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haofurui新蟲 (正式寫手)
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[求助]
求助翻譯幾段英文，謝謝
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Cardiac cell death by apoptosis is a key pathogenesis in ischemic and nonischemic cardiomyopathy (1), and cardiomyopathies are the main cause of heart failure, a major source of morbidity and mortality. Apoptosis was thought previously to be irreversible, but recent evidence indicates that early apoptosis is reversible, and that vulnerable cells can be rescued with timely intervention (2). The ability to monitor cardiac cell apoptosis, noninvasively and in real-time, longitudinally following coronary bypass surgery or angioplasty, cancer chemotherapy,or cardiac allograft rejection could reveal fundamental disease mechanisms, improve therapeutic monitoring, and guide future treatments. Cardiac magnetic resonance imaging (MRI) has high spatial and temporal resolution, does not expose patients to damaging radiation, which is ideal for an approach involving serial, longitudinal studies, and can simultaneously define cardiac anatomy and function. Thus, we aimed to develop a molecular MRI probe strategy to detect early cardiac cell apoptosis. An early event in apoptosis is translocation of phosphatidylserine(PS) from the cytoplasmic face of the membrane to the extracellular domain, where Annexin V (ANX), a soluble 36 kDa protein, can bind PS with high affinity (3) (Fig. 1). This principal underlies a well-validated, commercial assay for apoptosis using ANX conjugated to fluorescein isothiocyanate (ANX-FITC) and was first used in MRI to detect tumor cell apoptosis, by conjugating a similar PS-binding molecule, synaptotagmin, to a negative MRI contrast agent, superparamagnetic iron oxide (SPIO) (4). However, application of this approach to the heart has been limited. Recently, other groups have conjugated ANX to cross-linked iron oxide, gadolinium chelates, and/or fluorochromes to image cardiac apoptosis in mouse models of ischemia-reperfusion, genetic injury, and atherosclerosis (5–8). Here, we developed a different molecular MRI probe using two compounds approved individually by the FDA, human ANX and SPIO, and a clinical 3 T MRI scanner. We introduce a robust method to conjugate ANX-SPIO, and validate the sensitivity and specificity of the probe for apoptotic cardiomyocytes in vitro and in vivo. To do this, we utilize a clinically important, apoptosis-specific model of heart disease (doxorubicin cardiomyopathy) (9) to determine whether ANX-SPIO could detect apoptosis in vivo, without the overwhelming degree of necrosis found in ischemia- reperfusion models. We show that ANX-SPIO is a reliable probe for myocyte apoptosis and can detect reversal of apoptosis with appropriate drug treatment. |
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