The impact of different step rate threshold methods on physical activity intensity in older adults

BackgroundOlder adults benefit most from engaging in higher-intensity physical activity, which is often determined using step rate thresholds. Fixed step rate thresholds that correspond to moderate (MPA) and vigorous-intensity physical activity (VPA) have been developed for heuristic activity promotion. The activPAL monitor uses step rate thresholds to determine activity intensity. Stepping thresholds may also vary based on body mass index (BMI) or aerobic fitness level in older adults. Despite the various thresholds used in the literature, it is unclear whether they produce similar outcomes.Research QuestionHow does time spent in physical activity intensities compare between different step rate thresholds in older adults?MethodsThirty-eight participants (24♀; 67 ± 4 years; BMI: 26.6 ± 4.4 kg/m²) wore an activPAL monitor 24-hr/day for up to 7-d (total: 205-d). Aerobic fitness (V̇O₂max: 23 ± 8 ml/kg/min) was determined via indirect calorimetry during a maximal, graded cycling test. Time spent in each intensity category (light-physical-activity [LPA], MPA, VPA) was determined using the fixed (MPA/VPA) 100/130, 110/130, and activPAL step rate thresholds (74/212), as well as BMI-adjusted absolute (108.5 ± 2.5/134.0 ± 4.8) and BMI-adjusted relative (40%/60% V̇O₂max; 111.4 ± 14.7/132.0 ± 19.0) cut-offs. Times spent in each intensity category were compared between methods.ResultsThe activPAL and 100/130 thresholds yielded less LPA and more MPA than all other methods. The activPAL had no time spent in VPA at all. The BMI-adjusted absolute and relative thresholds produced statistically equivalent time in LPA and MPA (via equivalence testing), but not VPA. No two methods yielded similar time spent in LPA, MPA, or VPA.SignificanceThe choice of step rate threshold has a major impact on physical activity intensity outcomes in older adults. Inherently, strategies that adjust for older adults’ body size and/or aerobic fitness level provide a more individualized data processing strategy than fixed thresholds that assume the same threshold for all older adults     

Diffusion-weighted MRI and PET/CT reproducibility in epithelial ovarian cancers during neoadjuvant chemotherapy

PurposeTo investigate the reproducibility of diffusion-weighted (DW) MRI and ¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG)-Positron emission tomography/CT (PET/CT) in monitoring response to neoadjuvant chemotherapy in epithelial ovarian cancer.Materials and methodsTen women (median age, 67 years; range: 41.8–77.3 years) with stage IIIC-IV epithelial ovarian cancers were included in this prospective trial (NCT02792959) between 2014 and 2016. All underwent initial laparoscopic staging, four cycles of carboplatine-paclitaxel-based chemotherapy and interval debulking surgery. PET/CT and DW-MRI were performed at baseline (C0), after one cycle (C1) and before surgery (C4). Two nuclear physicians and two radiologists assessed five anatomic sites for the presence of ≥ 1 lesion. Target lesions in each site were defined and their apparent diffusion coefficient (ADC), maximal standardized uptake value (SUV-max), SUV-mean, SUL-peak, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were monitored (i.e., 10 patients × 5 sites × 3 time-points). Their relative early and late changes were calculated. Intra/inter-observer reproducibilities of qualitative and quantitative analysis were estimated with Kappa and intra-class correlation coefficients (ICCs).ResultsFor both modalities, inter- and intra-observer agreement percentages were excellent for initial staging but declined later for DW-MRI, leading to lower Kappa values for inter- and intra-observer variability (0.949 and 1 at C0, vs. 0.633 and 0.643 at C4, respectively) while Kappa values remained > 0.8 for PET/CT. Inter- and intra-observer ICCs were > 0.75 for SUV-max, SUL-peak, SUV-mean and their change regardless the time-point. ADC showed lower ICCs (range: 0.013–0.811). ANOVA found significant influences of the evaluation time, the measurement used (ADC, SUV-max, SUV-mean, SUV-max, SUL-peak, MTV or TLG) and their interaction on ICC values (P = 0.0023, P< 0.0001 and P =0.0028, respectively).ConclusionWhile both modalities demonstrated high reproducibility at baseline, only SUV-max, SUL-peak, SUV-mean and their changes maintained high reproducibility during chemotherapy.     

Deoxyelephantopin decreases the release of inflammatory cytokines in macrophage associated with attenuation of aerobic glycolysis via modulation of PKM2

Growing evidence suggests that activated immune cells undergo metabolic reprogramming in the regulation of the innate inflammatory response. Remarkably, macrophages activated by lipopolysaccharide (LPS) induce a switch from oxidative phosphorylation to aerobic glycolysis, and consequently results in release of proinflammatory cytokines. Pyruvate Kinase M2 (PKM2) plays a vital role in the process of macrophage activation, promoting the inflammatory response in sepsis and septic shock. Deoxyelephantopin (DET), a naturally occurring sesquiterpene lactone from Elephantopus scaber, has been shown to counteracts inflammation during fulminant hepatitis progression, but the underlying mechanism remains unclear. Here, we studied the function of the DET on macrophage activation and investigated the anti-inflammatory effects of DET associated with interfering with glycolysis in macrophage. Our results first demonstrated that DET attenuates LPS-induced interleukin-1β (IL-1β) and high-mobility group box 1 (HMGB1) release in vitro and in vivo and protected mice against lethal endotoxemia. Furthermore, DET decreased the expression of pyruvate dehydrogenase kinase 1 (PDK1), glucose transporter 1(GLUT1), lactate dehydrogenase A (LDHA), and reduced lactate production dose-dependently in macrophages. Moreover, we further revealed that DET attenuates aerobic glycolysis in macrophages associated with regulating the nuclear localization of PKM2. Our results provided a novel mechanism for DET suppression of macrophages activation implicated in anti-inflammatory therapy.     

PFKFB3参与脂多糖诱导肺成纤维细胞及肺组织有氧糖酵解的观察性研究

目的:观察脂多糖(lipopolysaccharide,LPS)诱导肺成纤维细胞及肺组织有氧糖酵解关键酶6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3(6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3,PFKFB3)表达及其与有氧糖酵解的关系,探讨在LPS诱导肺纤维化过程中肺成纤维细胞和肺组织有氧糖酵解的潜在机制。方法:将人胚肺成纤维细胞MRC-5细胞系采用随机数字表法分为PBS对照组(PBS组)和LPS组(每组3孔),Western blot检测LPS刺激细胞6h后PFKFB3表达情况,同时免疫荧光显示PFKFB3在细胞内的定位情况;于LPS刺激后48 h采用海马细胞能量代谢仪检测细胞耗氧率(oxygen consumption rate,OCR)和产酸率(extracellular acidification rate,ECAR),并采用比色法检测有氧糖酵解产物乳酸产生情况,同时Western blot检测LPS刺激48 h后Ⅰ型胶原蛋白合成情况。将24只C57BL/6小鼠按随机数字表法分为生理盐水对照组(C组)、LPS组(L组),每组12只,L组、C组连续5d分别腹腔注射5 mg/kg LPS、等容量生理盐水;每组各6只于造模后第7天无痛处死小鼠,取血浆和肺组织,Western blot和免疫荧光检测各组肺组织中PFKFB3表达情况,比色法检测各组小鼠血浆中乳酸的含量;剩余小鼠于造模后第28天取肺组织,一侧肺通过Western blot检测肺组织Ⅰ型胶原蛋白合成情况,另一侧肺做石蜡切片进行病理学检测。结果:与PBS组比较,LPS刺激细胞6h后PFKFB3表达明显升高(P<0.05);LPS刺激细胞48 h后,与PBS组比较,LPS组细胞耗氧率降低、产酸率增加,代谢产物乳酸含量明显升高(P<0.05),同时细胞Ⅰ型胶原蛋白合成显著增加(P<0.05)。与C组比较,L组小鼠腹腔注射LPS 7 d后肺组织中PFKFB3表达明显升高(P<0.05),血浆乳酸含量明显升高(P<0.05);LPS注射28 d后,L组小鼠Ⅰ型胶原蛋白表达明显升高(P<0.05),肺组织出现明显纤维化。结论:在LPS诱导的肺纤维化过程中,LPS可诱导肺成纤维细胞和肺组织中PFKFB3蛋白表达,该过程与其有氧糖酵解过程相关,PFKFB3的表达上调可能是LPS诱导肺成纤维细胞和肺组织有氧糖酵解和肺纤维化的关键环节。     

当前肿瘤代谢调节治疗面临的问题及思考

随着肿瘤代谢研究的进展，人们发现单一Warburg效应的糖代谢重编程可能不能代表全局定义的肿瘤代谢重编程。线粒体在肿瘤代谢重编程中起着重要的作用。根据前人的研究，我们总结出线粒体功能障碍可通过三种模式调控肿瘤代谢重编程：包括线粒体功能障碍诱导型、核基因突变诱导型、混合型。肿瘤细胞的代谢重编程又因基因型、肿瘤亚型、分化程度、微环境的差异而表现为灵活的代谢可塑性。肿瘤细胞可窃取肿瘤相关细胞的“代谢废物”，与肿瘤相关细胞相互依存、相互影响，表现出代谢共生的特征。除此之外，肿瘤细胞还可表现出稳定的杂合代谢表型，进而影响肿瘤的生物学行为。本文从当前肿瘤糖代谢调节治疗的研究现状出发，涉及当前代谢调节研究面临的问题，总结了线粒体功能障碍对代谢重编程的影响，并重点从肿瘤细胞的代谢可塑性、肿瘤细胞与肿瘤相关细胞之间的代谢耦联以及肿瘤细胞存在的杂合代谢表型等方面出发，讨论了糖代谢中糖酵解和线粒体氧化对于肿瘤代谢复杂性的影响，并针对复杂肿瘤糖代谢提出相应的对策。     

The association between markers of tumour cell metabolism,the tumour microenvironment and outcomes in patients with colorectal cancer

Tumour cell anaerobic metabolism has been reported to be a prognostic factor in colorectal cancer. The present study investigated the association between monocarboxylate transporter (MCT) 1, MCT 2, lactate dehydrogenase (LDH) 1 and LDH 5, the tumour microenvironment, and outcome in patients with colorectal cancer. A cohort of 150 patients with stage I-III CRC were utilised to assess tumour cell expression of MCT-1, MCT-2, LDH-1 and LDH-5 by immunohistochemistry. Expression levels were dichotomised and associations with tumour factors, the tumour microenvironment and survival analysed. Nuclear LDH-5 associates with poor prognosis (HR 1.68 95% CI 0.99–2.84, p = 0.050) and trends toward increased tumour stroma percentage (TSP, p = 0.125). Cytoplasmic MCT-2 also trends toward increased TSP (p = 0.081). When combined into a single score; nuclear LDH-5 + TSP significantly associated with decreased survival independent of stage (HR 2.61 95% CI 1.27–5.35, p = 0.009), increased tumour budding (p = 0.002) and decreased stromal T-lymphocytes (p = 0.014). Similarly, cytoplasmic MCT-2 + TSP significantly associated with decreased survival (HR 2.32 95% CI 1.31–4.11, p = 0.003), decreased necrosis (p = 0.039), and increased tumour budding (p = 0.004). The present study reports that the combination of TSP and nuclear LDH-5 was significantly associated with survival, increased tumour budding, and decreased stromal T-lymphocytes. This supports the hypothesis that increased stromal invasion promotes tumour progression via modulation of tumour metabolism. Moreover, MCT-2 and LDH-5 may provide promising therapeutic targets for patients with stromal-rich CRC.