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Journal of Cachexia Sarcopenia and Muscle最新文献

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Metabolic phenotyping with computed tomography deep learning for metabolic syndrome, osteoporosis and sarcopenia predicts mortality in adults 针对代谢综合征、骨质疏松症和肌肉疏松症的计算机断层扫描深度学习代谢表型可预测成人死亡率
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-22 DOI: 10.1002/jcsm.13487
Sang Wouk Cho, Seungjin Baek, Sookyeong Han, Chang Oh Kim, Hyeon Chang Kim, Yumie Rhee, Namki Hong
<div> <section> <h3> Background</h3> <p>Computed tomography (CT) body compositions reflect age-related metabolic derangements. We aimed to develop a multi-outcome deep learning model using CT multi-level body composition parameters to detect metabolic syndrome (MS), osteoporosis and sarcopenia by identifying metabolic clusters simultaneously. We also investigated the prognostic value of metabolic phenotyping by CT model for long-term mortality.</p> </section> <section> <h3> Methods</h3> <p>The derivation set (<i>n</i> = 516; 75% train set, 25% internal test set) was constructed using age- and sex-stratified random sampling from two community-based cohorts. Data from participants in the individual health assessment programme (<i>n</i> = 380) were used as the external test set 1. Semi-automatic quantification of body compositions at multiple levels of abdominal CT scans was performed to train a multi-layer perceptron (MLP)-based multi-label classification model. External test set 2 to test the prognostic value of the model output for mortality was built using data from individuals who underwent abdominal CT in a tertiary-level institution (<i>n</i> = 10 141).</p> </section> <section> <h3> Results</h3> <p>The mean ages of the derivation and external sets were 62.8 and 59.7 years, respectively, without difference in sex distribution (women 50%) or body mass index (BMI; 23.9 kg/m<sup>2</sup>). Skeletal muscle density (SMD) and bone density (BD) showed a more linear decrement across age than skeletal muscle area. Alternatively, an increase in visceral fat area (VFA) was observed in both men and women. Hierarchical clustering based on multi-level CT body composition parameters revealed three distinctive phenotype clusters: normal, MS and osteosarcopenia clusters. The L3 CT-parameter-based model, with or without clinical variables (age, sex and BMI), outperformed clinical model predictions of all outcomes (area under the receiver operating characteristic curve: MS, 0.76 vs. 0.55; osteoporosis, 0.90 vs. 0.79; sarcopenia, 0.85 vs. 0.81 in external test set 1; <i>P</i> < 0.05 for all). VFA contributed the most to the MS predictions, whereas SMD, BD and subcutaneous fat area were features of high importance for detecting osteoporosis and sarcopenia. In external test set 2 (mean age 63.5 years, women 79%; median follow-up 4.9 years), a total of 907 individuals (8.9%) died during follow-up. Among model-predicted metabolic phenotypes, sarcopenia alone (adjusted hazard ratio [aHR] 1.55), MS + sarcopenia (aHR 1.65), osteoporosis + sarcopenia (aHR 1.83) and all three combined (aHR 1.87) remained robust predictors of mortality after adjustment for age, sex and com
背景计算机断层扫描(CT)身体成分反映了与年龄相关的代谢失调。我们的目的是利用 CT 多层次身体成分参数开发一种多结果深度学习模型,通过同时识别代谢集群来检测代谢综合征(MS)、骨质疏松症和肌肉疏松症。我们还研究了 CT 模型的代谢表型对长期死亡率的预后价值。方法衍生集(n = 516;75% 训练集,25% 内部测试集)是通过从两个社区队列中进行年龄和性别分层随机抽样构建的。个人健康评估项目参与者的数据(n = 380)被用作外部测试集 1。对腹部 CT 扫描多层次的身体成分进行半自动量化,以训练基于多层感知器(MLP)的多标签分类模型。结果推导集和外部集的平均年龄分别为62.8岁和59.7岁,性别分布(女性占50%)和体重指数(BMI;23.9 kg/m2)无差异。与骨骼肌面积相比,骨骼肌密度(SMD)和骨密度(BD)随着年龄的增长呈线性下降趋势。另外,男性和女性的内脏脂肪面积(VFA)都有所增加。基于多层次 CT 身体成分参数的分层聚类显示了三个不同的表型群:正常群、多发性硬化症群和骨质疏松症群。基于 L3 CT 参数的模型,无论是否包含临床变量(年龄、性别和体重指数),对所有结果的预测均优于临床模型(接收器操作特征曲线下面积:MS, 0.76 vs. 0.0.5):在外部测试集 1 中,MS 为 0.76 vs. 0.55;骨质疏松症为 0.90 vs. 0.79;肌肉疏松症为 0.85 vs. 0.81;P 均为 0.05)。VFA对MS预测的贡献最大,而SMD、BD和皮下脂肪面积是检测骨质疏松症和肌肉疏松症的重要特征。在外部测试集 2(平均年龄 63.5 岁,女性占 79%;随访时间中位数为 4.9 年)中,共有 907 人(8.9%)在随访期间死亡。在模型预测的代谢表型中,单独的肌肉疏松症(调整后危险比 [aHR] 1.55)、多发性硬化症+肌肉疏松症(aHR 1.65)、骨质疏松症+肌肉疏松症(aHR 1.83)和三者合并(aHR 1.87)在调整年龄、性别和合并症后仍是预测死亡率的可靠指标。CT MLP 模型预测的代谢表型与长期死亡率相关,不受协变因素的影响。
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引用次数: 0
Differentially co-expressed myofibre transcripts associated with abnormal myofibre proportion in chronic obstructive pulmonary disease 与慢性阻塞性肺病肌纤维比例异常相关的肌纤维转录本差异共表达
IF 8.9 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-22 DOI: 10.1002/jcsm.13473
Joe W. Chiles III, Ava C. Wilson, Rachel Tindal, Kaleen Lavin, Samuel Windham, Harry B. Rossiter, Richard Casaburi, Anna Thalacker-Mercer, Thomas W. Buford, Rakesh Patel, J. Michael Wells, Marcas M. Bamman, Beatriz Y. Hanaoka, Mark Dransfield, Merry-Lynn N. McDonald
<div> <section> <h3> Background</h3> <p>Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD.</p> </section> <section> <h3> Methods</h3> <p>Forty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the <i>vastus lateralis</i> were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified <i>k</i>-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype.</p> </section> <section> <h3> Results</h3> <p>Abnormal myofibre proportion was defined in males with COPD (<i>n</i> = 29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (<i>n</i> = 17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, <i>P</i> = 0.022), 6-min walk distance (300 vs. 353 m, <i>P</i> = 0.039) and forced expiratory volume in 1 s-to-forced vital capacity ratio (0.42 vs. 0.48, <i>P</i> = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated <i>NEB</i>, <i>TPM1</i> and <i>TPM2</i> genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density.</p>
背景骨骼肌功能障碍是慢性阻塞性肺病(COPD)常见的肺外表现。骨骼肌肌球蛋白重链表达的改变(I型肌球蛋白重链表达减少,II型肌球蛋白重链表达增加)与慢性阻塞性肺病的严重程度有关。本研究的目的是:(1) 确定慢性阻塞性肺病男性和女性患者的肌纤维比例异常表型;(2) 识别与慢性阻塞性肺病肌纤维比例异常相关的转录本和转录网络。通过免疫荧光显微镜检测阔筋膜肌肉的纤维类型分布和横截面积,并进行 RNA 测序以生成全转录组基因表达数据。通过对 I 型和 IIx/IIax 型纤维比例进行性别分层 k-means 聚类,确定慢性阻塞性肺病患者的异常肌纤维比例,并与之前定义的标准进行对比。结果男性慢性阻塞性肺病患者(n = 29)的异常肌纤维比例被定义为 18% 的 I 型纤维和/或 22% 的 IIx/IIax 型纤维,女性慢性阻塞性肺病患者(n = 17)的异常肌纤维比例被定义为 36% 的 I 型纤维和/或 12% 的 IIx/IIax 型纤维。半数患有慢性阻塞性肺病的参与者被归类为肌纤维比例异常。与患有慢性阻塞性肺病且肌纤维比例异常的参试者相比,患有慢性阻塞性肺病且肌纤维比例异常的参试者的手握力中位数(26.1 对 34.0 千克,P = 0.022)、6 分钟步行距离(300 对 353 米,P = 0.039)和 1 秒用力呼气量与用力肺活量比率(0.42 对 0.48,P = 0.041)均低于患有慢性阻塞性肺病且肌纤维比例正常的参试者。有 29 个转录本与慢性阻塞性肺病患者的肌纤维比例异常相关,其中上调的 NEB、TPM1 和 TPM2 基因的倍数差异最大。共表达网络分析显示,两个转录本模块与肌纤维比例异常显著正相关。其中一个共表达模块包含与肌肉萎缩相关的基因,以及与 I 型和 II 型肌纤维相关的转录本,并富含与骨矿物质密度相关的基因位点。在与肌纤维比例异常相关的共表达网络中,同时富集了与 I 型和 IIa 型纤维相关的转录本,这表明多种纤维类型的转录调控发生了改变。
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引用次数: 0
Mortality burden of pre-treatment weight loss in patients with non-small-cell lung cancer: A systematic literature review and meta-analysis 非小细胞肺癌患者治疗前体重减轻的死亡率负担:系统文献综述和荟萃分析
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-22 DOI: 10.1002/jcsm.13477
Philip D. Bonomi, Jeffrey Crawford, Richard F. Dunne, Eric J. Roeland, Karen E. Smoyer, Mohd Kashif Siddiqui, Thomas D. McRae, Michelle I. Rossulek, James H. Revkin, Lisa C. Tarasenko

Cachexia, with weight loss (WL) as a major component, is highly prevalent in patients with cancer and indicates a poor prognosis. The primary objective of this study was to conduct a meta-analysis to estimate the risk of mortality associated with cachexia (using established WL criteria prior to treatment initiation) in patients with non-small-cell lung cancer (NSCLC) in studies identified through a systematic literature review. The review was conducted according to PRISMA guidelines. Embase® and PubMed were searched to identify articles on survival outcomes in adult patients with NSCLC (any stage) and cachexia published in English between 1 January 2016 and 10 October 2021. Two independent reviewers screened titles, abstracts and full texts of identified records against predefined inclusion/exclusion criteria. Following a feasibility assessment, a meta-analysis evaluating the impact of cachexia, defined per the international consensus criteria (ICC), or of pre-treatment WL ≥ 5% without a specified time interval, on overall survival in patients with NSCLC was conducted using a random-effects model that included the identified studies as the base case. The impact of heterogeneity was evaluated through sensitivity and subgroup analyses. The standard measures of statistical heterogeneity were calculated. Of the 40 NSCLC publications identified in the review, 20 studies that used the ICC for cachexia or reported WL ≥ 5% and that performed multivariate analyses with hazard ratios (HRs) or Kaplan–Meier curves were included in the feasibility assessment. Of these, 16 studies (80%; n = 6225 patients; published 2016–2021) met the criteria for inclusion in the meta-analysis: 11 studies (69%) used the ICC and 5 studies (31%) used WL ≥ 5%. Combined criteria (ICC plus WL ≥ 5%) were associated with an 82% higher mortality risk versus no cachexia or WL < 5% (pooled HR [95% confidence interval, CI]: 1.82 [1.47, 2.25]). Although statistical heterogeneity was high (I2 = 88%), individual study HRs were directionally aligned with the pooled estimate, and there was considerable overlap in CIs across included studies. A subgroup analysis of studies using the ICC (HR [95% CI]: 2.26 [1.80, 2.83]) or WL ≥ 5% (HR [95% CI]: 1.28 [1.12, 1.46]) showed consistent findings. Assessments of methodological, clinical and statistical heterogeneity indicated that the meta-analysis was robust. Overall, this analysis found that ICC-defined cachexia or WL ≥ 5% was associated with inferior survival in patients with NSCLC. Routine assessment of both weight and weight changes in the oncology clinic may help identify patients with NSCLC at risk for worse survival, better inform clinical decision-making and assess eligibility for cachexia clinical trials.

以体重减轻(WL)为主要表现的恶病质在癌症患者中非常普遍,预示着不良的预后。本研究的主要目的是进行一项荟萃分析,以估算通过系统性文献综述确定的研究中与恶病质相关的非小细胞肺癌(NSCLC)患者死亡风险(在开始治疗前使用既定的 WL 标准)。综述按照 PRISMA 指南进行。对Embase®和PubMed进行了检索,以确定2016年1月1日至2021年10月10日期间发表的关于NSCLC(任何分期)和恶病质成人患者生存结果的英文文章。两名独立审稿人根据预定义的纳入/排除标准筛选了已确定记录的标题、摘要和全文。在进行可行性评估后,采用随机效应模型评估了恶病质(根据国际共识标准(ICC)定义)或治疗前 WL ≥ 5%(无特定时间间隔)对 NSCLC 患者总生存期的影响,该模型将已确定的研究作为基础案例。通过敏感性分析和亚组分析评估了异质性的影响。计算了统计异质性的标准测量值。在综述中确定的 40 篇 NSCLC 出版物中,有 20 项研究使用了恶病质 ICC 或报告 WL ≥ 5%,并使用危险比 (HR) 或 Kaplan-Meier 曲线进行了多变量分析,这些研究被纳入了可行性评估。其中,16 项研究(80%;n = 6225 例患者;发表于 2016-2021 年)符合纳入荟萃分析的标准:11 项研究(69%)使用了 ICC,5 项研究(31%)使用了 WL ≥ 5%。综合标准(ICC 加 WL ≥ 5%)与无恶病质或 WL < 5% 相比,死亡率风险高出 82%(汇总 HR [95% 置信区间,CI]:1.82 [1.47, 2.25])。虽然统计异质性很高(I2 = 88%),但单项研究的 HR 与汇总估计值的方向一致,且纳入研究的 CI 有相当大的重叠。对使用 ICC(HR [95% CI]:2.26 [1.80, 2.83])或 WL ≥ 5%(HR [95% CI]:1.28 [1.12, 1.46])的研究进行的亚组分析显示了一致的结果。对方法学、临床和统计学异质性的评估表明,荟萃分析是稳健的。总体而言,该分析发现,ICC定义的恶病质或WL≥5%与NSCLC患者的生存率降低有关。在肿瘤临床中对体重和体重变化进行常规评估有助于识别有生存率下降风险的 NSCLC 患者,为临床决策提供更好的信息,并评估恶病质临床试验的资格。
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引用次数: 0
Improved therapeutic approach for spinal muscular atrophy via ubiquitination-resistant survival motor neuron variant 通过抗泛素化存活运动神经元变体改进脊髓性肌萎缩症的治疗方法
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-22 DOI: 10.1002/jcsm.13486
Joonwoo Rhee, Jong-Seol Kang, Young-Woo Jo, Kyusang Yoo, Ye Lynne Kim, Sang-Hyeon Hann, Yea-Eun Kim, Hyun Kim, Ji-Hoon Kim, Young-Yun Kong
<div> <section> <h3> Background</h3> <p>Zolgensma is a gene-replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). However, clinical trials of Zolgensma have raised two major concerns: insufficient therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre-symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination-resistant variant of survival motor neuron (SMN), SMN<sup>K186R</sup>, has improved therapeutic effects for SMA compared with wild-type SMN (SMN<sup>WT</sup>).</p> </section> <section> <h3> Methods</h3> <p>A severe SMA mouse model, SMA type 1.5 (<i>Smn</i><sup>−/−</sup>; <i>SMN2</i><sup>+/+</sup>; <i>SMN∆7</i><sup>+/−</sup>) mice, was used to compare the differences in therapeutic efficacy between AAV9-SMN<sup>WT</sup> and AAV9-SMN<sup>K186R</sup>. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle.</p> </section> <section> <h3> Results</h3> <p>AAV9-SMN<sup>K186R</sup>-treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9-SMN<sup>WT</sup>-treated mice. Lifespan increased by more than 10-fold in AAV9-SMN<sup>K186R</sup>-treated mice (144.8 ± 26.11 days) as compared with AAV9-SMN<sup>WT</sup>-treated mice (26.8 ± 1.41 days). AAV9-SMN<sup>K186R</sup>-treated mice showed an ascending weight pattern, unlike AAV9-SMN<sup>WT</sup>-treated mice, which only gained weight until P20 up to 5 g on average. Several motor function tests showed the improved therapeutic efficacy of SMN<sup>K186R</sup>. In the negative geotaxis test, AAV9-SMN<sup>K186R</sup>-treated mice turned their bodies in an upward direction successfully, unlike AAV9-SMN<sup>WT</sup>-treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9-SMN<sup>K186R</sup>-treated mice, unlike AAV9-SMN<sup>WT</sup>-treated mice that showed clasping phenotype for more than 20 out of 30 s. At this point, the number of motor neurons (1.5-fold) and the size of myofibers (2.1-fold) were significantly increased in AAV9-SMN<sup>K186R</sup>-treated mice compared with AAV9-SMN<sup>WT</sup>-treated mice without prominent neurotoxicity. AAV9-SMN<sup>K186R</sup> had fewer liver defects compared with AAV9-SMN<sup>WT</sup>, as judged by increased proliferation of hepatocytes (<i>P</i> < 0.0001) and insulin-like growth factor-1 production (<i
背景Zolgensma是一种基因替代疗法,有望治疗脊髓性肌萎缩症(SMA)。然而,Zolgensma 的临床试验引发了两大问题:疗效不足和不良反应。在最近的一项临床试验中,尽管进行了症状前治疗,但仍有 30% 的患者未能达到运动里程碑。此外,超过 20% 的患者因病毒剂量过大而出现肝毒性,即使在使用免疫抑制剂后也是如此。在此,我们旨在测试生存运动神经元(SMN)的泛素化抗性变体 SMNK186R 与野生型 SMN(SMNWT)相比是否能改善对 SMA 的治疗效果。结果与 AAV9-SMNWT 处理的小鼠相比,AAV9-SMNK186R 处理的小鼠在寿命、体重、运动神经元数量、肌肉重量和运动功能改善方面均有提高。与 AAV9-SMNWT 处理的小鼠(26.8 ± 1.41 天)相比,AAV9-SMNK186R 处理的小鼠寿命延长了 10 倍多(144.8 ± 26.11 天)。AAV9-SMNK186R处理的小鼠体重呈上升趋势,而AAV9-SMNWT处理的小鼠则不同,后者直到P20体重才平均增加5克。几项运动功能测试表明,SMNK186R 的疗效有所提高。在负向地心引力测试中,AAV9-SMNK186R处理的小鼠能成功地将身体向上翻转,而AAV9-SMNWT处理的小鼠则不同,它们从P23左右就不能向上翻转。在 AAV9-SMNK186R 处理的小鼠中很少观察到后肢紧握表型,不像 AAV9-SMNWT 处理的小鼠在 30 秒中有 20 秒以上表现出紧握表型。与 AAV9-SMNWT 处理的小鼠相比,AAV9-SMNK186R 处理的小鼠运动神经元的数量(1.5 倍)和肌纤维的大小(2.1 倍)显著增加,但没有明显的神经毒性。与 AAV9-SMNWT 相比,AAV9-SMNK186R 的肝脏缺陷较少,肝细胞增殖(P < 0.0001)和胰岛素样生长因子-1 生成(P < 0.0001)均有所增加。结论SMNK186R将为疗效不足的重症SMA患者提供更好的疗效。用AAV9-SMNK186R对SMA患者进行小剂量治疗可减少佐仑格玛的不良反应。总之,SMNK186R 作为一种治疗 SMA 的新疗法,具有同时提高疗效和减少不良反应的价值。
{"title":"Improved therapeutic approach for spinal muscular atrophy via ubiquitination-resistant survival motor neuron variant","authors":"Joonwoo Rhee,&nbsp;Jong-Seol Kang,&nbsp;Young-Woo Jo,&nbsp;Kyusang Yoo,&nbsp;Ye Lynne Kim,&nbsp;Sang-Hyeon Hann,&nbsp;Yea-Eun Kim,&nbsp;Hyun Kim,&nbsp;Ji-Hoon Kim,&nbsp;Young-Yun Kong","doi":"10.1002/jcsm.13486","DOIUrl":"10.1002/jcsm.13486","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Zolgensma is a gene-replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). However, clinical trials of Zolgensma have raised two major concerns: insufficient therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre-symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination-resistant variant of survival motor neuron (SMN), SMN&lt;sup&gt;K186R&lt;/sup&gt;, has improved therapeutic effects for SMA compared with wild-type SMN (SMN&lt;sup&gt;WT&lt;/sup&gt;).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A severe SMA mouse model, SMA type 1.5 (&lt;i&gt;Smn&lt;/i&gt;&lt;sup&gt;−/−&lt;/sup&gt;; &lt;i&gt;SMN2&lt;/i&gt;&lt;sup&gt;+/+&lt;/sup&gt;; &lt;i&gt;SMN∆7&lt;/i&gt;&lt;sup&gt;+/−&lt;/sup&gt;) mice, was used to compare the differences in therapeutic efficacy between AAV9-SMN&lt;sup&gt;WT&lt;/sup&gt; and AAV9-SMN&lt;sup&gt;K186R&lt;/sup&gt;. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;AAV9-SMN&lt;sup&gt;K186R&lt;/sup&gt;-treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9-SMN&lt;sup&gt;WT&lt;/sup&gt;-treated mice. Lifespan increased by more than 10-fold in AAV9-SMN&lt;sup&gt;K186R&lt;/sup&gt;-treated mice (144.8 ± 26.11 days) as compared with AAV9-SMN&lt;sup&gt;WT&lt;/sup&gt;-treated mice (26.8 ± 1.41 days). AAV9-SMN&lt;sup&gt;K186R&lt;/sup&gt;-treated mice showed an ascending weight pattern, unlike AAV9-SMN&lt;sup&gt;WT&lt;/sup&gt;-treated mice, which only gained weight until P20 up to 5 g on average. Several motor function tests showed the improved therapeutic efficacy of SMN&lt;sup&gt;K186R&lt;/sup&gt;. In the negative geotaxis test, AAV9-SMN&lt;sup&gt;K186R&lt;/sup&gt;-treated mice turned their bodies in an upward direction successfully, unlike AAV9-SMN&lt;sup&gt;WT&lt;/sup&gt;-treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9-SMN&lt;sup&gt;K186R&lt;/sup&gt;-treated mice, unlike AAV9-SMN&lt;sup&gt;WT&lt;/sup&gt;-treated mice that showed clasping phenotype for more than 20 out of 30 s. At this point, the number of motor neurons (1.5-fold) and the size of myofibers (2.1-fold) were significantly increased in AAV9-SMN&lt;sup&gt;K186R&lt;/sup&gt;-treated mice compared with AAV9-SMN&lt;sup&gt;WT&lt;/sup&gt;-treated mice without prominent neurotoxicity. AAV9-SMN&lt;sup&gt;K186R&lt;/sup&gt; had fewer liver defects compared with AAV9-SMN&lt;sup&gt;WT&lt;/sup&gt;, as judged by increased proliferation of hepatocytes (&lt;i&gt;P&lt;/i&gt; &lt; 0.0001) and insulin-like growth factor-1 production (&lt;i","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 4","pages":"1404-1417"},"PeriodicalIF":9.4,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13486","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140640314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The prevalence patterns and risk factor profiles of poor muscle health and its associated components in multiethnic older Asians: The PIONEER study 多种族亚裔老年人肌肉健康状况不佳及其相关因素的流行模式和风险因素概况:PIONEER 研究
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-22 DOI: 10.1002/jcsm.13483
Preeti Gupta, Tai-Anh Vu, Ryan E.K. Man, Eva K. Fenwick, Laura Tay, Ng Yee Sien, David Ng, Koh Hong Xiang Frederick, Eu-Leong Yong, Samuel T.H. Chew, Ecosse L. Lamoureux

Background

We aim to determine the multiethnic patterns of the prevalence and associated factors of poor muscle health and its associated components in older Chinese, Malays, and Indian Asian adults.

Methods

We included 2199 participants (mean age ± SD: 72.9 ± 8.3 years; 54.3% female) from the baseline assessment of the Population Health and Eye Disease Profile in Elderly Singaporeans (PIONEER; 2017–2022) cohort study. Poor muscle health was defined as the presence of either low muscle mass (DEXA), or low muscle strength (handgrip strength), or low physical performance (gait speed). Its components include poor muscle function (low muscle strength and/or low physical performance without low muscle mass), pre-sarcopenia (low muscle mass only), and any sarcopenia (low muscle mass with low muscle strength and/or low physical performance). Sociodemographic, clinical, and lifestyle factors were assessed using biochemistry, clinical tests, and validated questionnaires. Regression models were utilized to evaluate the independent risk factors of poor muscle health and its components.

Results

The national census-adjusted prevalence of poor muscle health (88%) was similar across the three ethnic groups. However, Chinese individuals had higher prevalence of pre-sarcopenia and any sarcopenia, and a lower prevalence of poor muscle function compared with Indians or Malays. We observed ethnic differences in modifiable risk factors (low physical activity, diabetes, osteoporosis, and obesity) of poor muscle health and its components. Although obesity was protective of pre-sarcopenia (RRR = 0.19, 95% CI: 0.11, 0.36) and any sarcopenia (RRR = 0.29, 95% CI: 0.18, 0.47) in the overall population and across ethnic groups, it was associated with 1.7 times (95% CI: 1.07, 2.67) the likelihood of poor muscle function in the entire population.

Conclusions

Almost 90% of community dwelling Singaporean aged ≥60 years have poor muscle health across the three ethnic groups with ethnic disparities in modifiable risk factors, highlighting an urgent need for community-wide targeted interventions to promote muscle health.

背景我们旨在确定华裔、马来裔和印度裔亚裔老年人肌肉健康状况不佳及其相关因素的多种族流行模式。方法我们纳入了2199名参与者(平均年龄±SD:72.9±8.3岁;54.3%为女性),他们来自新加坡老年人人口健康和眼疾概况(PIONEER;2017-2022年)队列研究的基线评估。肌肉健康状况不佳的定义是肌肉质量低(DEXA),或肌肉力量低(手握力量),或体能表现低(步速)。肌肉健康不良包括肌肉功能不良(低肌力和/或低体能,但无低肌肉质量)、前肌肉疏松症(仅低肌肉质量)和任何肌肉疏松症(低肌肉质量、低肌力和/或低体能)。社会人口学、临床和生活方式因素通过生化、临床测试和有效问卷进行评估。结果经全国人口普查调整后,三个种族群体的肌肉健康不良患病率(88%)相似。然而,与印度人或马来人相比,中国人患肌少症前期和任何肌少症的比例较高,而肌肉功能不佳的比例较低。我们观察到,肌肉健康状况差的可改变风险因素(体力活动少、糖尿病、骨质疏松症和肥胖)及其组成部分存在种族差异。虽然肥胖在总体人群和不同种族群体中对肌肉疏松症前期(RRR = 0.19,95% CI:0.11,0.36)和任何肌肉疏松症(RRR = 0.29,95% CI:0.18,0.47)具有保护作用,但在整个人群中,肥胖与肌肉功能不良的可能性相关联,是肌肉功能不良可能性的 1.7 倍(95% CI:1.07,2.67)。结论在三个族裔群体中,近 90% 年龄≥60 岁的新加坡社区居民肌肉健康状况不佳,可改变的风险因素在族裔间存在差异,这突出表明迫切需要在整个社区采取有针对性的干预措施来促进肌肉健康。
{"title":"The prevalence patterns and risk factor profiles of poor muscle health and its associated components in multiethnic older Asians: The PIONEER study","authors":"Preeti Gupta,&nbsp;Tai-Anh Vu,&nbsp;Ryan E.K. Man,&nbsp;Eva K. Fenwick,&nbsp;Laura Tay,&nbsp;Ng Yee Sien,&nbsp;David Ng,&nbsp;Koh Hong Xiang Frederick,&nbsp;Eu-Leong Yong,&nbsp;Samuel T.H. Chew,&nbsp;Ecosse L. Lamoureux","doi":"10.1002/jcsm.13483","DOIUrl":"10.1002/jcsm.13483","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>We aim to determine the multiethnic patterns of the prevalence and associated factors of poor muscle health and its associated components in older Chinese, Malays, and Indian Asian adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 2199 participants (mean age ± SD: 72.9 ± 8.3 years; 54.3% female) from the baseline assessment of the Population Health and Eye Disease Profile in Elderly Singaporeans (PIONEER; 2017–2022) cohort study. Poor muscle health was defined as the presence of either low muscle mass (DEXA), or low muscle strength (handgrip strength), or low physical performance (gait speed). Its components include poor muscle function (low muscle strength and/or low physical performance without low muscle mass), pre-sarcopenia (low muscle mass only), and any sarcopenia (low muscle mass with low muscle strength and/or low physical performance). Sociodemographic, clinical, and lifestyle factors were assessed using biochemistry, clinical tests, and validated questionnaires. Regression models were utilized to evaluate the independent risk factors of poor muscle health and its components.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The national census-adjusted prevalence of poor muscle health (88%) was similar across the three ethnic groups. However, Chinese individuals had higher prevalence of pre-sarcopenia and any sarcopenia, and a lower prevalence of poor muscle function compared with Indians or Malays. We observed ethnic differences in modifiable risk factors (low physical activity, diabetes, osteoporosis, and obesity) of poor muscle health and its components. Although obesity was protective of pre-sarcopenia (RRR = 0.19, 95% CI: 0.11, 0.36) and any sarcopenia (RRR = 0.29, 95% CI: 0.18, 0.47) in the overall population and across ethnic groups, it was associated with 1.7 times (95% CI: 1.07, 2.67) the likelihood of poor muscle function in the entire population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Almost 90% of community dwelling Singaporean aged ≥60 years have poor muscle health across the three ethnic groups with ethnic disparities in modifiable risk factors, highlighting an urgent need for community-wide targeted interventions to promote muscle health.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 4","pages":"1376-1387"},"PeriodicalIF":9.4,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13483","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140633968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sarcopenia, adiposity and large discordance between cystatin C and creatinine-based estimated glomerular filtration rate in patients with cancer 癌症患者的肌酸减少症、肥胖和胱抑素 C 与肌酐估算的肾小球滤过率之间的巨大差异
IF 8.9 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-22 DOI: 10.1002/jcsm.13469
Paul E. Hanna, Tianqi Ouyang, Ismail Tahir, Nurit Katz-Agranov, Qiyu Wang, Lea Mantz, Ian Strohbehn, Daiana Moreno, Destiny Harden, James E. Dinulos, Duru Cosar, Harish Seethapathy, Justin F. Gainor, Sachin J. Shah, Shruti Gupta, David E. Leaf, Florian J. Fintelmann, Meghan E. Sise
<div> <section> <h3> Background</h3> <p>Creatinine-based estimated glomerular filtration rate (eGFR<sub>CRE</sub>) may overestimate kidney function in patients with sarcopenia. While cystatin C-based eGFR (eGFR<sub>CYS</sub>) is less affected by muscle mass, it may underestimate kidney function in patients with obesity. We sought to evaluate the relationship between body composition defined by computed tomography (CT) scans and discordance between creatinine, eGFR<sub>CRE</sub> and eGFR<sub>CYS</sub> in adult patients with cancer.</p> </section> <section> <h3> Methods</h3> <p>This study is a cross-sectional study of consecutive adults with cancer with an abdominal CT scan performed within 90 days of simultaneous eGFR<sub>CRE</sub> and eGFR<sub>CYS</sub> measurements between May 2010 and January 2022. Muscle and adipose tissue cross-sectional areas were measured at the level of the third lumbar vertebral body using a validated deep-learning pipeline. CT-defined sarcopenia was defined using independent sex-specific cut-offs for skeletal muscle index (<39 cm<sup>2</sup>/m<sup>2</sup> for women and <55 cm<sup>2</sup>/m<sup>2</sup> for men). High adiposity was defined as the highest sex-specific quartile of the total (visceral plus subcutaneous) adiposity index in the cohort. The primary outcome was eGFR discordance, defined by eGFR<sub>CYS</sub> > 30% lower than eGFR<sub>CRE</sub>; the secondary outcome was eGFR<sub>CYS</sub> > 50% lower than eGFR<sub>CRE</sub>. The odds of eGFR discordance were estimated using multivariable logistic regression modelling. Unadjusted spline regression was used to evaluate the relationship between skeletal muscle index and the difference between eGFR<sub>CYS</sub> and eGFR<sub>CRE</sub>.</p> </section> <section> <h3> Results</h3> <p>Of the 545 included patients (mean age 63 ± 14 years, 300 [55%] females, 440 [80.7%] non-Hispanic white), 320 (58.7%) met the criteria for CT-defined sarcopenia, and 136 (25%) had high adiposity. A total of 259 patients (48%) had >30% eGFR discordance, and 122 (22.4%) had >50% eGFR discordance. After adjustment for potential confounders, CT-defined sarcopenia and high adiposity were both associated with >30% eGFR discordance (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.12–3.24; aOR 2.01, 95% CI 1.15–3.52, respectively) and >50% eGFR discordance (aOR 2.34, 95% CI 1.21–4.51; aOR 2.23, 95% CI 1.19–4.17, respectively). A spline model demonstrated that as skeletal muscle index decreases, the predicted difference between eGFR<sub>CRE</sub> and eGFR<sub>CYS</sub> widens considerably.</p> </section> <section>
背景基于肌酐的肾小球滤过率(eGFRCRE)可能会高估肌肉疏松症患者的肾功能。而基于胱抑素 C 的肾小球滤过率(eGFRCYS)受肌肉质量的影响较小,但可能会低估肥胖症患者的肾功能。我们试图评估由计算机断层扫描(CT)确定的身体成分与成年癌症患者肌酐、eGFRCRE 和 eGFRCYS 之间不一致的关系。这项研究是一项横断面研究,研究对象是在 2010 年 5 月至 2022 年 1 月期间,在同时测量 eGFRCRE 和 eGFRCYS 的 90 天内进行过腹部 CT 扫描的连续成年癌症患者。使用经过验证的深度学习管道测量了第三腰椎体水平的肌肉和脂肪组织横截面积。CT定义的 "肌肉疏松症 "是使用独立的特定性别骨骼肌指数临界值(女性为39 cm2/m2,男性为55 cm2/m2)来定义的。高脂肪被定义为队列中总脂肪(内脏加皮下)指数最高的性别特异性四分位数。主要结果是 eGFR 不一致,定义为 eGFRCYS 比 eGFRCRE 低 30%;次要结果是 eGFRCYS 比 eGFRCRE 低 50%。使用多变量逻辑回归模型估算了 eGFR 不一致的几率。结果 在纳入的 545 名患者(平均年龄 63 ± 14 岁,女性 300 [55%],非西班牙裔白人 440 [80.7%])中,320 人(58.7%)符合 CT 定义的肌肉疏松症标准,136 人(25%)有高脂肪。共有 259 名患者(48%)的 eGFR 不一致率为 30%,122 名患者(22.4%)的 eGFR 不一致率为 50%。在对潜在混杂因素进行调整后,CT 定义的肌肉疏松症和高脂肪均与 30% eGFR 不一致(调整后比值比 [aOR] 1.90,95% 置信区间 [CI] 分别为 1.12-3.24;aOR 2.01,95% CI 分别为 1.15-3.52)和 50% eGFR 不一致(aOR 2.34,95% CI 分别为 1.21-4.51;aOR 2.23,95% CI 分别为 1.19-4.17)有关。曲线模型显示,随着骨骼肌指数的降低,eGFRCRE 和 eGFRCYS 之间的预测差异会显著扩大。作为常规癌症治疗的一部分,从 CT 扫描中获得的身体成分分析所包含的宝贵信息会影响对 GFR 估计值的解释。
{"title":"Sarcopenia, adiposity and large discordance between cystatin C and creatinine-based estimated glomerular filtration rate in patients with cancer","authors":"Paul E. Hanna,&nbsp;Tianqi Ouyang,&nbsp;Ismail Tahir,&nbsp;Nurit Katz-Agranov,&nbsp;Qiyu Wang,&nbsp;Lea Mantz,&nbsp;Ian Strohbehn,&nbsp;Daiana Moreno,&nbsp;Destiny Harden,&nbsp;James E. Dinulos,&nbsp;Duru Cosar,&nbsp;Harish Seethapathy,&nbsp;Justin F. Gainor,&nbsp;Sachin J. Shah,&nbsp;Shruti Gupta,&nbsp;David E. Leaf,&nbsp;Florian J. Fintelmann,&nbsp;Meghan E. Sise","doi":"10.1002/jcsm.13469","DOIUrl":"10.1002/jcsm.13469","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Creatinine-based estimated glomerular filtration rate (eGFR&lt;sub&gt;CRE&lt;/sub&gt;) may overestimate kidney function in patients with sarcopenia. While cystatin C-based eGFR (eGFR&lt;sub&gt;CYS&lt;/sub&gt;) is less affected by muscle mass, it may underestimate kidney function in patients with obesity. We sought to evaluate the relationship between body composition defined by computed tomography (CT) scans and discordance between creatinine, eGFR&lt;sub&gt;CRE&lt;/sub&gt; and eGFR&lt;sub&gt;CYS&lt;/sub&gt; in adult patients with cancer.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This study is a cross-sectional study of consecutive adults with cancer with an abdominal CT scan performed within 90 days of simultaneous eGFR&lt;sub&gt;CRE&lt;/sub&gt; and eGFR&lt;sub&gt;CYS&lt;/sub&gt; measurements between May 2010 and January 2022. Muscle and adipose tissue cross-sectional areas were measured at the level of the third lumbar vertebral body using a validated deep-learning pipeline. CT-defined sarcopenia was defined using independent sex-specific cut-offs for skeletal muscle index (&lt;39 cm&lt;sup&gt;2&lt;/sup&gt;/m&lt;sup&gt;2&lt;/sup&gt; for women and &lt;55 cm&lt;sup&gt;2&lt;/sup&gt;/m&lt;sup&gt;2&lt;/sup&gt; for men). High adiposity was defined as the highest sex-specific quartile of the total (visceral plus subcutaneous) adiposity index in the cohort. The primary outcome was eGFR discordance, defined by eGFR&lt;sub&gt;CYS&lt;/sub&gt; &gt; 30% lower than eGFR&lt;sub&gt;CRE&lt;/sub&gt;; the secondary outcome was eGFR&lt;sub&gt;CYS&lt;/sub&gt; &gt; 50% lower than eGFR&lt;sub&gt;CRE&lt;/sub&gt;. The odds of eGFR discordance were estimated using multivariable logistic regression modelling. Unadjusted spline regression was used to evaluate the relationship between skeletal muscle index and the difference between eGFR&lt;sub&gt;CYS&lt;/sub&gt; and eGFR&lt;sub&gt;CRE&lt;/sub&gt;.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Of the 545 included patients (mean age 63 ± 14 years, 300 [55%] females, 440 [80.7%] non-Hispanic white), 320 (58.7%) met the criteria for CT-defined sarcopenia, and 136 (25%) had high adiposity. A total of 259 patients (48%) had &gt;30% eGFR discordance, and 122 (22.4%) had &gt;50% eGFR discordance. After adjustment for potential confounders, CT-defined sarcopenia and high adiposity were both associated with &gt;30% eGFR discordance (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.12–3.24; aOR 2.01, 95% CI 1.15–3.52, respectively) and &gt;50% eGFR discordance (aOR 2.34, 95% CI 1.21–4.51; aOR 2.23, 95% CI 1.19–4.17, respectively). A spline model demonstrated that as skeletal muscle index decreases, the predicted difference between eGFR&lt;sub&gt;CRE&lt;/sub&gt; and eGFR&lt;sub&gt;CYS&lt;/sub&gt; widens considerably.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 ","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 3","pages":"1187-1198"},"PeriodicalIF":8.9,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13469","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140634088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for sarcopenia 系统性可药用全基因组孟德尔随机化确定了肌少症的治疗靶点
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-21 DOI: 10.1002/jcsm.13479
Kang-Fu Yin, Ting Chen, Xiao-Jing Gu, Wei-Ming Su, Zheng Jiang, Si-Jia Lu, Bei Cao, Li-Yi Chi, Xia Gao, Yong-Ping Chen
<div> <section> <h3> Background</h3> <p>There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets.</p> </section> <section> <h3> Methods</h3> <p>We integrated druggable genome data, cis-eQTL/cis-pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia-related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome-wide MR (Phe-MR) approach and investigated actionable drugs for target genes using available databases.</p> </section> <section> <h3> Results</h3> <p>MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (<i>HP</i>, <i>HLA-DRA</i>, <i>MAP 3K3</i>, <i>MFGE8</i>, <i>COL15A1</i>, and <i>AURKA</i>) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up-regulation of <i>HP</i> [higher ALM (beta: 0.012, 95% CI: 0.007–0.018, <i>P</i> = 1.2*10<sup>−5</sup>) and higher grip strength (OR: 0.96, 95% CI: 0.94–0.98, <i>P</i> = 4.2*10<sup>−5</sup>)], <i>MAP 3K3</i> [higher ALM (beta: 0.24, 95% CI: 0.21–0.26, <i>P</i> = 1.8*10<sup>−94</sup>), higher grip strength (OR: 0.82, 95% CI: 0.75–0.90, <i>P</i> = 2.1*10<sup>−5</sup>), and faster walking pace (beta: 0.03, 95% CI: 0.02–0.05, <i>P</i> = 8.5*10<sup>−6</sup>)], and <i>MFGE8</i> [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06–0.11, <i>P</i> = 6.1*10<sup>−13</sup>; blood pQTL, beta: 0.05, 95% CI: 0.03–0.07, <i>P</i> = 3.8*10<sup>−09</sup>)], as well as the down-regulation of <i>HLA-DRA</i> [lower ALM (beta: -0.09, 95% CI: −0.11 to −0.08, <i>P</i> = 5.4*10<sup>−36</sup>) and lower grip strength (OR: 1.13, 95% CI: 1.07–1.20, <i>P</i> = 1.8*10<sup>−5</sup>)] and <i>COL15A1</i> [higher ALM (muscle eQTL, beta: -0.07, 95% CI: −0.10 to −0.04, <i>P</i> = 3.4*10<sup>−07</sup>; blood pQTL, beta: -0.05, 95% CI: −0.06 to −0.03, <i>P</i> = 1.6*10<sup>−07</sup>)], decreased the risk of sarcopenia. <i>AURKA</i> in blood (beta: -0.16, 95% CI: −0.22 to −0.09, <i>P</i> = 2.1*10<sup>−06</sup>) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, <i>P</i> = 5.3*10<sup>−05</sup>) tissues showed an inverse relationship with sarcopenia risk. The Phe-MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis suppor
背景目前还没有治疗肌肉疏松症的有效药物。方法我们整合了可药用基因组数据、人体血液和骨骼肌组织的顺式-eQTL/顺式-pQTL,以及肌肉疏松症相关性状的GWAS汇总数据,利用孟德尔随机化(MR)方法分析药物靶基因与肌肉疏松症之间的潜在因果关系。我们还采用了敏感性分析和贝叶斯共轭法来验证因果关系。我们还利用表观范围 MR(Phe-MR)方法评估了已确定的药物靶点的副作用或其他适应症,并利用现有数据库调查了靶基因的可治疗药物。其中 6 个基因(HP、HLA-DRA、MAP 3K3、MFGE8、COL15A1 和 AURKA)通过贝叶斯共定位(PPH4 >90%)得到进一步证实。HP [更高的 ALM(β:0.012,95% CI:0.007-0.018,P = 1.2*10-5)和更高的握力(OR:0.96,95% CI:0.94-0.98,P = 4.2*10-5)]、MAP 3K3 [更高的 ALM(β:0.24,95% CI:0.21-0.26,P = 1.8*10-94)、更高的握力(OR:0.82,95% CI:0.75-0.90,P = 2.1*10-5)和更快的步行速度(β:0.03,95% CI:0.02-0.05,P = 8.5*10-6)],以及 MFGE8 [更高的 ALM(肌肉 eQTL,β:0.09, 95% CI: 0.06-0.11, P = 6.1*10-13;血液 pQTL, beta:0.05,95% CI:0.03-0.07,P = 3.8*10-09)],以及 HLA-DRA 的下调[更低的 ALM(β:-0.09,95% CI:-0.11--0.08,P = 5.4*10-36)和更低的握力(OR:1.13,95% CI:1.07-1.20,P = 1.8*10-5)]和 COL15A1 的下调[更高的 ALM(肌肉 eQTL,β:-0.07,95% CI:0.03-0.07,P = 3.8*10-09)]:-0.07,95% CI:-0.10 至 -0.04,P = 3.4*10-07;血液 pQTL,β:-0.05,95% CI:-0.06 至 -0.03,P = 1.6*10-07)],降低了患肌肉疏松症的风险。血液(β:-0.16,95% CI:-0.22 至 -0.09,P = 2.1*10-06)和骨骼肌(β:0.03,95% CI:0.02 至 0.05,P = 5.3*10-05)组织中的 AURKA 与肌肉疏松症风险呈反向关系。Phe-MR表明,六种潜在的肌肉疏松症治疗靶点没有明显的不良反应。结论我们的研究表明,MAP 3K3、MFGE8、COL15A1、HP和HLA-DRA可能是治疗肌肉疏松症的潜在靶点,而补锌和溶组织梭菌胶原酶对肌肉疏松症的疗效则有待进一步验证。
{"title":"Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for sarcopenia","authors":"Kang-Fu Yin,&nbsp;Ting Chen,&nbsp;Xiao-Jing Gu,&nbsp;Wei-Ming Su,&nbsp;Zheng Jiang,&nbsp;Si-Jia Lu,&nbsp;Bei Cao,&nbsp;Li-Yi Chi,&nbsp;Xia Gao,&nbsp;Yong-Ping Chen","doi":"10.1002/jcsm.13479","DOIUrl":"10.1002/jcsm.13479","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We integrated druggable genome data, cis-eQTL/cis-pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia-related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome-wide MR (Phe-MR) approach and investigated actionable drugs for target genes using available databases.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (&lt;i&gt;HP&lt;/i&gt;, &lt;i&gt;HLA-DRA&lt;/i&gt;, &lt;i&gt;MAP 3K3&lt;/i&gt;, &lt;i&gt;MFGE8&lt;/i&gt;, &lt;i&gt;COL15A1&lt;/i&gt;, and &lt;i&gt;AURKA&lt;/i&gt;) were further confirmed by Bayesian colocalization (PPH4 &gt; 90%). The up-regulation of &lt;i&gt;HP&lt;/i&gt; [higher ALM (beta: 0.012, 95% CI: 0.007–0.018, &lt;i&gt;P&lt;/i&gt; = 1.2*10&lt;sup&gt;−5&lt;/sup&gt;) and higher grip strength (OR: 0.96, 95% CI: 0.94–0.98, &lt;i&gt;P&lt;/i&gt; = 4.2*10&lt;sup&gt;−5&lt;/sup&gt;)], &lt;i&gt;MAP 3K3&lt;/i&gt; [higher ALM (beta: 0.24, 95% CI: 0.21–0.26, &lt;i&gt;P&lt;/i&gt; = 1.8*10&lt;sup&gt;−94&lt;/sup&gt;), higher grip strength (OR: 0.82, 95% CI: 0.75–0.90, &lt;i&gt;P&lt;/i&gt; = 2.1*10&lt;sup&gt;−5&lt;/sup&gt;), and faster walking pace (beta: 0.03, 95% CI: 0.02–0.05, &lt;i&gt;P&lt;/i&gt; = 8.5*10&lt;sup&gt;−6&lt;/sup&gt;)], and &lt;i&gt;MFGE8&lt;/i&gt; [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06–0.11, &lt;i&gt;P&lt;/i&gt; = 6.1*10&lt;sup&gt;−13&lt;/sup&gt;; blood pQTL, beta: 0.05, 95% CI: 0.03–0.07, &lt;i&gt;P&lt;/i&gt; = 3.8*10&lt;sup&gt;−09&lt;/sup&gt;)], as well as the down-regulation of &lt;i&gt;HLA-DRA&lt;/i&gt; [lower ALM (beta: -0.09, 95% CI: −0.11 to −0.08, &lt;i&gt;P&lt;/i&gt; = 5.4*10&lt;sup&gt;−36&lt;/sup&gt;) and lower grip strength (OR: 1.13, 95% CI: 1.07–1.20, &lt;i&gt;P&lt;/i&gt; = 1.8*10&lt;sup&gt;−5&lt;/sup&gt;)] and &lt;i&gt;COL15A1&lt;/i&gt; [higher ALM (muscle eQTL, beta: -0.07, 95% CI: −0.10 to −0.04, &lt;i&gt;P&lt;/i&gt; = 3.4*10&lt;sup&gt;−07&lt;/sup&gt;; blood pQTL, beta: -0.05, 95% CI: −0.06 to −0.03, &lt;i&gt;P&lt;/i&gt; = 1.6*10&lt;sup&gt;−07&lt;/sup&gt;)], decreased the risk of sarcopenia. &lt;i&gt;AURKA&lt;/i&gt; in blood (beta: -0.16, 95% CI: −0.22 to −0.09, &lt;i&gt;P&lt;/i&gt; = 2.1*10&lt;sup&gt;−06&lt;/sup&gt;) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, &lt;i&gt;P&lt;/i&gt; = 5.3*10&lt;sup&gt;−05&lt;/sup&gt;) tissues showed an inverse relationship with sarcopenia risk. The Phe-MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis suppor","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 4","pages":"1324-1334"},"PeriodicalIF":9.4,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13479","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140634085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exploring the optimal indicator of short-term peridiagnosis weight dynamics to predict cancer survival: A multicentre cohort study 探索预测癌症生存率的围诊断期短期体重动态最佳指标: 一项多中心队列研究
IF 8.9 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-21 DOI: 10.1002/jcsm.13467
Liangyu Yin, Ling Zhang, Long Li, Ming Liu, Jin Zheng, Aiguo Xu, Quanjun Lyu, Yongdong Feng, Zengqing Guo, Hu Ma, Jipeng Li, Zhikang Chen, Hui Wang, Zengning Li, Chunling Zhou, Xi Gao, Min Weng, Qinghua Yao, Wei Li, Tao Li, Hanping Shi, Hongxia Xu
<div> <section> <h3> Background</h3> <p>Body weight and its changes have been associated with cancer outcomes. However, the associations of short-term peridiagnosis weight dynamics in standardized, clinically operational time frames with cancer survival remain largely unknown. This study aimed to screen for and evaluate the optimal indicator of short-term peridiagnosis weight dynamics to predict overall survival (OS) in patients with cancer.</p> </section> <section> <h3> Methods</h3> <p>This multicentre cohort study prospectively collected data from 7460 patients pathologically diagnosed with cancer between 2013 and 2019. Body weight data were recorded 1 month before, at the time of and 1 month following diagnosis. By permuting different types (point value in kg, point height-adjusted value in kg/m<sup>2</sup>, absolute change in kg or relative change in percentage) and time frames (prediagnosis, postdiagnosis or peridiagnosis), we generated 12 different weight-related indicators and compared their prognostic performance using Harrell's C-index, integrated discrimination improvement, continuous net reclassification improvement and time-dependent C-index. We analysed associations of peridiagnosis relative weight change (RWC) with OS using restricted cubic spine (RCS), Kaplan–Meier analysis and multivariable-adjusted Cox regression models.</p> </section> <section> <h3> Results</h3> <p>The study enrolled 5012 males and 2448 females, with a median age of 59 years. During a median follow-up of 37 months, 1026 deaths occurred. Peridiagnosis (1 month before diagnosis to 1 month following diagnosis) RWC showed higher prognostic performance (Harrell's C-index = 0.601, 95% confidence interval [CI] = [0.583, 0.619]) than other types of indicators including body mass index (BMI), absolute weight change, absolute BMI change, prediagnosis RWC and postdiagnosis RWC in the study population (all <i>P</i> < 0.05). Time-dependent C-index analysis also indicated that peridiagnosis RWC was optimal for predicting OS. The multivariable-adjusted RCS analysis revealed an N-shaped non-linear association between peridiagnosis RWC and OS (<i>P</i><sub><i>RWC</i></sub> < 0.001, <i>P</i><sub><i>non-linear</i></sub> < 0.001). Univariate survival analysis showed that the peridiagnosis RWC groups could represent distinct mortality risk stratifications (<i>P</i> < 0.001). Multivariable survival analysis showed that, compared with the maintenance group (weight change < 5%), the significant (gain >10%, hazard ratio [HR] = 0.530, 95% CI = [0.413, 0.680]) and moderate (gain 5–10%, HR = 0.588, 95% CI = [0.422, 0.819]) weight gain groups were both associated with improv
背景体重及其变化与癌症预后有关。然而,在标准化的临床操作时间框架内,围诊断期的短期体重动态与癌症生存率之间的关系在很大程度上仍不为人所知。这项研究旨在筛选和评估预测癌症患者总生存期(OS)的最佳指标。方法这项多中心队列研究前瞻性地收集了2013年至2019年期间经病理诊断为癌症的7460名患者的数据。体重数据记录于确诊前 1 个月、确诊时和确诊后 1 个月。通过对不同类型(以千克为单位的点值、以千克/平方米为单位的点身高调整值、以千克为单位的绝对变化或以百分比为单位的相对变化)和时间框架(诊断前、诊断后或围诊断期)进行置换,我们生成了 12 种不同的体重相关指标,并使用哈雷尔 C 指数、综合判别改进、持续净再分类改进和时间依赖性 C 指数对其预后性能进行了比较。我们使用限制性立方体脊柱(RCS)、卡普兰-梅耶尔分析和多变量调整 Cox 回归模型分析了围诊断期相对体重变化(RWC)与 OS 的相关性。中位随访时间为 37 个月,死亡人数为 1026 人。在研究人群中,围诊断期(诊断前 1 个月至诊断后 1 个月)RWC 的预后性能(哈雷尔 C 指数 = 0.601,95% 置信区间 [CI] = [0.583, 0.619])高于其他类型的指标,包括体重指数 (BMI)、体重绝对值变化、BMI 绝对值变化、诊断前 RWC 和诊断后 RWC(所有 P 均为 0.05)。时间依赖性C指数分析也表明,围诊断期RWC是预测OS的最佳指标。多变量调整 RCS 分析显示,围诊断期 RWC 与 OS 之间存在 N 型非线性关联(PRWC < 0.001,Pnon-linear < 0.001)。单变量生存分析表明,围诊断期 RWC 组可代表不同的死亡风险分层(P< 0.001)。多变量生存分析显示,与维持组(体重变化< 5%)相比,体重大幅增加组(增加>10%,危险比[HR] = 0.530,95% CI = [0.413,0.680])和中度增加组(增加5-10%,HR = 0.588,95% CI = [0.422,0.819])均与OS改善相关。相比之下,中度(体重减轻 5-10%,HR = 1.219,95% CI = [1.029,1.443])和显著(体重减轻 >10%,HR = 1.280,95% CI = [1.095,1.497])体重减轻组与较差的 OS 相关。这些发现强调了将体重监测的范围从诊断时扩大到过去和未来,并在临床可操作的时间范围内进行监测的重要性,以便识别和干预有可能因体重变化而过早死亡的患者。
{"title":"Exploring the optimal indicator of short-term peridiagnosis weight dynamics to predict cancer survival: A multicentre cohort study","authors":"Liangyu Yin,&nbsp;Ling Zhang,&nbsp;Long Li,&nbsp;Ming Liu,&nbsp;Jin Zheng,&nbsp;Aiguo Xu,&nbsp;Quanjun Lyu,&nbsp;Yongdong Feng,&nbsp;Zengqing Guo,&nbsp;Hu Ma,&nbsp;Jipeng Li,&nbsp;Zhikang Chen,&nbsp;Hui Wang,&nbsp;Zengning Li,&nbsp;Chunling Zhou,&nbsp;Xi Gao,&nbsp;Min Weng,&nbsp;Qinghua Yao,&nbsp;Wei Li,&nbsp;Tao Li,&nbsp;Hanping Shi,&nbsp;Hongxia Xu","doi":"10.1002/jcsm.13467","DOIUrl":"10.1002/jcsm.13467","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Body weight and its changes have been associated with cancer outcomes. However, the associations of short-term peridiagnosis weight dynamics in standardized, clinically operational time frames with cancer survival remain largely unknown. This study aimed to screen for and evaluate the optimal indicator of short-term peridiagnosis weight dynamics to predict overall survival (OS) in patients with cancer.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This multicentre cohort study prospectively collected data from 7460 patients pathologically diagnosed with cancer between 2013 and 2019. Body weight data were recorded 1 month before, at the time of and 1 month following diagnosis. By permuting different types (point value in kg, point height-adjusted value in kg/m&lt;sup&gt;2&lt;/sup&gt;, absolute change in kg or relative change in percentage) and time frames (prediagnosis, postdiagnosis or peridiagnosis), we generated 12 different weight-related indicators and compared their prognostic performance using Harrell's C-index, integrated discrimination improvement, continuous net reclassification improvement and time-dependent C-index. We analysed associations of peridiagnosis relative weight change (RWC) with OS using restricted cubic spine (RCS), Kaplan–Meier analysis and multivariable-adjusted Cox regression models.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The study enrolled 5012 males and 2448 females, with a median age of 59 years. During a median follow-up of 37 months, 1026 deaths occurred. Peridiagnosis (1 month before diagnosis to 1 month following diagnosis) RWC showed higher prognostic performance (Harrell's C-index = 0.601, 95% confidence interval [CI] = [0.583, 0.619]) than other types of indicators including body mass index (BMI), absolute weight change, absolute BMI change, prediagnosis RWC and postdiagnosis RWC in the study population (all &lt;i&gt;P&lt;/i&gt; &lt; 0.05). Time-dependent C-index analysis also indicated that peridiagnosis RWC was optimal for predicting OS. The multivariable-adjusted RCS analysis revealed an N-shaped non-linear association between peridiagnosis RWC and OS (&lt;i&gt;P&lt;/i&gt;&lt;sub&gt;&lt;i&gt;RWC&lt;/i&gt;&lt;/sub&gt; &lt; 0.001, &lt;i&gt;P&lt;/i&gt;&lt;sub&gt;&lt;i&gt;non-linear&lt;/i&gt;&lt;/sub&gt; &lt; 0.001). Univariate survival analysis showed that the peridiagnosis RWC groups could represent distinct mortality risk stratifications (&lt;i&gt;P&lt;/i&gt; &lt; 0.001). Multivariable survival analysis showed that, compared with the maintenance group (weight change &lt; 5%), the significant (gain &gt;10%, hazard ratio [HR] = 0.530, 95% CI = [0.413, 0.680]) and moderate (gain 5–10%, HR = 0.588, 95% CI = [0.422, 0.819]) weight gain groups were both associated with improv","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"15 3","pages":"1177-1186"},"PeriodicalIF":8.9,"publicationDate":"2024-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13467","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140633913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Association of endothelial dysfunction and peripheral arterial disease with sarcopenia in chronic kidney disease 慢性肾脏病患者内皮功能障碍和外周动脉疾病与肌肉疏松症的关系
IF 8.9 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-21 DOI: 10.1002/jcsm.13471
Bang-Gee Hsu, Chih-Hsien Wang, Yu-Hsien Lai, Chiu-Huang Kuo, Yu-Li Lin
<div> <section> <h3> Background</h3> <p>Endothelial dysfunction and peripheral arterial disease (PAD), which disturb skeletal muscle microperfusion, are highly prevalent in patients with chronic kidney disease (CKD). We evaluated the association of endothelial dysfunction and PAD with sarcopenia in patients with non-dialysis CKD.</p> </section> <section> <h3> Methods</h3> <p>This cross-sectional study included 420 patients with stages 3–5 non-dialysis CKD aged 69.0 ± 11.8 years. Skeletal muscle index (skeletal muscle mass/height<sup>2</sup>), handgrip strength, 6-m gait speed and strength of hip flexion and knee extension were measured. Sarcopenia was defined according to the Asian Working Group for Sarcopenia 2019. Endothelial dysfunction and PAD were assessed using the vascular reactivity index (VRI) and ankle–brachial index (ABI), respectively. A VRI < 1.0 was classified as poor endothelial function, and an ABI < 0.9 was defined as PAD. Additionally, endothelial and inflammatory biomarkers, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), asymmetric dimethylarginine, endothelin-1 (ET-1) and interleukin-6, were measured in a subgroup of 262 patients.</p> </section> <section> <h3> Results</h3> <p>Among the participants, 103 (24.5%) were classified as having sarcopenia. Compared with patients without sarcopenia, those with sarcopenia had significantly lower ABI (1.04 ± 0.16 vs. 1.08 ± 0.15, <i>P</i> = 0.028 for the right ABI; 1.01 ± 0.16 vs. 1.06 ± 0.16, <i>P</i> = 0.002 for the left ABI) and VRI (0.83 ± 0.57 vs. 1.08 ± 0.56, <i>P</i> < 0.001) and had higher serum levels of ICAM-1 (<i>P</i> < 0.001), VCAM-1 (<i>P</i> = 0.003) and ET-1 (<i>P</i> = 0.037). Multivariate logistic regression revealed that, beyond age and body mass index, the average ABI (odds ratio [OR]: 0.81/0.1 increase; 95% confidence interval [CI]: 0.67–0.98; <i>P</i> = 0.032) and VRI (OR: 0.93/0.1 increase; 95% CI: 0.88–0.98; <i>P</i> = 0.010) were independently associated with sarcopenia. Among the endothelial biomarkers measured, ICAM-1 (OR: 2.47/1-SD increase; 95% CI: 1.62–3.75) and VCAM-1 (OR: 1.91/1-SD increase; 95% CI: 1.27–2.87) were independent predictors of sarcopenia. Group stratification based on the cut-offs of VRI and ABI showed that those with both poor VRI and ABI had the greatest risk for sarcopenia (OR: 4.22; 95% CI: 1.69–10.49), compared with those with normal VRI and ABI.</p> </section> <section> <h3> Conclusions</h3> <p>Endothelial dysfunction and PAD are independently associated with sarcopenia in pat
背景内皮功能障碍和外周动脉疾病(PAD)会干扰骨骼肌的微灌注,在慢性肾脏病(CKD)患者中非常普遍。我们评估了非透析型慢性肾脏病患者的内皮功能障碍和 PAD 与肌肉疏松症的关系。方法这项横断面研究纳入了 420 名 3-5 期非透析型慢性肾脏病患者,年龄为 69.0 ± 11.8 岁。研究人员测量了患者的骨骼肌指数(骨骼肌质量/身高2)、手握力、6米步速以及屈髋和伸膝力量。根据 "2019 年亚洲肌肉疏松症工作组 "对 "肌肉疏松症 "进行了定义。血管反应指数(VRI)和踝肱指数(ABI)分别评估内皮功能障碍和PAD。VRI < 1.0 被归类为内皮功能不良,ABI < 0.9 被定义为 PAD。此外,在 262 名患者中还测量了内皮和炎症生物标志物,包括细胞间粘附分子-1(ICAM-1)、血管细胞粘附分子-1(VCAM-1)、不对称二甲基精氨酸、内皮素-1(ET-1)和白细胞介素-6。与无肌肉疏松症的患者相比,肌肉疏松症患者的 ABI 明显较低(右侧 ABI 为 1.04 ± 0.16 vs. 1.08 ± 0.15,P = 0.028;左侧 ABI 为 1.01 ± 0.16 vs. 1.06 ± 0.16,P = 0.002)。16,P = 0.002)和 VRI(0.83 ± 0.57 vs. 1.08 ± 0.56,P <0.001),血清中 ICAM-1 (P <0.001)、VCAM-1 (P = 0.003)和 ET-1 (P = 0.037)水平较高。多变量逻辑回归显示,除年龄和体重指数外,平均 ABI(几率比 [OR]:增加 0.81/0.1;95% 置信区间 [CI]:0.67-0.98;P = 0.032)和 VRI(OR:0.93/0.1 增加;95% CI:0.88-0.98;P = 0.010)与肌肉疏松症独立相关。在测量的内皮生物标志物中,ICAM-1(OR:2.47/1-SD 增加;95% CI:1.62-3.75)和 VCAM-1(OR:1.91/1-SD 增加;95% CI:1.27-2.87)是预测肌肉疏松症的独立指标。根据 VRI 和 ABI 临界值进行的分组分层显示,与 VRI 和 ABI 正常的患者相比,VRI 和 ABI 均较差的患者患肌肉疏松症的风险最大(OR:4.22;95% CI:1.69-10.49)。
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引用次数: 0
Metabolomics-driven discovery of therapeutic targets for cancer cachexia 代谢组学驱动的癌症恶病质治疗靶点的发现
IF 8.9 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-04-21 DOI: 10.1002/jcsm.13465
Pengfei Cui, Xiaoyi Li, Caihua Huang, Donghai Lin

Cancer cachexia (CC) is a devastating metabolic syndrome characterized by skeletal muscle wasting and body weight loss, posing a significant burden on the health and survival of cancer patients. Despite ongoing efforts, effective treatments for CC are still lacking. Metabolomics, an advanced omics technique, offers a comprehensive analysis of small-molecule metabolites involved in cellular metabolism. In CC research, metabolomics has emerged as a valuable tool for identifying diagnostic biomarkers, unravelling molecular mechanisms and discovering potential therapeutic targets. A comprehensive search strategy was implemented to retrieve relevant articles from primary databases, including Web of Science, Google Scholar, Scopus and PubMed, for CC and metabolomics. Recent advancements in metabolomics have deepened our understanding of CC by uncovering key metabolic signatures and elucidating underlying mechanisms. By targeting crucial metabolic pathways including glucose metabolism, amino acid metabolism, fatty acid metabolism, bile acid metabolism, ketone body metabolism, steroid metabolism and mitochondrial energy metabolism, it becomes possible to restore metabolic balance and alleviate CC symptoms. This review provides a comprehensive summary of metabolomics studies in CC, focusing on the discovery of potential therapeutic targets and the evaluation of modulating specific metabolic pathways for CC treatment. By harnessing the insights derived from metabolomics, novel interventions for CC can be developed, leading to improved patient outcomes and enhanced quality of life.

癌症恶病质(CC)是一种以骨骼肌萎缩和体重减轻为特征的破坏性代谢综合征,给癌症患者的健康和生存带来了沉重负担。尽管人们一直在努力,但仍缺乏针对癌症恶病质的有效治疗方法。代谢组学是一种先进的全息技术,可对参与细胞代谢的小分子代谢物进行全面分析。在CC研究中,代谢组学已成为确定诊断生物标志物、揭示分子机制和发现潜在治疗靶点的重要工具。我们采用了一种全面的搜索策略,从包括 Web of Science、Google Scholar、Scopus 和 PubMed 在内的主要数据库中检索有关 CC 和代谢组学的相关文章。代谢组学的最新进展通过发现关键代谢特征和阐明潜在机制,加深了我们对CC的了解。通过针对关键代谢途径(包括葡萄糖代谢、氨基酸代谢、脂肪酸代谢、胆汁酸代谢、酮体代谢、类固醇代谢和线粒体能量代谢)进行治疗,恢复代谢平衡和缓解CC症状成为可能。本综述全面总结了CC的代谢组学研究,重点关注潜在治疗靶点的发现以及对调节特定代谢途径治疗CC的评估。通过利用从代谢组学中获得的见解,可以开发出治疗CC的新型干预措施,从而改善患者的预后并提高生活质量。
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引用次数: 0
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Journal of Cachexia Sarcopenia and Muscle
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