V roce 2009 se metoda masivního paralelního sekvenování (NGS) prokázala jako velmi účinný nástroj při identifikaci variant, které souvisí s mnoha neurodegenerativními nemocemi. Množství genetických dat mělo významný dopad na klinickou diagnózu a zároveň významně přispělo k objevu molekulárních mechanismů, které jsou základem těchto onemocnění. Nicméně objasnění rolí nalezených variant identifikovaných NGS, a zejména variant nejasného významu (VUS), je náročné a je zcela klíčová spolupráce genetika, neurologa a neuropatologa. Vytvoření konsenzuálních postupů a vývoj veřejných genomických/fenotypových databází jsou proto zásadní pro usnadnění sdílení a ověřování údajů. Práce poskytuje systematický přehled nejčastějších mutací u neuropatologicky diagnostikovaných pacientů s neurodegenerativním onemocněním a shrnuje techniky genetické diagnostiky a význam bioinformatiky při interpretaci výsledků neurodegenerativních onemocnění na příkladu 5 zajímavých kazuistik.
In 2009, next-generation sequencing (NGS) proved to be a very powerful tool in identifying variants associated with many neurodegenerative diseases. Whole-exome sequencing and whole-genome sequencing are effective for identifying variants in new or unexpected genes responsible for inherited diseases, while targeted sequencing is useful in detecting variants in previously known disease-associated genes. The wealth of genetic data provided by NGS has had a significant impact on clinical diagnoses while contributing to these discoveries of the molecular mechanisms underlying disease. However, eluciding the roles of the found variants identified by NGS, and especially the variants of unclear significance (VUS), is challenging and the cooperation of a geneticist, a neurologist and a neuropathologist is absolutely key. The establishment of consensus guidelines and the development of public genomic/phenotypic databases are therefore essential to facilitate data sharing and validation. In this review article, we will provide a systematic overview of the most frequent mutations in neuropathologically diagnosed patients with neurodegenerative diseases and summarize genetic diagnostic techniques and the importance of bioinformatics in the interpretation of neurodegenerative disease results.
- MeSH
- Alzheimerova nemoc diagnóza genetika patologie MeSH
- amyotrofická laterální skleróza diagnóza genetika patologie MeSH
- Creutzfeldtova-Jakobova nemoc diagnóza genetika patologie MeSH
- diagnostické techniky molekulární MeSH
- frontotemporální lobární degenerace diagnóza genetika patologie MeSH
- genetická predispozice k nemoci genetika MeSH
- genetické testování metody MeSH
- Gerstmannova-Strausslerova-Scheinkerova nemoc diagnóza genetika patologie MeSH
- lidé MeSH
- neurodegenerativní nemoci * diagnóza genetika patologie MeSH
- vysoce účinné nukleotidové sekvenování metody MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Proteinase-activated receptors (PARs) were discovered more than 25 years ago and since then, their role in cancer has been under investigation. Research has primarily focused on the receptors located on the membrane of cancer cells and their impact on metabolism, intracellular signalling, and proliferation. Regarding the host response to cancer, studies have predominantly examined the relationship of thrombin receptors (PAR-1, PAR-3, and PAR-4) with blood clotting in distant metastatic spread. However, limited studies have examined the role of PARs, especially PAR-2, in the host anti-tumor immunity. This review article provides insights into the role of PAR-2 on cancer cells and immune competent cells involved in cancer development and progression. It also discussed the current knowledge of the importance of PAR-2 activation at various stages of cancer progression and its association with cancer-related pain.
- MeSH
- lidé MeSH
- nádory * metabolismus MeSH
- receptor PAR-1 metabolismus MeSH
- receptor PAR-2 * metabolismus MeSH
- signální transdukce fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
A 41-year-old man was admitted to hospital due to sudden loss of consciousness. A regional brain perfusion SPECT/low-dose CT showed abnormal 99m Tc-HMPAO uptake in the right hemisphere frontotemporally without any other supratentorial or infratentorial radiotracer uptake. A neuropathological examination disclosed a middle cerebral artery aneurysm. Presumably, vessel wall fibrosis prevented collapse. Multiple transmural dissections of the fibrotic aneurysmal wall were the source of the subarachnoid hemorrhage. This interesting image shows that radiotracer accumulation in cerebral artery aneurysms can be a diagnostic pitfall in brain death scintigraphy assessment.
It has been 30 years since the first member of the protease-activated receptor (PAR) family was discovered. This was followed by the discovery of three other receptors, including PAR2. PAR2 is a G protein-coupled receptor activated by trypsin site-specific proteolysis. The process starts with serine proteases acting between arginine and serine, creating an N-terminus that functions as a tethered ligand that binds, after a conformational change, to the second extracellular loop of the receptor, leading to activation of G-proteins. The physiological and pathological functions of this ubiquitous receptor are still elusive. This review focuses on PAR2 activation and its distribution under physiological and pathological conditions, with a particular focus on the pancreas, a significant producer of trypsin, which is the prototype activator of the receptor. The role in acute or chronic pancreatitis, pancreatic cancer, and diabetes mellitus will be highlighted.
- MeSH
- lidé MeSH
- nemoci slinivky břišní * diagnóza MeSH
- pankreas metabolismus MeSH
- receptor PAR-2 * metabolismus MeSH
- receptory spřažené s G-proteiny MeSH
- trypsin metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
AIMS: Inflammatory bowel diseases and colorectal cancer are serious intestinal disorders with continuously increasing incidence. Many aspects of etiopathogenesis still remain unclear. There is an urgent need to improve early diagnostics and markers indicating the progression of the disease. The aim of our study was to analyze the expression of matrix metalloproteinase-19 (MMP-19), and the receptor for advanced glycation end-products (RAGE) in different cell subpopulations in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) compared to the tissue in the vicinity of pathological processes. METHODS: Expression of both markers in epithelium, macrophages and vessels were evaluated in IBD and CRC groups. They were detected using immunohistochemistry in paraffin sections. RESULTS: There were significant differences between the expression of MMP-19 on macrophages and vessels among healthy and cancer tissues. In both, macrophages and vessels were significantly lower levels in cancer tissues. The expression of MMP-19 on vessels was also significantly different between peritumoral and cancer tissues (higher levels in peritumoral tissue). RAGE expression in macrophages was significantly different between healthy and cancer tissues and between peritumoral and cancer tissues. There was significantly lower expression in cancer tissues than in healthy and peritumoral tissues. Expression of RAGE in vessels was significantly different just in the comparison of healthy and peritumoral tissues (higher levels in healthy tissues). CONCLUSION: Both markers seem to be promising potential auxiliary markers in IBD and CRC diagnostics. They can also improve evaluation of disease progression.
- MeSH
- biologické markery metabolismus MeSH
- idiopatické střevní záněty * diagnóza metabolismus patologie MeSH
- kolorektální nádory * diagnóza metabolismus patologie MeSH
- lidé MeSH
- metaloproteinasy secernované do matrix MeSH
- receptor pro konečné produkty pokročilé glykace metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
