Elaine Holmes

Imperial College London, Londinium, England, United Kingdom

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Publications (283)1621.3 Total impact

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    ABSTRACT: We studied the extent and nature of renal involvement in a cohort of 117 adult patients with mitochondrial disease, by measuring urinary retinol-binding protein (RBP) and albumin; established markers of tubular and glomerular dysfunction, respectively. Seventy-five patients had the m.3243A>G mutation and the most frequent phenotypes within the entire cohort were 14 with MELAS, 33 with MIDD, and 17 with MERRF. Urinary RBP was increased in 29 of 75 of m.3243A>G patients, whereas albumin was increased in 23 of the 75. The corresponding numbers were 16 and 14, respectively, in the 42 non-m.3243A>G patients. RBP and albumin were higher in diabetic m.3243A>G patients than in nondiabetics, but there were no significant differences across the three major clinical phenotypes. The urine proteome (mass spectrometry) and metabonome (nuclear magnetic resonance) in a subset of the m.3243A>G patients were markedly different from controls, with the most significant alterations occurring in lysosomal proteins, calcium-binding proteins, and antioxidant defenses. Differences were also found between asymptomatic m.3243A>G carriers and controls. No patients had an elevated serum creatinine level, but 14% had hyponatremia, 10% had hypophosphatemia, and 14% had hypomagnesemia. Thus, abnormalities in kidney function are common in adults with mitochondrial disease, exist in the absence of elevated serum creatinine, and are not solely explained by diabetes.Kidney International advance online publication, 10 September 2014; doi:10.1038/ki.2014.297.
    Kidney international. 09/2014;
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    ABSTRACT: In this study, we performed gas chromatography time-of-flight mass spectrometry (GC-TOFMS)-based extracellular metabolic profiling on AβPP-transfected CHO cells (CHO-AβPP695) and its wildtype. Orthogonal partial least squares discriminant analysis (OPLS-DA) was then used to identify discriminant metabolites, which gave clues on the effects of AβPP transgene on cellular processes. To confirm the hypotheses generated based on the metabolic data, we performed biochemical assays to gather further evidence to support our findings. The OPLS-DA showed a robust differentiation following 24 h of incubation (Q2(cum) = 0.884) and 15 discriminant metabolites were identified. In contrast, extracellular Aβ42 was identified to increase significantly in CHO-AβPP695 only after incubation for 48 h. The observed 24-h metabolic fluxes were associated with increased mitochondrial AβPP and reduced mitochondrial viabilities, which occurred before extracellular Aβ accumulation. We also investigated the therapeutic potential of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, namely rosiglitazone (RSG) and pioglitazone (PIO), by employing the same approach to characterize the metabolic profiles of CHO-AβPP695 treated with RSG and PIO, with or without their respective receptor blockers. Treatment with PIO was found to reduce the perturbation of the discriminant metabolites in CHO-AβPP695 to a larger extent than treatment with RSG. We also attributed the PIO effects on the lowering of Aβ42, and restoration of mitochondrial activity to PPARγ and PPARα agonism, respectively. Taken together, PIO was demonstrated to be therapeutically superior to RSG. Our findings provide further insights into early disease stages in this AβPP model, and support the advancement of PIO in AD therapy.
    Journal of Alzheimer's disease: JAD 09/2014; · 4.17 Impact Factor
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    ABSTRACT: Proton NMR-based metabolic phenotyping of urine and blood plasma/serum samples provides important prognostic and diagnostic information and permits monitoring of disease progression in an objective manner. Much effort has been made in recent years to develop NMR instrumentation and technology to allow the acquisition of data in an effective, reproducible and high throughput approach that allows the study of general population samples from epidemiological collections for biomarkers of disease risk. The challenge remains to develop highly reproducible methods and standardized protocols that minimise technical or experimental bias, allowing realistic interlaboratory comparisons of subtle biomarker information. Here we present a detailed set of updated protocols that carefully consider major experimental conditions including sample preparation, spectrometer parameters, NMR pulse sequences, throughput, reproducibility, quality control and resolution. These results provide an experimental platform that facilitates NMR spectroscopy usage across different large cohorts of biofluid samples, enabling integration of global metabolic profiling that is a prerequisite for personalized healthcare.
    Analytical chemistry. 09/2014;
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    ABSTRACT: We have investigated the urinary and plasma metabolic phenotype of acute pancreatitis (AP) patients presenting to the emergency room at St. Mary's Hospital London with acute abdominal pain using 1H NMR spectroscopy and multivariate modelling. Patients were allocated to either the AP (n=15) or non-AP patients group (all other causes of abdominal pain, n=21) on the basis of the national guidelines. Patients were assessed for three clinical outcomes: 1) diagnosis of AP; 2) aetiology of AP caused by alcohol consumption and cholelithiasis; and 3) AP severity based on the Glasgow score. Samples from AP patients were characterized by high levels of urinary ketone bodies, glucose, plasma choline and lipid, and relatively low levels of urinary hippurate, creatine and plasma branched chain amino acids. AP could be reliably identified with a high degree of sensitivity and specificity (Q2= 0.76 and R2= 0.59) using panel of discriminatory biomarkers consisting of guanine, hippurate and creatine (urine), and valine, alanine and lipoproteins (plasma). Metabolic phenotyping was also able to distinguish between cholelithiasis and colonic inflammation amongst the heterogeneous non-AP group. This work has demonstrated that combinatorial biomarkers have a strong diagnostic and prognostic potential in AP with relevance to clinical decision making in the emergency unit.
    Journal of Proteome Research 08/2014; · 5.06 Impact Factor
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    ABSTRACT: Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). An NMR spectroscopic based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, 100 mg/kg) in urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whilst the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH were identified, including the elevation of hepatic phenylalanine, urocanate, acetate and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs.
    Toxicological sciences : an official journal of the Society of Toxicology. 08/2014;
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    ABSTRACT: Reasons for performing studyMetabonomics is emerging as a powerful tool for disease screening and investigating mammalian metabolism. This study aims to create a metabolic framework by producing a preliminary reference guide for the normal equine metabolic milieu.Objectives To metabolically profile plasma, urine and faecal water from healthy racehorses using high resolution 1H-NMR spectroscopy and to provide a list of dominant metabolites present in each biofluid for the benefit of future research in this area.Study designThis study was performed using seven Thoroughbreds in race training at a single time-point. Urine and faecal samples were collected non-invasively and plasma was obtained from samples taken for routine clinical chemistry purposes.Methods Biofluids were analysed using 1H-NMR spectroscopy. Metabolite assignment was achieved via a range of 1D and 2D experiments.ResultsA total of 102 metabolites were assigned across the three biological matrices. A core metabonome of 14 metabolites was ubiquitous across all biofluids. All biological matrices provided a unique window on different aspects of systematic metabolism. Urine was the most populated metabolite matrix with 65 identified metabolites, 39 of which were unique to this biological compartment. A number of these were related to gut microbial host co-metabolism. Faecal samples were the most metabolically variable between animals; acetate was responsible for the majority (28%) of this variation. Short chain fatty acids were the predominant features identified within this biofluid by 1H-NMR spectroscopy.Conclusions Metabonomics provides a platform for investigating complex and dynamic interactions between the host and its consortium of gut microbes and has the potential to uncover markers for health and disease in a variety of biofluids. Inherent variation in faecal extracts along with the relative abundance of microbial-mammalian metabolites in urine and invasive nature of plasma sampling, infers that urine is the most appropriate biofluid for the purposes of metabonomic analysis.
    Equine Veterinary Journal 08/2014; · 2.29 Impact Factor
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    ABSTRACT: Breast milk (BM) is a biofluid, which has a fundamental role in early-life nutrition and directly impacts on growth, neurodevelopment and health. Global metabolic profiling is increasingly being utilized to characterize complex metabolic changes in biological samples. However, in order to achieve broad metabolite coverage, it is necessary to employ more than one analytical platform, typically requiring multiple sample preparation protocols. In an effort to improve analytical efficiency and retain comprehensive coverage of the metabolome, a new extraction methodology was developed that successfully retains metabolites from BM in a single-phase using an optimized methyl-tert-butyl ether solvent system. We conducted this single-phase extraction procedure on a representative pool of BM, and characterized the metabolic composition using LC-QTOF-MS and GC-Q-MS for polar and lipidic metabolites. To ensure that the extraction method was reproducible and fit-for-purpose, the analytical procedure was evaluated on both platforms using 18 metabolites selected to cover a range of chromatographic retention times and biochemical classes. Having validated the method, the metabolic signature of BM composition was mapped as a metabolic reaction network highlighting interconnected biological pathways and showing that the LC-MS and GC-MS platforms targeted largely different domains of the network. Subsequently, the same protocol was applied to ascertain compositional differences between BM at week 1 (n=10) and 4 weeks (n=9) post-partum. This single-phase approach is more efficient in terms of time, simplicity, cost and sample volume than the existing two phase methods, and will be suited to high-throughput metabolic profiling studies of BM.
    Analytical chemistry. 07/2014;
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    ABSTRACT: Concomitant infections with Plasmodium and gastrointestinal nematodes are frequently observed in humans. At the metabolic level, the cross-talk between the host and multiple coexisting pathogens is poorly characterized. The purpose of this study was to give a comprehensive insight into the systemic metabolic phenotype of mice with a single or dual infection with Plasmodium berghei and Heligmosomoides bakeri. Four groups of eight NMRI female mice were infected with P. berghei or H. bakeri, or with both species concurrently. An additional group remained uninfected, and served as control. Mice were sacrificed at day 19 of the experiment. We collected samples from the liver, spleen, kidney, three intestinal regions, and four brain regions. All biological samples were subjected to (1)H nuclear magnetic resonance spectroscopy, combined with multivariate data analysis, to establish metabolic fingerprints of each tissue from the various infection groups. Compared to uninfected mice, single and dual species infection models showed unique metabolic profiles. P. berghei exerted major effects on glycolysis, tricarboxylic acid cycle, and nucleotide and amino acid metabolism in all studied tissues with the exception of the gut. H. bakeri was characterized by a dysregulation of choline and lipid metabolism in most tissues examined with a particularly strong imprint in the jejunum. Simultaneous co-infection with P. berghei and H. bakeri induced the strongest and most diverse effects in the liver and spleen but led to only minor changes in the intestinal and cerebral parts assessed. Infection with P. berghei showed more pronounced and systemic alterations in the mice metabolic profile than H. bakeri infection. The metabolic fingerprints in the co-infection models were driven by P. berghei infection, whilst the presence of H. bakeri in co-infections had little effect. However, simultaneous co-infection showed indeed the least metabolic disruptions in the peripheral tissues, namely the gut and brain.
    Molecular BioSystems 06/2014; · 3.35 Impact Factor
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    ABSTRACT: There is no clinically applicable biomarker for surveillance of hepatocellular carcinoma (HCC), as the sensitivity of serum α-fetoprotein (AFP), is too low for this purpose. Here, we determined the diagnostic performance of a panel of urinary metabolites of HCC patients from West Africa. Urine samples were collected from Nigerian and Gambian patients recruited on the case-control platform of the "Prevention of Liver Fibrosis and Cancer in Africa" (PROLIFICA) program. Urinary proton nuclear magnetic resonance ((1) H NMR) spectroscopy was used to metabolically phenotype 290 subjects: 63 with HCC, 32 with cirrhosis (Cir), 107 with non-cirrhotic liver disease (DC) and 88 healthy volunteers (NC). Urine samples from a further cohort, 463 subjects: (141 HCC, 56 Cir, 178 DC and 88 NC) were analysed and the results of which validated the initial cohort. The urinary metabotype of patients with HCC was distinct from those with Cir, DC and NC with areas under the receiver operating characteristic (ROC) curves of 0.86(0.78-0.94), 0.93(0.89-0.97) and 0.89(0.80-0.98) in the training set; and 0.81(0.73-0.89), 0.96(0.94-0.99) and 0.90(0.85-0.96) respectively in the validation cohort. A urinary metabolite panel, comprising: inosine, indole-3-acetate, galactose and an N-acetylated amino acid (NAA) showed a high sensitivity [86.9% (75.8 - 94.2)] and specificity [90.3% (74.2 - 98.0)] in the discrimination of HCC from cirrhosis, a finding that was corroborated in a validation cohort (ROC: urinary panel=0.72; AFP=0.58). Metabolites that were significantly increased in urine of HCC patients, and which correlated with clinical stage of HCC were NAA, dimethylglycine, 1-methylnicotinamide, methionine, acetylcarnitine, 2-oxoglutarate, choline, and creatine. Conclusion: The urinary metabotyping of this West African cohort identified and validated a metabolite panel which diagnostically outperforms serum AFP. (Hepatology 2014;).
    Hepatology 06/2014; · 12.00 Impact Factor
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    ABSTRACT: Exploratory or untargeted Ultra-High Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) profiling offers an overview of the complex lipid species diversity present in blood plasma. Here, we evaluate and compare eight sample preparation protocols for optimized blood plasma lipid extraction and measurement by UPLC-MS lipid profiling, including four protein precipitation methods (i.e., methanol, acetonitrile, isopropanol and isopropanol-acetonitrile) and four liquid-liquid extractions (i.e., methanol combined with chloroform; dichloromethane and methyl-tert butyl ether and isopropanol with hexane). The eight methods were then benchmarked using a set of qualitative and quantitative criteria selected to warrant compliance with high-throughput analytical workflows: removal efficiency, selectivity, repeatability and recovery efficiency of the sample preparation. We found that protein removal was more efficient by precipitation (99%) than extraction (95%). Additionally, isopropanol appeared to be the most straightforward and robust solvent (61.1% of features with CV < 20 %) whilst enabling a broad coverage and recovery of plasma lipid species. These results demonstrate that isopropanol precipitation is an excellent sample preparation procedure for high-throughput untargeted lipid profiling using UPLC-MS. Isopropanol precipitation is not limited to untargeted profiling and could also be of interest for targeted UPLC-MS/MS lipid analysis. Collectively, these data show that lipid profiling greatly benefits from an isopropanol precipitation in terms of simplicity, protein removal efficiency, repeatability, lipid recovery and coverage.
    Analytical Chemistry 05/2014; · 5.70 Impact Factor
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    ABSTRACT: We propose a novel statistical approach to improve the reliability of 1H NMR spectral analysis in complex metabolic studies. The Statistical HOmogeneous Cluster SpectroscopY (SHOCSY) algorithm aims to reduce the variation within biological classes by selecting subsets of homogenous 1H NMR spectra that contain specific spectroscopic metabolic signatures related to each biological class in a study. In SHOCSY, we used a clustering method to categorize the whole dataset into a number of clusters of samples with each cluster showing a similar spectral feature and hence biochemical composition, and then used an enrichment test to identify the associations between the clusters and the biological classes in the dataset. We evaluated the performance of the SHOCSY algorithm using a simulated 1H NMR dataset to emulate renal tubules toxicity and further exemplified this method with a 1H NMR spectroscopic study of hydrazine-induced liver toxicity study in rats. The SHOCSY algorithm improved the predictive ability of the orthogonal partial least square discriminatory analysis (OPLS-DA) model through the use of 'truly' representative samples in each biological class (i.e. homogenous subsets). This method ensures that the analyses are no longer confounded by idiosyncratic responders and thus improves the reliability of biomarker extraction. SHOCSY is a useful tool for removing irrelevant variation that interfere with the interpretation and predictive ability of models and has widespread applicability to other spectroscopic data as well as other 'omics' type of data.
    Analytical Chemistry 04/2014; · 5.70 Impact Factor
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    ABSTRACT: Background In renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to renal losses of water, electrolytes, and low-molecular-weight nutrients. For most types of isolated Fanconi's syndrome, the genetic cause and underlying defect remain unknown. Methods We clinically and genetically characterized members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome. We performed genomewide linkage analysis, gene sequencing, biochemical and cell-biologic investigations of renal proximal tubular cells, studies in knockout mice, and functional evaluations of mitochondria. Urine was studied with the use of proton nuclear magnetic resonance ((1)H-NMR) spectroscopy. Results We linked the phenotype of this family's Fanconi's syndrome to a single locus on chromosome 3q27, where a heterozygous missense mutation in EHHADH segregated with the disease. The p.E3K mutation created a new mitochondrial targeting motif in the N-terminal portion of EHHADH, an enzyme that is involved in peroxisomal oxidation of fatty acids and is expressed in the proximal tubule. Immunocytofluorescence studies showed mistargeting of the mutant EHHADH to mitochondria. Studies of proximal tubular cells revealed impaired mitochondrial oxidative phosphorylation and defects in the transport of fluids and a glucose analogue across the epithelium. (1)H-NMR spectroscopy showed elevated levels of mitochondrial metabolites in urine from affected family members. Ehhadh knockout mice showed no abnormalities in renal tubular cells, a finding that indicates a dominant negative nature of the mutation rather than haploinsufficiency. Conclusions Mistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi's syndrome; this indicates a central role of mitochondria in proximal tubular function. The dominant negative effect of the mistargeted protein adds to the spectrum of monogenic mechanisms of Fanconi's syndrome. (Funded by the European Commission Seventh Framework Programme and others.).
    New England Journal of Medicine 01/2014; 370(2):129-138. · 51.66 Impact Factor
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    ABSTRACT: Mass spectrometry imaging (MSI) provides the opportunity to investigate tumor biology from an entirely novel biochemical perspective and could lead to the identification of a new pool of cancer biomarkers. Effective clinical translation of histology-driven MSI in systems oncology requires precise colocalization of morphological and biochemical features as well as advanced methods for data treatment and interrogation. Currently proposed MSI workflows are subject to several limitations, including nonoptimized raw data preprocessing, imprecise image coregistration, and limited pattern recognition capabilities. Here we outline a comprehensive strategy for histology-driven MSI, using desorption electrospray ionization that covers (i) optimized data preprocessing for improved information recovery; (ii) precise image coregistration; and (iii) efficient extraction of tissue-specific molecular ion signatures for enhanced biochemical distinction of different tissue types. The proposed workflow has been used to investigate region-specific lipid signatures in colorectal cancer tissue. Unique lipid patterns were observed using this approach according to tissue type, and a tissue recognition system using multivariate molecular ion patterns allowed highly accurate (>98%) identification of pixels according to morphology (cancer, healthy mucosa, smooth muscle, and microvasculature). This strategy offers unique insights into tumor microenvironmental biochemistry and should facilitate compilation of a large-scale tissue morphology-specific MSI spectral database with which to pursue next-generation, fully automated histological approaches.
    Proceedings of the National Academy of Sciences 01/2014; · 9.81 Impact Factor
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    ABSTRACT: Preterm birth (PB) and fetal growth restriction (FGR) convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. Identifying early in pregnancy the unfavourable maternal conditions that can predict poor birth outcomes could help their prevention and management. Here we used an exploratory metabolic profiling approach (metabolomics) to investigate the association between birth outcomes and metabolites in maternal urine collected early in pregnancy as part of the prospective mother-child cohort Rhea study. Metabolomic techniques can simultaneously capture information about genotype and its interaction with the accumulated exposures experienced by an individual from their diet, environment, physical activity or disease (the exposome). As metabolic syndrome has previously been shown to be associated with PB in this cohort, we sought to gain further insight into PB-linked metabolic phenotypes and to define new predictive biomarkers.
    BMC medicine. 01/2014; 12:110.
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    ABSTRACT: Bariatric procedures such as the Roux-en-Y gastric bypass (RYGB) operation offer profound metabolic enhancement in addition to their well-recognized weight loss effects. They are associated with significant reduction in cardiovascular disease risk and mortality, which suggests a surgical modification on cardiac metabolism. Metabolic phenotyping of the cardiac tissue and plasma postsurgery may give insight into cardioprotective mechanisms. The aim of the study was to compare the metabolic profiles of plasma and heart tissue extracts from RYGB- and sham-operated Wistar rats to identify the systemic and cardiac signature of metabolic surgery. A total of 27 male Wistar rats were housed individually for a week and subsequently underwent RYGB (n = 13) or sham (n = 14) operation. At week 8 postoperation, a total of 27 plasma samples and 16 heart tissue samples (8 RYGB; 8 Sham) were collected from animals and analyzed using (1)H nuclear magnetic resonance (NMR) spectroscopy and ultra performance liquid chromatography (UPLC-MS) to characterize the global metabolite perturbation induced by RYGB operation. Plasma bile acids, phosphocholines, amino acids, energy-related metabolites, nucleosides and amine metabolites, and cardiac glycogen and amino acids were found to be altered in the RYGB operated group. Correlation networks were used to identify metabolite association. The metabolic phenotype of this bariatric surgical model inferred systematic change in both myocardial and systemic activity post surgery. The altered metabolic profile following bariatric surgery reflects an enhancement of cardiac energy metabolism through TCA cycle intermediates, cardiorenal protective activity, and biochemical caloric restriction. These surgically induced metabolic shifts identify some of the potential mechanisms that contribute toward bariatric cardioprotection through gut microbiota ecological fluxes and an enterocardiac axis to shield against metabolic syndrome of cardiac dysfunction.
    Journal of Proteome Research 11/2013; · 5.06 Impact Factor
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    ABSTRACT: MetaboNetworks is a tool to create custom sub-networks in Matlab using main reaction pairs as defined by the Kyoto Encyclopaedia of Genes and Genomes (KEGG) and can be used to explore transgenomic interactions, for example mammalian and bacterial associations. It calculates the shortest path between a set of metabolites (e.g. biomarkers from a metabonomic study) and plots the connectivity between metabolites as links in a network graph. The resulting graph can be edited and explored interactively. Furthermore, nodes and edges in the graph are linked to the KEGG compound and reaction pair webpages.Availability and Implementation: MetaboNetworks is available from http://www.mathworks.com/matlabcentral/fileexchange/42684. jmp111@ic.ac.uk and j.nicholson@imperial.ac.uk. Supplementary data are available at Bioinformatics online.
    Bioinformatics 10/2013; · 5.47 Impact Factor
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    ABSTRACT: The NMRI outbred mouse model is widely used for studying metabolic disease, toxicity, and infection, yet information regarding baseline metabolism of this murine strain is relatively sparse. Using different batches of female NMRI mice, we assessed the stability of the metabolic phenotype with increasing age and weight, and determined the influence of acclimatization on the metabolic profile of biofluids (urine, plasma, and faecal water). Differences in urinary concentrations of 3-ureidopropionate, 2-oxoisocaproate, trimethylamine, and glycine were detected between three batches of 9-week-old female NMRI mice using proton nuclear magnetic resonance ((1)H NMR) spectroscopy coupled with multivariate statistical analysis. An acclimatization period of 2 weeks was imposed after the mice entered the laboratory environment. Strong differences in the faecal metabolome pre- and post-acclimatization were found (reduction in amino acid concentrations), whilst the urine metabolome showed increased levels of trimethylamine-N-oxide, phenylacetyl glycine, and hippurate with decreased excretion of formate and betaine post-acclimatization. Temporal variation in the metabolite profiles over a 16-week study stabilized around 7-week-old animals. The results from this study strongly argue for inclusion of an acclimatization period prior to starting an investigative procedure, and suggest that the metabolic phenotypes of female NMRI mice are more stable at around 7 weeks of age. We have also identified a set of metabolites that are more susceptible to variation in concentration. This information can serve as a benchmark in order to establish confidence in systematic variation attributable to pathology or therapeutic intervention above the background metabolic variation in the NMRI mouse.
    Molecular BioSystems 10/2013; · 3.35 Impact Factor
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    ABSTRACT: Black compared with non-Hispanic white Americans have higher systolic and diastolic blood pressure and rates of prehypertension/hypertension. Reasons for these adverse findings remain obscure. Analyses here focused on relations of foods/nutrients/urinary metabolites and higher black blood pressure for 369 black compared with 1190 non-Hispanic white Americans aged 40 to 59 years from 8 population samples. Multiple linear regression, standardized data from four 24-hour dietary recalls per person, two 24-hour urine collections, and 8 blood pressure measurements were used to quantitate the role of foods, nutrients, and metabolites in higher black blood pressure. Compared with non-Hispanic white Americans, blacks' average systolic/diastolic pressure was higher by 4.7/3.4 mm Hg (men) and 9.0/4.8 mm Hg (women). Control for higher body mass index of black women reduced excess black systolic/diastolic pressure to 6.8/3.8 mm Hg. Lesser intake of vegetables, fruits, grains, vegetable protein, glutamic acid, starch, fiber, minerals, and potassium, and higher intake of processed meats, pork, eggs, and sugar-sweetened beverages, along with higher cholesterol and higher Na/K ratio, related to in higher black blood pressure. Control for 11 nutrient and 10 non-nutrient correlates reduced higher black systolic/diastolic pressure to 2.3/2.3 mm Hg (52% and 33% reduction in men) and to 5.3/2.8 mm Hg (21% and 27% reduction in women). Control for foods/urinary metabolites had little further influence on higher black blood pressure. Less favorable multiple nutrient intake by blacks than non-Hispanic white Americans accounted, at least in part, for higher black blood pressure. Improved dietary patterns can contribute to prevention/control of more adverse black blood pressure levels.
    Hypertension 10/2013; · 6.87 Impact Factor
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    ABSTRACT: To develop novel metabolite-based models for diagnosis and staging in colorectal cancer (CRC) using high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy. Previous studies have demonstrated that cancer cells harbor unique metabolic characteristics relative to healthy counterparts. This study sought to characterize metabolic properties in CRC using HR-MAS NMR spectroscopy. Between November 2010 and January 2012, 44 consecutive patients with confirmed CRC were recruited to a prospective observational study. Fresh tissue samples were obtained from center of tumor and 5 cm from tumor margin from surgical resection specimens. Samples were run in duplicate where tissue volume permitted to compensate for anticipated sample heterogeneity. Samples were subjected to HR-MAS NMR spectroscopic profiling and acquired spectral data were imported into SIMCA and MATLAB statistical software packages for unsupervised and supervised multivariate analysis. A total of 171 spectra were acquired (center of tumor, n = 88; 5 cm from tumor margin, n = 83). Cancer tissue contained significantly increased levels of lactate (P < 0.005), taurine (P < 0.005), and isoglutamine (P < 0.005) and decreased levels of lipids/triglycerides (P < 0.005) relative to healthy mucosa (RY = 0.94; QY = 0.72; area under the curve, 0.98). Colon cancer samples (n = 49) contained higher levels of acetate (P < 0.005) and arginine (P < 0.005) and lower levels of lactate (P < 0.005) relative to rectal cancer samples (n = 39). In addition unique metabolic profiles were observed for tumors of differing T-stage. HR-MAS NMR profiling demonstrates cancer-specific metabolic signatures in CRC and reveals metabolic differences between colonic and rectal cancers. In addition, this approach reveals that tumor metabolism undergoes modification during local tumor advancement, offering potential in future staging and therapeutic approaches.
    Annals of surgery 07/2013; · 7.90 Impact Factor

Publication Stats

13k Citations
1,621.30 Total Impact Points

Institutions

  • 2001–2014
    • Imperial College London
      • • Department of Surgery and Cancer
      • • Section of Computational and Systems Medicine (CSM)
      • • Faculty of Medicine
      Londinium, England, United Kingdom
  • 2007–2013
    • University of Cambridge
      • Department of Chemical Engineering and Biotechnology
      Cambridge, ENG, United Kingdom
  • 2012
    • Shanghai Jiao Tong University
      • School of Life Science and Biotechnology
      Shanghai, Shanghai Shi, China
    • Medway School Of Pharmacy
      Чатем, England, United Kingdom
  • 2008–2010
    • Northeast Institute of Geography and Agroecology
      • • Laboratory of Magnetic Resonance and Atomic and Molecular Physics
      • • Partner Institute for Computational Biology
      Beijing, Beijing Shi, China
    • Umeå University
      • Department of Chemistry
      Umeå, Vaesterbotten, Sweden
  • 2009
    • Wuhan Institute of Physics and Mathematics
      Wu-han-shih, Hubei, China
    • University of Aveiro
      • Department of Chemistry
      Aveiro, Aveiro, Portugal
    • Nestlé S.A.
      Vevey, Vaud, Switzerland
  • 2008–2009
    • Semmelweis University
      • Department of Pharmaceutical Chemistry
      Budapest, Budapest fovaros, Hungary
  • 2004–2009
    • Swiss Tropical and Public Health Institute
      • Department of Epidemiology and Public Health
      Basel, BS, Switzerland
    • SCYNEXIS, Inc.
      Durham, North Carolina, United States
  • 2000–2003
    • University of London
      Londinium, England, United Kingdom