Project description:This study aimed to compare – at a multi-omics level, inflammation, protease abundance and activity, microbiome, and proteome in sputum samples from patients with cystic fibrosis (CF, n=38) or chronic obstructive pulmonary disease (COPD, n=18) and healthy controls (n=10) to identify shared and unique pathways between these respiratory conditions. Sputum analysis revealed elevated inflammatory cell counts in both CF and COPD patients, with neutrophils being the dominant cell type. Key inflammatory markers, including IL-1β, TNF-α, TGF-β1, IL-8, and LTB4, were increased in both disease groups, with the highest levels observed in CF. Conversely, COPD patients exhibited higher levels of IL-5, IL-6, and IL-10. Microbiome analysis showed distinct clusters for each group, with CF patients often characterized by a preponderance of Pseudomonas. Hierarchical clustering unveiled robust interdependencies between microbiome parameters and inflammation, a richer and more diverse microbiome was associated with a healthier microbial community. This study uncovered significant disparities in inflammation, microbiome composition, and proteome profiles among CF, COPD, and healthy control cohorts. Neutrophilic inflammation and protease activity emerged as common factors in both diseases highlighting proteases as good targets for both indications, while distinct microbial signatures were identified. These findings offer valuable insights into the underlying mechanisms of CF and COPD and may inform future clinical strategies.
Project description:Rationale: We recently demonstrated that the triple combination CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves lung ventilation and airway mucus plugging determined by multiple-breath washout and magnetic resonance imaging in CF patients with at least one F508del allele. However, effects of ELX/TEZ/IVA on viscoelastic properties of airway mucus, chronic airway infection and inflammation have not been studied. Objectives: To examine the effects of ELX/TEZ/IVA on airway mucus rheology, microbiome and inflammation in CF patients with one or two F508del alleles aged 12 years and older. Methods: In this prospective observational study, we determined sputum rheology, microbiome, inflammation markers and proteome before and 1, 3 and 12 months after initiation of ELX/TEZ/IVA. Measurements and Main Results: CF patients with at least one F508del allele and healthy controls were enrolled in this study. ELX/TEZ/IVA improved the elastic and viscous modulus of CF sputum. Further, ELX/TEZ/IVA improved the microbiome α-diversity and decreased the relative abundance of Pseudomonas aeruginosa (P<0.05) in CF sputum. ELX/TEZ/IVA also reduced IL-8 and free NE activity, and shifted the CF sputum proteome towards healthy. Conclusions: Our data demonstrate that ELX/TEZ/IVA improves sputum viscoelastic properties, chronic airway infection and inflammation in CF patients with at least one F508del allele, however, without reaching levels close to healthy.
Project description:Sinonasal papilloma is the most common type of sinonasal tumor, with the inverted variant being the most frequent subtype. This variant is known for its potential for recurrence and propensity for malignant transformation. The aim of this study is to investigate the biomarkers and regulatory pathways involved in the development of sinonasal inverted papilloma (SNIP).
Project description:Comparative analysis of gene expression in murine sinonasal mucosa in wild-type and CC10-knockout littermates with allergic eosinophilic chronic rhinosinusitis. The data provide a comprehensive overview of genes expressed in the mouse sinonasal mucosa and show that the expression of several known and unidentified genes is modified by disruption of the CC10 gene. Total RNA isolated from sinonasal mucosae of 6- to 8-week-old mice, C57BL/6 strain, was used for this comparison. Three groups: wild-type control, wild-type with allergic eosinophilic chronic rhinosinusitis, and CC10-knockout with allergic eosinophilic chronic rhinosinusitis.
Project description:The diagnosis of sinonasal tumors is challenging due to a heterogeneous spectrum of various differential diagnoses as well as poorly defined, disputed entities such as sinonasal undifferentiated carcinomas (SNUCs). In this study, we apply machine learning algorithm based on DNA methylation patterns to classify sinonasal tumors with clinical-grade reliability. We further show that sinonasal tumors with SNUC morphology are not as undifferentiated as their current terminology suggests but rather reassigned to four distinct molecular classes defined by epigenetic, mutational and proteomic profiles. This includes two classes with neuroendocrine differentiation, characterized by IDH2 or SMARCA4/ARID1A mutations with an overall favorable clinical course, whereas tumors that are driven by SMARCB1-deficiency and tumors that represent previously misclassified adenoid cystic carcinomas are highly aggressive. Our findings have the potential to dramatically improve the diagnostic classification of sinonasal tumors and will fundamentally change the current perception of SNUCs.
Project description:The histopathological diagnosis of sinonasal tumors is challenging as it encompasses a heterogeneous spectrum of various differential diagnoses as well as poorly defined, disputed entities such as sinonasal undifferentiated carcinomas (SNUCs). In this study, we show that a machine learning algorithm based on DNA methylation is able to classify sinonasal tumors with clinical-grade reliability. We further show that tumors with SNUC morphology are not as undifferentiated as their current terminology suggests, but can be assigned to four molecular classes defined by distinct epigenic, mutational and proteomic profiles. This includes two classes with neuroendocrine differentiation, characterized by IDH2 or SWI/SNF chromatin remodeling complex mutations and overall favorable clinical course, highly aggressive tumors that are driven by SMARCB1-deficiency and tumors that represent previously misclassified adenoid-cystic carcinomas. Our findings have the potential to dramatically improve the diagnostic of challenging sinonasal tumors and could fundamentally change the current perception of SNUCs.