BACKGROUND AND OBJECTIVE: The minor T-allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real-world population of European IPF patients. METHODS: In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed. RESULTS: In a multi-variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42-49]) compared to non-carriers (29 months [CI: 26-33]; p = 4 × 10-12 ). CONCLUSION: MUC5B minor allele carriage associates with a better median transplant-free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients.
- MeSH
- alely MeSH
- genetická predispozice k nemoci MeSH
- genotyp MeSH
- idiopatická plicní fibróza * genetika MeSH
- lidé MeSH
- mucin 5B genetika MeSH
- polymorfismus genetický MeSH
- retrospektivní studie MeSH
- senioři MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cystic fibrosis (CF) is the most common genetic disease in Caucasians. CF is manifested by abnormal accumulation of mucus in the lungs, which serves as fertile ground for the growth of microorganisms leading to recurrent infections and ultimately, lung failure. Mucus in CF patients consists of DNA from dead neutrophils as well as mucins produced by goblet cells. MUC5AC mucin leads to pathological plugging of the airways whereas MUC5B has a protective role against bacterial infection. Therefore, decreasing the level of MUC5AC while maintaining MUC5B intact would in principle be a desirable mucoregulatory treatment outcome. Fenretinide prevented the lipopolysaccharide-induced increase of MUC5AC gene expression, without affecting the level of MUC5B, in a lung goblet cell line. Additionally, fenretinide treatment reversed the pro-inflammatory imbalance of fatty acids by increasing docosahexaenoic acid and decreasing the levels of arachidonic acid in a lung epithelial cell line and primary leukocytes derived from CF patients. Furthermore, for the first time we also demonstrate the effect of fenretinide on multiple unsaturated fatty acids, as well as differential effects on the levels of long- compared to very-long-chain saturated fatty acids which are important substrates of complex phospholipids. Finally, we demonstrate that pre-treating mice with fenretinide in a chronic model of P. aeruginosa lung infection efficiently decreases the accumulation of mucus. These findings suggest that fenretinide may offer a new approach to therapeutic modulation of pathological mucus production in CF.
- MeSH
- aplikace orální MeSH
- buněčné linie MeSH
- cystická fibróza komplikace genetika patologie MeSH
- fenretinid aplikace a dávkování MeSH
- fosfolipidy metabolismus MeSH
- hlen metabolismus MeSH
- krysa rodu rattus MeSH
- kyselina arachidonová metabolismus MeSH
- kyseliny dokosahexaenové metabolismus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- mucin 5AC metabolismus MeSH
- mucin 5B metabolismus MeSH
- myši inbrední CFTR MeSH
- myši MeSH
- plíce účinky léků metabolismus patologie MeSH
- pneumonie mikrobiologie patologie prevence a kontrola MeSH
- pseudomonádové infekce mikrobiologie patologie prevence a kontrola MeSH
- Pseudomonas aeruginosa patogenita MeSH
- respirační sliznice cytologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.
- MeSH
- ABC transportéry genetika MeSH
- celogenomová asociační studie MeSH
- DNA-helikasy genetika MeSH
- exoribonukleasy genetika MeSH
- genetická predispozice k nemoci MeSH
- genetická variace MeSH
- idiopatická plicní fibróza genetika MeSH
- interakce hostitele a patogenu genetika MeSH
- lidé MeSH
- logistické modely MeSH
- mucin 5B genetika MeSH
- promotorové oblasti (genetika) genetika MeSH
- protein A asociovaný s plicním surfaktantem genetika MeSH
- protein C asociovaný s plicním surfaktantem genetika MeSH
- proteiny aktivující GTPasu genetika MeSH
- proteiny vázající telomery genetika MeSH
- RNA genetika MeSH
- sekvenční analýza DNA MeSH
- stárnutí buněk genetika MeSH
- studie případů a kontrol MeSH
- telomerasa genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Cíl studie: Popis nových biomarkerů karcinomu endometria s využitím proteomických technik. Typ studie: Přehledový článek. Název a sídlo pracoviště: Lékařská fakulta Hradec Králové, Univerzita Karlova Praha. Porodnická a gynekologická klinika FN Hradec Králové. Metodika: Shrnutí literárních údajů o nových biomarkerech karcinomu endometria za využití proteomického přístupu. Závěr: Práce sumarizuje výsledky klinických a vědeckých prací zaměřených na biomarkery karcinomu endometria.
Objective: The purpose of this study was to focuse on recent developments on the evolving field of biomarker discovery and validation techniques using proteomics platforms for endometrial carcinoma. Design: Review. Setting: Department of Obstetrics and Gynecology Medical Faculty Charles University Hradec Kralove. Methods: The last decade has seen major changes in the technologies used to identify markers for diagnosing endometrial carcinoma. Currently the major developments were made in proteomics area. This new technology hold significant promise in identifying more robust markers for endometrial carcinoma. Conclusion: The present review summarizes the results of clinical and experimental research on biomarkers of endometrial carcinoma.
- Klíčová slova
- karcinom endometria, biomarker,
- MeSH
- chaperonin 10 MeSH
- cyklofilin A MeSH
- gelsolin MeSH
- klusterin MeSH
- mucin 5B MeSH
- nádorové biomarkery MeSH
- nádorové proteiny MeSH
- nádory endometria diagnóza MeSH
- proteiny vázající mastné kyseliny MeSH
- proteomika metody MeSH
- pyruvátkinasa MeSH
- receptory polymerů imunoglobulinů MeSH
- sekreční inhibitory proteinas MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice metody využití MeSH
- Publikační typ
- přehledy MeSH
