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Article ; Online: Developing a Strategy for Interventional Molecular Imaging of Oxidized Low-Density Lipoprotein in Atherosclerosis

Samata S. Pandey MSc / Dorian O. Haskard DM, FRCP, FMedSci / Ramzi Y. Khamis MB, ChB, PhD, MRCP

Molecular Imaging, Vol

2017 Volume 16

Abstract: The identification of vulnerable coronary artery atherosclerotic plaques offers the prospect of either localized or systematic therapeutic targeting in order to prevent myocardial infarction. Molecular imaging of atherosclerosis adds to morphological ... ...

Abstract	The identification of vulnerable coronary artery atherosclerotic plaques offers the prospect of either localized or systematic therapeutic targeting in order to prevent myocardial infarction. Molecular imaging of atherosclerosis adds to morphological imaging by focusing on the immunobiology hidden in and behind the endothelium and therefore may be able to improve the identification of prospective culprit lesions. Our focus has been on identifying arterial accumulation of oxidized low-density lipoprotein (oxLDL) by exploiting advances in knowledge of vascular pathobiology. Here, we reflect on our work developing near-infrared fluorescence imaging of oxLDL using LO1, a monoclonal autoantibody generated in our laboratory. We detail progress to date and discuss our vision on taking the work through the early translational pipeline toward a multitargeted approach in imaging rupture-prone atherosclerotic plaques. Ultimately, molecular imaging of coronary arteries should be able to assess the regional risk that is specific to a lesion, which can then be used in concert with global risk factors to personalize the therapeutic strategy for patients in a way that goes beyond generalized population-based therapies.
Keywords	Biology (General) ; QH301-705.5 ; Medical technology ; R855-855.5
Subject code	610
Language	English
Publishing date	2017-08-01T00:00:00Z
Publisher	Hindawi - SAGE Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: An Integrated Chemical Proteomics Approach for Quantitative Profiling of Intracellular ADP-Ribosylation

Karunakaran Kalesh / Saulius Lukauskas / Aaron J. Borg / Ambrosius P. Snijders / Vinay Ayyappan / Anthony K. L. Leung / Dorian O. Haskard / Peter A. DiMaggio

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 12

Abstract: Abstract ADP-ribosylation is integral to a diverse range of cellular processes such as DNA repair, chromatin regulation and RNA processing. However, proteome-wide investigation of its cellular functions has been limited due to numerous technical ... ...

Abstract	Abstract ADP-ribosylation is integral to a diverse range of cellular processes such as DNA repair, chromatin regulation and RNA processing. However, proteome-wide investigation of its cellular functions has been limited due to numerous technical challenges including the complexity of the poly(ADP-ribose) (PAR) chains, low abundance of the modification and lack of sensitive enrichment methods. We herein show that an adenosine analogue with a terminal alkyne functionality at position 2 of the adenine (2-alkyne adenosine or 2YnAd) is suitable for selective enrichment, fluorescence detection and mass spectrometry proteomics analysis of the candidate ADP-ribosylome in mammalian cells. Although similar labelling profiles were observed via fluorescence imaging for 2YnAd and 6YnAd, a previously reported clickable NAD+ precursor, quantitative mass spectrometry analysis of the two probes in MDA-MB-231 breast cancer cells revealed a significant increase in protein coverage of the 2YnAd probe. To facilitate global enrichment of ADP-ribosylated proteins, we developed a dual metabolic labelling approach that involves simultaneous treatment of live cells with both 2YnAd and 6YnAd. By combining this dual metabolic labelling strategy with highly sensitive tandem mass tag (TMT) isobaric mass spectrometry and hierarchical Bayesian analysis, we have quantified the responses of thousands of endogenous proteins to clinical PARP inhibitors Olaparib and Rucaparib.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evolution of the Macrophage CD163 Phenotype and Cytokine Profiles in a Human Model of Resolving Inflammation

Betsy J. Evans / Dorian O. Haskard / Gregory Sempowksi / R. Clive Landis

International Journal of Inflammation, Vol

2013 Volume 2013

Keywords	Medicine ; R ; Pathology ; RB1-214
Publishing date	2013-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Haptoglobin Genotype-Dependent Anti-Inflammatory Signaling in CD163+ Macrophages

R. Clive Landis / Pandelis Philippidis / Jan Domin / Joseph J. Boyle / Dorian O. Haskard

International Journal of Inflammation, Vol

2013 Volume 2013

Keywords	Medicine ; R ; Pathology ; RB1-214
Publishing date	2013-01-01T00:00:00Z
Publisher	Hindawi Publishing Corporation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Fahad Al-Rashed / Damien Calay / Marie Lang / Clare C. Thornton / Andrea Bauer / Allan Kiprianos / Dorian O. Haskard / Anusha Seneviratne / Joseph J. Boyle / Alex H. Schönthal / Caroline P. Wheeler-Jones / Justin C. Mason

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 17

Abstract: Abstract Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the ... ...

Abstract	Abstract Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mortality risk prediction of high-sensitivity C-reactive protein in suspected acute coronary syndrome

Amit Kaura / Adam Hartley / Vasileios Panoulas / Ben Glampson / Anoop S V Shah / Jim Davies / Abdulrahim Mulla / Kerrie Woods / Joe Omigie / Anoop D Shah / Mark R Thursz / Paul Elliott / Harry Hemmingway / Bryan Williams / Folkert W Asselbergs / Michael O'Sullivan / Graham M Lord / Adam Trickey / Jonathan Ac Sterne /

Dorian O Haskard / Narbeh Melikian / Darrel P Francis / Wolfgang Koenig / Ajay M Shah / Rajesh Kharbanda / Divaka Perera / Riyaz S Patel / Keith M Channon / Jamil Mayet / Ramzi Khamis

PLoS Medicine, Vol 19, Iss 2, p e

A cohort study.

2022 Volume 1003911

Abstract: Background There is limited evidence on the use of high-sensitivity C-reactive protein (hsCRP) as a biomarker for selecting patients for advanced cardiovascular (CV) therapies in the modern era. The prognostic value of mildly elevated hsCRP beyond ... ...

Abstract	Background There is limited evidence on the use of high-sensitivity C-reactive protein (hsCRP) as a biomarker for selecting patients for advanced cardiovascular (CV) therapies in the modern era. The prognostic value of mildly elevated hsCRP beyond troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndrome (ACS) is unknown. We evaluated whether a mildly elevated hsCRP (up to 15 mg/L) was associated with mortality risk, beyond troponin level, in patients with suspected ACS. Methods and findings We conducted a retrospective cohort study based on the National Institute for Health Research Health Informatics Collaborative data of 257,948 patients with suspected ACS who had a troponin measured at 5 cardiac centres in the United Kingdom between 2010 and 2017. Patients were divided into 4 hsCRP groups (<2, 2 to 4.9, 5 to 9.9, and 10 to 15 mg/L). The main outcome measure was mortality within 3 years of index presentation. The association between hsCRP levels and all-cause mortality was assessed using multivariable Cox regression analysis adjusted for age, sex, haemoglobin, white cell count (WCC), platelet count, creatinine, and troponin. Following the exclusion criteria, there were 102,337 patients included in the analysis (hsCRP <2 mg/L (n = 38,390), 2 to 4.9 mg/L (n = 27,397), 5 to 9.9 mg/L (n = 26,957), and 10 to 15 mg/L (n = 9,593)). On multivariable Cox regression analysis, there was a positive and graded relationship between hsCRP level and mortality at baseline, which remained at 3 years (hazard ratio (HR) (95% CI) of 1.32 (1.18 to 1.48) for those with hsCRP 2.0 to 4.9 mg/L and 1.40 (1.26 to 1.57) and 2.00 (1.75 to 2.28) for those with hsCRP 5 to 9.9 mg/L and 10 to 15 mg/L, respectively. This relationship was independent of troponin in all suspected ACS patients and was further verified in those who were confirmed to have an ACS diagnosis by clinical coding. The main limitation of our study is that we did not have data on underlying cause of death; however, ...
Keywords	Medicine ; R
Subject code	610 ; 616
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: High Serum Immunoglobulin G and M Levels Predict Freedom From Adverse Cardiovascular Events in Hypertension

Ramzi Y. Khamis / Alun D. Hughes / Mikhail Caga-Anan / Choon L. Chang / Joseph J. Boyle / Chiari Kojima / Paul Welsh / Naveed Sattar / Michael Johns / Peter Sever / Jamil Mayet / Dorian O. Haskard

EBioMedicine, Vol 9, Iss C, Pp 372-

A Nested Case-Control Substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

2016 Volume 380

Abstract: Aims: We aimed to determine whether the levels of total serum IgM and IgG, together with specific antibodies against malondialdehyde-conjugated low-density lipoprotein (MDA-LDL), can improve cardiovascular risk discrimination. Methods and Results: The ... ...

Abstract	Aims: We aimed to determine whether the levels of total serum IgM and IgG, together with specific antibodies against malondialdehyde-conjugated low-density lipoprotein (MDA-LDL), can improve cardiovascular risk discrimination. Methods and Results: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized 9098 patients in the UK and Ireland into the Blood Pressure-Lowering Arm. 485 patients that had cardiovascular (CV) events over 5.5 years were age and sex matched with 1367 controls. Higher baseline total serum IgG, and to a lesser extent IgM, were associated with decreased risk of CV events (IgG odds ratio (OR) per one standard deviation (SD) 0.80 [95% confidence interval, CI 0.72,0.89], p < 0.0001; IgM 0.83[0.75,0.93], p = 0.001), and particularly events due to coronary heart disease (CHD) (IgG OR 0.66 (0.57,0.76); p < 0.0001, IgM OR 0.81 (0.71,0.93); p = 0.002). The association persisted after adjustment for a basic model with variables in the Framingham Risk Score (FRS) as well as following inclusion of C-reactive protein (CRP) and N-terminal pro-B-type natriuretic peptide (NtProBNP). IgG and IgM antibodies against MDA-LDL were also associated with CV events but their significance was lost following adjustment for total serum IgG and IgM respectively. The area under the receiver operator curve for CV events was improved from the basic risk model when adding in total serum IgG, and there was improvement in continuous and categorical net reclassification (17.6% and 7.5% respectively) as well as in the integrated discrimination index. Conclusion: High total serum IgG levels are an independent predictor of freedom from adverse cardiovascular events, particularly those attributed to CHD, in patients with hypertension.
Keywords	Immunoglobulins ; Anti-oxidized-LDL antibodies ; Cardiovascular risk stratification ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	616
Language	English
Publishing date	2016-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Targeting Microbubble for Ultrasound Molecular Imaging.

James Shue-Min Yeh / Charles A Sennoga / Ellen McConnell / Robert Eckersley / Meng-Xing Tang / Sussan Nourshargh / John M Seddon / Dorian O Haskard / Petros Nihoyannopoulos

PLoS ONE, Vol 10, Iss 7, p e

2015 Volume 0129681

Abstract: Microbubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-( ...

Abstract	Microbubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld.To develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging.Microbubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab')2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (\|r\|≥0.8), demonstrating a high degree of non-invasive molecular quantification.Targeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described, may possess properties (i)-(iii) desired for clinical applications.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: IgM anti-malondialdehyde low density lipoprotein antibody levels indicate coronary heart disease and necrotic core characteristics in the Nordic Diltiazem (NORDIL) study and the Integrated Imaging and Biomarker Study 3 (IBIS-3)Research in Context

Victor J. van den Berg / Dorian O. Haskard / Artur Fedorowski / Adam Hartley / Isabella Kardys / Mikhail Caga-Anan / K. Martijn Akkerhuis / Rohit M. Oemrawsingh / Robert Jan van Geuns / Peter de Jaegere / Nicolas van Mieghem / Evelyn Regar / Jurgen M.R. Ligthart / Victor A.W.M. Umans / Patrick W. Serruys / Olle Melander / Eric Boersma / Ramzi Y. Khamis

EBioMedicine, Vol 36, Iss , Pp 63-

2018 Volume 72

Abstract: Background: Certain immunoglobulins (Ig) are proposed to have protective functions in atherosclerosis. Objectives: We tested whether serum levels of IgG and IgM autoantibodies against malondialdehyde low density lipoprotein (MDA-LDL) are associated with ... ...

Abstract	Background: Certain immunoglobulins (Ig) are proposed to have protective functions in atherosclerosis. Objectives: We tested whether serum levels of IgG and IgM autoantibodies against malondialdehyde low density lipoprotein (MDA-LDL) are associated with clinical coronary heart disease (CHD) and unfavorable plaque characteristics. Methods: NORDIL was a prospective study investigating adverse cardiovascular outcomes in hypertensive patients. IBIS-3 analyzed lesions in a non-culprit coronary artery with <50% stenosis using radiofrequency intravascular ultrasound (RF-IVUS) and near-infrared spectroscopy (NIRS). Imaging was repeated after a median of 386 days on rosuvastatin. Associations of antibodies with incident CHD and imaging parameters were assessed in the two sub-studies respectively. Findings: From 10,881 NORDIL patients, 87 had serum sampled at baseline and developed CHD over 4.5 years, matched to 227 controls. Higher titers of IgM anti-MDA-LDL had a protective effect on adverse outcomes, with odds ratio 0.29 (0.11, 0.76; p = 0.012; p = 0.016 for trend). Therefore, the effect was explored at the lesional level in IBIS-3. 143 patients had blood samples and RF-IVUS measurements available, and NIRS was performed in 90 of these. At baseline, IgM anti-MDA-LDL levels had a strong independent inverse relationship with lesional necrotic core volume (p = 0.027) and percentage of plaque occupied by necrotic core (p = 0.011), as well as lipid core burden index (p = 0.024) in the worst 4 mm segment. Interpretation: Our study supports the hypothesis that lower circulating levels of IgM anti-MDA-LDL are associated with clinical CHD development, and for the first time relates these findings to atherosclerotic plaque characteristics that are linked to vulnerability. Keywords: Necrotic core, Lipid core, Oxidized low density lipoprotein, Immunoglobulins, Near-infrared spectroscopy, Intravascular ultrasound
Keywords	Medicine ; R ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2018-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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