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
• Alleles MeSH
• Genetic Predisposition to Disease MeSH
• Genotype MeSH
• Idiopathic Pulmonary Fibrosis * genetics   MeSH
• Humans MeSH
• Mucin-5B genetics   MeSH
• Polymorphism, Genetic MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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
• Administration, Oral MeSH
• Cell Line MeSH
• Cystic Fibrosis complications   genetics   pathology   MeSH
• Fenretinide administration & dosage   MeSH
• Phospholipids metabolism   MeSH
• Mucus metabolism   MeSH
• Rats MeSH
• Arachidonic Acid metabolism   MeSH
• Docosahexaenoic Acids metabolism   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mucin 5AC metabolism   MeSH
• Mucin-5B metabolism   MeSH
• Mice, Inbred CFTR MeSH
• Mice MeSH
• Lung drug effects   metabolism   pathology   MeSH
• Pneumonia microbiology   pathology   prevention & control   MeSH
• Pseudomonas Infections microbiology   pathology   prevention & control   MeSH
• Pseudomonas aeruginosa pathogenicity   MeSH
• Respiratory Mucosa cytology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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
• ATP-Binding Cassette Transporters genetics   MeSH
• Genome-Wide Association Study MeSH
• DNA Helicases genetics   MeSH
• Exoribonucleases genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Variation MeSH
• Idiopathic Pulmonary Fibrosis genetics   MeSH
• Host-Pathogen Interactions genetics   MeSH
• Humans MeSH
• Logistic Models MeSH
• Mucin-5B genetics   MeSH
• Promoter Regions, Genetic genetics   MeSH
• Pulmonary Surfactant-Associated Protein A genetics   MeSH
• Pulmonary Surfactant-Associated Protein C genetics   MeSH
• GTPase-Activating Proteins genetics   MeSH
• Telomere-Binding Proteins genetics   MeSH
• RNA genetics   MeSH
• Sequence Analysis, DNA MeSH
• Cellular Senescence genetics   MeSH
• Case-Control Studies MeSH
• Telomerase genetics   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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.

• Keywords
• karcinom endometria, biomarker,
• MeSH
• Chaperonin 10 MeSH
• Cyclophilin A MeSH
• Gelsolin MeSH
• Clusterin MeSH
• Mucin-5B MeSH
• Biomarkers, Tumor MeSH
• Neoplasm Proteins MeSH
• Endometrial Neoplasms diagnosis   MeSH
• Fatty Acid-Binding Proteins MeSH
• Proteomics methods   MeSH
• Pyruvate Kinase MeSH
• Receptors, Polymeric Immunoglobulin MeSH
• Proteinase Inhibitory Proteins, Secretory MeSH
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods   utilization   MeSH
• Publication type
• Review MeSH