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Davies, S.

Publications and source records attributed to Davies, S..

24 records · Page 2Linked to original sources

Multi-proxy evidence for the impact of the Storegga Slide Tsunami on the early Holocene landscapes of the southern North Sea

Doggerland was a land mass occupying an area currently covered by the North Sea until marine inundation took place during the mid-Holocene, ultimately separating the British land mass from the rest of Europe. The Storegga Slide, which triggered a tsunami reflected in sediment deposits in the Northern North Sea, North East coastlines of the British Isles and across the North Atlantic, was a major event during this transgressive phase. The spatial extent of the Storegga tsunami however remains unconfirmed because to date no direct evidence for the event has been recovered from the southern North Sea. We present evidence that Storegga associated deposits occur in the southern North Sea. Palaeo-river systems have been identified using seismic survey in the southwestern North Sea and sedimentary cores extracted to track the Mid Holocene inundation. At the head of one palaeo-river system near the Outer Dowsing Deep, the Southern River, we observed an abrupt and catastrophic inundation stratum. Based on lithostratigraphic, macro and microfossils and sedimentary ancient DNA (sedaDNA) evidence, supported by optical stimulation luminescence (OSL) and radiocarbon dating, we conclude these deposits were a result of the Storegga event. Seismic identification of this stratum to adjacent cores indicated diminished traces of the tsunami, largely removed by subsequent erosional processes. Our results demonstrate the catastrophic impact of Storegga within this area of the Southern North Sea, but indicate that these effects were temporary and likely localized and mitigated by the dense woodland and topography of the area. We conclude clear physical remnants of the wave are likely to be restricted to inland basins and incised river valley systems.

paleontology↗

Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts

Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, impacting the accuracy of PDX modeling of human cancer. Here we exhaustively analyze copy number alterations (CNAs) in 1451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multi-region samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.

cancer biology↗

Systematic Establishment of Robustness and Standards in Patient-Derived Xenograft Experiments and Analysis

Patient-Derived Xenografts (PDXs) are tumor-in-mouse models for cancer. PDX collections, such as those supported by the NCI PDXNet program, are powerful resources for preclinical therapeutic testing. However, variations in experimental design and analysis procedures have limited interpretability. To determine the robustness of PDX studies, the PDXNet tested temozolomide drug response for three pre-validated PDX models (sensitive, resistant, and intermediate) across four blinded PDX Development and Trial Centers (PDTCs) using independently selected SOPs. Each PDTC was able to correctly identify the sensitive, resistant, and intermediate models, and statistical evaluations were concordant across all groups. We also developed and benchmarked optimized PDX informatics pipelines, and these yielded robust assessments across xenograft biological replicates. These studies show that PDX drug responses and sequence results are reproducible across diverse experimental protocols. Here we share the range of experimental procedures that maintained robustness, as well as standardized cloud-based workflows for PDX exome-seq and RNA-Seq analysis and for evaluating growth.

cancer biology↗

Genomic and epidemiological evidence of a dominant Panton-Valentine leucocidin-positive Methicillin Resistant Staphylococcus aureus lineage in Sri Lanka with spread to the United Kingdom and Australia

ObjectiveTo undertake the first detailed genomic analysis of methicillin-resistant Staphylococcus aureus (MRSA) isolated in Sri Lanka.\n\nMethodsA prospective observational study was performed on 94 MRSA isolates collected over a four month period from the Anuradhapura Teaching Hospital, Sri Lanka. Screening for mecA, mecC and the Panton-Valentine leucocidin (PVL)-associated lukS-PV/lukF-PV genes and molecular characterisation by spa typing was undertaken. Whole genome sequencing (WGS) and phylogenetic analysis was performed on selected multilocus sequence type (MLST) clonal complex 5 (CC5) isolates from Sri Lanka, England, Australia and Argentina.\n\nResultsAll 94 MRSA harboured the mecA gene. Nineteen spa types associated with nine MLST clonal complexes were identified. Most isolates were from skin and soft tissue infections (76.9%), with the remainder causing more invasive disease. Sixty two (65.9%) of isolates were PVL positive with the majority (56 isolates; 90.3%) belonging to a dominant CC5 lineage. This lineage, PVL-positive ST5-MRSA-IVc, was associated with community and hospital-onset infections. Based on WGS, representative PVL-positive ST5-MRSA-IVc isolates from Sri Lanka, England and Australia formed a single phylogenetic clade, suggesting wide geographical circulation.\n\nConclusionsWe present the most detailed genomic analysis of MRSA isolated in Sri Lanka to date. The analysis identified a PVL-positive ST5-MRSA-IVc that dominates MRSA clinical infections in Sri Lanka. Furthermore, transmission of the strain has occurred in the United Kingdom and Australia.

microbiology↗

Corals sustain growth but not skeletal density across the Florida Keys Reef Tract despite ongoing warming

Through the continuous growth of their carbonate skeletons, corals record invaluable information about past environmental conditions and their effect on colony fitness. Here, we characterize century-scale growth records of inner and outer reef corals across ~200 km of the Florida Keys Reef Tract (FKRT) using skeletal cores extracted from two ubiquitous reef-building species, Siderastrea siderea and Pseudodiploria strigosa. We find that corals across the FKRT have sustained extension and calcification rates over the past century but have experienced a long-term reduction in skeletal density, regardless of reef zone. Notably, P. strigosa colonies exhibit temporary reef zone-dependent reductions in extension rate corresponding to two known extreme temperature events in 1969-70 and 1997-98. We propose that the subtropical climate of the FKRT may buffer corals from chronic growth declines associated with climate warming, though the significant reduction in skeletal density may indicate underlying vulnerability to present and future trends in ocean acidification.

ecology↗

The prognostic effects of somatic mutations in ER-positive breast cancer

More than 50 genes are recurrently affected by somatic mutation in estrogen receptor positive (ER+) breast cancer but prognostic effects have not been definitively established. Primary tumor DNA was therefore subjected to targeted sequencing from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) patients. Independent validation of prognostic interactions was achieved using independent data from the METABRIC study. Associations between MAP3K1 and PIK3CA with luminal A status and TP53 mutations with Luminal B/non-luminal tumors were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutation was validated as a poor outcome driver. For MA12, poor outcome associated with PIK3R1 mutation was similarly validated. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false-discovery correction (q=0.0003). In conclusion, uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typify ER+ breast cancer.

genomics↗