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- Klaric, Lucija, et al.
(author)
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
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In: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
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Other publication (other academic/artistic)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
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- Adde, Magdalena, et al.
(author)
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Superior outcome in transformed follicular lymphoma compared to de novo aggressive B-cell lymphoma treated with high-dose therapy and autologous stem-cell support
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Other publication (other academic/artistic)abstract
- Purpose: To assess the outcome of high–dose therapy with autologous stem cell support (HDT) in patients with transformed follicular lymphoma compared to patients with de novo aggressive B-cell lymphoma, in a retrospective analysis of patients treated at two Swedish university hospitals. Patients and Methods: 117 patients, mean age 48 years (21-65), 79 with de novo aggressive B-cell lymphoma and 38 with transformed follicular lymphoma, were treated with high-dose-therapy (HDT) as consolidation. Thirteen patients with transformed follicular lymphoma had been treated with a single alkylating agent and 25 were chemonaive at transformation. After transformation, nine patients had HDT as part of first line aggressive therapy, and a further eight failed to obtain CR and had HDT upfront. Twenty-one patients received more than one treatment regimen before HDT. In the de novo aggressive lymphoma group five patients with high risk criteria, and 16 patients who failed to obtain CR, received HDT upfront (CR1), Fifty-eight patients received more than one regimen before HDT because of relapse. Rituximab was given as a single dose to five patients for in vivo purging of the stem cell graft. Results: With a median follow up of 11.5 years (8-20), event free survival (EFS) and overall survival (OS) were 35% and 44% respectively. When comparing the two groups, the ten- year EFS rates were 27% in the de novo group and 55% in the transformed group and the ten-year OS was 33 % and 67% respectively. Treatment related mortality was acceptable with 4% early and 3.5% late mortality. In a multivariate analysis, “transformed vs de novo aggressive” histopathology was the only factor significantly related to outcome. Conclusion: Both EFS and OS were much better in patients with transformed follicular lymphoma compared to patients with de novo aggressive B-cell lymphoma Although the introduction of rituximab certainly has improved the outcome in both groups, HDT should still be considered as a salvage strategy not only in cases of de novo aggressive B-cell lymphoma and especially in transformed follicular lymphoma relapsing after first line treatment..
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| 7. |
- Eriksson, Mikael, et al.
(author)
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Lucy död! Leve Max!
- 1979
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Other publication (pop. science, debate, etc.)
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| 9. |
- Eriksson, Sofia, et al.
(author)
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Historical perspepctives on landscape representation and forest composition in Woodland Key Habitats compared to formally protected forest in boreal Sweden
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Other publication (other academic/artistic)abstract
- Habitats of Swedish conservation interests are in general small and fragmented following the extensive and intensive forest management history. This study covering 71 000 ha of boreal Sweden investigates how history influences present-day distribution and composition of forests identified as high conservation value habitats and how they are protected. We also investigated if the habitat criteria used to describe reservations differed between reservation types and if habitat criteria were associated with the size of Woodland Key Habitats. The results show strong effects from historical ownership and historical forest type on the probability of an area being set aside as formally protected or as voluntary protected Woodland Key Habitats. We also found that both formal reservations and Woodland Key Habitats primarily cover coniferous forest in the age interval 70-110 years but not the presumably most valuable oldest coniferous category >110 or deciduous forests, which are as common in reservations as in other areas. Old deciduous forests (>110 years) are significantly more rare in formal reservations compared to the forest matrix. When viewed in a context of fragmentation and edge effects the results underline the importance of evaluating reserved areas and Woodland Key Habitats in a wider temporal and larger spatial perspective to optimize conservation management efforts. Maximal representation and biodiversity can be better achieved if new reservations are chosen to represent different ownership and forest history, and if they are selected in a landscape context related to present reservations and the present surrounding production forest.
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| 10. |
- Eriksson, Sofia, et al.
(author)
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Historical perspepctives on landscape representation and forest composition in Woodland Key Habitats compared to formally protected forest in boreal Sweden
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Other publication (other academic/artistic)abstract
- Habitats of Swedish conservation interests are in general small and fragmented following the extensive and intensive forest management history. This study covering 71 000 ha of boreal Sweden investigates how history influences present-day distribution and composition of forests identified as high conservation value habitats and how they are protected. We also investigated if the habitat criteria used to describe reservations differed between reservation types and if habitat criteria were associated with the size of Woodland Key Habitats. The results show strong effects from historical ownership and historical forest type on the probability of an area being set aside as formally protected or as voluntary protected Woodland Key Habitats. We also found that both formal reservations and Woodland Key Habitats primarily cover coniferous forest in the age interval 70-110 years but not the presumably most valuable oldest coniferous category >110 or deciduous forests, which are as common in reservations as in other areas. Old deciduous forests (>110 years) are significantly more rare in formal reservations compared to the forest matrix. When viewed in a context of fragmentation and edge effects the results underline the importance of evaluating reserved areas and Woodland Key Habitats in a wider temporal and larger spatial perspective to optimize conservation management efforts. Maximal representation and biodiversity can be better achieved if new reservations are chosen to represent different ownership and forest history, and if they are selected in a landscape context related to present reservations and the present surrounding production forest.
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