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- Koraeus, Mats
(författare)
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Stressing Knowledge : Organisational closed-ness and knowledge acquisition under pressure
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Organisations have been analytically conceptualised as being somewhat analogous to individuals for a long time. They have culture; they can learn; and they can behave in various odd ways. But how far can the simile be stretched? What other types of organisational cognition can we imagine? And what benefits can we gain by introducing new perspectives of this kind? This study shows that organisations can exhibit familiar symptoms of stress, such as closing themselves to the outside world and becoming unreceptive to external stimuli and input. They retreat to what is familiar and safe and put on blinders to hide anything that does not already fit with how they feel things should be, often in situations where they would be best served by being as open to and perceptive of these external stimuli as possible. Using a model of organisational behaviour that connects external pressure to an internal mode of operation and to specific knowledge-seeking behaviours, the study examines two case pairs—two success stories and two catastrophic failures—to examine patterns of organisational cognition. By comparing and contrasting the failure of the FBI during the 1993 Waco siege with its subsequent success during the 1996 Montana Freemen standoff, and doing the same with the Swedish Foreign Ministry’s handling of the 2004 Southeast Asian tsunami and the 2006 evacuation from the war in Lebanon, a pattern emerges where certain types of knowledge proved to be the key to staying as open-minded, responsive, and dynamic as these crises demanded. This knowledge can be used both during a crisis to resolve some of the confusion and time pressure that is endemic to such situations, as well as before a crisis to mitigate or even stave off the approaching chaos.
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| 4. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 6. |
- 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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| 7. |
- 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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- Hjulström, Björn, 1974-
(författare)
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Patterns in diversity : Geochemical analyses and settlement changes during the Iron Age - Early Medieval time in the Lake Mälaren region, Sweden
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The principal aims of this thesis were two-fold, encompassing both a geochemical approach and a focus on the settlement structure of the Lake Mälaren region of Sweden during the first millennium A.D. Although the two approaches were linked by their common final purpose, to gain a better understanding of the Iron Age – Early Medieval society of the region, the implications of the geochemical results are not limited to any particular area or period in time. Settlement is analysed on three levels: 1) the house, through typological changes, 2) the house and farm, through the identification of space-use areas and activities by means of geochemical analysis, and 3) farms and hamlets in the landscape, by studying settlement patterns. The material is derived partly from the author’s own excavations and partly from contract excavations. The importance of the excavation method and sampling strategy for the end-results of the analyses is discussed and emphasized. Lipid analysis by gas chromatography-mass spectrometry (GC-MS) and element analysis by atomic absorption spectrophotometer (AAS) made it possible to fill the void between archaeological features with meaningful information regarding space use, and it was also possible to identify the use of certain features with previously unknown function through lipid analysis. Space-use areas by reference to a modern context featuring well-known activities were identified with element analyses, while lipid analysis enabled these space-use areas to be connected with the actual activities. In archaeological contexts where lipid degradation has proceeded further such identification becomes more difficult and useful compound ratios and biomarkers for archaeological issues have been examined. The results of geochemical analyses and lipid analyses performed on ceramics made it possible to discuss the functions and meanings of houses in more detail and to consider different types of house foundations and categories of buildings in a wider context.
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