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| 2. |
- 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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| 3. |
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| 4. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 5. |
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| 6. |
- Zaidi, Syed H., et al.
(författare)
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Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival
- 2020
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR=0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR=1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds.
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| 7. |
- Lindberg, Fredrik, 1974, et al.
(författare)
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Urban Multi-scale Environmental Predictor (UMEP): An integrated tool for city-based climate services
- 2018
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Ingår i: Environmental Modelling and Software. - : Elsevier BV. - 1364-8152. ; 99, s. 70-87
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 The Authors UMEP (Urban Multi-scale Environmental Predictor), a city-based climate service tool, combines models and tools essential for climate simulations. Applications are presented to illustrate UMEP's potential in the identification of heat waves and cold waves; the impact of green infrastructure on runoff; the effects of buildings on human thermal stress; solar energy production; and the impact of human activities on heat emissions. UMEP has broad utility for applications related to outdoor thermal comfort, wind, urban energy consumption and climate change mitigation. It includes tools to enable users to input atmospheric and surface data from multiple sources, to characterise the urban environment, to prepare meteorological data for use in cities, to undertake simulations and consider scenarios, and to compare and visualise different combinations of climate indicators. An open-source tool, UMEP is designed to be easily updated as new data and tools are developed, and to be accessible to researchers, decision-makers and practitioners.
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| 8. |
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| 9. |
- Olierook, Hugo K.H., et al.
(författare)
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Age and geochemistry of magmatism on the oceanic Wallaby Plateau and implications for the opening of the Indian Ocean
- 2015
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Ingår i: Geology. - 0091-7613 .- 1943-2682. ; 43:11, s. 971-974
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Tidskriftsartikel (refereegranskat)abstract
- The temporal relationship between tectonic and volcanic activity on passive continental margins immediately before and after the initiation of mid-ocean ridge spreading is poorly understood because of the scarcity of volcanic samples on which to perform isotope geochronology. We present the first accurate geochronological constraints from a suite of volcanic and volcaniclastic rocks dredged from the 70,000 km2 submerged Wallaby Plateau situated on the Western Australian passive margin. Plagioclase 40Ar/39Ar and zircon U-Pb sensitive high-resolution ion microprobe ages indicate that a portion of the plateau formed at ca. 124 Ma. These ages are at least 6 m.y. younger than the oldest oceanic crust in adjacent abyssal plains (minimum = 130 Ma). Geochemical data indicate that the Wallaby Plateau volcanic samples are enriched tholeiitic basalt, similar to continental flood basalts, including the spatially and temporally proximal Bunbury Basalt in southwestern Australia. Thus, the Wallaby Plateau volcanism could be regarded as a (small) flood basalt event on the order of 104–105 km3. We suggest that magma could not erupt prior to 124 Ma because of the lack of space adjacent to the plateau. Eruption was made possible at 124 Ma via the opening of the Indian Ocean during the breakup of Greater India and Australia along the Wallaby-Zenith Fracture Zone. The scale of volcanism and the temporal proximity to breakup challenges the prevailing theory that the Western Australian margin formed as a volcanic passive margin. Given that the volume of volcanism is too small for typical flood basalts associated with volcanic passive margins, we suggest that the two end members, magma-poor and volcanic passive margins, should rather be treated as a continuum.
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| 10. |
- Olierook, Hugo K.H., et al.
(författare)
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Bunbury Basalt : Gondwana breakup products or earliest vestiges of the Kerguelen mantle plume?
- 2016
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Ingår i: Earth and Planetary Science Letters. - 0012-821X .- 1385-013X. ; 440, s. 20-32
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Tidskriftsartikel (refereegranskat)abstract
- In this contribution, we investigate the role of a mantle plume in the genesis of the Bunbury Basalt using high-precision 40Ar/39Ar geochronology and whole-rock geochemistry, and by using crustal basement thickness of the eastern Indian Ocean and the western Australian continent. The Bunbury Basalt is a series of lava flows and deep intrusive rocks in southwestern Australia thought to be the earliest igneous products from the proto-Kerguelen mantle plume. Nine new plateau ages indicate that the Bunbury Basalt erupted in three distinct phases, at 136.96±0.43 Ma, 132.71±0.43 Ma and 130.45±0.82 Ma. All Bunbury Basalt samples are enriched tholeiitic basalts with varying contributions from the continental lithosphere that are similar to other Kerguelen plume-products. Based on plate reconstructions and the present geochronological constraints, the eruption of the oldest Bunbury Basalt preceded the emplacement of the Kerguelen large igneous province by at least 10–20 m.y. Such age differences between a precursor and the main magmatic event are not uncommon but do require additional explanation. Low crustal stretching factors beneath the Bunbury Basalt (β≈1.4) indicate that decompression melting could not have been generated from asthenospheric mantle with a normal chemistry and geotherm. An elevated geotherm from the mantle plume coupled with the geochemical similarity between the Bunbury Basalt and other Kerguelen plume-products suggests a shared origin exists. However, new age constraints of the oldest Bunbury Basalt are synchronous with the breakup of eastern Gondwana and the initial opening of the Indian Ocean at ca. 137–136 Ma, which may mean an alternative explanation is possible. The enriched geochemistry can equally be explained by a patch of shallow mantle beneath the southern Perth Basin. The patch may have been enriched during Gondwana suturing at ca. 550–500 Ma, during early rifting events by magmatic underplating or by intruded melts into the subcontinental lithospheric mantle. This enriched geochemical signature would then be sufficient to trigger decompression melting from passive rifting between Greater India and Australia with no contribution from the Kerguelen hotspot. We conclude that although the proto-Kerguelen hotspot is certainly a possible explanation for the genesis of the Bunbury Basalt, decompression melting of an enriched patch of subcontinental lithospheric mantle is an alternative theory.
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| 11. |
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| 12. |
- O'Meara, C. P., et al.
(författare)
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Immunization with a MOMP-Based Vaccine Protects Mice against a Pulmonary Chlamydia Challenge and Identifies a Disconnection between Infection and Pathology
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- Chlamydia pneumoniae is responsible for up to 20% of community acquired pneumonia and can exacerbate chronic inflammatory diseases. As the majority of infections are either mild or asymptomatic, a vaccine is recognized to have the greatest potential to reduce infection and disease prevalence. Using the C. muridarum mouse model of infection, we immunized animals via the intranasal (IN), sublingual (SL) or transcutaneous (TC) routes, with recombinant chlamydial major outer membrane protein (MOMP) combined with adjuvants CTA1-DD or a combination of cholera toxin/CpG-oligodeoxynucleotide (CT/CpG). Vaccinated animals were challenged IN with C. muridarum and protection against infection and pathology was assessed. SL and TC immunization with MOMP and CT/CpG was the most protective, significantly reducing chlamydial burden in the lungs and preventing weight loss, which was similar to the protection induced by a previous live infection. Unlike a previous infection however, these vaccinations also provided almost complete protection against fibrotic scarring in the lungs. Protection against infection was associated with antigen-specific production of IFNγ, TNFα and IL-17 by splenocytes, however, protection against both infection and pathology required the induction of a similar pro-inflammatory response in the respiratory tract draining lymph nodes. Interestingly, we also identified two contrasting vaccinations capable of preventing infection or pathology individually. Animals IN immunized with MOMP and either adjuvant were protected from infection, but not the pathology. Conversely, animals TC immunized with MOMP and CTA1-DD were protected from pathology, even though the chlamydial burden in this group was equivalent to the unimmunized controls. This suggests that the development of pathology following an IN infection of vaccinated animals was independent of bacterial load and may have been driven instead by the adaptive immune response generated following immunization. This identifies a disconnection between the control of infection and the development of pathology, which may influence the design of future vaccines.
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| 13. |
- Ozolins, D., et al.
(författare)
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Second European multi-disciplinary conference of national strategies for Chlamydia trach. and human papillomavirus NSCP conf. in Berlin, 2013 enhanced detection, management and surveillance of sexually transmitted infections in Europe are essential!
- 2013
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Ingår i: International journal of immunopathology and pharmacology. - : SAGE Publications. - 0394-6320 .- 2058-7384. ; 26:4, s. 839-845
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Tidskriftsartikel (refereegranskat)abstract
- There is a need for updated guidance on detection, management and surveillance of sexually transmitted infections (STIs). Chlamydia, gonorrhoea and syphilis reporting needs to be mandatory in more European countries to aid collection of data. More widespread Chlamydia screening is needed in many countries as this is the only way to reduce complications. The role of Human Papillomavirus (HPV) screening in a situation where the prevalence of HPV infection has dropped significantly was also discussed in the context of the high cost of screening, the need for a relatively complex infrastructure, particularly in developing countries, and falling vaccination costs. An integrated HPV vaccination and screening policy could be the most appropriate with vaccination at 9-13 years as recommended by WHO and a single HPV screen at 35-39 years, possibly repeated thereafter every 10 years. Female and male HPV vaccination programmes could lead to near elimination of genital warts in both females and males. Surveillance of STIs should be intensified where needed; additional or better quality data should be collected including reasons for testing, denominator data to estimate positivity rates, diagnostic methods, concurrent STIs, sexual orientation and country of acquisition; more analytical rather than descriptive epidemiology is needed.
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