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Instruments / Technical Area	Publication Details	Published	Actions
I18-Microfocus Spectroscopy	Calcification microstructure reflects breast tissue microenvironment Sarah Gosling , Robert Scott , Charlene Greenwood , Pascaline Bouzy , Jayakrupakar Nallala , Iain D. Lyburn , Nicholas Stone , Keith Rogers Journal Of Mammary Gland Biology And Neoplasia 95 DOI: 10.1007/s10911-019-09441-3 Diamond Proposal Number(s): [12303] Open Access Show Abstract ▼ Abstract: Microcalcifications are important diagnostic indicators of disease in breast tissue. Tissue microenvironments differ in many aspects between normal and cancerous cells, notably extracellular pH and glycolytic respiration. Hydroxyapatite microcalcification microstructure is also found to differ between tissue pathologies, including differential ion substitutions and the presence of additional crystallographic phases. Distinguishing between tissue pathologies at an early stage is essential to improve patient experience and diagnostic accuracy, leading to better disease outcome. This study explores the hypothesis that microenvironment features may become immortalised within calcification crystallite characteristics thus becoming indicators of tissue pathology. In total, 55 breast calcifications incorporating 3 tissue pathologies (benign – B2, ductal carcinoma in-situ - B5a and invasive malignancy - B5b) from archive formalin-fixed paraffin-embedded core needle breast biopsies were analysed using X-ray diffraction. Crystallite size and strain were determined from 548 diffractograms using Williamson-Hall analysis. There was an increased crystallinity of hydroxyapatite with tissue malignancy compared to benign tissue. Coherence length was significantly correlated with pathology grade in all basis crystallographic directions (P < 0.01), with a greater difference between benign and in situ disease compared to in-situ disease and invasive malignancy. Crystallite size and non-uniform strain contributed to peak broadening in all three pathologies. Furthermore, crystallite size and non-uniform strain normal to the basal planes increased significantly with malignancy (P < 0.05). Our findings support the view that tissue microenvironments can influence differing formation mechanisms of hydroxyapatite through acidic precursors, leading to differential substitution of carbonate into the hydroxide and phosphate sites, causing significant changes in crystallite size and non-uniform strain.	Dec 2019
I04-Macromolecular Crystallography	A novel pyrazolopyrimidine ligand of human PGK1 and stress sensor DJ1 modulates the shelterin complex and telomere length regulation Alan E. Bilsland , Yu Liu , Andrew Turnbull , David Sumpton , Katrina Stevenson , Claire J. Cairney , Susan M. Boyd , Jon Roffey , David Jenkinson , W. Nicol Keith Neoplasia 21, 893 - 907 DOI: 10.1016/j.neo.2019.07.008 Open Access Show Abstract ▼ Abstract: Telomere signaling and metabolic dysfunction are hallmarks of cell aging. New agents targeting these processes might provide therapeutic opportunities, including chemoprevention strategies against cancer predisposition. We report identification and characterization of a pyrazolopyrimidine compound series identified from screens focused on cell immortality and whose targets are glycolytic kinase PGK1 and oxidative stress sensor DJ1. We performed structure–activity studies on the series to develop a photoaffinity probe to deconvolute the cellular targets. In vitro binding and structural analyses confirmed these targets, suggesting that PGK1/DJ1 interact, which we confirmed by immunoprecipitation. Glucose homeostasis and oxidative stress are linked to telomere signaling and exemplar compound CRT0063465 blocked hypoglycemic telomere shortening. Intriguingly, PGK1 and DJ1 bind to TRF2 and telomeric DNA. Compound treatment modulates these interactions and also affects Shelterin complex composition, while conferring cellular protection from cytotoxicity due to bleomycin and desferroxamine. These results demonstrate therapeutic potential of the compound series.	Sep 2019

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