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Povzetek: Glioblastoma multiforme is the most lethal of brain cancer, and it comprises a heterogeneous mixture of functionally distinct cancer cells that affect tumor progression. We examined the U87, U251, and U373 malignant cell lines as in vitro models to determine the impact of cellular cross-talk on their phenotypic alterations in co-cultures. These cells were also studied at the transcriptome level, to define the mechanisms of their observed mutually affected genomic stability, proliferation, invasion and resistance to temozolomide. This is the first direct demonstration of the neural and mesenchymal molecular fingerprints of U87 and U373 cells, respectively. U87-cell conditioned medium lowered the genomic stability of U373 (U251) cells, without affecting cell proliferation. In contrast, upon exposure of U87 cells to U373 (U251) conditioned medium, U87 cells showed increased genomic stability, decreased proliferation rates and increased invasion, due to a plethora of produced cytokines identified in the co-culture media. This cross talk altered the expression 264 genes in U87 cells that are associated with proliferation, inflammation, migration, and adhesion, and 221 genes in U373 cells that are associated with apoptosis, the cell cycle, cell differentiation and migration. Indirect and direct co-culturing of U87 and U373 cells showed mutually opposite effects on temozolomide resistance. In conclusion, definition of transcriptional alterations of distinct glioblastoma cells upon co-culturing provides better understanding of the mechanisms of glioblastoma heterogeneity, which will provide the basis for more informed glioma treatment in the future.
Ključne besede: glioblastoma heterogeneity, U87 cells, temozolomide resistance, cellular cross-talk, transcriptomics
Objavljeno v DiRROS: 29.07.2024; Ogledov: 225; Prenosov: 192
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Povzetek: Izhodišče: Finančna toksičnost (FT) predstavlja vse objektivne finančne posledice in subjektivne finančne skrbi, ki se pojavljajo pri bolnikih z rakom in njihovih svojcih zaradi bolezni in zdravljenja. Finančno breme, ki ga imajo slovenski bolniki z rakom, pred našo raziskavo še ni bilo opredeljeno, prav tako ni bil poznan vpliv FT na kakovost življenja (QoL).Namen: Cilj raziskave je bila ocena FT pri bolnikih z rakom v Sloveniji, njen vpliv na QoL bolnikov in preizkus dosedanjih inštrumentov za oceno FT in QoL.Metode: Za merjenje FT smo uporabili anketno metodologijo. Razvili smo lasten vprašalnik za oceno FT in uporabili mednaro-dno validirana vprašalnika FACIT-COST in EORTC QLQ-C30. Raziskava je bila prospektivna in presečna, potekala je na Onkolo-škem inštitutu Ljubljana od junija do oktobra 2023. Rezultati: Analizirali smo 590 veljavnih anket. Na podlagi vprašalnika FACIT-COST smo ugotovili, da večina anketiranih bolnikov (53,7 %) nima FT, pri 42,9 % anketiranih bolnikov pa je bila ta večinoma blaga do zmerna. Nizko FT med slovenski-mi bolniki z rakom smo potrdili tudi z vprašalnikom EORTC QLQ-C30 in lastnim vprašalnikom. Večina bolnikov (85,1 %) je ocenila, da zaradi bolezni in zdravljenja niso imeli večjih stroškov. Na podlagi kazalnika finančnega bremena FACIT-COST in EORTC QLQ-C30 smo ugotovili, da so rizične skupine za večjo FT predvsem bolniki z nižjim neto dohodkom na gospodinjstvo (p ≤0,001), mlajši bolniki (p < 0,001), bolniki z rakom dojk (p = 0,016), zaposleni (p < 0,001), pa tudi bolniki na aktivnem onkološkem zdravljenju (p = 0,039). Pri lastnem vprašalniku so se za statistično pomembne pokazali še nižja stopnja izobrazbe (p ≤ 0,001), pode-želsko okolje (p = 0,033) in vrsta zdravstvenega zavarovanja (p = 0,006). Vpliv veroizpovedi na FT na podlagi lastnega vprašalnika ni povezan z večjo FT, kot je to razvidno iz vprašalnikov FACI-T-COST in EORTC QLQ-C30. Potrdili smo tudi vpliv nižjega dohodka na slabšo QoL, ostali parametri, ki vplivajo na QoL, pa so še: zelo nizka ali zelo visoka stopnja izobrazbe, rak glave in vratu in aktivnost onkološkega zdravljenja.Zaključki: V Sloveniji večina bolnikov z rakom ne občuti FT, v 42,9 % pa je ta blaga do zmerna. FT je statistično značilno povezana z višino dohodka, starostjo, vrsto raka, zaposlitvenim statusom, aktivnostjo onkološkega zdravljenja, pa tudi s stopnjo izobrazbe, podeželskim okoljem in vrsto zdravstvenega zavarova-nja. Večja FT je povezana s slabšo QoL. Ta je povezana prav tako z višino dohodka, stopnjo izobrazbe, vrsto raka in aktivnostjo onkološkega zdravljenja.
Ključne besede: finančno breme, kakovost življenja, breme raka
Objavljeno v DiRROS: 26.07.2024; Ogledov: 215; Prenosov: 122
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Povzetek: The cancer stem cell model suggests that glioblastomas contain a subpopulation of stem-like tumor cells that reproduce themselves to sustain tumor growth. Targeting these cells thus represents a novel treatment strategy and therefore more specific markers that characterize glioblastoma stem cells need to be identified. In the present study, we performed transcriptomic analysis of glioblastoma tissues compared to normal brain tissues revealing sensible up-regulation of CD9 gene. CD9 encodes the transmembrane protein tetraspanin which is involved in tumor cell invasion, apoptosis and resistance to chemotherapy. Using the public REMBRANDT database for brain tumors, we confirmed the prognostic value of CD9, whereby a more than two fold up-regulation correlates with shorter patient survival. We validated CD9 gene and protein expression showing selective up-regulation in glioblastoma stem cells isolated from primary biopsies and in primary organotypic glioblastoma spheroids as well as in U87-MG and U373 glioblastoma cell lines. In contrast, no or low CD9 gene expression was observed in normal human astrocytes, normal brain tissue and neural stem cells. CD9 silencing in three CD133+ glioblastoma cell lines (NCH644, NCH421k and NCH660h) led to decreased cell proliferation, survival, invasion, and self-renewal ability, and altered expression of the stem-cell markers CD133, nestin and SOX2. Moreover, CD9-silenced glioblastoma stem cells showed altered activation patterns of the Akt, MapK and Stat3 signaling transducers. Orthotopic xenotransplantation of CD9-silenced glioblastoma stem cells into nude rats promoted prolonged survival. Therefore, CD9 should be further evaluated as a target for glioblastoma treatment.
Ključne besede: biomarker, CD9, glioblastoma stem cells, neural stem cells, tetraspanin
Objavljeno v DiRROS: 26.07.2024; Ogledov: 216; Prenosov: 149
Celotno besedilo (6,28 MB)
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Povzetek: Samples of polymer polyethylene terephthalate were exposed to a weakly ionized gaseous plasma to modify the polymer surface properties for better cell cultivation. The gases used for treatment were sulfur dioxide and oxygen of various partial pressures. Plasma was created by an electrodeless radio frequency discharge at a total pressure of 60 Pa. X-ray photoelectron spectroscopy showed weak functionalization of the samples’ surfaces with the sulfur, with a concentration around 2.5 at %, whereas the oxygen concentration remained at the level of untreated samples, except when the gas mixture with oxygen concentration above 90% was used. Atomic force microscopy revealed highly altered morphology of plasma-treated samples; however, at high oxygen partial pressures this morphology vanished. The samples were then incubated with human umbilical vein endothelial cells. Biological tests to determine endothelialization and possible toxicity of the plasma-treated polyethylene terephthalate samples were performed. Cell metabolic activity (MTT) and in vitro toxic effects of unknown compounds (TOX) were assayed to determine the biocompatibility of the treated substrates. The biocompatibility demonstrated a well-pronounced maximum versus gas composition which correlated well with development of the surface morphology.
Objavljeno v DiRROS: 25.07.2024; Ogledov: 177; Prenosov: 153
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Povzetek: The giant colonial ciliate Zoothamnium niveum harbors a monolayer of the gammaproteobacteria Cand. Thiobios zoothamnicoli on its outer surface. Cultivation experiments revealed maximal growth and survival under steady flow of high oxygen and low sulfide concentrations. We aimed at directly demonstrating the sulfur-oxidizing, chemoautotrophic nature of the symbionts and at investigating putative carbon transfer from the symbiont to the ciliate host. We performed pulse-chase incubations with 14C- and 13C-labeled bicarbonate under varying environmental conditions. A combination of tissue autoradiography and nanoscale secondary ion mass spectrometry coupled with transmission electron microscopy was used to follow the fate of the radioactive and stable isotopes of carbon, respectively. We show that symbiont cells fix substantial amounts of inorganic carbon in the presence of sulfide, but also (to a lesser degree) in the absence of sulfide by utilizing internally stored sulfur. Isotope labeling patterns point to translocation of organic carbon to the host through both release of these compounds and digestion of symbiont cells. The latter mechanism is also supported by ultracytochemical detection of acid phosphatase in lysosomes and in food vacuoles of ciliate cells. Fluorescence in situ hybridization of freshly collected ciliates revealed that the vast majority of ingested microbial cells were ectosymbionts.
Ključne besede: microbial ecology, symbiosis
Objavljeno v DiRROS: 24.07.2024; Ogledov: 195; Prenosov: 184
Celotno besedilo (6,49 MB)
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