Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are ...therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with “classical” (elderly-onset) PCA, we ...performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic “androgen-type” pathomechanism in EO-PCA.
► Genome sequencing revealed age-related genetic alterations in PCA ► Early-onset PCAs display a specific abundance of androgen-driven rearrangements ► These age-linked alterations coincide with activity levels of the androgen receptor ► This is an observation of age-specific DNA alterations in a common cancer
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The circadian clock and the cell cycle are major cellular systems that organize global physiology in temporal fashion. It seems conceivable that the potentially conflicting programs are coordinated. ...We show here that overexpression of MYC in U2OS cells attenuates the clock and conversely promotes cell proliferation while downregulation of MYC strengthens the clock and reduces proliferation. Inhibition of the circadian clock is crucially dependent on the formation of repressive complexes of MYC with MIZ1 and subsequent downregulation of the core clock genes BMAL1 (ARNTL), CLOCK and NPAS2. We show furthermore that BMAL1 expression levels correlate inversely with MYC levels in 102 human lymphomas. Our data suggest that MYC acts as a master coordinator that inversely modulates the impact of cell cycle and circadian clock on gene expression.
Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ...ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed inIG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Systematics of strange particle production in collisions of ultrarelativistic nuclei provides an insight into the properties of the strongly interacting matter. Hadrochemistry, the study of the ...relative yields, provides information about chemical freeze-out and the position of the system in the phase diagram. Strangeness production at Super Proton Synchrotron (SPS) energies is not fully explained by the thermal model of hadron gas. Data reported by one experiment show sharp structures as a function of energy which are interpreted as a signature for a phase transition, but due to discrepancies in the results between two different experiments, a conclusion can not be drawn. This thesis is part of an effort to build a database of the strangeness production at SPS energy. The particular subject of this work is a precise measurement of the production of $K_{S}^{0}$. The results are compared with two other experiments and the prediction of the thermal model. The high precision data shed light on the systematics of strangeness production and allow clarification of the experimental status. The study of transverse momentum spectra provides information about the temperature and the radial expansion of the system. Here, as in the case of particle yields, interesting structures are visible as a function of energy. A rapid increase in the number of degrees of freedom is visible in the SPS region. A large part of the strangeness is carried by the neutral strange baryon $\Lambda$. Here the experimental situation is even more complicated because the reconstruction of the $\Lambda$ yield requires large extrapolation to low transverse momentum. In this work first results on $\Lambda$ production will be presented.
Występowanie złóż rud cynku i ołowiu w skałach dolomitowych sprawia, że otrzymane koncentraty sfa-lerytowe zawierają domieszkę dolomitu. Praktyka wskazuje, że znaczna część wprowadzanego magnezu z ...surowcami cynkowymi przechodzi do ostatniej fazy produkcji, elektrolizy cynku. Obecność magnezu w elektrolicie obniża przewodnictwo elektryczne elektrolitu i powoduje pogorszenie wskaźników techniczno-ekonomicznych. Celem opisanych w tym artykule badań było opracowanie metody usuwania magnezu z surowego koncentratu sfalerytowego na drodze chemiczno-flotacyjnej, stosując zużyty elektrolit pochodzący z elektrolizy cynku. Opracowanie ukierunkowano wokół doświadczalnego zobrazowania istniejących zależności i ustalenia optymalnych warunków zaproponowanej procedury. Stopień wyługowania magnezu wynosił około 80%. Straty cynku wynosiły poniżej 2%, natomiast stężenie magnezu w roztworze wynosiło 20%. Z tych roztworów można odzyskiwać magnez i cynk, co będzie przedstawione w następnej publikacji.
Due to the occurrence of zinc and lead ore deposits in dolomite rocks, the sphalerite concentrates obtained from these ores contain an admixture of dolomite. In practice, a substantial amount of magnesium included in zinc ores passes to the last production stage, i.e. zinc electrolysis. The magnesium present in electrolyte impairs electrical conductance and appears in the technical and economical indexes. This paper deals the attempts to remove magnesium removal from initial sphalerite concentrates by means of chemical flotation using spent electrolyte derived from zinc electrolysis. The authors attempt to substantiate the existing relationships, as well as to derermine the optimum conditions for the procedure suggested. The leaching efficiency ofmagnesium amounted to about 80%, and is dependent upon the stage of the leaching. Losses of zinc were below 2%, and the magnesium concentration in solution amounted to about 20%. These solution can produce magnesium and zinc, which will be presented in the following paper.
Streszczenie
Występowanie złóż rud cynku i ołowiu w skałach dolomitowych sprawia, że otrzymane koncentraty sfa-lerytowe zawierają domieszkę dolomitu. Praktyka wskazuje, że znaczna część wprowadzanego ...magnezu z surowcami cynkowymi przechodzi do ostatniej fazy produkcji, elektrolizy cynku. Obecność magnezu w elektrolicie obniża przewodnictwo elektryczne elektrolitu i powoduje pogorszenie wskaźników techniczno-ekonomicznych. Celem opisanych w tym artykule badań było opracowanie metody usuwania magnezu z surowego koncentratu sfalerytowego na drodze chemiczno-flotacyjnej, stosując zużyty elektrolit pochodzący z elektrolizy cynku. Opracowanie ukierunkowano wokół doświadczalnego zobrazowania istniejących zależności i ustalenia optymalnych warunków zaproponowanej procedury. Stopień wyługowania magnezu wynosił około 80%. Straty cynku wynosiły poniżej 2%, natomiast stężenie magnezu w roztworze wynosiło 20%. Z tych roztworów można odzyskiwać magnez i cynk, co będzie przedstawione w następnej publikacji.
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