Hethersett, United Kingdom
Hethersett, United Kingdom

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Stegemann C.,King's College London | Drozdov I.,King's College London | Shalhoub J.,Imperial College London | Humphries J.,King's College London | And 9 more authors.
Circulation: Cardiovascular Genetics | Year: 2011

Background-We sought to perform a systematic lipid analysis of atherosclerotic plaques using emerging mass spectrometry techniques. Methods and Results-A chip-based robotic nanoelectrospray platform interfaced to a triple quadrupole mass spectrometer was adapted to analyze lipids in tissue sections and extracts from human endarterectomy specimens by shotgun lipidomics. Eighteen scans for different lipid classes plus additional scans for fatty acids resulted in the detection of 150 lipid species from 9 different classes of which 24 were detected in endarterectomies only. Further analyses focused on plaques from symptomatic and asymptomatic patients and stable versus unstable regions within the same lesion. Polyunsaturated cholesteryl esters with long-chain fatty acids and certain sphingomyelin species showed the greatest relative enrichment in plaques compared to plasma and formed part of a lipid signature for vulnerable and stable plaque areas in a systems-wide network analysis. In principal component analyses, the combination of lipid species across different classes provided a better separation of stable and unstable areas than individual lipid classes. Conclusions-This comprehensive analysis of plaque lipids demonstrates the potential of lipidomics for unraveling the lipid heterogeneity within atherosclerotic lesions. © 2011 American Heart Association, Inc.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: KBBE-2007-2-2-08 | Award Amount: 8.29M | Year: 2009

Dysregulation of lipid homeostasis is related to multiple major global healthcare problems today, including aging, diabetes and cardiovascular disease. It has already been shown that nutritional modulation of lipid homeostasis via direct supplementation, e.g., n-3 fatty acids, or via indirect mechanisms, e.g., dietary polyphenols, has beneficial effects on human health. There is growing evidence that ether phospholipids such as plasmalogens play a central role in mediating the beneficial effects, but the underlying mechanisms are not understood. ETHERPATHS will develop systems biology tools that will facilitate studies of dietary interventions aiming to modulate lipid homeostasis. Specifically, we will develop (1) models that enable studies of gut microbiota and its effect on host cell metabolism, (2) dynamic models of systemic lipid metabolism, and (3) pathway reconstruction methods to study tissue-specific effects of dietary interventions. All models will be optimized in the context of studies of dietary interventions and will be integrated into a sophisticated software platform. In silico strategies will be complemented by multiple experimental approaches, including (1) dietary interventions involving n-3 fatty acids and polyphenols, combined with tracer studies in vitro and in vivo (2) in vitro colon model (3) in vivo germ-free and conventional models of altered lipid metabolism, specifically of plasmalogen deficiency. ETHERPATHS includes academic and industrial partners with combined unique expertise in information technology, bioinformatics, metabolic and physiological modelling, systems engineering, biochemistry, microbiology, lipid metabolism, metabolomics, obesity and metabolic syndrome, and clinical nutrition. We expect the ETHERPATHS tools to be broadly applied in nutrition research, and anticipate that the novel findings generated within the project will be applied for development of new food products for better health.


Marshall P.,Glaxosmithkline | Toteu-Djomte V.,Glaxosmithkline | Bareille P.,Glaxosmithkline | Perry H.,Glaxosmithkline | And 3 more authors.
Analytical Chemistry | Year: 2010

Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) and liquid extraction surface analysis (LESA) with nanoelectrospray ionization mass spectrometry (nESI-MS) have both been successfully employed to determine the degree of percutaneous absorption of three novel nonsteroid glucocorticoid receptor (GR) agonists in porcine ear sections. Historically, the ability of a glucocorticoid to elicit a skin blanching response when applied at low dose in ethanol solution to the forearms of healthy human volunteers has been a reliable predictor of their topical anti-inflammatory activity. While all three nonsteroidal GR agonists under investigation caused a skin blanching effect, the responses did not correlate with in vitro GR agonist potencies and different time courses were also observed for the skin blanching responses. MALDI MSI and LESA with nESI-MS were used to investigate and understand these different responses. The findings of the investigation was that the depth of porcine skin penetration correlates to the degree of skin blanching obtained for the same three compounds in human volunteers. © 2010 American Chemical Society.


Schuhmann K.,Max Planck Institute of Molecular Cell Biology and Genetics | Schuhmann K.,TU Dresden | Almeida R.,Advion Biosciences Ltd | Almeida R.,University of Southern Denmark | And 5 more authors.
Journal of Mass Spectrometry | Year: 2012

Top-down shotgun lipidomics relies on direct infusion of total lipid extracts into a high-resolution tandem mass spectrometer and implies that individual lipids are recognized by their accurately determined m/z. Lipid ionization efficiency and detection specificity strongly depend on the acquisition polarity, and therefore it is beneficial to analyze lipid mixtures in both positive and negative modes. Hybrid LTQ Orbitrap mass spectrometers are widely applied in top-down lipidomics; however, rapid polarity switching was previously unfeasible because of the severe and immediate degradation of mass accuracy. Here, we report on a method to rapidly acquire high-resolution spectra in both polarity modes with sub-ppm mass accuracy and demonstrate that it not only simplifies and accelerates shotgun lipidomics analyses but also improves the lipidome coverage because more lipid classes and more individual species within each class are recognized. In this way, shotgun analysis of total lipid extracts of human blood plasma enabled to quantify 222 species from 15 major lipid classes within 7 min acquisition cycle. Copyright © 2012 John Wiley & Sons, Ltd.


Edwards R.L.,University of Birmingham | Creese A.J.,University of Birmingham | Baumert M.,Advion Biosciences Ltd. | Griffiths P.,Birmingham Childrens Hospital NHS Trust | And 2 more authors.
Analytical Chemistry | Year: 2011

Hemoglobinopathies are the most common inherited disorders. Newborn blood screening for clinically significant hemoglobin variants, including sickle (HbS), HbC, and HbD, has been adopted in many countries as it is widely acknowledged that early detection improves the outcome. We present a method for determination of Hb variants by direct surface sampling of dried blood spots by use of an Advion Triversa Nanomate automated electrospray system coupled to a highresolution mass spectrometer. The method involves no sample preparation. It is possible to unambiguously identify homozygous and heterozygous HbS, HbC, and HbD variants in <10 min without the need for additional confirmation. The method allows for repeated analysis of a single blood spot over a prolonged time period and is tolerant of blood spot storage conditions. © 2011 American Chemical Society.


Tomlinson L.,Glaxosmithkline | Fuchser J.,Bruker | Futterer A.,Bruker | Baumert M.,Advion Biosciences Ltd | And 3 more authors.
Rapid Communications in Mass Spectrometry | Year: 2014

RATIONALE The signal intensity of a given molecule across a tissue section when measured using mass spectrometry imaging (MSI) is prone to changes caused by the molecular heterogeneity across the surface of the tissue. Here we propose a strategy to investigate these effects using electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) on a single high-resolution mass spectrometry (HRMS) platform. METHODS A rat was administered with a single inhaled dose of a compound and sacrificed 1 h after dosing. Sections were prepared from the excised frozen lung and analysed using MALDI, liquid extraction surface analysis (LESA) nano-ESI-MS and nano-ESI liquid chromatography (LC)/MS. The ESI and MALDI ion sources were mounted either side of the ion transfer system of the same Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. RESULTS MALDI MSI clearly demonstrated widespread distribution of the dosed molecule throughout the lung, with the exception of a non-lung section of tissue on the same sample surface. Comparison of the lipid signals across the sample indicated a change in signal between the lung and the adipose tissue present on the same section. Use of ESI and MALDI, with and without an internal standard, supported the evaluation of changes in the signal of the dosed molecule across the tissue section. CONCLUSIONS The results demonstrate the successful application of a dual ion source HRMS system to the systematic evaluation of data from MALDI MSI, used to determine the distribution of an inhaled drug in the lung. The system discussed is of great utility in investigating the effects of ion suppression and evaluating the quantitative and qualitative nature of the MSI data. Copyright © 2014 John Wiley & Sons, Ltd.

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