| 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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| 2. |
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| 3. |
- Brennan, S. J., et al.
(författare)
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Photometric and spectroscopic evolution of the interacting transient AT 2016jbu(Gaia16cfr)
- 2022
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 513:4, s. 5642-5665
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Tidskriftsartikel (refereegranskat)abstract
- We present the results from a high-cadence, multiwavelength observation campaign of AT 2016jbu (aka Gaia16cfr), an interacting transient. This data set complements the current literature by adding higher cadence as well as extended coverage of the light-curve evolution and late-time spectroscopic evolution. Photometric coverage reveals that AT 2016jbu underwent significant photometric variability followed by two luminous events, the latter of which reached an absolute magnitude of MV ∼ −18.5 mag. This is similar to the transient SN 2009ip whose nature is still debated. Spectra are dominated by narrow emission lines and show a blue continuum during the peak of the second event. AT 2016jbu shows signatures of a complex, non-homogeneous circumstellar material (CSM). We see slowly evolving asymmetric hydrogen line profiles, with velocities of 500 km s−1 seen in narrow emission features from a slow-moving CSM, and up to 10 000 km s−1 seen in broad absorption from some high-velocity material. Late-time spectra (∼+1 yr) show a lack of forbidden emission lines expected from a core-collapse supernova and are dominated by strong emission from H, He I, and Ca II. Strong asymmetric emission features, a bumpy light curve, and continually evolving spectra suggest an inhibit nebular phase. We compare the evolution of H α among SN 2009ip-like transients and find possible evidence for orientation angle effects. The light-curve evolution of AT 2016jbu suggests similar, but not identical, circumstellar environments to other SN 2009ip-like transients.
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| 4. |
- Brennan, S. J., et al.
(författare)
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Progenitor, environment, and modelling of the interacting transient AT 2016jbu (Gaia16cfr)
- 2022
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 513:4, s. 5666-5685
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Tidskriftsartikel (refereegranskat)abstract
- We present the bolometric light curve, identification and analysis of the progenitor candidate, and preliminary modelling of AT 2016jbu (Gaia16cfr). We find a progenitor consistent with a ∼ 22–25 M⊙ yellow hypergiant surrounded by a dusty circumstellar shell, in agreement with what has been previously reported. We see evidence for significant photometric variability in the progenitor, as well as strong Hα emission consistent with pre-existing circumstellar material. The age of the environment, as well as the resolved stellar population surrounding AT 2016jbu, supports a progenitor age of >10 Myr, consistent with a progenitor mass of ∼22 M⊙. A joint analysis of the velocity evolution of AT 2016jbu and the photospheric radius inferred from the bolometric light curve shows the transient is consistent with two successive outbursts/explosions. The first outburst ejected material with velocity ∼650 km s−1, while the second, more energetic event ejected material at ∼4500 km s−1. Whether the latter is the core collapse of the progenitor remains uncertain. We place a limit on the ejected 56Ni mass of <0.016 M⊙. Using the Binary Population And Spectral Synthesis (BPASS) code, we explore a wide range of possible progenitor systems and find that the majority of these are in binaries, some of which are undergoing mass transfer or common-envelope evolution immediately prior to explosion. Finally, we use the SuperNova Explosion Code (SNEC) to demonstrate that the low-energy explosions within some of these binary systems, together with sufficient circumstellar material, can reproduce the overall morphology of the light curve of AT 2016jbu.
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| 8. |
- Mourikis, TP, et al.
(författare)
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Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3101-
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Tidskriftsartikel (refereegranskat)abstract
- The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.
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| 9. |
- Valenti, S., et al.
(författare)
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PESSTO spectroscopic classification of La Silla-Quest Transients
- 2012
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- PESSTO is the "Public ESO Spectroscopic Survey of Transient Objects" (http://www.pessto.org) using the ESO New Technology Telescope (NTT) at La Silla and the EFOSC2 (optical) and SOFI (near-IR) spectrographs. It is one of two currently running public spectroscopic surveys at ESO. The survey details are as follows: - PESSTO has 90 nights per year on the NTT: 9 lunations (August to April), 10 nights per lunation (we are not observing May-July).
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| 10. |
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| 11. |
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| 12. |
- Turkington, RC, et al.
(författare)
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Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma
- 2019
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:11, s. 1918-1927
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Tidskriftsartikel (refereegranskat)abstract
- Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC.DesignTranscriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS).ResultsA total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025).ConclusionThe DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.
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| 13. |
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| 14. |
- Lyman, J. D., et al.
(författare)
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Investigating the diversity of supernovae type Iax : a MUSE and NOT spectroscopic study of their environments
- 2018
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 473:1, s. 1359-1387
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Tidskriftsartikel (refereegranskat)abstract
- SN 2002cx-like Type Ia supernovae (also known as SNe Iax) represent one of the most numerous peculiar SN classes. They differ from normal SNe Ia by having fainter peak magnitudes, faster decline rates and lower photospheric velocities, displaying a wide diversity in these properties. We present both integral-field and long-slit visual-wavelength spectroscopy of the host galaxies and explosion sites of SNe Iax to provide constraints on their progenitor formation scenarios. The SN Iax explosion-site metallicity distribution is similar to that of core-collapse SNe and metal poor compared to either normal SNe Ia or SN 1991T-like events. Fainter members, speculated to form distinctly from brighter SN Iax, are found at a range of metallicities, extending to very metal poor environments. Although the SN Iax explosion-sites' ages and star formation rates are comparatively older and less intense than the distribution of star-forming regions across their host galaxies, we confirm the presence of young stellar populations (SPs) at explosion environments for most SNe Iax, expanded here to a larger sample. Ages of the young SPs (several x 10(7) to 10(8) yr) are consistent with predictions for young thermonuclear and electron-capture SN progenitors. The lack of extremely young SPs at the explosion sites disfavours very massive progenitors such as Wolf-Rayet explosions with significant fallback. We find weak ionized gas in the only SN Iax host without obvious signs of star formation. The source of the ionization remains ambiguous but appears unlikely to be mainly due to young, massive stars.
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| 15. |
- Milisavljevic, D., et al.
(författare)
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METAMORPHOSIS OF SN 2014C : DELAYED INTERACTION BETWEEN A HYDROGEN POOR CORE-COLLAPSE SUPERNOVA AND A NEARBY CIRCUMSTELLAR SHELL
- 2015
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 815:2
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Tidskriftsartikel (refereegranskat)abstract
- We present optical observations of supernova SN 2014C, which underwent an unprecedented slow metamorphosis from H-poor type Ib to H-rich type IIn over the course of one year. The observed spectroscopic evolution is consistent with the supernova having exploded in a cavity before encountering a massive shell of the progenitor star's stripped hydrogen envelope. Possible origins for the circumstellar shell include a brief Wolf-Rayet fast wind phase that overtook a slower red supergiant wind, eruptive ejection, or confinement of circumstellar material by external influences of neighboring stars. An extended high velocity Ha absorption feature seen in near-maximum light spectra implies that the progenitor star was not completely stripped of hydrogen at the time of core collapse. Archival pre-explosion Subaru Telescope Suprime-Cam and Hubble Space Telescope Wide Field Planetary Camera. 2 images of the region obtained in 2009 show a coincident source that is most likely a compact massive star cluster in NGC 7331 that hosted the progenitor system. By comparing the emission properties of the source with stellar population models that incorporate interacting binary stars we estimate the age of the host cluster to be 30-300 Myr, and favor ages closer to 30 Myr in light of relatively strong Ha emission. SN 2014C is the best observed member of a class of core-collapse supernovae that fill the gap between events that interact strongly with dense, nearby environments immediately after explosion and those that never show signs of interaction. Better understanding of the frequency and nature of this intermediate population can contribute valuable information about the poorly understood final stages of stellar evolution.
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| 16. |
- Pastorello, A., et al.
(författare)
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A giant outburst two years before the core-collapse of a massive star
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 829-832
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Tidskriftsartikel (refereegranskat)abstract
- The death of massive stars produces a variety of supernovae, which are linked to the structure of the exploding stars(1,2). The detection of several precursor stars of type II supernovae has been reported ( see, for example, ref. 3), but we do not yet have direct information on the progenitors of the hydrogen-deficient type Ib and Ic supernovae. Here we report that the peculiar type Ib supernova SN 2006jc is spatially coincident with a bright optical transient(4) that occurred in 2004. Spectroscopic and photometric monitoring of the supernova leads us to suggest that the progenitor was a carbon-oxygen Wolf - Rayet star embedded within a helium-rich circumstellar medium. There are different possible explanations for this pre-explosion transient. It appears similar to the giant outbursts of luminous blue variable stars (LBVs) of 60 - 100 solar masses(5), but the progenitor of SN 2006jc was helium- and hydrogen-deficient ( unlike LBVs). An LBV-like outburst of a Wolf - Rayet star could be invoked, but this would be the first observational evidence of such a phenomenon. Alternatively, a massive binary system composed of an LBV that erupted in 2004, and a Wolf - Rayet star exploding as SN 2006jc, could explain the observations.
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| 17. |
- Eldridge, Bill, et al.
(författare)
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An in vitro selection strategy for conferring protease resistance to ligand binding peptides
- 2009
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Ingår i: Protein Engineering Design & Selection. - : Oxford University Press (OUP). - 1741-0126 .- 1741-0134. ; 22:11, s. 691-698
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Tidskriftsartikel (refereegranskat)abstract
- One drawback to the use of peptides as therapeutics has been their susceptibility to proteolysis. Here, we have used an in vitro display technology, CIS display, to enhance the proteolytic resistance of ligand-binding peptides by selection of protecting motifs from a large peptide library. The premise to this selection was that certain linear peptides within a library could form structures capable of preventing the access of proteases to defined cleavage sites without affecting ligand binding. A diverse 12-mer peptide library was inserted between a FLAG epitope motif and a thrombin cleavage site and this construct was fused to the bacterial initiator protein RepA for CIS display selection. After five rounds of selection, protection motifs were isolated that were capable of preventing proteolytic cleavage of the adjacent thrombin site. Some of the selected peptides were also resistant to more promiscuous proteases, such as chymotrypsin and trypsin, which were not used in the selection. The observed resistance to thrombin, trypsin and chymotrypsin translated into increased resistance to plasma proteases in vitro and to an increase in circulating half-lives in rats. This method can be applied to enhancing the in vivo stability of therapeutic peptides.
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| 18. |
- Fraser, M., et al.
(författare)
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RED AND DEAD : THE PROGENITOR OF SN 2012aw IN M95
- 2012
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Ingår i: The Astrophysical Journal Letters. - 2041-8205. ; 759:1, s. L13-
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Tidskriftsartikel (refereegranskat)abstract
- Core-collapse supernovae (SNe) are the spectacular finale to massive stellar evolution. In this Letter, we identify a progenitor for the nearby core-collapse SN 2012aw in both ground-based near-infrared and space-based optical pre-explosion imaging. The SN itself appears to be a normal Type II Plateau event, reaching a bolometric luminosity of 10(42) erg s(-1) and photospheric velocities of similar to 11,000 km s(-1) from the position of the H beta P-Cygni minimum in the early SN spectra. We use an adaptive optics image to show that the SN is coincident to within 27 mas with a faint, red source in pre-explosion HST+WFPC2, VLT+ISAAC, and NTT+SOFI images. The source has magnitudes F555W = 26.70 +/- 0.06, F814W = 23.39 +/- 0.02, J = 21.1 +/- 0.2, K = 19.1 +/- 0.4, which, when compared to a grid of stellar models, best matches a red supergiant. Interestingly, the spectral energy distribution of the progenitor also implies an extinction of A(V) > 1.2 mag, whereas the SN itself does not appear to be significantly extinguished. We interpret this as evidence for the destruction of dust in the SN explosion. The progenitor candidate has a luminosity between 5.0 and 5.6 log L/L-circle dot, corresponding to a zero-age main-sequence mass between 14 and 26 M-circle dot (depending on A(V)), which would make this one of the most massive progenitors found for a core-collapse SN to date.
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| 19. |
- Hsiao, Tiger Yu-Yang, et al.
(författare)
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JWST Reveals a Possible z similar to 11 Galaxy Merger in Triply Lensed MACS0647-JD
- 2023
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 949:2
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Tidskriftsartikel (refereegranskat)abstract
- MACS0647-JD is a triply lensed z similar to 11 galaxy originally discovered with the Hubble Space Telescope. The three lensed images are magnified by factors of similar to 8, 5, and 2 to AB mag 25.1, 25.6, and 26.6 at 3.5 mu m. The brightest is over a magnitude brighter than other galaxies recently discovered at similar redshifts z > 10 with JWST. Here, we report new JWST imaging that clearly resolves MACS0647-JD as having two components that are either merging galaxies or stellar complexes within a single galaxy. The brighter larger component "A" is intrinsically very blue (ss similar to-2.6 +/- 0.1), likely due to very recent star formation and no dust, and is spatially extended with an effective radius similar to 70 +/- 24 pc. The smaller component "B" (r similar to 20-+ 58 pc) appears redder (ss similar to-2 +/- 0.2), likely because it is older (100-200 Myr) with mild dust extinction (AV similar to 0.1 mag). With an estimated stellar mass ratio of roughly 2:1 and physical projected separation similar to 400 pc, we may be witnessing a galaxy merger 430 million years after the Big Bang. We identify galaxies with similar colors in a high-redshift simulation, finding their star formation histories to be dissimilar, which is also suggested by the spectral energy distribution fitting, suggesting they formed further apart. We also identify a candidate companion galaxy "C" similar to 3 kpc away, likely destined to merge with A and B. Upcoming JWST Near Infrared Spectrograph observations planned for 2023 January will deliver spectroscopic redshifts and more physical properties for these tiny magnified distant galaxies observed in the early universe.
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| 20. |
- Åberg, Anna, et al.
(författare)
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Helicobacter pylori adapts to chronic infection and gastric disease via ph-responsive baba-mediated adherence
- 2017
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 21:3, s. 376-389
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Tidskriftsartikel (refereegranskat)abstract
- The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.
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