| 1. |
- Campbell, PJ, et al.
(author)
-
Pan-cancer analysis of whole genomes
- 2020
-
In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
-
Journal article (peer-reviewed)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.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Kanai, M, et al.
(author)
-
- 2023
-
swepub:Mat__t
|
|
| 6. |
- Arora, V, et al.
(author)
-
Systemic administration of a β2-adrenergic receptor agonist reduces mechanical allodynia and suppresses the immune response to surgery in a rat model of persistent post-incisional hypersensitivity
- 2021
-
In: Molecular pain. - : SAGE Publications. - 1744-8069. ; 17, s. 1744806921997206-
-
Journal article (peer-reviewed)abstract
- Beta 2 adrenergic receptor (β2 AR) activation in the central and peripheral nervous system has been implicated in nociceptive processing in acute and chronic pain settings with anti-inflammatory and anti-allodynic effects of β2-AR mimetics reported in several pain states. In the current study, we examined the therapeutic efficacy of the β2-AR agonist clenbuterol in a rat model of persistent postsurgical hypersensitivity induced by disruption of descending noradrenergic signaling in rats with plantar incision. We used growth curve modeling of ipsilateral mechanical paw withdrawal thresholds following incision to examine effects of treatment on postoperative trajectories. Depletion of spinal noradrenergic neurons delayed recovery of hypersensitivity following incision evident as a flattened slope compared to non-depleted rats (-1.8 g/day with 95% CI -2.4 to -1.085, p < 0.0001). Chronic administration of clenbuterol reduced mechanical hypersensitivity evident as a greater initial intercept in noradrenergic depleted (6.2 g with 95% CI 1.6 to 10.8, p = 0.013) and non-depleted rats (5.4 g with 95% CI 1.2 to 9.6, p = 0.018) with plantar incision compared to vehicle treated rats. Despite a persistent reduction in mechanical hypersensitivity, clenbuterol did not alter the slope of recovery when modeled over several days (p = 0.053) or five weeks in depleted rats (p = 0.64). Systemic clenbuterol suppressed the enhanced microglial activation in depleted rats and reduced the density of macrophage at the site of incision. Direct spinal infusion of clenbuterol failed to reduce mechanical hypersensitivity in depleted rats with incision suggesting that beneficial effects of β2-AR stimulation in this model are largely peripherally mediated. Lastly, we examined β2-AR distribution in the spinal cord and skin using in-situ hybridization and IHC. These data add to our understanding of the role of β2-ARs in the nervous system on hypersensitivity after surgical incision and extend previously observed anti-inflammatory actions of β2-AR agonists to models of surgical injury.
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Bulik, CM, et al.
(author)
-
The Eating Disorders Genetics Initiative (EDGI): study protocol
- 2021
-
In: BMC psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 21:1, s. 234-
-
Journal article (peer-reviewed)abstract
- BackgroundThe Eating Disorders Genetics Initiative (EDGI) is an international investigation exploring the role of genes and environment in anorexia nervosa, bulimia nervosa, and binge-eating disorder.MethodsA total of 14,500 individuals with eating disorders and 1500 controls will be included from the United States (US), Australia (AU), New Zealand (NZ), and Denmark (DK). In the US, AU, and NZ, participants will complete comprehensive online phenotyping and will submit a saliva sample for genotyping. In DK, individuals with eating disorders will be identified by the National Patient Register, and genotyping will occur using bloodspots archived from birth. A genome-wide association study will be conducted within EDGI and via meta-analysis with other data from the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED).DiscussionEDGI represents the largest genetic study of eating disorders ever to be conducted and is designed to rapidly advance the study of the genetics of the three major eating disorders (anorexia nervosa, bulimia nervosa, and binge-eating disorder). We will explicate the genetic architecture of eating disorders relative to each other and to other psychiatric and metabolic disorders and traits. Our goal is for EDGI to deliver “actionable” findings that can be transformed into clinically meaningful insights.Trial registrationEDGI is a registered clinical trial: clinicaltrials.govNCT04378101.
|
|
