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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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- Kostyukov, AI, et al.
(författare)
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Spreading of fatigue-related effects from active to inactive parts in the medial gastrocnemius muscle of the cat
- 2002
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Ingår i: European Journal of Applied Physiology. - : Springer Science and Business Media LLC. - 1439-6319 .- 1439-6327. ; 86:4, s. 295-307
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Tidskriftsartikel (refereegranskat)abstract
- In the medial gastrocnemius muscle of the decerebrate cat, the spatial spread of fatigue between active and inactive muscle parts was studied. Conditioning fatiguing stimulation (CFS) was applied to a part of the muscle to test whether it had an effect on the contraction efficiency in an unstimulated part. To exclude somato-sympathetic reflexes during CFS, a full rhizotomy of the lumbo-sacral spinal cord was performed. The same ipsilateral ventral root, either L7 or S1, was divided into seven filaments, one of which was used for the test stimulation, and four or five for CFS. The CFS consisted of 12 s sessions of distributed stimulation of five (or four) filaments at a rate of 40 s(-1), the sessions were repeated, every 40 s, 15 or more times. The test consisted of 12 s of regular stimulation at a rate of 10 s(-1), preceded and followed by a single stimulus. The tests applied just after CFS showed a strong decline of both tension and electromyogram (EMG), amounting to only [mean (SD)] 0.45 (0.18) and 0.51 (0.19) (n = 15), respectively, of the corresponding values in the tests before CFS. It thus turned out that depressive fatigue-related effects could spread within the muscle. At the same time, control reactions recorded in the lateral gastrocnemius during stimulation of its cut nerve did not change. Subsequent repetitions of the tests usually revealed a tendency towards restoration. The EMG reactions recovered more quickly than tension. The depression of EMG after CFS was accompanied by a slowing of the constituent M-waves; their latencies decreased during restoration. Distinct changes in the systemic blood pressure were observed during CFS. These changes were usually correlated well with muscle tension changes. The factors possibly underlying the observed effects may include diffusion of metabolites from active to inactive muscle fibres, lowering of the efficiency of neuro-muscular transmission due to squeezing of efferent motor terminals and changes in outer metabolite content, as well as local hypoxia due to increases in intramuscular pressure.
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