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  • Journal article
    Tarkin JM, Wall C, Gopalan D, Aloj L, Manavaki R, Fryer TD, Aboagye EO, Bennett MR, Peters JE, Rudd JHF, Mason JCet al., 2020,

    Novel approach to imaging active takayasu arteritis using somatostatin receptor positron emission tomography/magnetic resonance imaging.

    , Circulation: Cardiovascular Imaging, Vol: 13, Pages: 1-3, ISSN: 1941-9651

    Although 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is an important diagnostic test for Takayasu arteritis (TAK),118F-FDG lacks inflammatory cell selectivity and cannot accurately distinguish arteritis from metabolically active vascular remodeling.2 This observation has led to the search for more sensitive and specific PET tracers for TAK. Macrophage activation antigen SST2 (somatostatin receptor subtype-2) PET represents a potential alternative imaging biomarker for defining disease activity in TAK, as macrophages are a major feature of the inflammatory infiltrate. We aimed to determine the ability of SST2 PET/magnetic resonance imaging (MRI) to detect arteritis in 2 patients with clinically active TAK.

  • Journal article
    Shearn AIU, Aday S, Ben-Aicha S, Carnell-Morris P, Siupa A, Angelini GD, Clayton A, Boulanger C, Punjabi P, Emanueli C, Biglino Get al., 2020,

    Analysis of neat biofluids obtained during cardiac surgery using nanoparticle tracking analysis: methodological considerations

    , Frontiers in Cell and Developmental Biology, Vol: 8, Pages: 1-14, ISSN: 2296-634X

    Small extracellular vesicles (sEVs) are those nanovesicles 30–150 nm in size with a role in cell signalling and potential as biomarkers of disease. Nanoparticle tracking analysis (NTA) techniques are commonly used to measure sEV concentration in biofluids. However, this quantification technique can be susceptible to sample handing and machine settings. Moreover, some classes of lipoproteins are of similar sizes and could therefore confound sEV quantification, particularly in blood-derived preparations, such serum and plasma. Here we have provided methodological information on NTA measurements and systematically investigated potential factors that could interfere with the reliability and repeatability of results obtained when looking at neat biofluids (i.e., human serum and pericardial fluid) obtained from patients undergoing cardiac surgery and from healthy controls. Data suggest that variables that can affect vesicle quantification include the level of contamination from lipoproteins, number of sample freeze/thaw cycles, sample filtration, using saline-based diluents, video length and keeping the number of particles per frame within defined limits. Those parameters that are of less concern include focus, the “Maximum Jump” setting and the number of videos recorded. However, if these settings are clearly inappropriate the results obtained will be spurious. Similarly, good experimental practice suggests that multiple videos should be recorded. In conclusion, NTA is a perfectible, but still commonly used system for sEVs analyses. Provided users handle their samples with a highly robust and consistent protocol, and accurately report these aspects, they can obtain data that could potentially translate into new clinical biomarkers for diagnosis and monitoring of cardiovascular disease.

  • Journal article
    Porter A, Youngstein T, Tombetti E, Mason Jet al., 2020,

    Biologic therapy in supra-aortic Takayasu arteritis can improve symptoms of cerebral ischaemia without surgical intervention

    , Rheumatology, Vol: 59, Pages: iii28-iii32, ISSN: 0080-2727

    Background: Takayasu arteritis typically results in severe arterial injury with stenoses, occlusions and occasionally aneurysms. Involvement of the supra-aortic arteries is common, and in its most severe form may compromise cerebral blood supply, resulting in signs of cerebral ischaemia including visual impairment, dysphasia, hemiparesis, loss of consciousness and stroke. In addition to combination immunosuppression, the management paradigm for symptomatic cerebral ischaemia includes revascularisation. The invasive nature of this surgery, the risk of complications and the relatively high rate of re-stenosis is of concern to patients and physicians alike.The aim of this study was to determine whether combined immunosuppression with early escalation to biologic therapy improved outcomes and reduced the need for high risk surgical intervention Methods: A retrospective review of 145 Takayasu arteritis patients attending Imperial College Healthcare between 2010-2018 was conducted to identify those with cerebral ischaemia secondary to supra-aortic disease and to analyse their treatment and outcomes. Results: Eight patients (5.5%) were identified. Seven received long-term combined immunosuppressive therapy and six were prescribed biologics. The data revealed a higher than expected comprehensive response to therapy, with significant falls in disease activity, cerebral ischaemia score and prednisolone dose required, over a median follow-up of 37 months. Serial imaging analysis detected no arterial disease progression after the initiation of optimal therapy. Only one patient required surgical intervention for persistent neurological symptoms. Conclusion: Early use of biologic therapy in those with supra-aortic Takayasu arteritis presenting with cerebral ischaemia may reduce the numbers of patients requiring surgical intervention and improve outcomes.

  • Journal article
    Jalan A, Sammon D, Hartgerink J, Brear P, Stott K, Hamaia S, Hunter E, Walker D, Leitinger B, Farndale Ret al., 2020,

    Chain alignment of collagen I deciphered using computationally designed heterotrimers

    , Nature Chemical Biology, Vol: 16, Pages: 423-429, ISSN: 1552-4450

    The most abundant member of the collagen protein family, collagen I (COL1), is composed of two similar (chain A) and one unique (chain B) polypeptides that self-assemble with one amino acid offset into a heterotrimeric triple helix. Given the offset, chain B can occupy either the leading (BAA), middle (ABA) or trailing (AAB) position of the triple helix, yielding three isomeric biomacromolecules with different protein recognition properties. Despite five decades of intensive research, there is no consensus on the position of chain B in COL1. Here, three triple-helical heterotrimers that each contained a putative Von Willebrand Factor (VWF) and discoidin domain receptor (DDR) recognition sequence from COL1 were designed with chain B permutated in all three positions. AAB demonstrated a strong preference for both VWF and DDR and also induced higher levels of cellular DDR phosphorylation. Thus, we resolve this long-standing mystery and show that COL1 adopts an AAB register.

  • Journal article
    Corcoran D, Juskaite V, Xu Y, Gorlitz F, Alexandrov Y, Dunsby C, French P, Leitinger Bet al., 2019,

    DDR1 autophosphorylation is a result of aggregation into dense clusters

    , Scientific Reports, Vol: 9, ISSN: 2045-2322

    The collagen receptor DDR1 is a receptor tyrosine kinase that promotes progression ofa wide range of human disorders. Little is known about how ligand binding triggers DDR1 kinase activity. We previously reported that collagen induces DDR1 activation through lateral dimer association and phosphorylation between dimers, a process that requires specific transmembrane association. Here we demonstrate ligand-induced DDR1 clustering by widefield and super-resolution imaging and provide evidence for a mechanism whereby DDR1 kinase activity is determined by its molecular density. Ligand binding resulted in initial DDR1 reorganisation into morphologically distinct clusters with unphosphorylated DDR1. Further compaction over time led to clusters with highly aggregated and phosphorylated DDR1. Ligand-induced DDR1 clustering was abolished by transmembrane mutations but did not require kinase activity. Our results significantly advance our understanding of the molecular events underpinning ligand-induced DDR1 kinase activity and provide an explanation for the unusually slow DDR1 activation kinetics.

  • Journal article
    Hultman K, Edsfeldt A, Björkbacka H, Dunér P, Sundius L, Nitulescu M, Persson A, Boyle JJ, Nilsson J, Hultgårdh-Nilsson A, Bengtsson E, Gonçalves Iet al., 2019,

    Cartilage oligomeric matrix protein associates with a vulnerable plaque phenotype in human atherosclerotic plaques

    , Stroke, Vol: 50, ISSN: 0039-2499

    Background and Purpose- Extracellular matrix proteins are important in atherosclerotic disease by influencing plaque stability and cellular behavior but also by regulating inflammation. COMP (cartilage oligomeric matrix protein) is present in healthy human arteries and expressed by smooth muscle cells. A recent study showed that transplantation of COMP-deficient bone marrow to apoE-/- mice increased atherosclerotic plaque formation, indicating a role for COMP also in bone marrow-derived cells. Despite the evidence of a role for COMP in murine atherosclerosis, knowledge is lacking about the role of COMP in human atherosclerotic disease. Methods- In the present study, we investigated if COMP was associated with a stable or a vulnerable human atherosclerotic plaque phenotype by analyzing 211 carotid plaques for COMP expression using immunohistochemistry. Results- Plaque area that stained positive for COMP was significantly larger in atherosclerotic plaques associated with symptoms (n=110) compared with asymptomatic plaques (n=101; 9.7% [4.7-14.3] versus 5.6% [2.8-9.8]; P=0.0002). COMP was positively associated with plaque lipids (r=0.32; P=0.000002) and CD68 cells (r=0.15; P=0.036) but was negatively associated with collagen (r=-0.16; P=0.024), elastin (r=-0.14; P=0.041), and smooth muscle cells (r=-0.25; P=0.0002). COMP was positively associated with CD163 (r=0.37; P=0.00000006), a scavenger receptor for hemoglobin/haptoglobin and a marker of Mhem macrophages, and with intraplaque hemorrhage, measured as glycophorin A staining (r=0.28; P=0.00006). Conclusions- The present study shows that COMP is associated to symptomatic carotid atherosclerosis, CD163-expressing cells, and a vulnerable atherosclerotic plaque phenotype in humans.

  • Conference paper
    Dixit P, Anwar M, Saif J, Chamorro-Jorganes A, Dumas M, Angelini G, Punjabi P, Srivastava P, Katare R, Petretto E, Emanueli Cet al., 2019,

    Impaired secretion of clusterin in pericardial fluid of diabetics, a deleterious outcome for the cardiac micro-vasculature

    , Congress of the European-Society-of-Cardiology (ESC) / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 3912-3912, ISSN: 0195-668X
  • Conference paper
    Poovathoor AJ, Belete S, Afoke J, Spalding D, Punjabi Pet al., 2019,

    Cardiopulmonary exercise testing and major hepatobiliary surgery: An effective way to judge fitness for surgery?

    , International Surgical Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland (ASGBI), Publisher: WILEY, Pages: 68-69, ISSN: 0007-1323
  • Journal article
    Moscarelli M, Fiorentino F, Suleiman M-S, Emanueli C, Reeves BC, Punjabi PP, Angelini GDet al., 2019,

    Remote ischaemic preconditioning in isolated aortic valve and coronary artery bypass surgery: a randomized trial

    , EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY, Vol: 55, Pages: 905-912, ISSN: 1010-7940
  • Journal article
    Kalna V, Yang Y, Peghaire C, Frudd K, hannah R, Shah A, Osuna Almagro L, Boyle J, gottgens B, Ferrer J, Randi A, Birdsey Get al., 2019,

    The transcription factor ERG regulates super-enhancers associated with an endothelial-specific gene expression program

    , Circulation Research, Vol: 124, Pages: 1337-1349, ISSN: 0009-7330

    Rationale:The ETS (E-26 transformation-specific) transcription factor ERG (ETS-related gene) is essential for endothelial homeostasis, driving expression of lineage genes and repressing proinflammatory genes. Loss of ERG expression is associated with diseases including atherosclerosis. ERG’s homeostatic function is lineage-specific, because aberrant ERG expression in cancer is oncogenic. The molecular basis for ERG lineage-specific activity is unknown. Transcriptional regulation of lineage specificity is linked to enhancer clusters (super-enhancers).Objective:To investigate whether ERG regulates endothelial-specific gene expression via super-enhancers.Methods and Results:Chromatin immunoprecipitation with high-throughput sequencing in human umbilical vein endothelial cells showed that ERG binds 93% of super-enhancers ranked according to H3K27ac, a mark of active chromatin. These were associated with endothelial genes such as DLL4 (Delta-like protein 4), CLDN5 (claudin-5), VWF (von Willebrand factor), and CDH5 (VE-cadherin). Comparison between human umbilical vein endothelial cell and prostate cancer TMPRSS2 (transmembrane protease, serine-2):ERG fusion-positive human prostate epithelial cancer cell line (VCaP) cells revealed distinctive lineage-specific transcriptome and super-enhancer profiles. At a subset of endothelial super-enhancers (including DLL4 and CLDN5), loss of ERG results in significant reduction in gene expression which correlates with decreased enrichment of H3K27ac and MED (Mediator complex subunit)-1, and reduced recruitment of acetyltransferase p300. At these super-enhancers, co-occupancy of GATA2 (GATA-binding protein 2) and AP-1 (activator protein 1) is significantly lower compared with super-enhancers that remained constant following ERG inhibition. These data suggest distinct mechanisms of super-enhancer regulation in endothelial cells and highlight the unique role of ERG in controlling a core subset of super-enhancers. Most disease-assoc

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