33 research outputs found
CHK1 inhibition is synthetically lethal with loss of B-family DNA polymerase function in human lung and colorectal cancer cells
Checkpoint kinase 1 (CHK1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair and DNA replication. Smallmolecule CHK1 inhibitors sensitise cancer cells to genotoxic agents and have shown single agent preclinical activity in cancers with high levels of replication stress. However, the underlying genetic determinants of CHK1 inhibitor sensitivity remain unclear. We used the developmental clinical drug SRA737 in an unbiased largescale siRNA screen to identify novel mediators of CHK1 inhibitor sensitivity and uncover potential combination therapies and biomarkers for patient selection. We identified members of the B-family of DNA polymerases (POLA1, POLE and POLE2) whose silencing sensitised the human A549 non small cell lung cancer (NSCLC) and SW620 colorectal cancer cell lines to SRA737. B-family polymerases were validated using multiple siRNAs in a panel of NSCLC and colorectal cancer cell lines. Replication stress, DNA damage and apoptosis were increased in human cancer cells following depletion of the B-family DNA polymerases combined with SRA737 treatment. Moreover, pharmacological blockade of B-family DNA polymerases using aphidicolin or CD437 combined with CHK1 inhibitors led to synergistic inhibition of cancer cell proliferation. Furthermore, low levels of POLA1, POLE and POLE2 protein expression in NSCLC and colorectal cancer cells correlated with single agent CHK1 inhibitor sensitivity and may constitute biomarkers of this phenotype. These findings provide a potential basis for combining CHK1 and B-family polymerase inhibitors in cancer therapy
The wide-field, multiplexed, spectroscopic facility WEAVE : survey design, overview, and simulated implementation
Funding for the WEAVE facility has been provided by UKRI STFC, the University of Oxford, NOVA, NWO, Instituto de AstrofĂsica de Canarias (IAC), the Isaac Newton Group partners (STFC, NWO, and Spain, led by the IAC), INAF, CNRS-INSU, the Observatoire de Paris, RĂ©gion Ăle-de-France, CONCYT through INAOE, Konkoly Observatory (CSFK), Max-Planck-Institut fĂŒr Astronomie (MPIA Heidelberg), Lund University, the Leibniz Institute for Astrophysics Potsdam (AIP), the Swedish Research Council, the European Commission, and the University of Pennsylvania.WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366-959 nm at R ⌠5000, or two shorter ranges at R ⌠20,000. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for ⌠3 million stars and detailed abundances for ⌠1.5 million brighter field and open-cluster stars; (ii) survey ⌠0.4 million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey âŒÂ 400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in z 1 million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at z > 2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.PostprintPeer reviewe
The wide-field, multiplexed, spectroscopic facility WEAVE: Survey design, overview, and simulated implementation
WEAVE, the new wide-field, massively multiplexed spectroscopic survey
facility for the William Herschel Telescope, will see first light in late 2022.
WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a
nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini'
integral field units (IFUs), and a single large IFU. These fibre systems feed a
dual-beam spectrograph covering the wavelength range 366959\,nm at
, or two shorter ranges at . After summarising the
design and implementation of WEAVE and its data systems, we present the
organisation, science drivers and design of a five- to seven-year programme of
eight individual surveys to: (i) study our Galaxy's origins by completing
Gaia's phase-space information, providing metallicities to its limiting
magnitude for 3 million stars and detailed abundances for
million brighter field and open-cluster stars; (ii) survey million
Galactic-plane OBA stars, young stellar objects and nearby gas to understand
the evolution of young stars and their environments; (iii) perform an extensive
spectral survey of white dwarfs; (iv) survey
neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and
kinematics of stellar populations and ionised gas in cluster galaxies;
(vi) survey stellar populations and kinematics in field galaxies
at ; (vii) study the cosmic evolution of accretion
and star formation using million spectra of LOFAR-selected radio sources;
(viii) trace structures using intergalactic/circumgalactic gas at .
Finally, we describe the WEAVE Operational Rehearsals using the WEAVE
Simulator.Comment: 41 pages, 27 figures, accepted for publication by MNRA
The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma
We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations
The wide-field, multiplexed, spectroscopic facility WEAVE: Survey design, overview, and simulated implementation
WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366â959\,nm at RâŒ5000, or two shorter ranges at RâŒ20000. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for âŒ3 million stars and detailed abundances for âŒ1.5 million brighter field and open-cluster stars; (ii) survey âŒ0.4 million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey âŒ400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in z1 million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at z>2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator
Measurement of CP asymmetries and branching fraction ratios of Bâ decays to two charm mesons
The asymmetries of seven decays to two charm mesons are measured using data corresponding to an integrated luminosity of of proton-proton collisions collected by the LHCb experiment. Decays involving a or meson are analysed by reconstructing only the or decay products. This paper presents the first measurement of and , and the most precise measurement of the other five asymmetries. There is no evidence of violation in any of the analysed decays. Additionally, two ratios between branching fractions of selected decays are measured.The CP asymmetries of seven B decays to two charm mesons are measured using data corresponding to an integrated luminosity of 9 fb of proton-proton collisions collected by the LHCb experiment. Decays involving a D or meson are analysed by reconstructing only the D or decay products. This paper presents the first measurement of (BâD) and (BâD), and the most precise measurement of the other five CP asymmetries. There is no evidence of CP violation in any of the analysed decays. Additionally, two ratios between branching fractions of selected decays are measured.[graphic not available: see fulltext]The asymmetries of seven decays to two charm mesons are measured using data corresponding to an integrated luminosity of of proton-proton collisions collected by the LHCb experiment. Decays involving a or meson are analysed by reconstructing only the or decay products. This paper presents the first measurement of and , and the most precise measurement of the other five asymmetries. There is no evidence of violation in any of the analysed decays. Additionally, two ratios between branching fractions of selected decays are measured
An evaluation of the ability of pifithrin-α and -ÎČ to inhibit p53 function in two wild-type p53 human tumor cell lines
CHK1 inhibition is synthetically lethal with loss of B-family DNA polymerase function in human lung and colorectal cancer cells
Checkpoint kinase 1 (CHK1) is a key mediator of the DNA damage response that regulates cell cycle progression, DNA damage repair and DNA replication. Smallmolecule CHK1 inhibitors sensitise cancer cells to genotoxic agents and have shown single agent preclinical activity in cancers with high levels of replication stress. However, the underlying genetic determinants of CHK1 inhibitor sensitivity remain unclear. We used the developmental clinical drug SRA737 in an unbiased largescale siRNA screen to identify novel mediators of CHK1 inhibitor sensitivity and uncover potential combination therapies and biomarkers for patient selection. We identified members of the B-family of DNA polymerases (POLA1, POLE and POLE2) whose silencing sensitised the human A549 non small cell lung cancer (NSCLC) and SW620 colorectal cancer cell lines to SRA737. B-family polymerases were validated using multiple siRNAs in a panel of NSCLC and colorectal cancer cell lines. Replication stress, DNA damage and apoptosis were increased in human cancer cells following depletion of the B-family DNA polymerases combined with SRA737 treatment. Moreover, pharmacological blockade of B-family DNA polymerases using aphidicolin or CD437 combined with CHK1 inhibitors led to synergistic inhibition of cancer cell proliferation. Furthermore, low levels of POLA1, POLE and POLE2 protein expression in NSCLC and colorectal cancer cells correlated with single agent CHK1 inhibitor sensitivity and may constitute biomarkers of this phenotype. These findings provide a potential basis for combining CHK1 and B-family polymerase inhibitors in cancer therapy
The burden of proof and its role in argumentation
The notion of âthe burden of proofâ plays an important role in real-world argumentation contexts, in particular in law. It has also been given a central role in normative accounts of argumentation, and has been used to explain a range of classic argumentation fallacies. We argue that in law the goal is to make practical decisions whereas in critical discussion the goal is frequently simply to increase or decrease degree of belief in a proposition. In the latter case, it is not necessarily important whether that degree of belief exceeds a particular threshold (e.g., âreasonable doubtâ). We explore the consequences of this distinction for the role that the âburden of proofâ has played in argumentation and in theories of fallacy