BACKGROUND: The genetic and epigenetic alterations observed in acute myeloid leukemia (AML) contribute to its heterogeneity, influencing disease progression response to therapy, and patient outcomes. The use of antisense oligonucleotides (ASOs) technology allows for the design of oligonucleotide inhibitors based on gene sequence information alone, enabling precise targeting of key molecular pathways or specific genes implicated in AML. METHODS AND RESULTS: Midostaurin, a FLT3 specific inhibitor and ASOs targeting particular genes, exons, or mutations was conducted using AML models. This ASOs treatment was designed to bind to exon 7 of the MBNL1 (muscleblind-like) gene. Another target was the FLT3 gene, focusing on two aspects: (a) FLT3-ITD (internal tandem duplication), to inhibit the expression of this aberrant gene form, and (b) the FLT3 in general. Treated and untreated cells were analyzed using quantitative PCR (qPCR), dot blot, and Raman spectroscopy. This study contrasts midostaurin with ASOs that inhibit FLT3 protein production or its isoforms via mRNA degradation. A trend of increased FLT3 expression was observed in midostaurin-treated cells, while ASO-treated cells showed decreased expression, though these changes were not statistically significant. CONCLUSIONS: In AML, exon 7 of MBNL1 is involved in several cellular processes and in this study, exon 7 of MBNL1 was targeted for method optimization, with the highest block of the exon 7 gene variant observed 48 h post-transfection. Midostaurin, a multitargeted kinase inhibitor, acts against the receptor tyrosine kinase FLT3, a critical molecule in AML pathogenesis. While midostaurin blocks FLT3 signaling pathways, it paradoxically increases FLT3 expression.
- MeSH
- akutní myeloidní leukemie * genetika farmakoterapie MeSH
- antisense oligonukleotidy * farmakologie genetika MeSH
- exony genetika MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- proteiny vázající RNA genetika metabolismus MeSH
- regulace genové exprese u leukemie účinky léků MeSH
- staurosporin * analogy a deriváty farmakologie MeSH
- tyrosinkinasa 3 podobná fms * genetika antagonisté a inhibitory metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Recent advances in endoscopic technology have allowed detailed observation of the gastric mucosa, including Raman microscopy and spectroscopy. To explore the possibilities for future diagnostic use, we discuss the measurements and molecular markers found in this tissue. The Raman spectra of 16 samples of antral mucosa and 16 samples of corpus gastric mucosa obtained from healthy donors were analysed. A stable protocol for measuring reproducible spectra was established. These data suggest that many biomarkers can be used for the rapid analysis of metabolic states and future investigations into the pathogenesis of gastrointestinal diseases.
- Publikační typ
- časopisecké články MeSH
Acute myeloid leukaemia (AML) is a complex haematological malignancy characterised by diverse genetic alterations leading to abnormal proliferation of myeloid precursor cells. One of the most significant genetic alterations in AML involves mutations in the FLT3 gene, which plays a critical role in haematopoiesis and haematopoietic homeostasis. This review explores the current understanding of FLT3 gene mutations and isoforms and the importance of the FLT3 protein in AML. FLT3 mutations, including internal tandem duplications (FLT3-ITD) and point mutations in the tyrosine kinase domain (FLT3-TKD), occur in 25-30% in AML and are associated with poor prognosis. FLT3-ITD mutations lead to constitutive activation of the FLT3 signalling pathway, promoting cell survival and proliferation. FLT3-TKD mutations affect the tyrosine kinase domain and affect AML prognosis in various ways. Furthermore, FLT3 isoforms, including shorter variants, contribute to the complexity of FLT3 biology. Additionally, nonpathological polymorphisms in FLT3 are being explored for their potential impact on AML prognosis and treatment response. This review also discusses the development of molecular treatments targeting FLT3, including first-generation and next-generation tyrosine kinase inhibitors, highlighting the challenges of resistance that often arise during therapy. The final chapter describes FLT3 protein domain rearrangements and their relevance to AML pathogenesis.
- MeSH
- akutní myeloidní leukemie * genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- protein - isoformy genetika MeSH
- tyrosinkinasa 3 podobná fms genetika MeSH
- tyrosinkinasy MeSH
- viabilita buněk MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Kopřivka je časté onemocnění s typickým klinickým obrazem. Přestože je kopřivka poměrně jasnou diagnózou, u více než 20 % populace je nutné v rámci diferenciální diagnostiky vyloučit závažnější příčiny. V článku je uvedena základní klasifikace, patofyziologie, nejčastější příčiny, diagnostika a základní léčba kopřivky.
Urticaria is widely considered disease with typical skin reaction. Although the clinical diagnosis of urticaria is relatively straightforward, in more than 20% of the population it is necessary to exclude more serious causes as part of the differential diagnosis. Etiology of urticaria is mentioned in the article with regard to its pathophysiological background.
- MeSH
- antihistaminika terapeutické užití MeSH
- chronická urtikarie diagnóza etiologie imunologie MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- kožní nemoci etiologie klasifikace MeSH
- lidé MeSH
- mastocyty imunologie MeSH
- urtikarie * diagnóza etiologie farmakoterapie klasifikace patofyziologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
This article compares two important pathophysiological states, Kawasaki disease, and multisystem inflammatory syndrome, in children associated with COVID-19 (MIS-C). Both occur predominantly in children, have a temporal association with an infectious agent, and are associated with immune-system alteration and systemic inflammation under certain circumstances. The two share common pathophysiology, including enhancement of interleukin-1 neutrophils, activation of the inflammasome, pyroptosis, or NETosis. Moreover, the clinical presentation of the diseases overlaps. However, they are indeed two separate diseases, proven by the differences in the epidemiological and etiological aspects and the pathophysiological processes involved in the development and frequency of some clinical signs. This article highlights potentially exciting areas that have not yet been studied in detail, which could help better understand the development of these diseases.
- MeSH
- COVID-19 * MeSH
- dítě MeSH
- Kawasakiho syndrom * diagnóza MeSH
- lidé MeSH
- syndrom systémové zánětlivé reakce MeSH
- zánět MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- dítě MeSH
- lidé MeSH
- postakutní syndrom COVID-19 * diagnóza patofyziologie MeSH
- rizikové faktory MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
Polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are ubiquitous and toxic contaminants. Their atmospheric deposition fluxes on the regional scale were quantified based on simultaneous sampling during 1 to 5 years at 1 to 6 background/rural sites in the Czech Republic and Austria. The samples were extracted and analysed by means of gas chromatography coupled to mass spectrometry. For all seasons and sites, total deposition fluxes for Σ15PAHs ranged 23-1100 ng m-2 d-1, while those for Σ6PCBs and Σ12OCPs ranged 64-4400 and 410-7800 pg m-2 d-1, respectively. Fluoranthene and pyrene were the main contributors to the PAH deposition fluxes, accounting on average for 19% each, while deposition fluxes of PCBs and OCPs were dominated by PCB153 (26%) and γ-hexachlorobenzene (30%), respectively. The highest deposition flux of Σ15PAHs was generally found in spring, while no seasonality was found for PCB deposition. For deposition fluxes for Σ12OCPs, no clear spatial trend was found, confirming the perception of long-lived regional pollutants. Although most OCPs and PCBs hardly partition to the particulate phase in ambient air, on average, 42% of their deposition fluxes were found on filters, confirming the perception that particle deposition is more efficient than dry gaseous deposition. Due to methodological constraints, fluxes derived from bulk deposition samplers should be understood as lower estimates, in particular with regard to those substances which in ambient aerosols mostly partition to the particulate phase.
- MeSH
- chlorované uhlovodíky analýza MeSH
- hexachlorbenzen analýza MeSH
- látky znečišťující vzduch analýza MeSH
- monitorování životního prostředí * MeSH
- pesticidy analýza MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
- polychlorované bifenyly analýza MeSH
- polycyklické aromatické uhlovodíky analýza MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Evropa MeSH
- Rakousko MeSH
