for potential antenatal treatment is currently being investigated. Despite these advances, there is still a subset of patients who are ineligible for treatment with modulators or highly effective therapy.

PMID:40374426 | DOI:10.1016/j.anpede.2025.503857

Diabetes Care. 2025 May 15:dc250044. doi: 10.2337/dc25-0044. Online ahead of print.

ABSTRACT

OBJECTIVE: A number of disease-modifying therapies have been introduced for people with cystic fibrosis (CF) over the past two decades. The cumulative effects of this changing landscape on CF-related diabetes (CFRD) are unclear. We examined trends in CFRD epidemiology over time using data from the U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR).

RESEARCH DESIGN AND METHODS: CFFPR data from 2003 to 2018 were queried to determine annual screening, incidence, and prevalence rates of CFRD. Individuals with incident CFRD were compared with individuals without CFRD. Survival analyses were performed to estimate the cumulative hazard of CFRD given predictors of interest over the 15 years of study. Data were also grouped into three time periods (2003-2008, 2009-2013, and 2014-2018) to investigate whether the hazard of developing CFRD varied over time.

RESULTS: CFRD screening rates increased from 2003 to 2018, particularly in 10- to 18-year-olds. Although screening rates increased in adults, overall rates remained low. In 10- to 18-year-olds, the incidence of CFRD was stable over time, while incident cases in adults steadily decreased, approaching incident rates in adolescents. Despite this, the prevalence of CFRD has gradually increased in adults, likely reflecting increased longevity. Age, female sex, Black race, severe mutation class, liver disease, poorer lung function, pancreatic insufficiency, enteric feeds, and low and high BMI were all risk factors associated with CFRD.

CONCLUSIONS: Findings support the need for the development of tailored CFRD screening algorithms and increased subspecialists to care for a growing population of adults with CF and CF-associated comorbidities.

PMID:40372381 | DOI:10.2337/dc25-0044

Antimicrob Agents Chemother. 2025 May 15:e0003025. doi: 10.1128/aac.00030-25. Online ahead of print.

ABSTRACT

Patients with cystic fibrosis have dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR), and this predisposes them to nontuberculous mycobacteria (NTM), including Mycobacterium abscessus (MAB), infection. We found that one of the CFTR modulators, ivacaftor, kills MAB in a concentration-dependent manner, with killing efficacy comparable to amikacin and imipenem, drugs in guideline-based regimens. Using clinical isolates of MAB, amikacin 1/4× MIC concentration combined with ivacaftor killed 2.67 log10 CFU/mL MAB.

PMID:40372084 | DOI:10.1128/aac.00030-25

Otolaryngol Pol. 2025 Mar 19;79(3):1-8. doi: 10.5604/01.3001.0055.0503.

ABSTRACT

&lt;b&gt;Introduction:&lt;/b&gt; In the pathophysiology of chronic upper respiratory tract inflammation, an important role is attributed to the disturbances of the patient&apos;s microbiome in terms of diversity and functioning, to the decreased abundance of commensal bacteria and the increase of pathogenic bacteria. In recent years, there has been growing scientific interest in the role of probiotics - administered both locally and orally - in the management of various diseases, particularly inflammatory conditions such as chronic rhinosinusitis. &lt;br&gt;&lt;br&gt;&lt;b&gt;Aim:&lt;/b&gt; To assess the use of nasal rinsing with probiotics in patients with rhinitis and rhinosinusitis (primary and secondary). &lt;br&gt;&lt;br&gt;&lt;b&gt;Material and methods:&lt;/b&gt; A total of 51 patients (31 women and 20 men) were included in the study, including 24 patients with granulomatosis with polyangiitis during immunosuppressive therapy (12 women and 12 men) and 27 patients (19 women and 8 men) with rhinitis (chronic rhinosinusitis with polyps, chronic rhinosinusitis without nasal polyps, atrophic rhinitis with nasal septum perforation, and allergic rhinitis). Exclusion criteria were: cystic fibrosis, primary ciliary dyskinesia, pregnancy, severe lung, heart, kidney disease, use of oral probiotics, use of intranasal probiotics in the last 6 months, sinus surgery in the last 6 months, lack of consent to participate in the study, antibiotic therapy in the last 2 months. Patients were scheduled to undergo nasal rinsing with a probiotic solution, with the following parameters assessed before and after the procedure: SNOT-22 scores and the severity of nasal lesions according to the Lund-Kennedy scale. In the group of patients with rhinitis, the ENS-6 questionnaire was also conducted and symptoms assessed on the VAS scale (visual analogue scale): nasal discharge, nasal obstruction, facial pain, impaired sense of smell, nasal irritation, nasal itching, and severity of crusting. &lt;br&gt;&lt;br&gt;&lt;b&gt;Results:&lt;/b&gt; The study showed that nasal rinsing with a probiotic solution is well tolerated and does not cause any adverse effects. In both groups, a reduction in symptoms was observed based on the SNOT-22 questionnaire (p = 0.002 in GPA, ns - in rhinitis/ rhinosinusitis). According to the Lund-Kennedy scale, the reduction in the intensity of changes in both groups was statistically significant. In addition, patients with primary rhinitis or rhinosinusitis also experienced a reduction in nasal mucosa irritation and crusting intranasal (p&lt;0.05). &lt;br&gt;&lt;br&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Probiotic nasal rinsing appears to have a beneficial effect on the condition of the nasal mucosa in patients with both primary and secondary (GPA-related) rhinosinusitis and is generally well tolerated.

PMID:40371957 | DOI:10.5604/01.3001.0055.0503