Non-invasive Assessment of Skeletal Muscle Loss in Cancer Patients

描述(由申请人提供)： 摘要这项研究的长期目标是开发一种非侵入性的方法来评估癌症患者病程早期3MH的新产生，以此来评估哪些患者是未来发展为骨骼肌萎缩的高风险患者。该方法基于：1)已知的3-甲基组氨酸(3MH)从上述患者的肌肉蛋白质分解中产生的增加，这是由于他们独特的疾病-宿主相互作用的结果，以及2)早期的证据表明，可以使用同位素稀释法在体内测量3MH的从头产生。我们设想了一种相对简单的方法，它完全是非侵入性的，但能够评估癌症患者骨骼肌丢失的过程。该方法依赖于这样一种假设，即口服一剂3-甲基组氨酸(D-3mh)后，在自由的3mh池中示踪剂/踪迹(D-3mh/3mh)的衰变曲线末端部分的斜率(&gt；12小时后)与肌原纤维蛋白降解的速率常数成正比，并可从现场尿样中确定。在我们的第一阶段研究中，我们通过在9名健康成年男性(4名年轻男性，5名老年男性)身上测试以下假设来确定我们整体方法的可行性，结果表明：(I)现场尿样中的同位素浓缩与相应的血浆样本相同，(Ii)直到并包括给药时间的肉类摄入量不影响同位素衰变曲线末端的斜率，以及(Iii)该方法对 测量年轻个体和年长个体之间3Mh产生率的差异。测试这些假设的有效性是第一阶段研究的中心焦点，对于开发一种既科学合理又非侵入性和临床相关的方法至关重要。在第二阶段，我们建议进行一项统计上强大的前瞻性研究，以证明用我们的方法在新诊断的癌症患者中测量末端衰减曲线的斜率(速率常数)可以预测肌肉萎缩的未来发展。我们预计，第一阶段和第二阶段联合研究的结果将导致制造和销售一种合适的“测试试剂盒”，用于早期识别高危患者的肌肉分解代谢升高，以便进行医疗干预并防止未来的肌肉萎缩。

DESCRIPTION (provided by applicant): Abstract The long-term objective of this research is to develop a non-invasive approach for assessment of de novo 3MH production in cancer patients early in the course of the disease as a way of assessing which patients are at high risk for future development of skeletal muscle atrophy. The approach is based on: 1) the known increase in de novo production of 3-methylhistidine (3MH) from muscle protein breakdown in said patients as a consequence of their unique disease-host interactions, and 2) earlier demonstration that de novo 3MH production can be measured in vivo using isotope dilution. We envision a relatively simple method that is totally non-invasive yet able to assess the course of skeletal muscle loss in cancer patients. The approach depends on the hypothesis that after an oral dose of deuterated 3-methylhistidine (D-3MH), the slope of the terminal portion of the decay curve (> 12 hours post-dosing) for the tracer/tracee (D-3MH/3MH) in the free 3MH pool is directly proportional to the rate constant for myofibrillar protein degradation and can be determined from spot urine samples. During our Phase I research we established the feasibility of our overall approach by testing the following hypotheses in nine healthy adult males (four young, five older) by showing: (i) isotope enrichment in spot urine samples is identical with the corresponding plasma samples, (ii) meat intake up to and including the time of dosing does not influence the slope of the terminal portion of the isotope decay curve, and (iii) that the method is sufficiently sensitive to measure differences in the rate of 3MH production between young and older individuals. Testing the validity of these hypotheses was the central focus of the Phase-I research and crucial to the development of an approach that is both scientifically sound as well as non-invasive and clinically relevant. During Phase-II, we propose to conduct a statistically powerful prospective investigation to demonstrate that measurement of slope of the terminal decay curve (rate constant) with our approach in newly diagnosed cancer patients predicts future development of muscle wasting. We expect the outcome of the combined Phase-I and Phase-II research to lead to the manufacture and marketing of a suitable "Test Kit" for early identification of elevated muscle catabolism in at-risk patients so that medical intervention can take place and prevent future muscle atrophy.