Alisdair J MacDonald

The University of Edinburgh, Edinburgh, Scotland, United Kingdom

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Publications (17)37.42 Total impact

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    ABSTRACT: Purpose: Skeletal muscle wasting and weight loss are characteristic features of cancer cachexia and contribute to impaired function, increased morbidity and poor tolerance of chemotherapy. This study used a novel technique to measure habitual myofibrillar protein synthesis in cancer patients compared with healthy controls. Experimental design: An oral heavy water (87.5g deuterium oxide) tracer was administered as a single dose. Serum samples were taken over the subsequent week followed by a quadriceps muscle biopsy. Deuterium enrichment was measured in body water, serum alanine and alanine in the myofibrillar component of muscle using Gas Chromatography-Pyrolysis-Isotope Ratio Mass Spectrometry and the protein synthesis rate calculated from the rate of tracer incorporation. Net change in muscle mass over the preceding 3 months was calculated from serial CT scans and allowed estimation of protein breakdown. Results: 7 healthy volunteers, 6 weight-stable and 7 weight-losing (≥5% weight loss) patients undergoing surgery for upper GI cancer were recruited. Serial CT scans were available in 10 patients, who lost skeletal muscle mass preoperatively at a rate of 5.6%/100d. Myofibrillar protein fractional synthetic rate was 0.058, 0.061 and 0.073 %/h in controls, weight-stable and weight-losing patients respectively. Weight-losing patients had higher synthetic rates than controls (p=0.03). Conclusion: Contrary to previous studies, there was no evidence of suppression of myofibrillar protein synthesis in patients with cancer cachexia. Our finding implies a small increase in muscle breakdown may account for muscle wasting.
    Clinical Cancer Research 11/2014; · 8.19 Impact Factor
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    ABSTRACT: The aim of this study was to test the safety, tolerability and efficacy of a novel combination of an anabolic β2-agonist and an appetite stimulant in patients with cancer cachexia. Thirteen patients (M/F 5:8) with advanced malignancy and involuntary weight loss received oral formoterol (80 μg/day) and megestrol acetate (480 mg/day) for up to 8 weeks. Quadriceps size (MRI), quadriceps and hand-grip strength, lower limb extensor power, physical activity and quality of life were measured at baseline and at 8 weeks. Response criteria were specified pre-trial, with a major response defined as an increase in muscle size ≥4 % or function ≥10 %. Six patients withdrew before 8 weeks, reflecting the frail, comorbid population. In contrast, six out of seven (86 %) patients completing the course achieved a major response for muscle size and/or function. In the six responders, mean quadriceps volume increased significantly (left 0.99 vs. 1.05 L, p = 0.012; right 1.02 vs. 1.06 L, p = 0.004). There was a trend towards an increase in quadriceps and handgrip strength (p > 0.05). The lack of appetite symptom score declined markedly (76.2 vs. 23.8; p = 0.005), indicating improvement. Adverse reactions were few, the commonest being tremor (eight reports), peripheral oedema (three), tachycardia (two) and dyspepsia (two). In this frail cohort with advanced cancer cachexia, an 8-week course of megestrol and formoterol in combination was safe and well tolerated. Muscle mass and/or function were improved to a clinically significant extent in most patients completing the course. This combination regimen warrants further investigation in larger, randomized trials.
    Supportive Care in Cancer 01/2014; · 2.09 Impact Factor
  • Clinical Nutrition Supplements 09/2013; 32(1):53.
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    ABSTRACT: Conventionally, myofibrillar protein synthesis is measured over time periods of hours. In clinical studies, interventions occur over weeks. Functional measures over such periods may be more representative. We aimed to develop a novel method to determine myofibrillar protein fractional synthetic rate (FSR) to estimate habitual rates, while avoiding intravenous tracer infusions. Four healthy males were given 100 g water enriched to 70 Atom % with (2) H2 O as a single oral bolus. Vastus-lateralis needle biopsies were performed and plasma samples collected, 3-13 days post-dose. (2) H enrichment in body water was measured in plasma using continuous flow isotope ratio mass spectrometry (IRMS). Myofibrillar protein was isolated from muscle biopsies and acid hydrolysed. (2) H enrichment of protein-bound and plasma-free alanine was measured by gas chromatography (GC)/pyrolysis/IRMS. Myofibrillar protein FSR was calculated (% day(-1) ). The tracer bolus raised the initial enrichment of body water to 1514 ppm (2) H excess. Water elimination followed a simple exponential. The average elimination half-time was 8.3 days. Plasma alanine, labelled during de novo synthesis, followed the same elimination kinetics as water. The weighted average myofibrillar protein FSR from the four subjects was 1.38 % day(-1) (range, 1.0-1.9 % day(-1) ). Myofibrillar protein FSR was measured in free-living healthy individuals over 3-13 days. Using a single oral (2) H2 O bolus, endogenous labelling of alanine occurred in a predictable manner giving estimates of synthesis comparable with published values. Furthermore, the protocol does not compromise the ability to measure other important metabolic processes such as total energy expenditure. Copyright © 2013 John Wiley & Sons, Ltd.
    Rapid Communications in Mass Spectrometry 08/2013; 27(15):1769-1777. · 2.51 Impact Factor
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    ABSTRACT: The mechanisms underlying muscle wasting in patients with cancer remain poorly understood, and consequently there remains an unmet clinical need for new biomarkers and treatment strategies. Microarrays were used to examine the transcriptome in single biopsies from healthy controls (n = 6) and in paired biopsies [pre-resection baseline (weight-loss 7%) and 8 month post-resection follow-up (disease-free/weight-stable for previous 2 months)] from quadriceps muscle of patients with upper gastrointestinal cancer (UGIC; n = 12). Before surgery, 1,868 genes were regulated compared with follow-up (false discovery rate, 6%). Ontology analysis showed that regulated genes belonged to both anabolic and catabolic biologic processes with overwhelming downregulation in baseline samples. No literature-derived genes from preclinical cancer cachexia models showed higher expression in baseline muscle. Comparison with healthy control muscle (n = 6) revealed that despite differences in the transcriptome at baseline (941 genes regulated), the muscle of patients at follow-up was similar to control muscle (2 genes regulated). Physical activity (step count per day) did not differ between the baseline and follow-up periods (P = 0.9), indicating that gene expression differences reflected the removal of the cancer rather than altered physical activity levels. Comparative gene expression analysis using exercise training signatures supported this interpretation. Metabolic and protein turnover-related pathways are suppressed in weight-losing patients with UGIC whereas removal of the cancer appears to facilitate a return to a healthy state, independent of changes in the level of physical activity.
    Clinical Cancer Research 03/2012; 18(10):2817-27. · 8.19 Impact Factor
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    ABSTRACT: There is a sparsity of data on the impact of cachexia on human muscle function. This study examined the relationship between cachexia, quality of life and the mass/function/mechanical quality of lower limb skeletal muscle in gastrointestinal cancer patients. Quadriceps strength and lower limb power were measured in 54 patients with gastrointestinal cancer (n = 24 ≥ 10% weight-loss) and 18 healthy controls. Quadriceps cross-sectional area was measured in 33/54 patients and in all controls using MRI. Muscle mechanical quality was defined as quadriceps strength/unit quadriceps cross-sectional area. Quality of life was assessed using the EORTC QLQ-C30. Patients with weight-loss ≥ 10% were classified as cachectic. In male cachectic patients, quadriceps strength (p = 0.003), lower limb power (p = 0.026), quadriceps cross-sectional area (p = 0.019) and muscle quality (p = 0.008) were reduced compared with controls. In female cachectic patients, quadriceps strength (p = 0.001) and muscle quality (p = 0.001) were reduced compared with controls. Physical function (p = 0.013) and fatigue (p = 0.004) quality of life scores were reduced in male cachectic compared with non-cachectic patients, but not in females. Muscle quality is reduced in cancer patients. The degree of impairment of lower limb muscle mass, quality and function and the impact on quality of life varies with weight-loss and sex.
    Clinical nutrition (Edinburgh, Scotland) 01/2012; 31(4):499-505. · 3.27 Impact Factor
  • Clinical Nutrition 01/2012; · 3.94 Impact Factor
  • Alisdair J MacDonald, Carolyn A Greig, Vickie Baracos
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    ABSTRACT: Cross-sectional (C-S) imaging is now commonly used to measure body composition in clinical studies. This review highlights the advantages, limitations and suggested future directions for this technique. Current understanding of C-S imaging reproducibility, tissue identification and segmentation methods, comparison between imaging techniques and estimates of whole body composition using a single image are described. C-S imaging can reliably measure muscle and fat distribution and uniquely discriminate between intra-abdominal organ and muscle component of fat-free mass. It precisely tracks changes within an individual, but is less able to distinguish true differences in whole body estimates between individuals.
    Current opinion in supportive and palliative care 12/2011; 5(4):342-9.
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    ABSTRACT: We have investigated the use of human urine as a non-invasive medium to screen for molecular biomarkers of carcinomas of the upper gastrointestinal (uGI) tract using SELDI-TOF-MS. A total of 120 urine specimens from 60 control and 60 uGI cancer patients were analysed to establish a potential biomarker fingerprint for the weak cation exchanger CM10 chip surface, which was validated by blind testing using a further 59 samples from 33 control and 26 uGI cancer patients. Using Biomarker Pattern software, we established a model with a sensitivity of 98% and specificity of 95% for the learning sample set, and a sensitivity of 96% and specificity of 72% for the validation data set. Model variable importance included six peptides with m/z of 10,230, 10,436, 10,574, 10,311, 10,467, and 10,118 of which the 10, 230 molecular species was the main decider (sensitivity 86% and specificity 80%). Initial protein database searching identified 10,230 as S100-A6, 10,436 as S100-P, 10,467 as S100-A9, and 10,574 as S100-A12 of which S100-A6 and S100-A9 were confirmed by Western blotting. We have demonstrated that SELDI-TOF-MS as a screening tool is a rapid and valid methodology in the search for urinary cancer biomarkers, and is potentially useful in defining and consolidating biomarker patterns for uGI cancer screening.
    PROTEOMICS - CLINICAL APPLICATIONS 06/2011; 5(5-6):289-99. · 1.81 Impact Factor
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    ABSTRACT: BACKGROUND: Intramyocellular lipids are an important source of fuel for mitochondrial fat oxidation and play an important role in intramuscular lipid homeostasis. We hypothesised that due to the phenotype associated with cancer cachexia, there would exist an association between increasing weight loss and the number/size of intramyocellular lipid droplets. METHODS: Nineteen cancer patients and 6 controls undergoing surgery were recruited. A rectus abdominis biopsy was performed and processed for transmission electron microscopy (TEM). The number of intramyocellular lipid droplets and lipid droplet diameter were calculated from the TEM images. CT scans, performed as part of patients' routine care, were analysed to determine amount of adipose (intermuscular, visceral and subcutaneous) and muscle tissue. RESULTS: Compared with controls, cancer patients had increased numbers of lipid droplets (mean (SD) 1.8 (1.9) vs. 6.4 (9.1) per ×2,650 field, respectively, p = 0.036). Mean (SD) lipid droplet diameter was also higher in cancer patients compared with controls (0.42 (0.13) vs. 0.24 (0.21) μm, p = 0.015). Mean lipid droplet count correlated positively with the severity of weight loss (R = 0.51, p = 0.025) and negatively with CT-derived measures of intermuscular fat (R = -0.53, p = 0.022) and visceral fat (R = -0.51, p = 0.029). CONCLUSIONS: This study suggests that the number and size of intramyocellular lipid droplets is increased in the presence of cancer and increases further with weight loss/loss of adipose mass in other body compartments.
    Journal of Cachexia, Sarcopenia and Muscle 06/2011; 2(2):111-117. · 7.41 Impact Factor
  • Clinical Nutrition Supplements 01/2011; 6(1):41-42.
  • Clinical Nutrition Supplements 01/2011; 6(1):42-42.
  • Clinical Nutrition Supplements 01/2011; 6(1):141-141.
  • Clinical Nutrition Supplements 01/2011; 6(1):42-42.
  • Clinical Nutrition Supplements 01/2011; 6(1):141-141.
  • Clinical Nutrition Supplements 01/2011; 6(1):142-142.
  • Clinical Nutrition Supplements.