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- Glasbey, JC, et al.
(författare)
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- 2021
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swepub:Mat__t
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- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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- Cheung, BB, et al.
(författare)
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A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma
- 2021
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 40:13, s. 2367-2381
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Tidskriftsartikel (refereegranskat)abstract
- Histone deacetylase (HDAC) inhibitors are effective in MYCN-driven cancers, because of a unique need for HDAC recruitment by the MYCN oncogenic signal. However, HDAC inhibitors are much more effective in combination with other anti-cancer agents. To identify novel compounds which act synergistically with HDAC inhibitor, such as suberanoyl hydroxamic acid (SAHA), we performed a cell-based, high-throughput drug screen of 10,560 small molecule compounds from a drug-like diversity library and identified a small molecule compound (SE486-11) which synergistically enhanced the cytotoxic effects of SAHA. Effects of drug combinations on cell viability, proliferation, apoptosis and colony forming were assessed in a panel of neuroblastoma cell lines. Treatment with SAHA and SE486-11 increased MYCN ubiquitination and degradation, and markedly inhibited tumorigenesis in neuroblastoma xenografts, and, MYCN transgenic zebrafish and mice. The combination reduced ubiquitin-specific protease 5 (USP5) levels and increased unanchored polyubiquitin chains. Overexpression of USP5 rescued neuroblastoma cells from the cytopathic effects of the combination and reduced unanchored polyubiquitin, suggesting USP5 is a therapeutic target of the combination. SAHA and SE486-11 directly bound to USP5 and the drug combination exhibited a 100-fold higher binding to USP5 than individual drugs alone in microscale thermophoresis assays. MYCN bound to the USP5 promoter and induced USP5 gene expression suggesting that USP5 and MYCN expression created a forward positive feedback loop in neuroblastoma cells. Thus, USP5 acts as an oncogenic cofactor with MYCN in neuroblastoma and the novel combination of HDAC inhibitor with SE486-11 represents a novel therapeutic approach for the treatment of MYCN-driven neuroblastoma.
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- Parker, JL, et al.
(författare)
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Time-dependent adhesion between glass surfaces in dilute surfactant solutions
- 1993
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Ingår i: Langmuir. - 0743-7463 .- 1520-5827. ; 9, s. 1965-1967
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Tidskriftsartikel (refereegranskat)abstract
- Measurements of surface forces between glass surfaces in very dilute cationic surfactant solutions at pH 10 are presented. As the surfaces approach the forces are purely repulsive and correspond exactly to the interaction of glass surfaces in aqueous solution at the same pH. However, a small adhesion is observed on separation, the magnitude of which is dependent on the time the surfaces are left in contact. The adhesion arises due to adsorption of surfactant in a narrow gap around the contact area and is induced by the favorable interaction of hydrophobic tails across the gap. The time dependence of the adhesion suggests that the adsorption is diffusion limited.
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- Rutland, MW, et al.
(författare)
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Surface forces between silica surfaces in cationic surfactant solutions: Adsorption and bilayer formation at normal and high pH
- 1994
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Ingår i: Langmuir. - 0743-7463 .- 1520-5827. ; 10, s. 1110-1121
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Tidskriftsartikel (refereegranskat)abstract
- Forces have been measured between glass surfaces in CTAB solutions at pH 10 and the adsorption, inferred from the fitted surface potentials and the measured adhesion, has been shown to be strongly dependent on the surface charge and the competing ions. At very low CTAB concentrations adsorption can only be detected after the surfaces are left in contact, and this results in a time dependent adhesion consistent with diffusion controlled adsorption of CTAB in the annulus around the contact area. At slightly higher concentrations (between 3 and 6 x10-6 M) a hydrophobic monolayer forms and purely attractive hydrophobic interactions are measured indicating that the surfaces are close to electro neutrality. This concentration is much lower than that required to achieve neutral surfaces at pH 5.6 for glass or for mica surfaces. It is argued that after charge reversal the forces can be fitted with DLVO theory, assuming a plane of charge away from the surface. Bilayer formation occurs at the CMC (1x10-3 M) for low pH and below the CMC at elevated pH. The density of surfactant in the outer layer of the bilayer on silica at normal and elevated pH is much lower than that on mica at a comparable bulk CTAB concentration. As a result it is possible to disrupt the bilayers and push the surfaces into a hydrophobic contact. The thickness of the bilayer and the surface charge density obtained from fitting the force law as well as the nature of the force law during compression of the bilayer leads to the conclusion that CTAB adsorbs to glass as patches of bilayers or surface aggregates. Dynamic rearrangements within the surface layer have also been observed.
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