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Journal articleWang M, He Y, Hu H, et al., 2026,
Protective role of fatty acid oxidation against epithelial barrier dysfunction in allergic asthma.
, Redox Rep, Vol: 31BACKGROUND: Fatty acid oxidation (FAO) is implicated in lung diseases, but its role in bronchial asthma is not fully understood. We investigated its effect on airway epithelial barrier integrity. METHODS: Using a house dust mite (HDM)-induced murine asthma model and HDM, IL-4, IL-13, or TNF-α stimulated human primary bronchial epithelial cells (BECs) and bronchial epithelial (Beas-2b) cells, we modulated FAO with L-carnitine (agonist) and Etomoxir (inhibitor). BECs and Beas-2b cells were infected with lentivirus-mediated CPT1A shRNA prior to stimulation. Barrier function, mitochondrial oxidative stress, inflammation, and metabolism were assessed. RESULTS: FAO level in lungs negatively correlated with increased inflammation and tissue injury in HDM-induced asthmatic mice (all p < 0.05), while positively regulating tight junction protein expression. In BECs and Beas-2b cells, Etomoxir treatment and CPT1A knockdown exacerbated the impairment of FAO caused by various stimulants (all p < 0.05). Furthermore, FAO negatively regulated HDM/cytokine-induced epithelial barrier damage, hyperactive inflammatory response, and mitochondrial dysfunction in Beas-2b cells (all p < 0.05). In contrast, treatment with L-carnitine significantly alleviated these pathophysiological features in both in vivo and in vitro models. CONCLUSION: FAO plays a protective role in the occurrence and development of asthma by maintaining airway epithelial cell homeostasis and barrier function.
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Journal articleFreeman A, Rink S, Bansal AT, et al., 2026,
Multimorbidity phenotypes and associated characteristics in severe asthma: an observational study of European severe asthma registries.
, Lancet Reg Health Eur, Vol: 63BACKGROUND: The phenotypic nature of multimorbidity in severe asthma is poorly understood. Our aims in this study were to define multimorbidity phenotypes and their characteristics in severe asthma across Europe by identifying and characterising co-aggregation of comorbidities. METHODS: Cross-sectional patient data were analysed from the pan-European Severe Heterogenous Asthma Research Collaboration: Patient Centred (SHARP) Central database of national severe asthma registries. Patients were grouped by four European regions (North, South, East, and West). Hierarchical clustering of comorbidities was applied to characterise the correlation structure of the ten commonest comorbidities within these geographical regions. Subsequent multimorbidity phenotypes (MMP) and their clinical features were then defined. FINDINGS: Data were available for 2690 severe asthma patients and 23 comorbidities from 11 countries. Three comorbidity clusters were consistently seen across the four European regions: 1) osteoporosis plus steroid-induced weight gain, 2) eczema plus rhinitis, and 3) chronic sinusitis plus nasal polyps. Four further comorbidities (obesity, bronchiectasis, gastro-oesophageal reflux disease, psychological factors) showed variable clustering. Multimorbidity was ubiquitous. Patients were assigned multimorbidity phenotypes (MMP) according to comorbidity cluster alignment. MMP sn (sinonasal-associated) and MMP u (no specific cluster alignment) were commonest. MMP ster (steroid-associated multimorbidity) had highest maintenance oral steroid (m-OCS) use, and Body Mass Index, plus worst lung function, asthma control, and asthma exacerbation frequency. MMP max (maximal multimorbidity) showed high prevalence of variably assigned comorbidities, higher m-OCS and biologic treatment needs. INTERPRETATION: Multimorbidity is common in severe asthma and can be classified into replicable novel phenotypes with characteristic clinical traits and outcomes. Recognising these phenotypes c
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Journal articleXie M, Chang Q, Li C, et al., 2026,
TRPA1 mediates ozone-induced murine model of COPD through the Wnt5a/GSK-3β/β-catenin pathway.
, Environ Pollut, Vol: 393Ambient ozone (O3), a ubiquitous oxidant gas and key component of photochemical smog, damages the airway epithelium, provokes oxidative stress, and sustains chronic inflammation, which favors the onset and advancement of chronic obstructive pulmonary disease (COPD). Yet the molecular sensors linking long-term ozone exposure to COPD remain incompletely defined. We examined whether the oxidant-sensitive channel Transient receptor potential ankyrin 1 (TRPA1) mediates ozone-driven murine model of COPD through the Wnt5a/GSK3β/β-catenin pathway. C57BL/6J or TRPA1-deficient mice underwent ozone exposure (2.5 ppm, 3 h/session) every 3 days for 2 months, following administration of either the TRPA1 antagonist A967079 or the Wnt5a/GSK3β/β-catenin inhibitor XAV-939. Similarly, BEAS-2B cells treated with A967079 or XAV-939 or TRPA1-silenced cells were subjected to ozone (1 ppm, 3 h/day) for 4 consecutive days. Oxidative stress, inflammatory responses, emphysematous changes, mitochondrial dysfunction, and airway remodeling were assessed. In addition, gene set variation analysis (GSVA) was used to quantify Reactome Wnt5a/GSK3β/β-catenin pathway activity through public COPD transcriptomic cohorts. Pharmacological inhibition or genetic deficiency of TRPA1 significantly attenuated ozone-induced lung function impairment, and ozone-triggered oxidative stress, emphysematous changes, mitochondrial dysfunction, and airway remodeling. Notably, pharmacological suppression of the Wnt5a/GSK3β/β-catenin pathway using XAV-939 produced comparable protective effects to TRPA1 blockade in both ozone-exposed murine models and BEAS-2B cells. GSVA demonstrated tissue-specific associations between TRPA1 and Wnt5a/GSK3β/β-catenin pathway in COPD patients. TRPA1 mediates crucially ozone-induced COPD through modulation of the Wnt5a/GSK-3β/β-catenin signaling. Therapeutic targeting of both TRPA1 and Wnt5a/GSK3β/β-cat
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Journal articleDinh C-T, Lee Y-L, Chang L-T, et al., 2026,
Assessing the impact of air pollution on anemia: a comprehensive review and meta-analysis.
, Expert Rev Hematol, Pages: 1-10INTRODUCTION: Air pollution and household fuel use may impair hematologic health through inflammation and oxidative stress. We synthesized evidence on associations of ambient/household air pollution with anemia risk and erythrocyte indices. METHODS: We searched PubMed, Embase, and Web of Science (inception-27 September 2025). Two reviewers independently screened and extracted data, and assessed risk of bias using Joanna Briggs Institute checklists. Random-effects meta-analyses pooled risk ratios (RRs) per 10 µg/m3 for particulate matter with aerodynamic diameter ≤10 µm (PM10), ≤2.5 µm (PM2.5), and nitrogen dioxide (NO2), and by household fuel type. RESULTS: Thirty-six studies were included. Each 10 µg/m3 increase in PM2.5 and NO2 was associated with higher anemia risk (RR 1.200, 95% CI 1.041-1.384, I2 98.2%; RR 1.127, 95% CI 1.025-1.241, I2 98.0%). Solid and biomass fuel increased anemia risk (RR 1.143, 95% CI 1.027-1.274, I2 82.9%; RR 1.271, 95% CI 1.050-1.539, I2 91.7%). PM10 was associated with lower hemoglobin (0.074 g/dL, 95% CI -0.124 to -0.023, I2 90.7%). Effects were generally stronger in males and in low- and middle-income countries. CONCLUSIONS: Ambient and household air pollution are associated with increased anemia risk and reductions in hemoglobin; high heterogeneity and observational designs limit causal inference.
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Journal articleWen H, Kole T, Carpaij OA, et al., 2026,
Nasal Airway Transcriptome Reflects Selected Asthma-Associated Gene Signatures in the Lower Airways.
, AllergyBACKGROUND: Transcriptomic analysis of bronchial brushes reveals asthma-associated gene signatures but is limited by the invasiveness of bronchoscopy. Based on the "united airways" hypothesis, we evaluated whether and to what extent nasal brushes reflect asthma-associated transcriptomic changes in the lower airways. METHODS: In the ARMS study, we included 26 asthma patients and 28 healthy controls, all fully clinically characterized. Nasal and bronchial brushes were collected for RNA sequencing. We used edgeR and WGCNA to identify asthma-associated genes and modules in bronchial brushes. We assessed their expression patterns in ARMS nasal brushes and validated the findings in the independent ATLANTIS study (n = 427). RESULTS: We identified 51 asthma-associated genes in the lower airways, of which 40 were up-regulated and 11 were down-regulated in asthma compared to healthy controls. Seven of the 40 up-regulated genes were also up-regulated in ARMS nasal brushes and validated in ATLANTIS: CLCA1, FETUB, CST1, NTRK2, CDH26, TPSAB1, and DHX35. WGCNA revealed two modules that were consistently elevated in asthma across bronchial and nasal brushes in ARMS and confirmed in ATLANTIS. One module represents IL-13 related inflammation, whereas the other represents mast cell activity. CONCLUSION: The asthma-associated gene signatures of the lower and upper airways show a limited but biologically coherent overlap, with seven genes and two gene modules consistently elevated in asthma. The shared gene signatures reflect two separate components of type 2 inflammation: IL-13 related inflammation and mast cell activity. Selected nasal gene signatures offer a non-invasive tool to identify asthma endotypes with distinct molecular mechanisms driving underlying disease biology.
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Journal articleCarlsten C, Salvi S, Wong GWK, et al., 2026,
Supplements and medications for respiratory resilience against air pollution
, ERJ Open Research, Pages: 01127-2025<jats:p>Air pollution is a major threat to respiratory health. We review the current literature on accessible interventions that could help patients build resilience against this threat. We explore the potential benefits of antioxidant-rich diets, including supplements such as fish oil, vitamins C, D, E and prebiotics, which have shown promise in reducing inflammation and oxidative stress, thereby mitigating air pollution-related respiratory decline. Nasal washes are commonly used to clear nasal passages, which could support may aid to clearing pollutants from the nasal passages and improve mucociliary clearance. Furthermore, medications such as nonsteroidal anti-inflammatory drugs and intranasal corticosteroids may have been reported to reduce pollutant- related airway inflammation and lung function deterioration triggered by pollutant exposure. Given the generally favourable safety profile of these interventions, they are reasonable to consider in consultation with a care provider. Further research is needed to establish optimal dosing, safety and long-term efficacy, particularly for those exposed to chronic air pollution. Healthcare professionals should work together to further identify and implement effective interventions to mitigate the impact of air pollution on respiratory health.</jats:p>
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Journal articleLee B, Anpalagan H, Wong E, et al., 2026,
Hormone replacement therapy and the risk of asthma attacks: population-based cohort study
, ERJ Open Research, ISSN: 2312-0541Background Women experience higher rates and greater severity of asthma after puberty, suggesting that sex hormones play a key role in airway disease. Hormone replacement therapy (HRT), which acutely alters circulating sex hormone levels, provides a useful model to examine their effects on asthma attacks. We sought to examine the association between HRT use and asthma attacks. Methods We obtained a cohort of women with asthma, aged 45 to 60 years, using nationwide U.K. primary care health records linked to hospital and mortality data, 2004-2020, to compare HRT-users to non-users. We applied inverse-probability of treatment weighting and Cox proportional hazards, accounting for demographics, asthma severity and comorbidities; stratifying by potential modifiers: body mass index (BMI), blood eosinophil count, smoking and HRT-type (oestrogen-only, progesterone-only and combined). Results 182,010 women were eligible for the study, of whom 9,663 were incident HRT users and 172,347 were non-users. Median age was 52 years (IQR: 50-55 years). HRT-users and non-users were broadly similar in terms of BMI, smoking history but non-users had slightly higher proportions residing in more deprived areas, with more comorbidities, higher reliever use and asthma attacks in the year before study entry, but lower use of preventer inhalers. After applying weighting, there was no association found between HRT use and asthma attacks (weighted-HR 0.97, 95% CI 0.90-1.04). There was no modification of that association by blood eosinophil level, BMI, smoking history or HRT-type. Conclusion Hormone replacement therapy use is not associated with asthma attacks in women with established asthma aged 45 to 60 years old.
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Journal articleAlimohammadi M, Tahmasebi S, Amani D, et al., 2026,
MiR-146a-armed exosomes reverse immunosuppressive networks in NSCLC by dual-targeting of MYD88/STAT3 and PD-L1 axes.
, Int Immunopharmacol, Vol: 172BACKGROUND: MiR-146a has been found to be a tumor suppressor and is downregulated in NSCLC cells. This study investigated the effects of delivering miR-146a via tumor-derived exosomes (TEX-MiR-146a) on the behavior of malignant cells and immunological modulation in NSCLC models. METHODS: miR-146a expression was evaluated in A-549 and normal MRC-5 lung epithelial cells. Exosomes were isolated from A-549 cells, loaded with a miR-146a mimic, and characterized for size, morphology, surface markers, and loading efficiency. In vitro, the functional effects of TEXmiR-146a were compared to controls using tests for cell survival, apoptosis, migration, invasion, wound healing, colony formation, and gene expression. Co-culture immunological assays, including T cell subset and cytokine profiling, were also performed using patient-derived peripheral blood mononuclear cells (PBMCs). RESULTS: TEXmiR-146a efficiently loaded miR-146a into cells (60.1 % ± 4.0 efficiency, P < 0.0001). Treatment with TEXmiR-146a (25 μg/ml) significantly reduced the viability of A-549 cells by ∼51 % after 48 h (P < 0.0001). Cell migration and invasion were inhibited by >50 %, with migrating cells reduced to 116.7 ± 7.09 (P < 0.001) and invading cells to 171.7 ± 6.028 (P < 0.001), respectively, compared to controls. Pro-apoptotic genes Bax/Bcl-2 (P = 0.0002) and Caspase-3 were upregulated (P = 0.0003), while metastatic and immunoregulatory genes VEGF-A, MMP-9, STAT3, MYD88, and PD-L1 were downregulated (all P < 0.05). In patient PBMCs, TEXmiR-146a increased the frequency of cytotoxic CD8+ T cells (24.75 ± 1.23 % versus 20.15 ± 1.26 %, P < 0.0001) and decreased Treg cells (2.01 ± 1.22 % versus 4.04 ± 1.72 %, P = 0.015) compared to th
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Journal articleAnanth S, Wedzicha JA, 2026,
COPD exacerbations: Major events in the course of the disease
, PRESSE MEDICALE, Vol: 55, ISSN: 0755-4982 -
Journal articleLin Z, Huang J, He L, et al., 2026,
Integrative genomics reveal genetic links of chronic cough with risk factors and brain regional volumes
, ERJ Open Research, Vol: 12, Pages: 00844-2025<jats:sec> <jats:title>Objectives</jats:title> <jats:p>Chronic cough is a common condition, particularly among women in their sixties, and is associated with a high disease burden and reduced quality of life. Limited understanding of its risk factors and genetic associations represents a barrier to its effective management.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>We used genome-wide association study datasets for respiratory and other diseases, as well as behavioural phenotypes from the UK Biobank, FinnGen, Global Biobank Meta-analysis Initiative and Psychiatric Genomics Consortium. We identified pleiotropic genetic associations with chronic cough using linkage disequilibrium score regression, pleiotropy analysis and Bayesian colocalisation analysis. We conducted Mendelian randomisation analysis to determine the association between brain regional volumes and chronic cough risk.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>We identified 19 significant genetic correlations between chronic cough and various risk factors and associations. Among 74 pleiotropic genomic loci identified, the 4p14 locus had the strongest effect on cough-associated asthma, with RFC1 linked to cerebellar ataxia, neuropathy and vestibular areflexia syndrome. Gene enrichment analyses highlighted that the central nervous system and ion channel activity play roles in the pathogenesis of cough. A reduction in the volume of isthmus cingulate, thalamus proper and pallidum was associated with an increased risk of chronic cough. In ageing-associated cough, the direct effect of ageing on chronic cough showed an increased odds ratio of 1.044, while a reduction in left pal
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Journal articleToumpanakis D, Kim Y, Usmani OS, 2026,
Small Airways Disease in Patients With COPD: A Question-and-Answer Approach for Everyday Clinical Practice.
, Chest, Vol: 169, Pages: 641-651TOPIC IMPORTANCE: Small airways are recognized as the main site of disease progression and airflow limitation in patients with COPD. Whereas conventional lung function testing, for example spirometry, is nonspecific to small airways disease (SAD), the advent and wider availability of techniques sensitive to SAD, such as oscillometry, has improved our understanding of the clinical importance of small airways dysfunction. Despite this progress, a gap between the recent advances in knowledge of SAD and its implementation in daily clinical practice remains. We aimed to answer key questions that would allow practitioners (eg, family doctors, internists, pulmonologists) to introduce oscillometry into their clinical practice. REVIEW FINDINGS: COPD pathogenesis is characterized by SAD, with an increasing prevalence with more advanced disease. Evaluation of small airways dysfunction with sensitive techniques (eg, oscillometry, nitrogen washout) contributes to early disease detection and plays a significant role in almost every aspect of disease assessment, including confirmation of diagnosis, functional severity grading, and monitoring of lung function decline. Moreover, small airways dysfunction shows equivalent or even better correlation with patient-reported outcomes, including symptoms, quality of life, and exacerbations, compared with conventional lung function testing. This suggests a role for small airways assessment as a treatable trait in COPD to target and monitor therapeutic interventions. SUMMARY: Accumulating evidence and recent advances have delineated the role of small airways assessment in COPD and warrant its implementation in the management plan of patients with COPD in daily clinical practice.
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Journal articleXuan S, Wu Y, Liu F, et al., 2026,
CD207-Positive Dendritic Cells Promote Emphysema Through CD8+ T Cell Pathway in Chronic Obstructive Pulmonary Disease.
, Adv Sci (Weinh), Vol: 13Emphysema remains a major challenge in the management of chronic obstructive pulmonary disease (COPD). This study identifies CD207-positive dendritic cells (CD207+ DCs) as pivotal mediators of emphysema progression. In patients with COPD, the abundance of CD207+ DCs in small airways correlates with both emphysema severity and lung function decline (FEV1%pred). In a murine emphysema model, adoptive transfer of CD207+ DCs reversed the attenuation of emphysema, inflammation and CD8+ T-cell expansion in CD207-knockout mice. Mechanistically, cigarette smoke-induced epithelial GM-CSF drives the expansion of CD207+ DCs. Upon activation by damage-associated molecular patterns (DAMPs), these DCs promote CD8+ T cell proliferation and activation via Birbeck granule-mediated MHC-I antigen cross-presentation. Collectively, these findings demonstrate that CD207+ DCs orchestrate a pathogenic CD8+ T-cell response in emphysema and represent a promising therapeutic target.
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Journal articleKinoshita R, Sathyapala A, Polkey MI, 2026,
Has the time come for workplace screening for obstructive sleep apnoea (OSA)?
, Thorax -
Journal articleKumar A, Chan R, Zounemat-Kermani N, et al., 2026,
Small Airways Dysfunction and Remission in Adults With Asthma: A Longitudinal Exploratory Analysis of the AssessmenT of smalL Airways involvemeNT In aSthma (ATLANTIS) Study.
, AllergyBACKGROUND: Asthma remission is a feasible treatment goal. However, remission definitions vary, and predictive biomarkers remain underexplored. METHODS: We conducted a post hoc analysis of ATLANTIS (NCT02123667), a multinational prospective study including 684 adult asthmatics. Remission was defined by 3-component (3C) and 4-component (4C) criteria. 3C remission included: (1) ACQ-6 < 1.5, (2) no maintenance oral corticosteroids, (3) no exacerbations. An absolute decline < 10% in pre-bronchodilator FEV1% predicted, was added for the 4C definition. Multivariate logistic regression identified remission predictors. A novel Low Disease Activity (LDA) score was developed using factor analysis of five clinical variables (ACQ-6, FeNO, BEC, and FEV1) including an innovative small airways dysfunction questionnaire tool (SADT). Nasal transcriptomics were analysed for differential gene expression and pathway enrichment and were replicated in U-BIOPRED (NCT01976767) using sputum transcriptomics. U-BIOPRED was included only to study omics replication of remission pathways identified in ATLANTIS. FINDINGS: Remission occurred in 48% (3C) and 45% (4C) of patients. Predictors included male sex, better lung function, fewer previous exacerbations, and higher SADT (fewer small airways symptoms). LDA identified milder disease and was associated with remission [OR 3C 4.43 (2.80, 7.10) and 4C 3.46 (2.23, 5.43)], improved QoL [OR 2.07 (1.65, 2.60)], and fewer future exacerbations [OR 0.43 (0.22, 0.85)]. Transcriptomic analyses revealed remission-associated upregulation of interleukin 4/13 signalling and downregulation of coagulation pathways, in both ATLANTIS and U-BIOPRED. INTERPRETATION: SAD was associated with reduced asthma remission. A novel LDA tool demonstrated clinical utility in stratifying prospective asthma risk. Key immunologic and haemostatic pathways may underpin remission, offering potential targets for future intervention.
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Journal articleHo V, Baker J, Fenwick P, et al., 2026,
Single cell microfluidic quantification of miRNA-21 and miRNA-34a reveals miRNA interactions in small airway epithelial cells and fibroblasts from COPD patients
, American Journal of Physiology - Lung Cellular and Molecular Physiology, ISSN: 1040-0605Rationale: MicroRNA-21 and microRNA-34a are implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but their cell-specific expression patterns and interactions within individual airway cells remain unexplored.Objective: To develop a single cell microfluidic platform for dual, amplification-free detection of miR-21-5p and miR-34a-5p in primary small airway cells from COPD patients.Methods: Small airway epithelial cells (SAEC) and fibroblasts (SAF) were isolated from COPD patients and non-smokers (n = 6–8 per group). A microfluidic chip with dual miRNA sandwich hybridisation assays was used to quantify miR-21-5p and miR-34a-5p in single cells. Expression of miRNAs and their target genes was evaluated under oxidative stress using qPCR and Western blotting.Main Results: Single cell analysis revealed significantly higher miR-21-5p and miR-34a-5p expression in COPD-derived cells compared to controls. MiR-21 exhibited greater variability than miR-34a, and their positive correlation in control cells was disrupted in COPD. Oxidative stress elevated miR-21 and miR-34a while reducing expression of miR-21 targets and increasing senescence markers (p21Cip1/Waf1, p16INK4a). MiR-21 antagomir restored expression of suppressed targets in both cell types.Conclusions: Our novel single cell microfluidic platform enables precise, simultaneous detection of miR-21 and miR-34a in single small airway cells. This allows the interrelationship between the miRNAs to be assessed within the same cell. MiR-21 and miR-34a represent promising therapeutic targets for restoring gene regulatory balance in COPD.
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Journal articleWilliams TJ, Kermani NZ, Gonzales-Huerta LE, et al., 2026,
A Role for Non-Canonical Caspases in Fungal Allergic Airway Disease.
, Clin Exp Allergy -
Journal articleRoth-Walter F, Adcock IM, Benito-Villalvilla C, et al., 2026,
Update on Non-Biological and RNA-Based Therapeutics in Chronic Inflammatory Diseases: Precision Medicine Through Small Molecules: An EAACI Position Paper.
, AllergyIn the last decades, critical advancements in research technology and knowledge on disease mechanisms steered therapeutic approaches for chronic inflammatory diseases towards unprecedented target specificity. For allergic and chronic lung diseases, biologic drugs pioneered this goal, acquiring on the way-through the clinical use of monoclonal antibodies-a deeper understanding of how inflammatory and immune pathways are configured in disease-specific patterns. In this biomarker-driven approach, synthetic small molecule drugs (SMDs) were perceived as lagging behind in innovation for their relative lack of specificity. This was, however, mostly due to a shift in focus towards biologics rather than true obsolescence of SMDs. In the same timeframe, in fact, advances in structural biology and medicinal chemistry, bioinformatics and artificial intelligence held steadily SMDs' innovation and relevance. The use of kinase inhibitors, well established in the treatment of cancer and rheumatological diseases, is now approved for some allergic skin diseases and is approaching asthma and COPD with several clinical trials; moreover, new therapeutics targeting mast cell receptors and molecules involved in innate immunity are entering preclinical and clinical testing. Alongside, the portfolio of biologics is harboring the expansion of RNA therapeutics, which gained global recognition during the COVID-19 pandemic due to RNA vaccines. Different types of RNA therapeutics, including those based on different non-coding RNAs, are advancing to agency approval and market, thanks to improvements in molecule stability and delivery systems. In summary, the evidence presented in this position paper illustrates that precision medicine is becoming a goal shared between synthetic SMDs and biologics, both protein/antibody-based and RNA therapeutics. We review the current state, unmet needs and opportunities within this evolving landscape, highlighting how small molecular species, both synthetic as S
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Journal articleTomas Catala A, 2026,
In vivo functional profiling and structural characterisation of the human GLP1R A316T variant
, Science Advances, ISSN: 2375-2548Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D)and obesity, yet patient responses are variable, with GLP1R gene variation potentially linked to therapeutic outcomes. A GLP1R natural missense variant, A316T, protects against T2D and cardiovascular disease. Here, we generated and characterised a human GLP1R A316T mouse model. Human GLP1RA316T/A316T mice displayed lower fasting blood glucose versus wildtype littermates even under metabolic stress, as well as slower weight gain and alterations in islet cytoarchitecture, glucagon secretion and liver metabolism under a high-fat, high sucrose diet. This was however associated with blunted responses to pharmacological GLP-1RAs in vivo. Further investigations in b-cell models demonstrated that human GLP1R A316T exhibits characteristics of constitutive activation but dampened GLP-1RA responses. Results are further supported by cryo-EM analyses and molecular dynamics simulations of GLP-1R A316T structure, collectively demonstrating that the A316T variant governs basal GLP-1R activity and pharmacological responses to GLP-1R-targeting therapies.
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Journal articleFu H, Sun P, Yuan X, et al., 2026,
Epithelial-Associated CD207+ DCs Link Allergen Sensing and IL-25-Driven Th2 Inflammation in Asthma.
, AllergyBACKGROUND: IL-25 is a key epithelial-derived alarmin associated with T2-high asthma, yet its downstream mechanisms remain poorly defined. CD207 (Langerin)+ dendritic cells (DCs) are localized at the airway epithelial interface. However, whether these cells respond to epithelial-derived cytokines and contribute to the Th2 immune response in asthma remains unclear. METHODS: Single-cell RNA-seq from healthy human lungs was analyzed to define the transcriptomic features of CD207+ DCs. Their function was validated in a house dust mite (HDM)-induced asthma model using Cd207-/- mice. Flow cytometry was performed on lung and mediastinal lymph nodes. DC-T cell co-cultures were used to assess Th2 polarization. Epithelial-DC interactions were evaluated using transwell co-culture with ALI-differentiated tracheal epithelial cells. Clinical relevance was examined in airway samples from asthma patients in the U-BIOPRED cohort. RESULTS: CD207+ DCs were enriched in intraepithelial compartments and exhibited increased MHC-II and Claudin-1 expression. In asthma, their abundance correlated with T2 signatures and Th2 markers (CRTH2, ST2). CD207 deletion reduced HDM uptake, Th2 cytokines, airway inflammation, and Th2 differentiation. IL-25 induced CD207+ DCs and enhanced their Th2-polarizing capacity in vitro. An IL-25-CD207 co-expression score correlated with IL-4/IL-5/IL-13 levels and was higher in steroid-naïve patients with severe asthma. CONCLUSION: Our study identifies CD207+ DCs as epithelial-associated antigen-presenting cells that bridge IL-25 signaling and Th2 polarization in allergic asthma. Targeting the IL-25-CD207 axis may offer therapeutic opportunities for T2-high asthma.
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Journal articleKlimek L, Mullol J, Hummel T, et al., 2026,
The Unmet Need of Olfactory Testing in Inflammatory Disorders of the Upper Airways-An EAACI Position Paper.
, AllergyThe sense of smell, with its extensive evolutionary history, is highly prone to disorders that can have a profound impact on daily life. Anosmia affects approximately 5% of the population, with an additional 15% exhibiting reduced olfactory function. The prevalence of olfactory dysfunction (OD) varies by population and age group, and standardized testing reveals a broad range of impacts. OD includes various causes, most commonly aging, inflammation of the olfactory epithelium, upper respiratory tract infections (URTI), traumatic brain injury, and neurological conditions. The recent COVID-19 pandemic has highlighted the association between viral infections and olfactory dysfunction, with severe hyposmia/anosmia being an early marker of infection. Despite its importance, the assessment of olfactory function remains inconsistent across clinical practices. Psychophysical smell tests, while vital for diagnosis and patient management, are underutilized, especially outside of specialized centers. Standardized testing methods are crucial for objective diagnosis, but significant challenges, including test variability, lack of comparability, and healthcare reimbursement issues, persist. The European Academy of Allergy and Immunology (EAACI) advocates for improvements in the quality and standardization of chemosensory assessments. Future efforts must prioritize education, incentives for better testing, and the integration of digital tools to expand access to olfactory testing and diagnosis in remote or quarantine situations. However, office-based testing remains irreplaceable, even with advancements in telemedicine.
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