Elaine Holmes

Imperial College London, Londinium, England, United Kingdom

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Publications (314)1890.07 Total impact

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    ABSTRACT: Inflammation and metabolism are closely interlinked. Both undergo significant dysregulation following surgery for congenital heart disease, contributing to organ failure and morbidity. In this study, we combined cytokine and metabolic profiling to examine the effect of postoperative tight glycemic control compared with conventional blood glucose management on metabolic and inflammatory outcomes in children undergoing congenital heart surgery. The aim was to evaluate changes in key metabolites following congenital heart surgery and to examine the potential of metabolic profiling for stratifying patients in terms of expected clinical outcomes. Laboratory and clinical study. University Hospital and Laboratory. Of 28 children undergoing surgery for congenital heart disease, 15 underwent tight glycemic control postoperatively and 13 were treated conventionally. Metabolic profiling of blood plasma was undertaken using proton nuclear magnetic resonance spectroscopy. A panel of metabolites was measured using a curve-fitting algorithm. Inflammatory cytokines were measured by enzyme-linked immunosorbent assay. The data were assessed with respect to clinical markers of disease severity (Risk Adjusted Congenital heart surgery score-1, Pediatric Logistic Organ Dysfunction, inotrope score, duration of ventilation and pediatric ICU-free days). Changes in metabolic and inflammatory profiles were seen over the time course from surgery to recovery, compared with the preoperative state. Tight glycemic control did not significantly alter the response profile. We identified eight metabolites (3-D-hydroxybutyrate, acetone, acetoacetate, citrate, lactate, creatine, creatinine, and alanine) associated with surgical and disease severity. The strength of proinflammatory response, particularly interleukin-8 and interleukin-6 concentrations, inversely correlated with PICU-free days at 28 days. The interleukin-6/interleukin-10 ratio directly correlated with plasma lactate. This is the first report on the metabolic response to cardiac surgery in children. Using nuclear magnetic resonance to monitor the patient journey, we identified metabolites whose concentrations and trajectory appeared to be associated with clinical outcome. Metabolic profiling could be useful for patient stratification and directing investigations of clinical interventions.
    Critical care medicine 04/2015; DOI:10.1097/CCM.0000000000000982 · 6.15 Impact Factor
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    ABSTRACT: Tenofovir disoproxil fumarate (TDF) is an antiretroviral drug used for the treatment of Human Immunodeficiency Virus and Hepatitis B infections. A metabolite that has previously not been observed in the circulation of humans was detected by LC-MS/MS in early time point plasma samples following administration of TDF to healthy volunteers. The metabolite was identified using a range of LC-MS/MS-based techniques as a monoester of TDF, derived from the partially hydrolyzed bis-ester prodrug. TDF, when spiked into plasma, was observed to degrade first to the putative monoester and subsequently to tenofovir. The presence of this unstable metabolite in some samples has implications for sample collection, handling and storage in studies of tenofovir where serum concentrations are determined.
    Bioanalysis 04/2015; 7(6):643-652. DOI:10.4155/bio.14.300 · 3.03 Impact Factor
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    ABSTRACT: The composition and structure of the pregnancy vaginal microbiome may influence susceptibility to adverse pregnancy outcomes. Studies on the pregnant vaginal microbiome have largely been limited to Northern American populations. Using MiSeq sequencing of 16S rRNA gene amplicons, we characterised the vaginal microbiota of a mixed British cohort of women (n = 42) who experienced uncomplicated term delivery and who were sampled longitudinally throughout pregnancy (8-12, 20-22, 28-30 and 34-36 weeks gestation) and 6 weeks postpartum. We show that vaginal microbiome composition dramatically changes postpartum to become less Lactobacillus spp. dominant with increased alpha-diversity irrespective of the community structure during pregnancy and independent of ethnicity. While the pregnancy vaginal microbiome was characteristically dominated by Lactobacillus spp. and low alpha-diversity, unlike Northern American populations, a significant number of pregnant women this British population had a L. jensenii-dominated microbiome characterised by low alpha-diversity. L. jensenii was predominantly observed in women of Asian and Caucasian ethnicity whereas L. gasseri was absent in samples from Black women. This study reveals new insights into biogeographical and ethnic effects upon the pregnancy and postpartum vaginal microbiome and has important implications for future studies exploring relationships between the vaginal microbiome, host health and pregnancy outcomes.
    Scientific Reports 03/2015; 5:8988. DOI:10.1038/srep08988 · 5.08 Impact Factor
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    ABSTRACT: Metabolic profiling studies aim towards global metabolome coverage of the examined biological systems. However, wide metabolome coverage has proven difficult to achieve, mostly due to the diverse physicochemical properties of small molecules, obligating analysts to seek multi-platform and multi-method approaches. Challenges are even greater when it comes to applications on tissue samples, where tissue lysis and metabolite extraction can induce significant systematic variation. We develop a pipeline for obtaining the aqueous and organic compounds from diseased arterial tissue using two consecutive extractions and followed by a different untargeted UPLC-MS analysis method, for each extract. Methods were rationally chosen and optimized to address the different physicochemical properties of each extract: hydrophilic interaction liquid chromatography (HILIC) for the aqueous extract and reversed-phase for the organic. This pipeline can be generic for tissue analysis as demonstrated by applications on different tissue types. The experimental set-up and fast turnaround time of the two methods contributed towards obtaining highly reproducible features with exceptional chromatographic performance (CV %< 0.5%), making this pipeline suitable for metabolic profiling applications. We structurally assigned 226 metabolites from a range of chemical classes (e.g. carnitines, α-amino acids, purines, pyrimidines, phospholipids, sphingolipids, free fatty acids and glycerolipids) which were mapped to their corresponding pathways, biological functions and known disease mechanisms. The combination of the two untargeted UPLC-MS methods showed high metabolite complementarity. We demonstrate the application of this pipeline to cardiovascular disease, where we show that the analyzed diseased groups (n=120) of arterial tissue could be distinguished based on their metabolic profiles.
    Analytical Chemistry 02/2015; DOI:10.1021/ac503775m · 5.83 Impact Factor
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    ABSTRACT: Current optimum medical treatments have had limited success in the primary prevention of cardiovascular events underscoring the need for new pharmaceutical targets and enhanced understanding of mechanistic metabolic dysregulation. Here, we use a combination of novel metabolic profiling methodologies, based on ultra performance liquid chromatography coupled to mass spectrometry (UPLC-MS), followed by chemometric modeling, data integration and pathway mapping, to create a systems level metabolic atlas of atherogenesis. We apply this workflow to compare arterial tissue incorporating plaque lesions to intimal thickening tissue (immediate pre-plaque stage). We find changes in several metabolite species consistent with well-established pathways in atherosclerosis, such as the cholesterol, purine, pyrimidine, and ceramide pathways. We then illustrate differential levels of previously unassociated lipids to atherogenesis, namely phosphatidylethanolamine-ceramides (t-test p-values: 3.8x10(-6)-9.8x10(-12)). Most importantly, these molecules appear to be interfacing two pathways recognized for their involvement in atherosclerosis: ceramide and cholesterol. Furthermore, we show that β-oxidation intermediates (i.e. acylcarnitines) manifest a pattern indicating truncation of the process and overall dysregulation of fatty acid metabolism and mitochondrial dysfunction. We develop a metabolic framework which offers the ability of mapping significant statistical associations between detected biomarkers. These dysregulated molecules and consequent pathway modulations may provide novel targets for pharmacotherapeutic intervention.
    Journal of Proteome Research 01/2015; 14(3). DOI:10.1021/pr5009898 · 5.00 Impact Factor
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    ABSTRACT: Aspartame is a commonly used intense artificial sweetener, being approximately 200 times sweeter than sucrose. There have been concerns over aspartame since approval in the 1980s including a large anecdotal database reporting severe symptoms. The objective of this study was to compare the acute symptom effects of aspartame to a control preparation. This was a double-blind randomized cross over study conducted in a clinical research unit in United Kingdom. Forty-eight individual who has self reported sensitivity to aspartame were compared to 48 age and gender matched aspartame non-sensitive individuals. They were given aspartame (100mg)-containing or control snack bars randomly at least 7 days apart. The main outcome measures were acute effects of aspartame measured using repeated ratings of 14 symptoms, biochemistry and metabonomics. Aspartame sensitive and non-sensitive participants differed psychologically at baseline in handling feelings and perceived stress. Sensitive participants had higher triglycerides (2.05 ± 1.44 vs. 1.26 ± 0.84mmol/L; p value 0.008) and lower HDL-C (1.16 ± 0.34 vs. 1.35 ± 0.54 mmol/L; p value 0.04), reflected in 1H NMR serum analysis that showed differences in the baseline lipid content between the two groups. Urine metabonomic studies showed no significant differences. None of the rated symptoms differed between aspartame and control bars, or between sensitive and control participants. However, aspartame sensitive participants rated more symptoms particularly in the first test session, whether this was placebo or control. Aspartame and control bars affected GLP-1, GIP, tyrosine and phenylalanine levels equally in both aspartame sensitive and non-sensitive subjects. Using a comprehensive battery of psychological tests, biochemistry and state of the art metabonomics there was no evidence of any acute adverse responses to aspartame. This independent study gives reassurance to both regulatory bodies and the public that acute ingestion of aspartame does not have any detectable psychological or metabolic effects in humans. ISRCTN Registry ISRCTN39650237.
    PLoS ONE 01/2015; 10(3):e0116212. DOI:10.1371/journal.pone.0116212 · 3.53 Impact Factor
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    ABSTRACT: Maternal Body Mass Index (BMI) is positively associated with infant obesity risk. Breast milk contains a number of hormones that may influence infant metabolism during the neonatal period; these may have additional downstream effects on infant appetite regulatory pathways, thereby influencing propensity towards obesity in later life. To conduct a systematic review of studies examining the association between maternal BMI and the concentration of appetite-regulating hormones in breast milk. Pubmed was searched for studies reporting the association between maternal BMI and leptin, adiponectin, insulin, ghrelin, resistin, obestatin, Peptide YY and Glucagon-Like Peptide 1 in breast milk. Twenty six studies were identified and included in the systematic review. There was a high degree of variability between studies with regard to collection, preparation and analysis of breast milk samples. Eleven of fifteen studies reporting breast milk leptin found a positive association between maternal BMI and milk leptin concentration. Two of nine studies investigating adiponectin found an association between maternal BMI and breast milk adiponectin concentration; however significance was lost in one study following adjustment for time post-partum. No association was seen between maternal BMI and milk adiponectin in the other seven studies identified. Evidence for an association between other appetite regulating hormones and maternal BMI was either inconclusive, or lacking. A positive association between maternal BMI and breast milk leptin concentration is consistently found in most studies, despite variable methodology. Evidence for such an association with breast milk adiponectin concentration, however, is lacking with additional research needed for other hormones including insulin, ghrelin, resistin, obestatin, peptide YY and glucagon-like peptide-1. As most current studies have been conducted with small sample sizes, future studies should ensure adequate sample sizes and standardized methodology.
    PLoS ONE 12/2014; 9(12):e115043. DOI:10.1371/journal.pone.0115043 · 3.53 Impact Factor
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    ABSTRACT: Objectives:The invasive nature of biopsy alongside issues with categorical staging and sampling error has driven research into noninvasive biomarkers for the assessment of liver fibrosis in order to stratify and personalize treatment of patients with liver disease. Here, we sought to determine whether a metabonomic approach could be used to identify signatures reflective of the dynamic, pathological metabolic perturbations associated with fibrosis in chronic hepatitis C (CHC) patients.Methods:Plasma nuclear magnetic resonance (NMR) spectral profiles were generated for two independent cohorts of CHC patients and healthy controls (n=50 original and n=63 validation). Spectral data were analyzed and significant discriminant biomarkers associated with fibrosis (as graded by enhanced liver fibrosis (ELF) and METAVIR scores) identified using orthogonal projection to latent structures (O-PLS).Results:Increased severity of fibrosis was associated with higher tyrosine, phenylalanine, methionine, citrate and, very-low-density lipoprotein (vLDL) and lower creatine, low-density lipoprotein (LDL), phosphatidylcholine, and N-Acetyl-α1-acid-glycoprotein. Although area under the receiver operator characteristic curve analysis revealed a high predictive performance for classification based on METAVIR-derived models, <40% of identified biomarkers were validated in the second cohort. In the ELF-derived models, however, over 80% of the biomarkers were validated.Conclusions:Our findings suggest that modeling against a continuous ELF-derived score of fibrosis provides a more robust assessment of the metabolic changes associated with fibrosis than modeling against the categorical METAVIR score. Plasma metabolic phenotypes reflective of CHC-induced fibrosis primarily define alterations in amino-acid and lipid metabolism, and hence identify mechanistically relevant pathways for further investigation as therapeutic targets.Am J Gastroenterol advance online publication, 23 December 2014; doi:10.1038/ajg.2014.370.
    The American Journal of Gastroenterology 12/2014; 110(1). DOI:10.1038/ajg.2014.370 · 9.21 Impact Factor
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    ABSTRACT: Parasitic infections such as Leishmania induce a cascade of host physiological responses, including metabolic and immunological changes. Infection with Leishmania major protozoa causes cutaneous leishmaniasis in humans, a neglected tropical disease with suboptimal disease management. To understand the determinants of pathology, we studied L. major infection in two mouse models: the self-healing C57BL/6 strain and the non-healing BALB/c strain. Metabolic profiling of urine, plasma and faeces via proton NMR spectroscopy was performed, a method that has shown great promise in discovering parasite-specific imprints on global host metabolism. Plasma cytokine status and faecal microbiome were also characterised, as additional metrics of the host response to infection. Results demonstrated differences in glucose and lipid metabolism, distinctive immunological phenotypes, and shifts in microbial composition between the two models. We present a novel approach to integrate such metrics using correlation network analyses, whereby self-healing mice demonstrated an orchestrated interaction between the biological measures shortly after infection. In contrast, the response observed in non-healing mice was delayed and fragmented. Our study suggests that trans-system communication across host metabolism, the innate immune system and gut microbiome is key for a successful host response to L. major and provides a new concept, potentially translatable to other diseases. Please visit journal website to download full copy (free, subject to membership) at: http://dx.doi.org/10.1021/pr5008202
    Journal of Proteome Research 11/2014; 14(1). DOI:10.1021/pr5008202 · 5.00 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 10/2014; 60(4). DOI:10.1002/hep.27264 · 11.19 Impact Factor
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    Dataset: JPRobese
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    ABSTRACT: Animal models are invaluable tools which allow us to investigate the microbiome-host dialogue. However, experimental design introduces biases in the data that we collect, also potentially leading to biased conclusions. With obesity at pandemic levels animal models of this disease have been developed; we investigated the role of experimental design on one such rodent model. We used 454 pyrosequencing to profile the faecal bacteria of obese (n = 6) and lean (homozygous n = 6; heterozygous n = 6) Zucker rats over a 10 week period, maintained in mixed-genotype cages, to further understand the relationships between the composition of the intestinal bacteria and age, obesity progression, genetic background and cage environment. Phylogenetic and taxon-based univariate and multivariate analyses (non-metric multidimensional scaling, principal component analysis) showed that age was the most significant source of variation in the composition of the faecal microbiota. Second to this, cage environment was found to clearly impact the composition of the faecal microbiota, with samples from animals from within the same cage showing high community structure concordance, but large differences seen between cages. Importantly, the genetically induced obese phenotype was not found to impact the faecal bacterial profiles. These findings demonstrate that the age and local environmental cage variables were driving the composition of the faecal bacteria and were more deterministically important than the host genotype. These findings have major implications for understanding the significance of functional metagenomic data in experimental studies and beg the question; what is being measured in animal experiments in which different strains are housed separately, nature or nurture?
    PLoS ONE 09/2014; 9(9):e100916. DOI:10.1371/journal.pone.0100916 · 3.53 Impact Factor
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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; DOI:10.1038/ki.2014.297 · 8.52 Impact Factor
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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; 44(1). DOI:10.3233/JAD-140429 · 3.61 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; 86(19). DOI:10.1021/ac5025039 · 5.83 Impact Factor
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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; DOI:10.1021/pr500161w · 5.00 Impact Factor

Publication Stats

19k Citations
1,890.07 Total Impact Points

Institutions

  • 1999–2015
    • Imperial College London
      • • Department of Surgery and Cancer
      • • Molecular Medicine
      • • Faculty of Medicine
      Londinium, England, United Kingdom
  • 2011
    • Imperial College Healthcare NHS Trust
      Londinium, England, United Kingdom
  • 2009
    • Nestlé S.A.
      Vevey, Vaud, Switzerland
  • 2006
    • University of Innsbruck
      Innsbruck, Tyrol, Austria
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 2005–2006
    • Umeå University
      Umeå, Västerbotten, Sweden
  • 1995–2005
    • University of London
      • Imperial College School of Medicine
      Londinium, England, United Kingdom
  • 2004
    • Princeton University
      • Office of Population Research
      Princeton, New Jersey, United States
  • 1996
    • University of Aveiro
      • Division of Chemistry
      Aveiro, Aveiro, Portugal
    • Birkbeck, University of London
      Londinium, England, United Kingdom