Software Cost Estimation and Control

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Coordination in COTS-Based Development

NRC publication: Ye

Table of Contents Organizing and Program Committee Overview Tools for Commercial Component Assembly

1 st International Workshop on Incorporatin

Molecular magnetic resonance imaging of myeloperoxidase activity identifies culprit lesions and predicts future atherothrombosis

Acknowledgements: We acknowledge the support of the Heart Research Institute mass spectrometry facility and the University of New South Wales Biological Resource Imaging Laboratory.Funder: National Health & Medical Research Council of Australia; DOI: https://doi.org/10.13039/501100000925Funder: National Heart Foundation; DOI: https://doi.org/10.13039/501100001516Funder: University of New South Wales; DOI: https://doi.org/10.13039/501100001773Funder: NSW Department of HealthFunder: AstraZeneca; DOI: https://doi.org/10.13039/100004325Abstract Aims Unstable atherosclerotic plaques have increased activity of myeloperoxidase (MPO). We examined whether molecular magnetic resonance imaging (MRI) of intraplaque MPO activity predicts future atherothrombosis in rabbits and correlates with ruptured human atheroma. Methods and results Plaque MPO activity was assessed in vivo in rabbits (n = 12) using the MPO-gadolinium (Gd) probe at 8 and 12 weeks after induction of atherosclerosis and before pharmacological triggering of atherothrombosis. Excised plaques were used to confirm MPO activity by liquid chromatography–tandem mass spectrometry (LC–MSMS) and to determine MPO distribution by histology. MPO activity was higher in plaques that caused post-trigger atherothrombosis than plaques that did not. Among the in vivo MRI metrics, the plaques’ R1 relaxation rate after administration of MPO-Gd was the best predictor of atherothrombosis. MPO activity measured in human carotid endarterectomy specimens (n = 30) by MPO-Gd–enhanced MRI was correlated with in vivo patient MRI and histological plaque phenotyping, as well as LC–MSMS. MPO-Gd retention measured as the change in R1 relaxation from baseline was significantly greater in histologic and MRI-graded American Heart Association (AHA) type VI than type III–V plaques. This association was confirmed by comparing AHA grade to MPO activity determined by LC–MSMS. Conclusion We show that elevated intraplaque MPO activity detected by molecular MRI employing MPO-Gd predicts future atherothrombosis in a rabbit model and detects ruptured human atheroma, strengthening the translational potential of this approach to prospectively detect high-risk atherosclerosis. </jats:sec

Molecular magnetic resonance imaging of myeloperoxidase activity identifies culprit lesions and predicts future atherothrombosis

Acknowledgements: We acknowledge the support of the Heart Research Institute mass spectrometry facility and the University of New South Wales Biological Resource Imaging Laboratory.Funder: National Health & Medical Research Council of Australia; DOI: https://doi.org/10.13039/501100000925Funder: National Heart Foundation; DOI: https://doi.org/10.13039/501100001516Funder: University of New South Wales; DOI: https://doi.org/10.13039/501100001773Funder: NSW Department of HealthFunder: AstraZeneca; DOI: https://doi.org/10.13039/100004325Lay Summary: Cardiovascular diseases, including heart attacks and strokes, are the leading cause of death worldwide. Most heart attacks and strokes occur because of atherosclerosis, a chronic disease of the arteries caused by reduced blood flow to the heart and brain. Atherosclerotic plaques are characterized by the accumulation of lipids and inflammatory cells. A type of atherosclerotic plaques called ‘unstable plaque’ can suddenly rupture causing blood clots that abruptly block the arteries, and this can lead to loss of blood supply to the heart and brain. In recent years, inflammation of the arteries has emerged as a key driver and therapeutic target for stroke and heart attack. However, existing diagnostic methods and medical therapies do not specifically target inflammation so that residual inflammatory risk remains untreated and undetected. Therefore, there is a clinical need to specifically identify patients with active inflammation of the arteries who may benefit from targeted treatment. Recent findings have demonstrated that the inflammatory enzyme myeloperoxidase causes the formation of unstable plaque in animal models of the disease and is abundant in life-threatening human atherosclerotic plaques that are at risk of rupturing. This identifies myeloperoxidase as a ground-breaking diagnostic tool and therapeutic target. Similarly, the development of novel targeted therapies that inhibit myeloperoxidase has shown promising results in human studies and a capacity to treat unstable plaques in animal models. This paper demonstrates the utility and application of imaging of myeloperoxidase activity by magnetic resonance imaging (MRI) to identify/detect unstable atherosclerotic plaques non-invasively. It confirms the link between myeloperoxidase activity and rupture of ‘unstable’ plaque and reports myeloperoxidase’s role as a novel non-invasive imaging biomarker for detecting life-threatening plaques prior to a potentially fatal event