| 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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| 6. |
- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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| 7. |
- Meech, K. J., et al.
(författare)
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EPOXI: Comet 103P/Hartley 2 Observations from a Worldwide Campaign
- 2011
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Ingår i: Astrophysical Journal Letters. - London : IOP. - 2041-8213 .- 2041-8205. ; 734:L1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Earth- and space-based observations provide synergistic information for space mission encounters by providing data over longer timescales, at different wavelengths and using techniques that are impossible with an in situ flyby. We report here such observations in support of the EPOXI spacecraft flyby of comet 103P/Hartley 2. The nucleus is small and dark, and exhibited a very rapidly changing rotation period. Prior to the onset of activity, the period was ~16.4?hr. Starting in 2010 August the period changed from 16.6?hr to near 19?hr in December. With respect to dust composition, most volatiles and carbon and nitrogen isotope ratios, the comet is similar to other Jupiter-family comets. What is unusual is the dominance of CO 2 -driven activity near perihelion, which likely persists out to aphelion. Near perihelion the comet nucleus was surrounded by a large halo of water-ice grains that contributed significantly to the total water production.
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| 8. |
- van Bragt, JJMH, et al.
(författare)
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Characteristics and treatment regimens across ERS SHARP severe asthma registries
- 2020
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 55:1
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.
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| 9. |
- Dork, T, et al.
(författare)
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Two truncating variants in FANCC and breast cancer risk
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 12524-
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Tidskriftsartikel (refereegranskat)abstract
- Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
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| 13. |
- Menden, MP, et al.
(författare)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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| 15. |
- Fages, A., et al.
(författare)
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Tracking Five Millennia of Horse Management with Extensive Ancient Genome Time Series
- 2019
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Ingår i: Cell. - : Elsevier BV. - 0092-8674. ; 177:6
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Tidskriftsartikel (refereegranskat)abstract
- Horse domestication revolutionized warfare and accelerated travel, trade, and the geographic expansion of languages. Here, we present the largest DNA time series for a non-human organism to date, including genome-scale data from 149 ancient animals and 129 ancient genomes (>= 1-fold coverage), 87 of which are new. This extensive dataset allows us to assess the modem legacy of past equestrian civilisations. We find that two extinct horse lineages existed during early domestication, one at the far western (Iberia) and the other at the far eastern range (Siberia) of Eurasia. None of these contributed significantly to modern diversity. We show that the influence of Persian-related horse lineages increased following the Islamic conquests in Europe and Asia. Multiple alleles associated with elite-racing, including at the MSTN "speed gene," only rose in popularity within the last millennium. Finally, the development of modem breeding impacted genetic diversity more dramatically than the previous millennia of human management.
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| 19. |
- Ahrens, J, et al.
(författare)
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First measurement of the helicity-dependent (gamma)over-right-arrow(p)over-right-arrow -> p eta differential cross-section
- 2003
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Ingår i: European Physical Journal A. Hadrons and Nuclei. - : Springer Science and Business Media LLC. - 1434-6001. ; 17:2, s. 241-244
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Tidskriftsartikel (refereegranskat)abstract
- The helicity dependence of the (γ) over right arrow(p) over right arrow -+ peta reaction has been measured for the first time at a center-of-mass angle theta(eta)*= 70degrees in the photon energy range from 780 MeV to 790 MeV. The experiment, performed at the Mainz microtron MAMI, used a 4pi-detector system, a circularly polarized, tagged photon beam. and a longitudinally polarized frozen-spin target. The helicity 3/2 cross-section is found to be small and the results for helicity 1/2 agree with predictions from the MAID analysis.
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| 21. |
- Ahrens, J, et al.
(författare)
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Helicity dependence of the (gamma)over-right-arrow (p)over-right-arrow -> n pi(+) pi(0) reaction in the second resonance region
- 2003
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Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - 0370-2693. ; 551:1-2, s. 49-55
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Tidskriftsartikel (refereegranskat)abstract
- The helicity dependence of the total cross section for the (γ) over right arrow(p) over right arrownpi(+) pi(0) reaction has been measured for the first time at incident photon energies from 400 to 800 MeV The measurement was performed with the large acceptance detector DAPHNE at the tagged photon beam facility of the MAMI accelerator in Mainz. This channel is found to be excited predominantly when the photon and proton have a parallel spin orientation, due to the intermediate production of the D-13 resonance. (C) 2002 Elsevier Science B.V. All rights reserved.
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| 22. |
- Ahrens, J, et al.
(författare)
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Helicity dependence of the gamma p -> N pi channels and multipole analysis in the Delta region
- 2004
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Ingår i: European Physical Journal A. Hadrons and Nuclei. - : Springer Science and Business Media LLC. - 1434-6001. ; 21:2, s. 323-333
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Tidskriftsartikel (refereegranskat)abstract
- A high-quality double-polarization data set for the helicity dependence of the total and differential cross-sections for both gammap --> Npi channels in the Delta region has been obtained in the framework of the GDH experiment. The experiment, performed at the Mainz microtron MAMI, used a 4pi detection system, a circularly polarized photon beam, and a longitudinally polarized frozen-spin target. These data are included in the database to perform a multipole analysis to determine the properties of the Delta(1232)-resonance. For the resonant Delta(1232) multipoles we find a very good agreement with previous analyses, while the nonresonant ones show significant deviations.
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| 23. |
- Ahrens, J, et al.
(författare)
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Intermediate resonance excitation in the gamma p -> p pi(0)pi(0) reaction
- 2005
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Ingår i: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 624:3-4, s. 173-180
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Tidskriftsartikel (refereegranskat)abstract
- The helicity dependence of the total cross section for the (gamma) over right arrow(p) over right arrow -> p pi(0)pi(0) reaction has been measured for the first time at incident photon energies from 400 to 800 MeV. The measurement, performed at the tagged photon beam facility of the MAMI accelerator in Mainz, used the large acceptance detector DAPHNE and a longitudinally polarized frozen-spin target. This channel is found to be excited predominantly when the photon and proton have a parallel spin orientation, most likely due to the intermediate production of the D-13(1520) resonance. However, the contribution of the antiparallel spin configuration, arising from other reaction mechanisms, is also not negligible. This result gives important new information to resolve the existing model discrepancies in the identification of the nucleon resonances contributing to this channel.
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| 24. |
- Bergmann, U, et al.
(författare)
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High-resolution X-ray spectroscopy of rare events : a different look at local structure and chemistry
- 2001
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Ingår i: Journal of Synchrotron Radiation. - Univ Calif Berkeley, Lawrence Berkeley Lab, Phys Biosci Div, Berkeley, CA 94720 USA. Univ Calif Davis, Dept Appl Sci, Davis, CA 95616 USA. CALTECH, Jet Prop Lab, Pasadena, CA 91109 USA. : MUNKSGAARD INT PUBL LTD. - 0909-0495 .- 1600-5775. ; 8, s. 199-203
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Tidskriftsartikel (refereegranskat)abstract
- The combination of large-acceptance high-resolution X-ray optics with bright synchrotron sources permits quantitative analysis of rare events such as X-ray fluorescence from very dilute systems, weak fluorescence transitions or X-ray Raman scattering. Transition-metal K beta fluorescence contains information about spin and oxidation state; examples of the characterization of the Mn oxidation states in the oxygen-evolving complex of photosystem II and Mn-consuming spores from the marine bacillus SG-1 are presented. Weaker features of the K beta spectrum resulting from valence-level and 'interatomic' ligand to metal transitions contain detailed information on the ligand-atom type, distance and orientation. Applications of this spectral region to characterize the local structure of model compounds are presented. X-ray Raman scattering (XRS) is an extremely rare event, but also represents a unique technique to obtain bulk-sensitive low-energy (<600 eV) X-ray absorption fine structure (XAFS) spectra using hard ( 10 keV) X-rays. A photon is inelastically scattered, losing part of its energy to promote an electron into an unoccupied level. In many cases, the cross section is proportional to that of the corresponding absorption process yielding the same X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) features. XRS finds application for systems that defy XAFS analysis at low energies, e.g. liquids or highly concentrated complex systems, reactive compounds and samples under extreme conditions (pressure, temperature). Recent results are discussed.
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