"No.CZ.02.1.01/0.0/0.0/16_019/0000868" Dotaz Zobrazit nápovědu
Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR = 2.4, p = 0.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. Conversely, we identified significantly upregulated EZH2 and CD70 as potential future therapeutic options. For the first time, we report on the tumor microenvironment of EMM, revealing CD8+ T cells and NK cells as predominant immune effector cells using single-cell sequencing. Finally, this is the first longitudinal study in EMM revealing the molecular changes from the time of diagnosis to EMM relapse.
- MeSH
- kostní dřeň patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom * genetika patologie MeSH
- mutace MeSH
- nádorové biomarkery genetika MeSH
- nádorové mikroprostředí * genetika MeSH
- prognóza MeSH
- senioři MeSH
- vysoce účinné nukleotidové sekvenování * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Xylaria species associated with termite nests or soil have been considered rare species in nature and the few which have been reported upon have been found to act as a rich source of bioactive metabolites. This study evaluated 10 ethyl acetate extracts of five new Xylaria species associated with termite nests or soil for their antioxidant activity, and cytotoxicity against different cancer and normal cell lines. DPPH and ABTS radical scavenging activities of the extracts demonstrated strong capacity with low IC50 values. The highest observed activities belonged to X. vinacea SWUF18-2.3 having IC50 values of 0.194 ± 0.031 mg/mL for DPPH assay and 0.020 ± 0.004 mg/mL for ABTS assay. Total phenolic content ranged from 0.826 ± 0.123 to 3.629 ± 0.381 g GAE/g crude extract which correlated with antioxidant activities. The high total phenolic content could contribute to the high antioxidant activities. Cytotoxicity was recorded against A549, HepG2, HeLa and PNT2 and resulted in broad spectrum to specific activity depending on the cell lines. The highest activities were observed with X. subintraflava SWUF16-11.1 which resulted in 11.15 ± 0.32 to 13.17 ± 2.37% cell viability at a concentration of 100 µg/mL. Moreover, LC-MS fingerprints indicated over 61 peaks from all isolates. There were 18 identified and 43 unidentified compounds compared to mass databases. The identified compounds were from various groups of diterpenoids, diterpenes, cytochalasin, flavones, flavonoids, polyphenols, steroids and derivatives, triterpenoids and tropones. These results indicate that Xylaria spp. has abundant secondary metabolites that could be further explored for their therapeutic properties.
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Plasmacytoid dendritic cells (pDCs) play prominent roles in mediating innate and adaptive immune responses. However, it is unclear how pDCs contribute to the immunosuppressive tumor microenvironment described in multiple myeloma (MM). METHODS: Newly diagnosed myeloma patients (MM, n = 37) were analyzed to determine the pDC counts in comparison to peripheral blood (PB, n = 53) and bone marrow (BM, n = 10) samples of age-matched healthy donors (HD) using flow cytometry. Second, proliferation of myeloma tumor cells in the presence of freshly isolated pDCs was examined. Third, production of IFNα by pDCs co-cultured with MM cells was determined by intracellular staining. RESULTS: We found a highly significant reduction of circulating pDCs (p < 0.0001) and in bone marrow (p < 0.0001) of MM patients compared to HD. We also observed a significant decrease of pDCs (p = 0.004) in BM in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 12). Importantly, we determined that pDCs promote proliferation specifically of MM cells and not the stromal cells and that pDCs secrete IFNα upon co-culture with MM tumor cells. CONCLUSIONS: Our results show altered pDC frequencies in the BM microenvironment in MGUS and MM patients at diagnosis. We showed the tumor-promoting function of pDCs that may mediate immune deficiencies affecting long-term disease control and treatment outcome.
- Publikační typ
- časopisecké články MeSH
Dihydrofuranocoumarin, chalepin (1) and furanocoumarin, chalepensin (2) are 3-prenylated bioactive coumarins, first isolated from the well-known medicinal plant Ruta chalepensis L. (Fam: Rutaceae) but also distributed in various species of the genera Boenminghausenia, Clausena and Ruta. The distribution of these compounds appears to be restricted to the plants of the family Rutaceae. To date, there have been a considerable number of bioactivity studies performed on coumarins 1 and 2, which include their anticancer, antidiabetic, antifertility, antimicrobial, antiplatelet aggregation, antiprotozoal, antiviral and calcium antagonistic properties. This review article presents a critical appraisal of publications on bioactivity of these 3-prenylated coumarins in the light of their feasibility as novel therapeutic agents and investigate their natural distribution in the plant kingdom, as well as a plausible biosynthetic route.
- MeSH
- Clausena chemie MeSH
- furokumariny biosyntéza farmakologie MeSH
- kumariny chemie MeSH
- léčivé rostliny chemie MeSH
- lidé MeSH
- rostlinné extrakty metabolismus farmakologie MeSH
- Ruta chemie MeSH
- Rutaceae chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Hepatocyte dedifferentiation is a major source of hepatocellular carcinoma (HCC), but its mechanisms are unknown. We explored the p73 expression in HCC tumors and studied the effects of transcriptionally active p73β (TAp73β) in HCC cells. Expression profiles of p73 and patient clinical data were collected from the Genomic Data Commons (GDC) data portal and the TSVdb database, respectively. Global gene expression profiles were determined by pan-genomic 54K microarrays. The Gene Set Enrichment Analysis method was used to identify TAp73β-regulated gene sets. The effects of TAp73 isoforms were analyzed in monolayer cell culture, 3D-cell culture and xenograft models in zebrafish using western blot, flow cytometry, fluorescence imaging, real-time polymerase chain reaction (RT-PCR), immunohistochemistry and morphological examination. TAp73 isoforms were significantly upregulated in HCC, and high p73 expression correlated with poor patient survival. The induced expression of TAp73β caused landscape expression changes in genes involved in growth signaling, cell cycle, stress response, immunity, metabolism and development. Hep3B cells overexpressing TAp73β had lost hepatocyte lineage biomarkers including ALB, CYP3A4, AFP, HNF4α. In contrast, TAp73β upregulated genes promoting cholangiocyte lineage such as YAP, JAG1 and ZO-1, accompanied with an increase in metastatic ability. Our findings suggest that TAp73β may promote malignant dedifferentiation of HCC cells.
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Organic molecules that bind to cannabinoid receptors are called cannabinoids, and they have similar pharmacological properties like the plant, Cannabis sativa L. Hyphenated liquid chromatography (LC), incorporating high-performance liquid chromatography (HPLC) and ultra-performance liquid chromatography (UPLC, also known as ultrahigh-performance liquid chromatography, UHPLC), usually coupled to an ultraviolet (UV), UV-photodiode array (PDA) or mass spectrometry (MS) detector, has become a popular analytical tool for the analysis of naturally occurring cannabinoids in various matrices. OBJECTIVE: To review literature on the use of various LC-based analytical methods for the analysis of naturally occurring cannabinoids published since 2010. METHODOLOGY: A comprehensive literature search was performed utilising several databases, like Web of Knowledge, PubMed and Google Scholar, and other relevant published materials including published books. The keywords used, in various combinations, with cannabinoids being present in all combinations, in the search were Cannabis, hemp, cannabinoids, Cannabis sativa, marijuana, analysis, HPLC, UHPLC, UPLC, quantitative, qualitative and quality control. RESULTS: Since 2010, several LC methods for the analysis of naturally occurring cannabinoids have been reported. While simple HPLC-UV or HPLC-UV-PDA-based methods were common in cannabinoids analysis, HPLC-MS, HPLC-MS/MS, UPLC (or UHPLC)-UV-PDA, UPLC (or UHPLC)-MS and UPLC (or UHPLC)-MS/MS, were also used frequently. Applications of mathematical and computational models for optimisation of different protocols were observed, and pre-analyses included various environmentally friendly extraction protocols. CONCLUSIONS: LC-based analysis of naturally occurring cannabinoids has dominated the cannabinoids analysis during the last 10 years, and UPLC and UHPLC methods have been shown to be superior to conventional HPLC methods.
INTRODUCTION: Artemisinin (1), a well-known natural antimalarial drug, is a sesquiterpene lactone that contains a unique peroxide bridge. Since its discovery, the amount of research into the analysis of artemisinin has increased considerably, and it has been further intensified since the Noble Prize win by Tu Youyou in the year 2015 for the discovery of artemisinin. OBJECTIVE: To review literature on the extraction and analysis of artemisinin, published during 2017-present, and to present an appraisal of those methods. METHODOLOGY: Extensive literature search was carried out which involved, but not limited to, the use of, various databases, like Web of Knowledge, PubMed and Google Scholar, and relevant published materials including published books. The keywords used, in various combinations, with artemisinin being present in all combinations, in the search were artemisinin, Artemisia annua, analysis, extraction, quantitative, qualitative and quality control. RESULTS: During the period covered in this review, several methods of analysis of artemisinin have been reported, the most of which were liquid chromatography (LC)-based methods. However, the use of new methods like near-infrared analysis, fluorometirc analysis and molecular imprinting, and a significant increase in the use of computational tools have been observed. Mainly several methods involving supercritical fluid extraction and ultrasound-assisted extraction of artemisinin have dominated the extraction area. CONCLUSIONS: Newer analytical tools, as well as improved protocols for the known analytical tools, for qualitative and quantitative determination of artemisinin (1), have been made available by various researchers during the period covered by this review. Supercritical fluid extraction and ultrasound-assisted extraction are still the methods of choice for extraction of artemisinin.
Cell-to-cell communication is a fundamental process in every multicellular organism. In addition to membrane-bound and released factors, the sharing of cytosolic components represents a new, poorly explored signaling route. An extraordinary example of this communication channel is the direct transport of mitochondria between cells. In this review, we discuss how intercellular mitochondrial transfer can be used by cancer cells to sustain their high metabolic requirements and promote drug resistance and describe relevant molecular players in the context of current and future cancer therapy.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
