ORCID Profile
0000-0001-6654-3620
Current Organisations
University of Southampton
,
University College London
,
Heriot-Watt University
,
Queen's University Belfast
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Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426845
Abstract: Supplementary Materials and Methods
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426839.V1
Abstract: High throughput spheroid screen results (z scores) in the MCF10 progression series. Gene rank for the validation screen (average z scores across cell lines).
Publisher: Copernicus GmbH
Date: 04-03-2021
DOI: 10.5194/EGUSPHERE-EGU21-9048
Abstract: & & The localisation of structural damage, in the form of faults and fractures, along a distinct and emergent fault plane is the key driving mechanism for catastrophic failure in the brittle Earth. However, due to the speed at which stable crack growth transitions to dynamic rupture, the precise mechanisms involved in localisation as a pathway to fault formation remain unknown. Understanding these mechanisms is critical to understanding and forecasting earthquakes, including induced seismicity, landslides and volcanic eruptions, as well as failure of man-made materials and structures. We used time-resolved synchrotron x-ray microtomography to image in-situ damage localisation at the micron scale and at bulk axial strain rates down to 10& sup& -7& /sup& s& sup& -1& /sup& . By controlling the rate of micro-fracturing events during a triaxial deformation experiment, we deliberately slowed the strain localisation process from seconds to minutes as failure approached. This approach, originally established to indirectly image fault nucleation and propagation with acoustic emissions, is completely novel in synchrotron x-ray microtomography and has enabled us to image directly processes that are normally too transient even for fast synchrotron imaging methods. Here, we first present the experimental apparatus and control system used to acquire the data, followed by damage localisation and shear zone development in a s le of Clashach sandstone viewed in unprecedented detail. Time-resolved microtomography images demonstrate a strong intrinsic correlation between shear and dilatant strain in the localised zone, with bulk shear strain accomodated by the nucleation and rotation of en-echelon tensile microcracks within a grain-scale shear band. Rotation is accompanied by antithetic to synthetic shear sliding of neighbouring crack surfaces as they rotate. The evolving 4D strain field, measured with incremental digital volume correlation between pairs of recorded x-ray tomographic volumes, independently confirm the correlation between shear and dilatant strain and show how strain localises spontaneously, first through exploration of several competing shear bands at peak stress before transitioning to failure along the optimally-oriented final fault plane. In order to & #8216 ground-truth& #8217 inferences made from bulk measurements and seismic waves (the primary method of detecting deformation at the field-scale where direct imaging of the subsurface is impossible), we (a) compare rupture energy estimates from local slip measurements with those from bulk slip data, and (b) use AE source location estimates to identify in idual cracks and other local changes in the microstucture that may explain the AE source.& &
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426842
Abstract: Gene list for the spheroid screen
Publisher: Copernicus GmbH
Date: 15-05-2023
DOI: 10.5194/EGUSPHERE-EGU23-7933
Abstract: Catastrophic failure in brittle, porous materials initiates when structural damage, in the form of smaller-scale fractures, localises along an emergent failure plane or 'fault' in a transition from stable crack growth to dynamic rupture. Due to the extremely rapid nature of this critical transition, the precise micro-mechanisms involved are poorly understood and difficult to capture. However, these mechanisms are crucial drivers for devastating phenomena such as earthquakes, including induced seismicity, landslides and volcanic eruptions, as well as large-scale infrastructure collapse. Here we observe these micro-mechanisms directly by controlling the rate of micro-fracturing events to slow down the transition in a unique triaxial deformation experiment that combines acoustic monitoring with contemporaneous in-situ x-ray imaging of the microstructure. The results [1] provide the first integrated picture of how damage and associated micro-seismic events emerge and evolve together during localisation and failure and allow us to ground truth some previous inferences from mechanical and seismic monitoring alone. They also highlight where such inferences miss important kinematically-governed grain-scale mechanisms prior to and during shear failure.The evolving damage imaged in the 3D x-ray volumes and local strain fields undergoes a breakdown sequence involving several stages: (i) self-organised exploration of candidate shear zones close to peak stress, (ii) spontaneous tensile failure of in idual grains due to point loading and pore-emanating fractures within an emergent and localised shear zone, validating many inferences from acoustic emissions monitoring, (iii) formation of a proto-cataclasite due to grain rotation and fragmentation, highlighting both the control of grain size on failure and the relative importance of aseismic mechanisms such as crack rotation in accommodating bulk shear deformation. Dilation and shear strain remain strongly correlated both spatially and temporally throughout s le weakening, confirming the existence of a cohesive zone, but with crack damage distributed throughout the shear zone rather than concentrated solely in a breakdown zone at the propagating front of a pre-existing discontinuity.Contrary to common assumption, we find seismic litude is not correlated with local imaged strain large local strain often occurs with small acoustic emissions, and vice versa. The seismic strain partition coefficient is very low overall and locally highly variable. Local strain is therefore predominantly aseismic, explained in part by grain/crack rotation along the emergent shear zone. The shear fracture energy calculated from local dilation and shear strain on the fault is half of that inferred from the bulk deformation, with a smaller critical slip distance, indicating that less energy is required for local breakdown in the shear zone compared with models of uniform slip.This improvement in process-based understanding holds out the prospect of reducing systematic errors in forecasting system-sized catastrophic failure in a variety of applications.[1] Cartwright-Taylor et al. 2022, Nature Communications 13, 6169, 0.1038/s41467-022-33855-z
Publisher: Springer Science and Business Media LLC
Date: 19-02-2021
DOI: 10.1038/S41598-021-83215-Y
Abstract: Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. The unfolded protein response (UPR) can be cytoprotective but when acutely activated can lead to cell death. In this study, we sought to enhance the acute activation of the UPR using radiation and ONC201, an UPR activator. Treating PCa cells with ONC201 quickly increased the expression of all the key regulators of the UPR and reduced the oxidative phosphorylation, with cell death occurring 72 h later. We exploited this time lag to sensitize prostate cancer cells to radiation through short-term treatment with ONC201. To understand how priming occurred, we performed RNA-Seq analysis and found that ONC201 suppressed the expression of cell cycle and DNA repair factors. In conclusion, we have shown that ONC201 can prime enhanced radiation response.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6512466
Abstract: Abstract Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model i in vivo /i –like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor s les was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. Significance: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426827.V1
Abstract: Enrichment analysis from TCGA RNA-seq and RPPA data comparing CREBBPaltered versus wild-type patients.
Publisher: Wiley
Date: 19-10-2016
DOI: 10.1002/PATH.4778
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426830.V1
Abstract: Phosphorylated, acetylated peptides and total proteins identified in HAP1 CREBBP WT and mutant spheroids.
Publisher: Copernicus GmbH
Date: 27-03-2022
DOI: 10.5194/EGUSPHERE-EGU22-5818
Abstract: & & Catastrophic failure in brittle, porous materials initiates when structural damage, in the form of smaller-scale fractures, localises along an emergent failure plane or 'fault' in a transition from stable crack growth to dynamic rupture. Due to the extremely rapid nature of this critical transition, the precise micro-mechanisms involved are poorly understood and difficult to capture. However, these mechanisms are crucial drivers for devastating phenomena such as earthquakes, including induced seismicity, landslides and volcanic eruptions, as well as large-scale infrastructure collapse. Here we observe these micro-mechanisms directly by controlling the rate of micro-fracturing events to slow down the transition in a unique triaxial deformation experiment that combines acoustic monitoring with contemporaneous & em& in-situ& /em& x-ray imaging of the microstructure. The results provide the first integrated picture of how damage and associated micro-seismic events emerge and evolve together during localisation and failure and allow us to ground truth some previous inferences from mechanical and seismic monitoring alone. They also highlight where such inferences miss important kinematically-governed grain-scale mechanisms prior to and during shear failure.& & & & The evolving damage imaged in the 3D x-ray volumes and local strain fields undergoes a breakdown sequence involving several stages: (i) self-organised exploration of candidate shear zones close to peak stress, (ii) spontaneous tensile failure of in idual grains due to point loading and pore-emanating fractures within an emergent and localised shear zone, validating many inferences from acoustic emissions monitoring, and (iii) formation of a proto-cataclasite due to grain rotation and fragmentation, highlighting both the control of grain size on failure and the relative importance of aseismic mechanisms such as crack rotation in accommodating bulk shear deformation. Dilation and shear strain remain strongly correlated both spatially and temporally throughout s le weakening, confirming the existence of a cohesive zone, but with crack damage distributed throughout the shear zone rather than concentrated solely in a breakdown zone at the propagating front of a pre-existing discontinuity.& & & & Contrary to common assumption, we find seismic litude is not correlated with local imaged strain large local strain often occurs with small acoustic emissions, and vice versa. The seismic strain partition coefficient is very low overall and locally highly variable. Local strain is therefore predominantly aseismic, explained in part by grain/crack rotation along the emergent shear zone. The shear fracture energy calculated from local dilation and shear strain on the fault is half of that inferred from the bulk deformation, with a smaller critical slip distance, indicating that less energy is required for local breakdown in the shear zone compared with models of uniform slip.& & & & This improvement in process-based understanding holds out the prospect of reducing systematic errors in forecasting system-sized catastrophic failure in a variety of applications.& &
Publisher: Elsevier BV
Date: 07-2021
Publisher: International Union of Crystallography (IUCr)
Date: 16-10-2020
DOI: 10.1107/S160057752001173X
Abstract: An X-ray transparent experimental triaxial rock deformation apparatus, here named `Mjölnir', enables investigations of brittle-style rock deformation and failure, as well as coupled thermal, chemical and mechanical processes relevant to a range of Earth subsurface environments. Designed to operate with cylindrical s les up to 3.2 mm outside-diameter and up to 10 mm length, Mjölnir can attain up to 50 MPa confining pressure and in excess of 600 MPa axial load. The addition of heaters extends the experimental range to temperatures up to 140°C. Deployment of Mjolnir on synchrotron beamlines indicates that full 3D datasets may be acquired in a few seconds to a few minutes, meaning full 4D investigations of deformation processes can be undertaken. Mjölnir is constructed from readily available materials and components and complete technical drawings are included in the supporting information.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426848.V1
Abstract: Supplementary Figures and legends
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426827
Abstract: Enrichment analysis from TCGA RNA-seq and RPPA data comparing CREBBPaltered versus wild-type patients.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426848
Abstract: Supplementary Figures and legends
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426842.V1
Abstract: Gene list for the spheroid screen
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426836
Abstract: Validation screen of the top 50 ranked genes in 2D and 3D.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426830
Abstract: Phosphorylated, acetylated peptides and total proteins identified in HAP1 CREBBP WT and mutant spheroids.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2021
DOI: 10.1158/0008-5472.CAN-20-1822
Abstract: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.
Publisher: Copernicus GmbH
Date: 04-03-2021
DOI: 10.5194/EGUSPHERE-EGU21-15691
Abstract: & & Catastrophic failure is a critical phenomenon present in Earth systems on a variety of scales, and is associated with the evolution of damage leading to system-size failure. Laboratory testing of rock failure permits characterization of fracture network evolution at the micro-scale to understand the interaction of cracks, pores and grain boundaries to an applied stress field, and the relationship between deformation and seismic response. Previous studies have relied on acoustic emissions (hearing) or X-ray imaging (seeing) to study the process of localization, which involves spontaneous self-organization of smaller cracks along faults and fractures on localised zones of deformation. To combine hearing and seeing of the microscopic processes and their control of system-sized failure, a novel x-ray transparent cell was used for deformation experiments of rock s les, which permits integration of acoustic monitoring with fast synchrotron x-ray imaging. To increase temporal characterization of damage beyond the temporal resolution of the fast 3D synchrotron system, acoustic emission (AE) feedback control was used to regulate the applied stress and slow down the deformation processes. As a result, there is increased temporal resolution of the incremental deformation between successive x-ray scanned states allowing synchronized comparison of acoustic emissions to x-ray scans. Here, we present the seismic analysis used to characterize the velocity evolution of the rock s les, and the location and characteristics of in idual AE events in relation to microscopic deformation processes. Time-lapse velocity measurements are linked to internal stress changes and structural damage corresponding to seismic and aseismic deformation processes, while acoustic emissions are a direct indication of local cracking.& We show that we can successfully locate AE events in 3D using only two sensors on either end of the s le, based on ellipsoid mapping, and x-ray image to event correlation. We explore temporal and spatial statistics of AE signatures and how those are linked to the strain field in the s les measured with incremental digital volume correlation between pairs of recorded x-ray tomograms. The direct observation of AE and X-ray images enables quantification of relevant seismic (local cracking leading to AE) to aseismic (elastic loading and silent irreversible damage) processes, with information extracted over fine temporal resolution throughout the deformation process through the AE-feedback control.& &
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426836.V1
Abstract: Validation screen of the top 50 ranked genes in 2D and 3D.
Publisher: Springer Science and Business Media LLC
Date: 26-01-2021
DOI: 10.1038/S41416-020-01185-W
Abstract: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. For pregnanediol-3-glucuronide, there were no genome-wide significant associations for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10 –18 ) in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10 –8 ). The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6512466.V1
Abstract: Abstract Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model i in vivo /i –like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor s les was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. Significance: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors. /
Publisher: American Geophysical Union (AGU)
Date: 29-07-2020
DOI: 10.1029/2020JB019642
Abstract: Catastrophic failure of brittle rocks is important in managing risk associated with system‐sized material failure. Such failure is caused by nucleation, growth, and coalescence of microcracks that spontaneously self‐organize along localized damage zones under compressive stress. Here we present X‐ray microtomography observations that elucidate the in situ micron‐scale processes, obtained from novel tri‐axial compression experiments conducted in a synchrotron. We examine the effect of microstructural heterogeneity in the starting material (Ailsa Craig microgranite known for being virtually crack‐free) on crack network evolution and localization. To control for heterogeneity, we introduced a random nanoscale crack network into one s le by thermal stressing, leaving a second s le as‐received. By assessing the time‐dependent statistics of crack size and spatial distribution, we test the hypothesis that the degree of starting heterogeneity influences the order and predictability of the phase transition between intact and failed states. We show that this is indeed the case at the system‐scale. The initially more heterogeneous (heat‐treated) s le showed clear evidence for a second‐order transition: inverse power law acceleration in correlation length with a well‐defined singularity near failure and distinct changes in the scaling exponents. The more homogeneous (untreated) s le showed evidence for a first‐order transition: exponential increase in correlation length associated with distributed damage and unstable crack nucleation ahead of abrupt failure. In both cases, anisotropy in the initial porosity dictated the fault orientation, and system‐sized failure occurred when the correlation length approached the grain size. These results have significant implications for the predictability of catastrophic failure in different materials.
Publisher: Wiley
Date: 22-12-2014
DOI: 10.1002/PATH.4483
Publisher: Oxford University Press (OUP)
Date: 12-08-2020
DOI: 10.1093/JNCI/DJAA101
Abstract: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10–06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P & 5 × 10–08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor–positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10–30). These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426845.V1
Abstract: Supplementary Materials and Methods
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22426839
Abstract: High throughput spheroid screen results (z scores) in the MCF10 progression series. Gene rank for the validation screen (average z scores across cell lines).
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: Ireland
Start Date: 2017
End Date: 2021
Funder: Natural Environment Research Council
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