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INTRODUCTION: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by deficiencies in social interactions and communication, combined with restricted and repetitive behavioral issues. OBJECTIVES: As little is known about the etiopathophysiology of ASD and early diagnosis is relatively subjective, we aim to employ a targeted, fully quantitative metabolomics approach to biochemically profile post-mortem human brain with the overall goal of identifying metabolic pathways that may have been perturbed as a result of the disease while uncovering potential central diagnostic biomarkers. METHODS: Using a combination of 1H NMR and DI/LC-MS/MS we quantitatively profiled the metabolome of the posterolateral cerebellum from post-mortem human brain harvested from people who suffered with ASD (n = 11) and compared them with age-matched controls (n = 10). RESULTS: We accurately identified and quantified 203 metabolites in post-mortem brain extracts and performed a metabolite set enrichment analyses identifying 3 metabolic pathways as significantly perturbed (p < 0.05). These include Pyrimidine, Ubiquinone and Vitamin K metabolism. Further, using a variety of machine-based learning algorithms, we identified a panel of central biomarkers (9-hexadecenoylcarnitine (C16:1) and the phosphatidylcholine PC ae C36:1) capable of discriminating between ASD and controls with an AUC = 0.855 with a sensitivity and specificity equal to 0.80 and 0.818, respectively. CONCLUSION: For the first time, we report the use of a multi-platform metabolomics approach to biochemically profile brain from people with ASD and report several metabolic pathways which are perturbed in the diseased brain of ASD sufferers. Further, we identified a panel of biomarkers capable of distinguishing ASD from control brains. We believe that these central biomarkers may be useful for diagnosing ASD in more accessible biomatrices.
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Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Metabolômica , Transtorno do Espectro Autista/diagnóstico , HumanosRESUMO
OBJECTIVE: To identify potential biomarkers during ex vivo lung perfusion (EVLP) using metabolomics approach. SUMMARY BACKGROUND DATA: EVLP increases the number of usable donor lungs for lung transplantation (LTx) by physiologic assessment of explanted marginal lungs. The underlying paradigm of EVLP is the normothermic perfusion of cadaveric lungs previously flushed and stored in hypothermic preservation fluid, which allows the resumption of active cellular metabolism and respiratory function. Metabolomics of EVLP perfusate may identify metabolic profiles of donor lungs associated with early LTx outcomes. METHODS: EVLP perfusate taken at 1and 4 hperfusion were collected from 50 clinical EVLP cases, and submitted to untargeted metabolic profiling with mass spectrometry. The findings were correlated with early LTx outcomes. RESULTS: Following EVLP, 7 cases were declined for LTx. In the remaining transplanted cases, 9 cases developed primary graft dysfunction (PGD) 3. For the metabolic profile at EVLP-1h, a logistic regression model based on palmitoyl-sphingomyelin, 5-aminovalerate, and decanoylcarnitine yielded a receiver operating characteristic (ROC) curve with an area under the curve (AUC) of 0.987 in differentiating PGD 3 from Non-PGD 3 outcomes. For the metabolic profile at EVLP-4h, a logistic regression model based on N2-methylguanosine, 5-aminovalerate, oleamide, and decanoylcarnitine yielded a ROC curve with AUC 0.985 in differentiating PGD 3 from non-PGD 3 outcomes. CONCLUSIONS: Metabolomics of EVLP perfusate revealed a small panel of metabolites highly correlated with early LTx outcomes, and may be potential biomarkers that can improve selection of marginal lungs on EVLP. Further validation studies are needed to confirm these findings.
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Biomarcadores/metabolismo , Transplante de Pulmão , Pulmão/metabolismo , Metabolômica/métodos , Soluções para Preservação de Órgãos/metabolismo , Preservação de Órgãos/métodos , Disfunção Primária do Enxerto/prevenção & controle , Seguimentos , Humanos , Pulmão/cirurgia , Disfunção Primária do Enxerto/metabolismo , Estudos Retrospectivos , Doadores de TecidosRESUMO
Currently little is known about the underlying pathophysiology associated with SIDS, and no objective biomarkers exist for the accurate identification of those at greatest risk of dying from SIDS. Using targeted metabolomics, we aim to profile the medulla oblongata of infants who have died from SIDS (n = 16) and directly compare their biochemical profile with age matched controls. Combining data acquired using 1H NMR and targeted DI-LC-MS/MS, we have identified fatty acid oxidation as a pivotal biochemical pathway perturbed in the brains of those infants who have from SIDS (p = 0.0016). Further we have identified a potential central biomarker with an AUC (95% CI) = 0.933 (0.845-1.000) having high sensitivity (0.933) and specificity (0.875) values for discriminating between control and SIDS brains. This is the first reported study to use targeted metabolomics for the study of PM brain from infants who have died from SIDS. We have identified pathways associated with the disease and central biomarkers for early screening/diagnosis.
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Ácidos Graxos/metabolismo , Bulbo/metabolismo , Metaboloma , Morte Súbita do Lactente/diagnóstico , Autopsia , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Bulbo/patologia , Metabolômica/métodos , Fatores de Risco , Morte Súbita do Lactente/patologiaRESUMO
Huntington's disease (HD) is an autosomal neurodegenerative disorder affecting approximately 5-10 persons per 100,000 worldwide. The pathophysiology of HD is not fully understood but the age of onset is known to be highly dependent on the number of CAG triplet repeats in the huntingtin gene. Using (1)H NMR spectroscopy this study biochemically profiled 39 brain metabolites in post-mortem striatum (n=14) and frontal lobe (n=14) from HD sufferers and controls (n=28). Striatum metabolites were more perturbed with 15 significantly affected in HD cases, compared with only 4 in frontal lobe (p<0.05; q<0.3). The metabolite which changed most overall was urea which decreased 3.25-fold in striatum (p<0.01). Four metabolites were consistently affected in both brain regions. These included the neurotransmitter precursors tyrosine and l-phenylalanine which were significantly depleted by 1.55-1.58-fold and 1.48-1.54-fold in striatum and frontal lobe, respectively (p=0.02-0.03). They also included l-leucine which was reduced 1.54-1.69-fold (p=0.04-0.09) and myo-inositol which was increased 1.26-1.37-fold (p<0.01). Logistic regression analyses performed with MetaboAnalyst demonstrated that data obtained from striatum produced models which were profoundly more sensitive and specific than those produced from frontal lobe. The brain metabolite changes uncovered in this first (1)H NMR investigation of human HD offer new insights into the disease pathophysiology. Further investigations of striatal metabolite disturbances are clearly warranted.
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Encéfalo/metabolismo , Doença de Huntington/metabolismo , Estudos de Casos e Controles , Corpo Estriado/metabolismo , Lobo Frontal/metabolismo , Humanos , Inositol/metabolismo , Leucina/metabolismo , Espectroscopia de Ressonância Magnética , Redes e Vias Metabólicas , MetabolomaRESUMO
INTRODUCTION: Endometrial cancer (EC) is associated with metabolic disturbances including obesity, diabetes and metabolic syndrome. Identifying metabolite biomarkers for EC detection has a crucial role in reducing morbidity and mortality. OBJECTIVE: To determine whether metabolomic based biomarkers can detect EC overall and early-stage EC. METHODS: We performed NMR and mass spectrometry based metabolomic analyses of serum in EC cases versus controls. A total of 46 early-stage (FIGO stages I-II) and 10 late-stage (FIGO stages III-IV) EC cases constituted the study group. A total of 60 unaffected control samples were used. Patients and controls were divided randomly into a discovery group (n = 69) and an independent validation group (n = 47). Predictive algorithms based on biomarkers and demographic characteristics were generated using logistic regression analysis. RESULTS: A total of 181 metabolites were evaluated. Extensive changes in metabolite levels were noted in the EC versus the control group. The combination of C14:2, phosphatidylcholine with acyl-alkyl residue sum C38:1 (PCae C38:1) and 3-hydroxybutyric acid had an area under the receiver operating characteristics curve (AUC) (95% CI) = 0.826 (0.706-0.946) and a sensitivity = 82.6%, and specificity = 70.8% for EC overall. For early EC prediction: BMI, C14:2 and PC ae C40:1 had an AUC (95% CI) = 0.819 (0.689-0.95) and a sensitivity = 72.2% and specificity = 79.2% in the validation group. CONCLUSIONS: EC is characterized by significant perturbations in important cellular metabolites. Metabolites accurately detected early-stage EC cases and EC overall which could lead to the development of non-invasive biomarkers for earlier detection of EC and for monitoring disease recurrence.
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Ácido 3-Hidroxibutírico/sangue , Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer/métodos , Neoplasias do Endométrio/diagnóstico , Metabolômica/métodos , Fosfatidilcolinas/sangue , Adulto , Idoso , Bioensaio/métodos , Estudos de Casos e Controles , Feminino , Humanos , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Ressonância Magnética Nuclear Biomolecular/métodos , Curva ROC , Sensibilidade e EspecificidadeRESUMO
MetaboAnalyst (www.metaboanalyst.ca) is a web server designed to permit comprehensive metabolomic data analysis, visualization and interpretation. It supports a wide range of complex statistical calculations and high quality graphical rendering functions that require significant computational resources. First introduced in 2009, MetaboAnalyst has experienced more than a 50X growth in user traffic (>50 000 jobs processed each month). In order to keep up with the rapidly increasing computational demands and a growing number of requests to support translational and systems biology applications, we performed a substantial rewrite and major feature upgrade of the server. The result is MetaboAnalyst 3.0. By completely re-implementing the MetaboAnalyst suite using the latest web framework technologies, we have been able substantially improve its performance, capacity and user interactivity. Three new modules have also been added including: (i) a module for biomarker analysis based on the calculation of receiver operating characteristic curves; (ii) a module for sample size estimation and power analysis for improved planning of metabolomics studies and (iii) a module to support integrative pathway analysis for both genes and metabolites. In addition, popular features found in existing modules have been significantly enhanced by upgrading the graphical output, expanding the compound libraries and by adding support for more diverse organisms.
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Metabolômica/métodos , Software , Biomarcadores/análise , Perfilação da Expressão Gênica , Internet , Curva ROC , Tamanho da AmostraRESUMO
DrugBank (http://www.drugbank.ca) is a comprehensive online database containing extensive biochemical and pharmacological information about drugs, their mechanisms and their targets. Since it was first described in 2006, DrugBank has rapidly evolved, both in response to user requests and in response to changing trends in drug research and development. Previous versions of DrugBank have been widely used to facilitate drug and in silico drug target discovery. The latest update, DrugBank 4.0, has been further expanded to contain data on drug metabolism, absorption, distribution, metabolism, excretion and toxicity (ADMET) and other kinds of quantitative structure activity relationships (QSAR) information. These enhancements are intended to facilitate research in xenobiotic metabolism (both prediction and characterization), pharmacokinetics, pharmacodynamics and drug design/discovery. For this release, >1200 drug metabolites (including their structures, names, activity, abundance and other detailed data) have been added along with >1300 drug metabolism reactions (including metabolizing enzymes and reaction types) and dozens of drug metabolism pathways. Another 30 predicted or measured ADMET parameters have been added to each DrugCard, bringing the average number of quantitative ADMET values for Food and Drug Administration-approved drugs close to 40. Referential nuclear magnetic resonance and MS spectra have been added for almost 400 drugs as well as spectral and mass matching tools to facilitate compound identification. This expanded collection of drug information is complemented by a number of new or improved search tools, including one that provides a simple analyses of drug-target, -enzyme and -transporter associations to provide insight on drug-drug interactions.
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Bases de Dados de Compostos Químicos , Descoberta de Drogas , Farmacocinética , Internet , Preparações Farmacêuticas/química , Relação Quantitativa Estrutura-AtividadeRESUMO
The Small Molecule Pathway Database (SMPDB, http://www.smpdb.ca) is a comprehensive, colorful, fully searchable and highly interactive database for visualizing human metabolic, drug action, drug metabolism, physiological activity and metabolic disease pathways. SMPDB contains >600 pathways with nearly 75% of its pathways not found in any other database. All SMPDB pathway diagrams are extensively hyperlinked and include detailed information on the relevant tissues, organs, organelles, subcellular compartments, protein cofactors, protein locations, metabolite locations, chemical structures and protein quaternary structures. Since its last release in 2010, SMPDB has undergone substantial upgrades and significant expansion. In particular, the total number of pathways in SMPDB has grown by >70%. Additionally, every previously entered pathway has been completely redrawn, standardized, corrected, updated and enhanced with additional molecular or cellular information. Many SMPDB pathways now include transporter proteins as well as much more physiological, tissue, target organ and reaction compartment data. Thanks to the development of a standardized pathway drawing tool (called PathWhiz) all SMPDB pathways are now much more easily drawn and far more rapidly updated. PathWhiz has also allowed all SMPDB pathways to be saved in a BioPAX format. Significant improvements to SMPDB's visualization interface now make the browsing, selection, recoloring and zooming of pathways far easier and far more intuitive. Because of its utility and breadth of coverage, SMPDB is now integrated into several other databases including HMDB and DrugBank.
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Bases de Dados de Compostos Químicos , Redes e Vias Metabólicas , Gráficos por Computador , Humanos , Internet , Doenças Metabólicas/metabolismo , Preparações Farmacêuticas/metabolismo , Proteínas/química , Proteínas/metabolismoRESUMO
BACKGROUND: Recent progress toward the elucidation of benzylisoquinoline alkaloid (BIA) metabolism has focused on a small number of model plant species. Current understanding of BIA metabolism in plants such as opium poppy, which accumulates important pharmacological agents such as codeine and morphine, has relied on a combination of genomics and metabolomics to facilitate gene discovery. Metabolomics studies provide important insight into the primary biochemical networks underpinning specialized metabolism, and serve as a key resource for metabolic engineering, gene discovery, and elucidation of governing regulatory mechanisms. Beyond model plants, few broad-scope metabolomics reports are available for the vast number of plant species known to produce an estimated 2500 structurally diverse BIAs, many of which exhibit promising medicinal properties. RESULTS: We applied a multi-platform approach incorporating four different analytical methods to examine 20 non-model, BIA-accumulating plant species. Plants representing four families in the Ranunculales were chosen based on reported BIA content, taxonomic distribution and importance in modern/traditional medicine. One-dimensional (1)H NMR-based profiling quantified 91 metabolites and revealed significant species- and tissue-specific variation in sugar, amino acid and organic acid content. Mono- and disaccharide sugars were generally lower in roots and rhizomes compared with stems, and a variety of metabolites distinguished callus tissue from intact plant organs. Direct flow infusion tandem mass spectrometry provided a broad survey of 110 lipid derivatives including phosphatidylcholines and acylcarnitines, and high-performance liquid chromatography coupled with UV detection quantified 15 phenolic compounds including flavonoids, benzoic acid derivatives and hydroxycinnamic acids. Ultra-performance liquid chromatography coupled with high-resolution Fourier transform mass spectrometry generated extensive mass lists for all species, which were mined for metabolites putatively corresponding to BIAs. Different alkaloids profiles, including both ubiquitous and potentially rare compounds, were observed. CONCLUSIONS: Extensive metabolite profiling combining multiple analytical platforms enabled a more complete picture of overall metabolism occurring in selected plant species. This study represents the first time a metabolomics approach has been applied to most of these species, despite their importance in modern and traditional medicine. Coupled with genomics data, these metabolomics resources serve as a key resource for the investigation of BIA biosynthesis in non-model plant species.
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Alcaloides/metabolismo , Benzilisoquinolinas/metabolismo , Magnoliopsida/genética , Metaboloma , Proteínas de Plantas/genética , Berberidaceae/genética , Berberidaceae/metabolismo , Magnoliopsida/metabolismo , Menispermaceae/genética , Menispermaceae/metabolismo , Papaveraceae/genética , Papaveraceae/metabolismo , Proteínas de Plantas/metabolismo , Ranunculaceae/genética , Ranunculaceae/metabolismoRESUMO
OBJECTIVE: We sought to perform validation studies of previously published and newly derived first-trimester metabolomic algorithms for prediction of early preeclampsia (PE). STUDY DESIGN: Nuclear magnetic resonance-based metabolomic analysis was performed on first-trimester serum in 50 women who subsequently developed early PE and in 108 first-trimester controls. Random stratification and allocation was used to divide cases into a discovery group (30 early PE and 65 controls) for generation of the biomarker model(s) and a validation group (20 early PE and 43 controls) to ensure an unbiased assessment of the predictive algorithms. Cross-validation testing on the different algorithms was performed to confirm their robustness before use. Metabolites, demographic features, clinical characteristics, and uterine Doppler pulsatility index data were evaluated. Area under the receiver operator characteristic curve (AUC), 95% confidence interval (CI), sensitivity, and specificity of the biomarker models were derived. RESULTS: Validation testing found that the metabolite-only model had an AUC of 0.835 (95% CI, 0.769-0.941) with a 75% sensitivity and 74.4% specificity and for the metabolites plus uterine Doppler pulsatility index model it was 0.916 (95% CI, 0.836-0.996), 90%, and 88.4%, respectively. Predictive metabolites included arginine and 2-hydroxybutyrate, which are known to be involved in vascular dilation, and insulin resistance and impaired glucose regulation, respectively. CONCLUSION: We found confirmatory evidence that first-trimester metabolomic biomarkers can predict future development of early PE.
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Algoritmos , Biomarcadores/metabolismo , Metabolômica , Pré-Eclâmpsia/metabolismo , Primeiro Trimestre da Gravidez/metabolismo , Artéria Uterina/diagnóstico por imagem , Adulto , Área Sob a Curva , Estudos de Casos e Controles , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/diagnóstico por imagem , Gravidez , Fluxo Pulsátil , Ultrassonografia Doppler , Adulto JovemRESUMO
OBJECTIVE: The objective of the study was to identify metabolomic markers in maternal first-trimester serum for the detection of fetal congenital heart defects (CHDs). STUDY DESIGN: Mass spectrometry (direct injection/liquid chromatography and tandem mass spectrometry) and nuclear magnetic resonance spectrometry-based metabolomic analyses were performed between 11 weeks' and 13 weeks 6 days' gestation on maternal serum. A total of 27 CHD cases and 59 controls were compared. There were no known or suspected chromosomal or syndromic abnormalities indicated. RESULTS: A total of 174 metabolites were identified and quantified using the 2 analytical methods. There were 14 overlapping metabolites between platforms. We identified 123 metabolites that demonstrated significant differences on a univariate analysis in maternal first-trimester serum in CHD vs normal cases. There was a significant disturbance in acylcarnitine, sphingomyelin, and other metabolite levels in CHD pregnancies. Predictive algorithms were developed for CHD detection. High sensitivity (0.929; 95% confidence interval [CI], 0.92-1.00) and specificity (0.932; 95% CI, 0.78-1.00) for CHD detection were achieved (area under the curve, 0.992; 95% CI, 0.973-1.0). CONCLUSION: In the first such report, we demonstrated the feasibility of the use of metabolomic developing biomarkers for the first-trimester prediction of CHD. Abnormal lipid metabolism appeared to be a significant feature of CHD pregnancies.
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Cardiopatias Congênitas/diagnóstico , Metabolômica/métodos , Adulto , Cromatografia Líquida , Feminino , Humanos , Modelos Logísticos , Espectroscopia de Ressonância Magnética , Gravidez , Primeiro Trimestre da Gravidez , Espectrometria de Massas em TandemRESUMO
A new computer program, called SHIFTX2, is described which is capable of rapidly and accurately calculating diamagnetic (1)H, (13)C and (15)N chemical shifts from protein coordinate data. Compared to its predecessor (SHIFTX) and to other existing protein chemical shift prediction programs, SHIFTX2 is substantially more accurate (up to 26% better by correlation coefficient with an RMS error that is up to 3.3× smaller) than the next best performing program. It also provides significantly more coverage (up to 10% more), is significantly faster (up to 8.5×) and capable of calculating a wider variety of backbone and side chain chemical shifts (up to 6×) than many other shift predictors. In particular, SHIFTX2 is able to attain correlation coefficients between experimentally observed and predicted backbone chemical shifts of 0.9800 ((15)N), 0.9959 ((13)Cα), 0.9992 ((13)Cß), 0.9676 ((13)C'), 0.9714 ((1)HN), 0.9744 ((1)Hα) and RMS errors of 1.1169, 0.4412, 0.5163, 0.5330, 0.1711, and 0.1231 ppm, respectively. The correlation between SHIFTX2's predicted and observed side chain chemical shifts is 0.9787 ((13)C) and 0.9482 ((1)H) with RMS errors of 0.9754 and 0.1723 ppm, respectively. SHIFTX2 is able to achieve such a high level of accuracy by using a large, high quality database of training proteins (>190), by utilizing advanced machine learning techniques, by incorporating many more features (χ(2) and χ(3) angles, solvent accessibility, H-bond geometry, pH, temperature), and by combining sequence-based with structure-based chemical shift prediction techniques. With this substantial improvement in accuracy we believe that SHIFTX2 will open the door to many long-anticipated applications of chemical shift prediction to protein structure determination, refinement and validation. SHIFTX2 is available both as a standalone program and as a web server ( http://www.shiftx2.ca ).
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Ressonância Magnética Nuclear Biomolecular/métodos , Proteínas/química , Software , Isótopos de Carbono/química , Ligação de Hidrogênio , Isótopos de Nitrogênio/química , Conformação Proteica , PrótonsRESUMO
To date more than 3700 genome-wide association studies (GWAS) have been published that look at the genetic contributions of single nucleotide polymorphisms (SNPs) to human conditions or human phenotypes. Through these studies many highly significant SNPs have been identified for hundreds of diseases or medical conditions. However, the extent to which GWAS-identified SNPs or combinations of SNP biomarkers can predict disease risk is not well known. One of the most commonly used approaches to assess the performance of predictive biomarkers is to determine the area under the receiver-operator characteristic curve (AUROC). We have developed an R package called G-WIZ to generate ROC curves and calculate the AUROC using summary-level GWAS data. We first tested the performance of G-WIZ by using AUROC values derived from patient-level SNP data, as well as literature-reported AUROC values. We found that G-WIZ predicts the AUROC with <3% error. Next, we used the summary level GWAS data from GWAS Central to determine the ROC curves and AUROC values for 569 different GWA studies spanning 219 different conditions. Using these data we found a small number of GWA studies with SNP-derived risk predictors that have very high AUROCs (>0.75). On the other hand, the average GWA study produces a multi-SNP risk predictor with an AUROC of 0.55. Detailed AUROC comparisons indicate that most SNP-derived risk predictions are not as good as clinically based disease risk predictors. All our calculations (ROC curves, AUROCs, explained heritability) are in a publicly accessible database called GWAS-ROCS (http://gwasrocs.ca). The G-WIZ code is freely available for download at https://github.com/jonaspatronjp/GWIZ-Rscript/.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Curva ROC , Software , Bases de Dados Genéticas , Humanos , Padrões de Herança , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Medição de Risco/métodos , Fatores de RiscoRESUMO
Background: Stillbirth remains a major problem in both developing and developed countries. Omics evaluation of stillbirth has been highlighted as a top research priority. Objective: To identify new putative first-trimester biomarkers in maternal serum for stillbirth prediction using metabolomics-based approach. Methods: Targeted, nuclear magnetic resonance (NMR) and mass spectrometry (MS), and untargeted liquid chromatography-MS (LC-MS) metabolomic analyses were performed on first-trimester maternal serum obtained from 60 cases that subsequently had a stillbirth and 120 matched controls. Metabolites by themselves or in combination with clinical factors were used to develop logistic regression models for stillbirth prediction. Prediction of stillbirths overall, early (<28 weeks and <32 weeks), those related to growth restriction/placental disorder, and unexplained stillbirths were evaluated. Results: Targeted metabolites including glycine, acetic acid, L-carnitine, creatine, lysoPCaC18:1, PCaeC34:3, and PCaeC44:4 predicted stillbirth overall with an area under the curve [AUC, 95% confidence interval (CI)] = 0.707 (0.628-0.785). When combined with clinical predictors the AUC value increased to 0.740 (0.667-0.812). First-trimester targeted metabolites also significantly predicted early, unexplained, and placental-related stillbirths. Untargeted LC-MS features combined with other clinical predictors achieved an AUC (95%CI) = 0.860 (0.793-0.927) for the prediction of stillbirths overall. We found novel preliminary evidence that, verruculotoxin, a toxin produced by common household molds, might be linked to stillbirth. Conclusions: We have identified novel biomarkers for stillbirth using metabolomics and demonstrated the feasibility of first-trimester prediction.
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Biomarcadores/sangue , Metaboloma , Metabolômica/métodos , Primeiro Trimestre da Gravidez/sangue , Diagnóstico Pré-Natal/métodos , Natimorto , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Cromatografia Líquida , Estudos de Viabilidade , Feminino , Humanos , Recém-Nascido , Nascido Vivo , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Gravidez , Primeiro Trimestre da Gravidez/metabolismo , Prognóstico , Adulto JovemRESUMO
Using 1H NMR metabolomics, we biochemically profiled saliva samples collected from healthy-controls (nâ=â12), mild cognitive impairment (MCI) sufferers (nâ=â8), and Alzheimer's disease (AD) patients (nâ=â9). We accurately identified significant concentration changes in 22 metabolites in the saliva of MCI and AD patients compared to controls. This pilot study demonstrates the potential for using metabolomics and saliva for the early diagnosis of AD. Given the ease and convenience of collecting saliva, the development of accurate and sensitive salivary biomarkers would be ideal for screening those at greatest risk of developing AD.
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Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico , Metabolômica/métodos , Espectroscopia de Prótons por Ressonância Magnética/métodos , Saliva/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/metabolismo , Diagnóstico Precoce , Feminino , Humanos , Modelos Logísticos , Masculino , Entrevista Psiquiátrica Padronizada , Curva ROCRESUMO
AIM: To identify demographic, clinical, metabolomic, and lifestyle related predictors of relapse in adult ulcerative colitis (UC) patients. METHODS: In this prospective pilot study, UC patients in clinical remission were recruited and followed-up at 12 mo to assess a clinical relapse, or not. At baseline information on demographic and clinical parameters was collected. Serum and urine samples were collected for analysis of metabolomic assays using a combined direct infusion/liquid chromatography tandem mass spectrometry and nuclear magnetic resolution spectroscopy. Stool samples were also collected to measure fecal calprotectin (FCP). Dietary assessment was performed using a validated self-administered food frequency questionnaire. RESULTS: Twenty patients were included (mean age: 42.7 ± 14.8 years, females: 55%). Seven patients (35%) experienced a clinical relapse during the follow-up period. While 6 patients (66.7%) with normal body weight developed a clinical relapse, 1 UC patient (9.1%) who was overweight/obese relapsed during the follow-up (P = 0.02). At baseline, poultry intake was significantly higher in patients who were still in remission during follow-up (0.9 oz vs 0.2 oz, P = 0.002). Five patients (71.4%) with FCP > 150 µg/g and 2 patients (15.4%) with normal FCP (≤ 150 µg/g) at baseline relapsed during the follow-up (P = 0.02). Interestingly, baseline urinary and serum metabolomic profiling of UC patients with or without clinical relapse within 12 mo showed a significant difference. The most important metabolites that were responsible for this discrimination were trans-aconitate, cystine and acetamide in urine, and 3-hydroxybutyrate, acetoacetate and acetone in serum. CONCLUSION: A combination of baseline dietary intake, fecal calprotectin, and metabolomic factors are associated with risk of UC clinical relapse within 12 mo.
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Colite Ulcerativa/metabolismo , Comportamento Alimentar , Complexo Antígeno L1 Leucocitário/análise , Metabolômica , Produtos Avícolas , Ácido 3-Hidroxibutírico/sangue , Acetamidas/urina , Acetoacetatos/sangue , Acetona/sangue , Ácido Aconítico/urina , Adulto , Biomarcadores/análise , Cromatografia Líquida , Doença Crônica , Colite Ulcerativa/sangue , Colite Ulcerativa/urina , Cistinúria/urina , Inquéritos sobre Dietas , Fezes/química , Feminino , Seguimentos , Humanos , Estilo de Vida , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Recidiva , Indução de Remissão , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: Our primary objective was to apply metabolomic pathway analysis of first trimester maternal serum to provide an insight into the pathogenesis of late-onset preeclampsia (late-PE) and thereby identify plausible therapeutic targets for PE. METHODS: NMR-based metabolomics analysis was performed on 29 cases of late-PE and 55 unaffected controls. In order to achieve sufficient statistical power to perform the pathway analysis, these cases were combined with a group of previously analyzed specimens, 30 late-PE cases and 60 unaffected controls. Specimens from both groups of cases and controls were collected in the same clinical centers during the same time period. In addition, NMR analyses were performed in the same lab and using the same techniques. RESULTS: We identified abnormalities in branch chain amino acids (valine, leucine and isoleucine) and propanoate, glycolysis, gluconeogenesis and ketone body metabolic pathways. The results suggest insulin resistance and metabolic syndrome, mitochondrial dysfunction and disturbance of energy metabolism, oxidative stress and lipid dysfunction in the pathogenesis of late PE and suggest a potential role for agents that reduce insulin resistance in PE. CONCLUSIONS: Branched chain amino acids are known markers of insulin resistance and strongly predict future diabetes development. The analysis provides independent evidence linking insulin resistance and late-PE and suggests a potentially important therapeutic role for pharmacologic agents that reduce insulin resistance for late-PE.
Assuntos
Isoleucina/sangue , Leucina/sangue , Metabolômica , Pré-Eclâmpsia/etiologia , Primeiro Trimestre da Gravidez/sangue , Valina/sangue , Adulto , Algoritmos , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Leucina/metabolismo , Redes e Vias Metabólicas , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/terapia , Gravidez , Estudos Prospectivos , Reprodutibilidade dos Testes , Adulto JovemRESUMO
BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly recognized as an important clinical entity. Preclinical studies have shown differences in the pathophysiology between HFpEF and HF with reduced ejection fraction (HFrEF). Therefore, we hypothesized that a systematic metabolomic analysis would reveal a novel metabolomic fingerprint of HFpEF that will help understand its pathophysiology and assist in establishing new biomarkers for its diagnosis. METHODS AND RESULTS: Ambulatory patients with clinical diagnosis of HFpEF (n = 24), HFrEF (n = 20), and age-matched non-HF controls (n = 38) were selected for metabolomic analysis as part of the Alberta HEART (Heart Failure Etiology and Analysis Research Team) project. 181 serum metabolites were quantified by LC-MS/MS and 1H-NMR spectroscopy. Compared to non-HF control, HFpEF patients demonstrated higher serum concentrations of acylcarnitines, carnitine, creatinine, betaine, and amino acids; and lower levels of phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins. Medium and long-chain acylcarnitines and ketone bodies were higher in HFpEF than HFrEF patients. Using logistic regression, two panels of metabolites were identified that can separate HFpEF patients from both non-HF controls and HFrEF patients with area under the receiver operating characteristic (ROC) curves of 0.942 and 0.981, respectively. CONCLUSIONS: The metabolomics approach employed in this study identified a unique metabolomic fingerprint of HFpEF that is distinct from that of HFrEF. This metabolomic fingerprint has been utilized to identify two novel panels of metabolites that can separate HFpEF patients from both non-HF controls and HFrEF patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02052804.
Assuntos
Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Metabolômica , Volume Sistólico , Idoso , Estudos de Casos e Controles , Demografia , Feminino , Insuficiência Cardíaca/sangue , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Peptídeos/sangue , Curva ROCRESUMO
BACKGROUND: Fatty acid amide hydrolase 2 (FAAH2) is a hydrolase that mediates the degradation of endocannabinoids in man. Alterations in the endocannabinoid system are associated with a wide variety of neurologic and psychiatric conditions, but the phenotype and biochemical characterization of patients with genetic defects of FAAH2 activity have not previously been described. We report a male with autistic features with an onset before the age of 2 years who subsequently developed additional features including anxiety, pseudoseizures, ataxia, supranuclear gaze palsy, and isolated learning disabilities but was otherwise cognitively intact as an adult. METHODS AND RESULTS: Whole exome sequencing identified a rare missense mutation in FAAH2, hg19: g.57475100G > T (c.1372G > T) resulting in an amino acid change (p.Ala458Ser), which was Sanger confirmed as maternally inherited and absent in his healthy brother. Alterations in lipid metabolism with abnormalities of the whole blood acyl carnitine profile were found. Biochemical and molecular modeling studies confirmed that the p.Ala458Ser mutation results in partial inactivation of FAAH2. Studies in patient derived fibroblasts confirmed a defect in FAAH2 activity resulting in altered levels of endocannabinoid metabolites. CONCLUSIONS: We propose that genetic alterations in FAAH2 activity contribute to neurologic and psychiatric disorders in humans.