| 1. |
- 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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| 4. |
- Elhai, M, et al.
(författare)
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Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study
- 2019
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Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 78:7, s. 979-987
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Tidskriftsartikel (refereegranskat)abstract
- To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice.MethodsWe performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab.Results254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47–5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55–1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56–3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83–9.62]; p=0.019 as compared with controls vs 3 [0.66–5.35]; p=0.012).ConclusionRituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.
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| 5. |
- Sumaila, U. Rashid, et al.
(författare)
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WTO must ban harmful fisheries subsidies
- 2021
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 6. |
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| 7. |
- Ashton, Nicholas J., et al.
(författare)
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Plasma and CSF biomarkers in a memory clinic: Head-to-head comparison of phosphorylated tau immunoassays
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:5, s. 1913-1924
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. Methods In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (A beta 42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF A beta 42/p-tau ratio. Results All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF A beta 42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94). Discussion Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD. Highlights Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts.
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| 8. |
- Ferraguti, Martina, et al.
(författare)
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Ecological determinants of avian malaria infections : An integrative analysis at landscape, mosquito and vertebrate community levels
- 2018
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Ingår i: Journal of Animal Ecology. - : Wiley. - 0021-8790. ; 87:3, s. 727-740
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Tidskriftsartikel (refereegranskat)abstract
- Vector and host communities, as well as habitat characteristics, may have important but different impacts on the prevalence, richness and evenness of vector-borne parasites. We investigated the relative importance of (1) the mosquito community composition, (2) the vertebrate community composition and (3) landscape characteristics on the prevalence, richness and evenness of avian Plasmodium. We hypothesized that parasite prevalence will be more affected by vector-related parameters, while host parameters should be also important to explain Plasmodium richness and evenness. We sampled 2,588 wild house sparrows (Passer domesticus) and 340,829 mosquitoes, and we performed vertebrate censuses at 45 localities in the Southwest of Spain. These localities included urban, rural and natural landscapes that were characterized by several habitat variables. Twelve Plasmodium lineages were identified in house sparrows corresponding to three major clades. Variation partitioning showed that landscape characteristics explained the highest fraction of variation in all response variables (21.0%-44.8%). Plasmodium prevalence was in addition explained by vector-related variables (5.4%) and its interaction with landscape (10.2%). Parasite richness and evenness were mostly explained by vertebrate community-related variables. The structuring role of landscape characteristics in vector and host communities was a key factor in determining parasite prevalence, richness and evenness, although the role of each factor differed according to the parasite parameters studied. These results show that the biotic and abiotic contexts are important to explain the transmission dynamics of mosquito-borne pathogens in the wild.
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| 9. |
- Ferraguti, Martina, et al.
(författare)
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Environmental, geographical and time-related impacts on avian malaria infections in native and introduced populations of house sparrows (Passer domesticus), a globally invasive species
- 2023
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 32:5, s. 809-823
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The increasing spread of vector-borne diseases has resulted in severe health concerns for humans, domestic animals and wildlife, with changes in land use and the introduction of invasive species being among the main possible causes for this increase. We explored several ecological drivers potentially affecting the local prevalence and richness of avian malaria parasite lineages in native and introduced house sparrows (Passer domesticus) populations. Location: Global. Time period: 2002–2019. Major taxa studied: Avian Plasmodium parasites in house sparrows. Methods: We analysed data from 2,220 samples from 69 localities across all continents, except Antarctica. The influence of environment (urbanization index and human density), geography (altitude, latitude, hemisphere) and time (bird breeding season and years since introduction) were analysed using generalized additive mixed models (GAMMs) and random forests. Results: Overall, 670 sparrows (30.2%) were infected with 22 Plasmodium lineages. In native populations, parasite prevalence was positively related to urbanization index, with the highest prevalence values in areas with intermediate urbanization levels. Likewise, in introduced populations, prevalence was positively associated with urbanization index; however, higher infection occurred in areas with either extreme high or low levels of urbanization. In introduced populations, the number of parasite lineages increased with altitude and with the years elapsed since the establishment of sparrows in a new locality. Here, after a decline in the number of parasite lineages in the first 30 years, an increase from 40 years onwards was detected. Main conclusions: Urbanization was related to parasite prevalence in both native and introduced bird populations. In invaded areas, altitude and time since bird introduction were related to the number of Plasmodium lineages found to be infecting sparrows.
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| 10. |
- Heidegger, A., et al.
(författare)
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Development and inter-laboratory validation of the VISAGE enhanced tool for age estimation from semen using quantitative DNA methylation analysis
- 2022
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Ingår i: Forensic Science International: Genetics. - : Elsevier BV. - 1872-4973. ; 56
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Tidskriftsartikel (refereegranskat)abstract
- The analysis of DNA methylation has become an established method for chronological age estimation. This has triggered interest in the forensic community to develop new methods for age estimation from biological crime scene material. Various assays are available for age estimation from somatic tissues, the majority from blood. Age prediction from semen requires different DNA methylation markers and the only assays currently developed for forensic analysis are based on SNaPshot or pyrosequencing. Here, we describe a new assay using massively parallel sequencing to analyse 13 candidate CpG sites targeted in two multiplex PCRs. The assay has been validated by five consortium laboratories of the VISible Attributes through GEnomics (VISAGE) project within a collaborative exercise and was tested for reproducible quantification of DNA methylation levels and sensitivity with DNA methylation controls. Furthermore, DNA extracts and stains on Whatman FTA cards from two semen samples were used to evaluate concordance and mimic casework samples. Overall, the assay yielded high read depths (> 1000 reads) at all 13 marker positions. The methylation values obtained indicated robust quantification with an average standard deviation of 2.8% at the expected methylation level of 50% across the 13 markers and a good performance with 50 ng DNA input into bisulfite conversion. The absolute difference of quantifications from one participating laboratory to the mean quantifications of concordance and semen stains of remaining laboratories was approximately 1%. These results demonstrated the assay to be robust and suitable for age estimation from semen in forensic investigations. In addition to the 13-marker assay, a more streamlined protocol combining only five age markers in one multiplex PCR was developed. Preliminary results showed no substantial differences in DNA methylation quantification between the two assays, indicating its applicability with the VISAGE age model for semen developed with data from the complete 13-marker tool.
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| 11. |
- Jiménez-Peñuela, Jéssica, et al.
(författare)
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Differences in fatty acids composition between Plasmodium infected and uninfected house sparrows along an urbanization gradient
- 2022
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697. ; 815
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Tidskriftsartikel (refereegranskat)abstract
- Anthropogenic activities such as intensification of agriculture, animal husbandry and expansion of cities can negatively impact wildlife through its influence on the availability of high-quality food resources and pathogen transmission. The house sparrow (Passer domesticus), an urban exploiter, is undergoing a population decline. Nutritional constrains and infectious diseases has been highlighted as potential causes. Fatty acids (FAs) play an important role in modulating certain immune responses needed to combat parasite infections. FAs are highly influenced by dietary availability and have been shown to vary between urban and rural birds. Habitat anthropization also affects avian malaria epidemiology but little attention has been given to the relationship between blood parasite infection, host FAs composition and anthropization. Here, we analysed 165 juvenile birds either infected by Plasmodium or uninfected, captured at 15 localities grouped in triplets containing urban, rural and natural habitats. The total level of FAs was higher in birds from urban than from rural habitats, suggesting a greater availability of fat-rich foods sources. Furthermore, Plasmodium infected birds had higher relative levels of ω-3 polyunsaturated fatty acids (PUFAs) but lower of ω-6 PUFAs than uninfected birds. In concordance, the ω-6/ω-3 ratio was also lower in infected than in uninfected birds, but only from natural habitats, likely driven by the slightly higher ω-3 PUFAs in infected birds from natural habitats. Birds from anthropized environments may metabolize the ω-3 PUFAs to promote anti-inflammatory responses against stressors, which would result in lower ω-3 affecting their response against Plasmodium. Alternatively, lower ω-6 PUFAs may influence birds susceptibility to infection due to a weaker pro-inflammatory response. These descriptive results do not allow us to identify the causality of these associations but highlight the need to further investigate the relevance of FAs for birds to fight infectious diseases in habitats with different degree of urbanization.
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| 12. |
- Kersulyte, Dangeruta, et al.
(författare)
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Helicobacter pylori from Peruvian amerindians : traces of human migrations in strains from remote Amazon, and genome sequence of an Amerind strain
- 2010
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:11, s. e15076-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The gastric pathogen Helicobacter pylori is extraordinary in its genetic diversity, the differences between strains from well-separated human populations, and the range of diseases that infection promotes.PRINCIPAL FINDINGS: Housekeeping gene sequences from H. pylori from residents of an Amerindian village in the Peruvian Amazon, Shimaa, were related to, but not intermingled with, those from Asia. This suggests descent of Shimaa strains from H. pylori that had infected the people who migrated from Asia into The Americas some 15,000+ years ago. In contrast, European type sequences predominated in strains from Amerindian Lima shantytown residents, but with some 12% Amerindian or East Asian-like admixture, which indicates displacement of ancestral purely Amerindian strains by those of hybrid or European ancestry. The genome of one Shimaa village strain, Shi470, was sequenced completely. Its SNP pattern was more Asian- than European-like genome-wide, indicating a purely Amerind ancestry. Among its unusual features were two cagA virulence genes, each distinct from those known from elsewhere; and a novel allele of gene hp0519, whose encoded protein is postulated to interact with host tissue. More generally, however, the Shi470 genome is similar in gene content and organization to those of strains from industrialized countries.CONCLUSIONS: Our data indicate that Shimaa village H. pylori descend from Asian strains brought to The Americas many millennia ago; and that Amerind strains are less fit than, and were substantially displaced by, hybrid or European strains in less isolated communities. Genome comparisons of H. pylori from Amerindian and other communities should help elucidate evolutionary forces that have shaped pathogen populations in The Americas and worldwide.
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| 13. |
- Phillips, C., et al.
(författare)
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A compilation of tri-allelic SNPs from 1000 Genomes and use of the most polymorphic loci for a large-scale human identification panel
- 2020
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Ingår i: Forensic Science International. - : ELSEVIER IRELAND LTD. - 1872-4973 .- 1878-0326. ; 46
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Tidskriftsartikel (refereegranskat)abstract
- In a directed search of 1000 Genomes Phase III variation data, 271,934 tri-allelic single nucleotide polymorphisms (SNPs) were identified amongst the genotypes of 2,504 individuals from 26 populations. The majority of tri-allelic SNPs have three nucleotide substitution-based alleles at the same position, while a much smaller proportion, which we did not compile, have a nucleotide insertion/deletion plus substitution alleles. SNPs with three alleles have higher discrimination power than binary loci but keep the same characteristic of optimum amplification of the fragmented DNA found in highly degraded forensic samples. Although most of the tri-allelic SNPs identified had one or two alleles at low frequencies, often single observations, we present a full compilation of the genome positions, rs-numbers and genotypes of all tri-allelic SNPs detected by the 1000 Genomes project from the more detailed analyses it applied to Phase III sequence data. A total of 8,705 tri-allelic SNPs had overall heterozygosities (averaged across all 1000 Genomes populations) higher than the binary SNP maximum value of 0.5. Of these, 1,637 displayed the highest average heterozygosity values of 0.6-0.666. The most informative tri-allelic SNPs we identified were used to construct a large-scale human identification panel for massively parallel sequencing, designed for the identification of missing persons. The large-scale MPS identification panel comprised: 1,241 autosomal tri-allelic SNPs and 29 X tri-allelic SNPs (plus 46 microhaplotypes adapted for genotyping from reduced length sequences). Allele frequency estimates are detailed for African, European, South Asian and East Asian population groups plus the Peruvian population sampled by 1000 Genomes for the 1,270 tri-allelic SNPs of the final MPS panel. We describe the selection criteria, kinship simulation experiments and genomic analyses used to select the tri-allelic SNP components of the panel. Approximately 5 % of the tri-allelic SNPs selected for the large-scale MPS identification panel gave three-genotype patterns in single individual samples or discordant genotypes for genomic control DNAs. A likely explanation for some of these unreliably genotyped loci is that they map to multiple sites in the genome - high-lighting the need for caution and detailed scrutiny of multiple-allele variant data when designing future forensic SNP panels, as such patterns can arise from common structural variation in the genome, such as segmental duplications.
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