Transforming Growth Factor ß1 and Gap Junction Protein Alpha 4 Gene Heterogeneity in Relation to the Severity of Clinical Disease in Cystic Fibrosis.

Background: High TGFβ1-producing variants cause severe clinical disease in F508del homozygous patients. Lately, we showed that a single nucleotide polymorphism (SNP), rs41266431, in the GJA4 gene modifies the disease severity of cystic fibrosis (CF). Our aim was to investigate whether the clinical phenotype associated with GJA4 variants was independent of TGFβ1 variants.

Non-respiratory health-related quality of life in people with cystic fibrosis receiving elexacaftor/tezacaftor/ivacaftor.

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) heterozygous for F508del and a minimal function mutation (F/MF) or homozygous for F508del (F/F) in two pivotal Phase 3 trials, significantly improving percentage predicted forced expiratory volume in 1 second, Cystic Fibrosis Questionnaire-Revised, Respiratory Domain (CFQ-R RD) scores, and sweat chloride concentration. Here, we analyzed the 11 non-respiratory domains (non-RDs) of the CFQ-R, which assess general health-related quality of life (i.e.

Mannose-Binding Lectin (MBL) and Gap Junction Protein Alpha 4 (GJA4) Gene Heterogeneity in Relation to Severity of Clinical Disease in Cystic Fibrosis.

Background: Recently, we provided evidence that a single nucleotide polymorphism (SNP), rs41266431, on the gap junction protein alpha 4 (GJA4) gene, acts as a modifier for clinical disease severity in patients with cystic fibrosis (CF). These features are very similar to those of variants of the mannose-binding lectin (MBL). This study aimed to clarify whether the clinical disease phenotype associated with GJA4 variants is independent of MBL variants.

Imprinting of bronchial epithelial cells upon rhinovirus infection in people with asthma.

Background: Defective translocation of the translational repressor TIAR (T-cell internal antigen receptor) in bronchial epithelial cells (BECs) from asthma patients underlies epithelial hyperresponsiveness, reflected by an exaggerated production of a select panel of inflammatory cytokines such as CXCL-8, interleukin (IL)-6, granulocyte colony-stimulating factor, CXCL-10, upon exposure to tumour necrosis factor (TNF) and IL-17A. With this study we aimed to clarify whether epithelial hyperresponsiveness is a consistent finding, is changed upon exposure to rhinovirus (RV)-A16 and applies to the bronchoconstrictor endothelin-1.

Methods: BECs were obtained from asthma patients (n=18) and healthy individuals (n=11), 1 day before and 6 days post-RV-A16 exposure.

Targeted exhaled breath analysis for detection of Pseudomonas aeruginosa in cystic fibrosis patients.

Background: Pseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation.

Individual and Group Response of Treatment with Ivacaftor on Airway and Gut Microbiota in People with CF and a S1251N Mutation.

Ivacaftor has been shown to restore the functionality of the S1251N (also known as c.3752G>A) mutated CFTR, which may cause alterations in both airway and gut physiology and micro-environment, resulting in a change of microbiota in these organs. The aim of the present study was to analyze the effects of ivacaftor on the microbial community composition of both airway and gut in subjects with CF carrying one S1251N mutation, using a 16S rRNA gene-based sequencing approach.

Lumacaftor/ivacaftor changes the lung microbiome and metabolome in cystic fibrosis patients.

Rationale: Targeted cystic fibrosis (CF) therapy with lumacaftor/ivacaftor partly restores chloride channel function and improves epithelial fluid transport in the airways. Consequently, changes may occur in the microbiome, which is adapted to CF lungs.

Objectives: To investigate the effects of lumacaftor/ivacaftor on respiratory microbial composition and microbial metabolic activity by repeatedly sampling the lower respiratory tract.

Impact of a Variant on Clinical Disease Phenotype in Homozygous Patients With Cystic Fibrosis.

Background: Lung disease phenotype varies widely even in the (homozygous) genotype. Leukocyte-driven inflammation is important for pulmonary disease pathogenesis in cystic fibrosis (CF). Blood cytokines correlate negatively with pulmonary function homozygous patients, and gap junction proteins (GJA) might be related to the influx of blood cells into the lung and influence disease course.

Quantitative Method for the Analysis of Ivacaftor, Hydroxymethyl Ivacaftor, Ivacaftor Carboxylate, Lumacaftor, and Tezacaftor in Plasma and Sputum Using Liquid Chromatography With Tandem Mass Spectrometry and Its Clinical Applicability.

Background: The novel cystic fibrosis transmembrane conductance regulator (CFTR) modulators, ivacaftor, lumacaftor, and tezacaftor, are the first drugs directly targeting the underlying pathophysiological mechanism in cystic fibrosis (CF); however, independent studies describing their pharmacokinetics are lacking. The aim of this study was to develop a quantification method for ivacaftor and its 2 main metabolites, lumacaftor and tezacaftor, in plasma and sputum using liquid chromatography with tandem mass spectrometry.

Methods: The developed method used a small sample volume (20 µL) and simple pretreatment method; protein precipitation solution and internal standard were added in one step to each sample.

Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation.

Background: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein and ivacaftor, in different combinations.

Methods: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein.

Phosphodiesterase 4 inhibitors attenuate virus-induced activation of eosinophils from asthmatics without affecting virus binding.

Acute respiratory virus infections, such as influenza and RSV, are predominant causes of asthma exacerbations. Eosinophils act as a double-edged sword in exacerbations in that they are activated by viral infections but also can capture and inactivate respiratory viruses. Phosphodiesterase type 4 (PDE4) is abundantly expressed by eosinophils and has been implicated in their activation.

Corticosteroid Withdrawal-Induced Loss of Control in Mild to Moderate Asthma Is Independent of Classic Granulocyte Activation.

Background: Loss of asthma control and asthma exacerbations are associated with increased sputum eosinophil counts. However, whether eosinophils, or the also present neutrophils, actively contribute to the accompanying inflammation has not been extensively investigated.

Methods: Twenty-three patients with mild to moderate asthma were included in a standardized prospective inhaled corticosteroid (ICS) withdrawal study; 22 of the patients experienced loss of asthma control.

Home videos of cystic fibrosis patients using tobramycin inhalation powder: Relation of flow and cough.

Background: Many cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa are on maintenance tobramycin inhalation therapy. Cough is reported as a side effect of tobramycin inhalation powder (TIP) in 48% of the patients. Objectives of this study were to investigate the association between the inspiratory flow of TIP and cough and to study the inhalation technique.

Eosinophils capture viruses, a capacity that is defective in asthma.

Background: Activated eosinophils cause major pathology in stable and exacerbating asthma; however, they can also display protective properties like an extracellular antiviral activity. Initial murine studies led us to further explore a potential intracellular antiviral activity by eosinophils.

Methods: To follow eosinophil-virus interaction, respiratory syncytial virus (RSV) and influenza virus were labeled with a fluorescent lipophilic dye (DiD).

Rectal Organoids Enable Personalized Treatment of Cystic Fibrosis.

In vitro drug tests using patient-derived stem cell cultures offer opportunities to individually select efficacious treatments. Here, we provide a study that demonstrates that in vitro drug responses in rectal organoids from individual patients with cystic fibrosis (CF) correlate with changes in two in vivo therapeutic endpoints. We measured individual in vitro efficaciousness using a functional assay in rectum-derived organoids based on forskolin-induced swelling and studied the correlation with in vivo effects.

Anti-IL-5 in Mild Asthma Alters Rhinovirus-induced Macrophage, B-Cell, and Neutrophil Responses (MATERIAL). A Placebo-controlled, Double-Blind Study.

Rationale: Eosinophils drive pathophysiology in stable and exacerbating eosinophilic asthma, and therefore treatment is focused on the reduction of eosinophil numbers. Mepolizumab, a humanized monoclonal antibody that neutralizes IL-5 and efficiently attenuates eosinophils, proved clinically effective in severe eosinophilic asthma but not in mild asthma.

Objectives: To study the effect of mepolizumab on virus-induced immune responses in mild asthma.

Potential importance of protease activated receptor (PAR)-1 expression in the tumor stroma of non-small-cell lung cancer.

Background: Protease activated receptor (PAR)-1 expression is increased in a variety of tumor cells. In preclinical models, tumor cell PAR-1 appeared to be involved in the regulation of lung tumor growth and metastasis; however the role of PAR-1 in the lung tumor microenvironment, which is emerging as a key compartment in driving cancer progression, remained to be explored.

Methods: In the present study, PAR-1 gene expression was determined in lung tissue from patients with non-small-cell lung cancer (NSCLC) using a combination of publicly available RNA microarray datasets and in house-made tissue microarrays including tumor biopsies of 94 patients with NSCLC (40 cases of adenocarcinoma, 42 cases of squamous cell carcinoma and 12 cases of other type of NSCLC at different stages).

β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.

We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function.We used intestinal organoids to screen a GPCR-modulating compound library and identified β2-adrenergic receptor agonists as the most potent inducers of CFTR function.β2-Agonist-induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules.

Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis.

Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects.

Oral and inhaled corticosteroid use and risk of recurrent pulmonary embolism.

Introduction: Chronic inflammatory diseases predispose for development of a first pulmonary embolism (PE). Previous studies showed that corticosteroids, which are the mainstay of treatment for inflammatory diseases, enhance the risk of a first venous thromboembolism. Yet, it is unknown whether corticosteroids also predispose for recurrent events.

Prothrombotic state in patients with severe and prednisolone-dependent asthma.

Background: Epidemiologic studies have shown that asthmatic patients, in particular those with severe disease, have increased risk of pulmonary embolism. It is unknown whether these patients have a prothrombotic state under stable conditions.

Objective: We sought to compare coagulation and fibrinolysis parameters between healthy subjects and patients with mild, severe, and prednisolone-dependent asthma under stable conditions and to investigate whether hemostatic markers correlate with airway inflammation.