Nutrition and Anabolic Interventions in Cancer Cachexia

项目摘要/摘要 癌症恶病质严重消耗骨骼肌块，导致身体功能和 生活质量下降。在临床领域，营养不良和恶病质是同义词。然而，恶病质 比单纯的卡路里缺乏要复杂得多，因为改善营养状况并不能逆转或防止 肌肉萎缩。我们的初步数据显示，骨骼肌蛋白质对合成代谢的反应 癌症患者体内的氨基酸刺激功能受损。 我们认为，癌症患者骨骼肌蛋白质平衡的失衡可以通过持续治疗来改变 肿瘤和体液分解代谢因子引起的全身性和局限性骨骼肌炎。 具体地说，这些因素通过影响肌肉蛋白质的合成和平衡来改变肌肉蛋白质平衡的调节。 崩溃了。合成受到影响是因为分解代谢因子降低了关键分子的血浆浓度。 支链氨基酸，如亮氨酸，从而抑制对营养来源的合成代谢的刺激。 分解受影响是因为分解代谢因子，如肿瘤坏死因子？(肿瘤坏死因子？)增强核电 B因子(NF-B)，进而通过泛素-蛋白酶体系统激活肌肉蛋白分解。我们的数据 表明癌症患者骨骼肌表现出核因子-β的激活增强和增强 炎症性负担。最近，我们发现3个月的睾丸素治疗下调了泛素的表达 以及E3泛素连接酶MuRF1和MAFbx/Atrogin-1基因的表达以及阻断a 肌动球蛋白破坏初期新的14-kD肌动蛋白片段。我们的总体假设是 亮氨酸增强必需氨基酸(L-必需氨基酸)的抗厌食和抗呕吐作用 伴随着睾丸素的合成代谢和抗合成代谢特性，将增加瘦肉量 晚期(IIB期、IIIA期和IIIB期)或复发宫颈癌患者通过增加对 分别通过抑制蛋白质合成和激活肌肉蛋白水解酶。 我们将进行一项随机、双盲、安慰剂对照的干预研究，旨在临床和 机械地评估针对以下目标的新的营养(L-EAA)和药物(睾酮)疗法 结合标准护理(SOC)治疗，防止与癌症相关的肌肉萎缩或使其正常化。 我们将确定这一新的治疗方法在以下方面的疗效 晚期或复发宫颈癌患者：1)瘦体重和肌肉力量，2)肌肉 蛋白质周转；3)骨骼肌萎缩的炎性生物标志物和信号通路。项目叙事 宫颈癌是女性中第二常见的癌症，全球有47万新病例 每年。这项研究将测试营养和激素是否可以防止与癌症相关的肌肉损失。我们的 这项研究很重要，因为在所有癌症死亡中，肌肉极度萎缩至少占20%。结果 这项研究可能会带来更好的预防癌症相关体重减轻的方法，并提高生活质量 以及那些受宫颈癌影响的人的存活率。

Project Summary/Abstract Cancer cachexia severely depletes skeletal muscle mass leading to impairments in physical function and a diminished quality of life. In the clinical realm, malnutrition and cachexia are synonymous. However, cachexia is more complex than mere caloric deficiency, since improving nutritional status does not reverse or prevent muscle wasting. Our preliminary data show that the response of skeletal muscle protein to the anabolic stimulus of amino acids is impaired in cancer patients. We propose that the dysregulation of skeletal muscle protein balance in cancer patients is altered by persistent systemic and localized skeletal muscle inflammation derived from tumoral and humoral catabolic factors. Specifically, these factors alter the regulation of muscle protein balance by affecting both synthesis and breakdown. Synthesis is affected because catabolic factors diminish the plasma concentrations of key branched-chain amino acids such as leucine, thereby suppressing the stimulus for nutrition-derived anabolism. Breakdown is affected because catabolic factors such as tumor necrosis factor-? (TNF-?) enhance nuclear factor-?B (NF-?B), which in turn activates muscle proteolysis via the ubiquitin-proteasome system. Our data demonstrate that skeletal muscle in cancer patients exhibits increased activation of NF-?B and enhanced inflammatory burden. More recently, we found that 3 months of testosterone therapy downregulates ubiquitin and the E3 ubiquitin ligases MuRF1 and MAFbx/Atrogin-1 gene expression along with blocking cleavage of a novel 14-kD actin fragment in the initial step of actomyosin destruction. Our general hypothesis is that the antianorectic and anticachectic effects of leucine-enhanced essential amino acids (L-EAA) supplemented concomitantly with testosterone's anabolic and anticatabolic properties will enhance lean muscle mass in patients with advanced (stages IIB, IIIA and IIIB) or recurrent cervical carcinoma by increasing the stimulus for protein synthesis, and by inhibiting the activation of muscle proteolysis, respectively. We will conduct a randomized, double-blind, placebo-controlled intervention study designed to clinically and mechanistically assess novel nutritional (L-EAA) and pharmacologic (testosterone) therapies aimed at preventing or normalizing cancer-related muscle wasting in conjunction with standard of care (SOC) treatment. We will determine the efficacy of this novel therapeutic approach on the following outcome measures in patients with advanced or recurrent cervical carcinoma: 1) lean body mass and muscle strength, 2) muscle protein turnover, and 3) inflammatory biomarkers and signaling pathways of atrophy in skeletal muscle. Project Narrative Cervical cancer is the second most prevalent cancer in women, with 470,000 new cases occurring globally each year. This study will test whether nutrition and hormones can prevent cancer-related muscle loss. Our study is important because extreme muscle loss is responsible for at least 20% of all cancer deaths. Results from this study may lead to better ways of preventing cancer-related weight loss, and improve the quality of life and survival of those affected by cervical cancer.