- MeSH
- hlavní histokompatibilní komplex imunologie MeSH
- molekulární sekvence - údaje MeSH
- mutace MeSH
- myši MeSH
- receptory kyseliny retinové MeSH
- rekombinantní proteiny genetika metabolismus MeSH
- transkripční faktory genetika MeSH
- tretinoin metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- MeSH
- kyselina valproová * farmakologie MeSH
- nádorové buňky kultivované * účinky léků MeSH
- nádory kostní dřeně * farmakoterapie genetika MeSH
- p21 aktivované kinasy * genetika účinky léků MeSH
- průtoková cytometrie metody MeSH
- regulace genové exprese u leukemie * genetika účinky léků MeSH
- retinoidy * farmakologie MeSH
- synergismus léků * MeSH
- techniky in vitro MeSH
- transkripční faktory * genetika účinky léků MeSH
- Publikační typ
- práce podpořená grantem MeSH
Akútna myeloidná leukémia (AML) je značne heterogénny podtyp leukémie, ktorý predstavuje 25 % všetkých detských leukémií. Prítomnosťou genetických mutácií v kmeňových krvotvorných/progenitorových bunkách produkuje kostná dreň veľké množstvo abnormálnych nediferencovaných leukocytov (blastov), čo výrazne narúša správnu diferenciáciu buniek. AML je indukovaná dvomi zásahmi. Chromozomálna translokácia počas hematopoézy vnútromaternicového vývoja predstavuje prvý zásah. Tak vzniknú preleukemické fúzne gény (PFG), ktoré sa môžu neskôr transformovať druhým zásahom (bodová genetická mutácia - delécia, inzercia...) na funkčný malígny klon. Medzi charakteristické fúzne gény AML patria napríklad AML1-ETO, PML‐RARA či MLL‐AF9, ktoré následne produkujú hybridné proteíny so zmenenou funkciou. Viaceré štúdie poukazujú na to, že tieto PFG sú považované za dôležitý prognostický nástroj pri hodnotení ochorení. Zatiaľ čo výskyt PFG charakteristických pre akútnu lymfoblastickú leukémiu (ALL) je relatívne dobre preskúmaný a odhadoval sa na 1 až 5 % v pupočníkovej krvi zdravých novorodencov, PFG relevantné pre AML stále nie sú dostatočne objasnené.
Acute myeloid leukemia (AML) is a highly heterogeneous subtype of leukemia, accounting for 25 % of childhood leukemias. By the presence of genetic mutations in hematopoietic/ progenitor stem cells, the bone marrow produces a large number of abnormal undifferentiated leukocytes (blasts), which significantly impairs the proper differentiation of cells. AML is induced by two interventions. Chromosomal translocation during hematopoiesis of intrauterine development is the first intervention. This creates preleukemic fusion genes (PFG), which can later be transformed by a second intervention (point genetic mutation - deletion, insertion ...) into a functional malignant clone. Characteristic AML fusion genes include AML1-ETO, PML-RARA or MLL-AF9, which in turn produce hybrid proteins with altered function. Several studies suggest that these PFGs are considered an important prognostic tool in disease assessment. While the incidence of PFG characteristic of acute lymphoblastic leukemia (ALL) has been relatively well studied by several research groups and has been estimated at 1 to 5% in the umbilical cord blood of healthy neonates, PFG relevant to AML are still not sufficiently clarified.
- MeSH
- akutní myeloidní leukemie * diagnóza genetika MeSH
- alfa receptor kyseliny retinové genetika MeSH
- fúzní onkogenní proteiny * genetika MeSH
- lidé MeSH
- protein PEBP2A2 genetika MeSH
- protein promyelocytické leukemie genetika MeSH
- protoonkogenní protein MLL genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
In higher metazoans, the nuclear hormone receptors activate transcription trough their specific adaptors, nuclear hormone receptor adaptors NCoA, which are absent in lower metazoans. The Nine amino acid TransActivation Domain, 9aaTAD, was reported for a large number of the transcription activators that recruit general mediators of transcription. In this study, we demonstrated that the 9aaTAD from NHR-49 receptor of nematode C.elegans activates transcription as a small peptide. We showed that the ancient 9aaTAD domains are conserved in the nuclear hormone receptors including human HNF4, RARa, VDR and PPARg. Also their small 9aaTAD peptides effectively activated transcription in absence of the NCoA adaptors. We also showed that adjacent H11 domains in ancient and modern hormone receptors have an inhibitory effect on their 9aaTAD function.
- MeSH
- aktivace transkripce * MeSH
- alfa receptor kyseliny retinové chemie metabolismus MeSH
- Caenorhabditis elegans chemie metabolismus MeSH
- hepatocytární jaderný faktor 4 chemie metabolismus MeSH
- lidé MeSH
- molekulární modely MeSH
- peptidy chemie metabolismus MeSH
- PPAR gama chemie metabolismus MeSH
- proteinové domény MeSH
- proteiny Caenorhabditis elegans chemie metabolismus MeSH
- receptory cytoplazmatické a nukleární chemie metabolismus MeSH
- receptory kalcitriolu chemie metabolismus MeSH
- sekvence aminokyselin MeSH
- sekvenční seřazení MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The main objective of this study was to analyze changes in the antiproliferative effect of vitamin D3, in the form of calcitriol and calcidiol, via its combined application with all-trans retinoic acid (ATRA) in osteosarcoma cell lines. The response to treatment with calcitriol and calcidiol alone was specific for each cell line. Nevertheless, we observed an enhanced effect of combined treatment with ATRA and calcitriol in the majority of the cell lines. Although the levels of respective nuclear receptors did not correlate with the sensitivity of cells to these drugs, vitamin D receptor (VDR) upregulation induced by ATRA was found in cell lines that were the most sensitive to the combined treatment. In addition, all these cell lines showed high endogenous levels of retinoic acid receptor α (RARα). Our study confirmed that the combination of calcitriol and ATRA can achieve enhanced antiproliferative effects in human osteosarcoma cell lines in vitro. Moreover, we provide the first evidence that ATRA is able to upregulate VDR expression in human osteosarcoma cells. According to our results, the endogenous levels of RARα and VDR could be used as a predictor of possible synergy between ATRA and calcitriol in osteosarcoma cells.
- MeSH
- alfa receptor kyseliny retinové metabolismus MeSH
- kalcifediol aplikace a dávkování MeSH
- kalcitriol aplikace a dávkování MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- osteosarkom farmakoterapie metabolismus MeSH
- protinádorové látky aplikace a dávkování MeSH
- protokoly protinádorové kombinované chemoterapie MeSH
- receptory kalcitriolu metabolismus MeSH
- screeningové testy protinádorových léčiv MeSH
- tretinoin aplikace a dávkování MeSH
- vitaminy aplikace a dávkování MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
It was hypothesised that mitochondrial iron overload in patients with refractory anemia with ring sideroblasts (RARS) results from mitochondrial DNA (mtDNA) mutations. To analyse the mtDNA sequence of iron storing mitochondria sensitively, we developed new protocols for selective erythroblasts isolation, mtDNA PCR amplification and sequencing. Using this approach, we found in each of the three RARS patients examined a unique spectrum of homoplasmic mtDNA point mutations affecting several mtDNA genes. Prediction analyses suggest that identified mutations do not result in major perturbations of mitochondrial functions and are tolerated. We discuss a mechanism explaining how the mutations identified may contribute to RARS pathogenesis.
Antigen-presenting cells (APCs) are master regulators of the immune response by directly interacting with T cells to orchestrate distinct functional outcomes. Several types of professional APC exist, including conventional dendritic cells, B cells and macrophages, and numerous other cell types have non-classical roles in antigen presentation, such as thymic epithelial cells, endothelial cells and granulocytes. Accumulating evidence indicates the presence of a new family of APCs marked by the lineage-specifying transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt) and demonstrates that these APCs have key roles in shaping immunity, inflammation and tolerance, particularly in the context of host-microorganism interactions. These RORγt+ APCs include subsets of group 3 innate lymphoid cells, extrathymic autoimmune regulator-expressing cells and, potentially, other emerging populations. Here, we summarize the major findings that led to the discovery of these RORγt+ APCs and their associated functions. We discuss discordance in recent reports and identify gaps in our knowledge in this burgeoning field, which has tremendous potential to advance our understanding of fundamental immune concepts.
- MeSH
- antigen prezentující buňky metabolismus MeSH
- endoteliální buňky MeSH
- jaderné receptory - podrodina 1, skupina F, člen 3 * metabolismus MeSH
- lidé MeSH
- lymfocyty * MeSH
- přirozená imunita MeSH
- transportní proteiny metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
