Imperial College London

ProfessorZoltanTakats

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Professor of Analytical Chemistry
 
 
 
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Contact

 

+44 (0)20 7594 2760z.takats

 
 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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160 results found

Jones EA, Simon D, Karancsi T, Balog J, Pringle SD, Takats Zet al., 2019, Matrix Assisted Rapid Evaporative Ionization Mass Spectrometry., Anal Chem, Vol: 91, Pages: 9784-9791

Rapid evaporative ionization mass spectrometry (REIMS) is a highly versatile technique allowing the sampling of a range of biological solid or liquid samples with no sample preparation. The cost of such a direct approach is that certain sample types provide only moderate amounts of chemical information. Here, we introduce a matrix assisted version of the technique (MA-REIMS), where an aerosol of a pure solvent, such as isopropanol, is mixed with the sample aerosol generated by rapid evaporation of the sample, and it is shown to enhance the signal intensity obtained from a REIMS sampling event by over 2 orders of magnitude. Such an increase greatly expands the scope of the technique, while providing additional benefits such as reducing the fouling of the REIMS source and allowing for a simple method of constant introduction of a calibration correction compound for accurate mass measurements. A range of experiments are presented in order to investigate the processes that occur within this modified approach, and applications where such enhancements are critical, such as intrasurgical tissue identification, are discussed.

Journal article

Whiley L, Chekmeneva E, Berry DJ, Jimenez B, Yuen AHY, Salam A, Hussain H, Witt M, Takats Z, Nicholson JK, Lewis MRet al., 2019, Systematic isolation and structure elucidation of urinary metabolites optimized for the analytical-scale molecular profiling laboratory, Analytical Chemistry, ISSN: 0003-2700

Annotation and identification of metabolite biomarkers is critical for their biological interpretation in metabolic phenotyping studies, presenting a significant bottleneck in the successful implementation of untargeted metabolomics. Here, a systematic multi-step protocol was developed for the purification and de novo structural elucidation of urinary metabolites. The protocol is most suited for instances where structure elucidation and metabolite annotation are critical for the downstream biological interpretation of metabolic phenotyping studies. First, a bulk urine pool was desalted using ion-exchange resins enabling large-scale fractionation using precise iterations of analytical scale chromatography. Primary urine fractions were collected and assembled into a “fraction bank” suitable for long-term laboratory storage. Secondary and tertiary fractionations exploited differences in selectivity across a range of reversed-phase chemistries, achieving the purification of metabolites of interest yielding an amount of material suitable for chemical characterisation. To exemplify the application of the systematic workflow in a diverse set of cases, four metabolites with a range of physico-chemical properties were selected and purified from urine and subjected to chemical formula and structure elucidation by respective magnetic resonance mass spectrometry (MRMS) and NMR analyses. Their structures were fully assigned as teterahydropentoxyline, indole-3-acetic-acid-O-glucuronide, p-cresol glucuronide, and pregnanediol-3-glucuronide. Unused effluent was collected, dried and returned to the fraction bank, demonstrating the viability of the system for repeat use in metabolite annotation with a high degree of efficiency.

Journal article

Inglese P, Correia G, Pruski P, Glen RC, Takats Zet al., 2019, Colocalization features for classification of tumors using desorption electrospray ionization mass spectrometry imaging, Analytical Chemistry, Vol: 91, Pages: 6530-6540, ISSN: 0003-2700

Supervised modeling of mass spectrometry imaging (MSI) data is a crucial component for the detection of the distinct molecular characteristics of cancerous tissues. Currently, two types of supervised analyses are mainly used on MSI data: pixel-wise segmentation of sample images and whole-sample-based classification. A large number of mass spectra associated with each MSI sample can represent a challenge for designing models that simultaneously preserve the overall molecular content while capturing valuable information contained in the MSI data. Furthermore, intensity-related batch effects can introduce biases in the statistical models. Here we introduce a method based on ion colocalization features that allows the classification of whole tissue specimens using MSI data, which naturally preserves the spatial information associated the with the mass spectra and is less sensitive to possible batch effects. Finally, we propose data visualization strategies for the inspection of the derived networks, which can be used to assess whether the correlation differences are related to coexpression/suppression or disjoint spatial localization patterns and can suggest hypotheses based on the underlying mechanisms associated with the different classes of analyzed samples.

Journal article

Black C, Chevallier OP, Cooper KM, Haughey SA, Balog J, Takats Z, Elliott CT, Cavin Cet al., 2019, Rapid detection and specific identification of offals within minced beef samples utilising ambient mass spectrometry, SCIENTIFIC REPORTS, Vol: 9, ISSN: 2045-2322

Journal article

Steven RT, Shaw M, Dexter A, Murta T, Green FM, Robinson KN, Gilmore IS, Takats Z, Bunch Jet al., 2019, Construction and testing of an atmospheric-pressure transmission-mode matrix assisted laser desorption ionisation mass spectrometry imaging ion source with plasma ionisation enhancement, ANALYTICA CHIMICA ACTA, Vol: 1051, Pages: 110-119, ISSN: 0003-2670

Journal article

Cameron SJS, Bodai Z, Temelkuran B, Perdones-Montero A, Bolt F, Burke A, Alexander-Hardiman K, Salzet M, Fournier I, Rebec M, Takáts Zet al., 2019, Utilisation of Ambient Laser Desorption Ionisation Mass Spectrometry (ALDI-MS) improves lipid-based microbial species level identification, Scientific Reports, Vol: 9, ISSN: 2045-2322

The accurate and timely identification of the causative organism of infection is important in ensuring the optimum treatment regimen is prescribed for a patient. Rapid evaporative ionisation mass spectrometry (REIMS), using electrical diathermy for the thermal disruption of a sample, has been shown to provide fast and accurate identification of microorganisms directly from culture. However, this method requires contact to be made between the REIMS probe and microbial biomass; resulting in the necessity to clean or replace the probes between analyses. Here, optimisation and utilisation of ambient laser desorption ionisation (ALDI) for improved speciation accuracy and analytical throughput is shown. Optimisation was completed on 15 isolates of Escherichia coli, showing 5 W in pulsatile mode produced the highest signal-to-noise ratio. These parameters were used in the analysis of 150 clinical isolates from ten microbial species, resulting in a speciation accuracy of 99.4% - higher than all previously reported REIMS modalities. Comparison of spectral data showed high levels of similarity between previously published electrical diathermy REIMS data. ALDI does not require contact to be made with the sample during analysis, meaning analytical throughput can be substantially improved, and further, increases the range of sample types which can be analysed in potential direct-from-sample pathogen detection.

Journal article

Mason SE, Poynter L, Takats Z, Darzi A, Kinross JMet al., 2019, Optical technologies for endoscopic real-time histologic assessment of colorectal polyps: a meta-analysis, American Journal of Gastroenterology, ISSN: 1572-0241

OBJECTIVES: Accurate, real-time, endoscopic risk stratification of colorectal polyps would improve decision-making and optimize clinical efficiency. Technologies to manipulate endoscopic optical outputs can be used to predict polyp histology in vivo; however, it remains unclear how accuracy has progressed and whether it is sufficient for routine clinical implementation. METHODS: A meta-analysis was conducted by searching MEDLINE, Embase, and the Cochrane Library. Studies were included if they prospectively deployed an endoscopic optical technology for real-time in vivo prediction of adenomatous colorectal polyps. Polyposis and inflammatory bowel diseases were excluded. Bayesian bivariate meta-analysis was performed, presenting 95% confidence intervals (CI). RESULTS: One hundred two studies using optical technologies on 33,123 colorectal polyps were included. Digital chromoendoscopy differentiated neoplasia (adenoma and adenocarcinoma) from benign polyps with sensitivity of 92.2% (90.6%-93.9% CI) and specificity of 84.0% (81.5%-86.3% CI), with no difference between constituent technologies (narrow-band imaging, Fuji intelligent Chromo Endoscopy, iSCAN) or with only diminutive polyps. Dye chromoendoscopy had sensitivity of 92.7% (90.1%-94.9% CI) and specificity of 86.6% (82.9%-89.9% CI), similarly unchanged for diminutive polyps. Spectral analysis of autofluorescence had sensitivity of 94.4% (84.0%-99.1% CI) and specificity of 50.9% (13.2%-88.8% CI). Endomicroscopy had sensitivity of 93.6% (85.3%-98.3% CI) and specificity of 92.5% (81.8%-98.1% CI). Computer-aided diagnosis had sensitivity of 88.9% (74.2%-96.7% CI) and specificity of 80.4% (52.6%-95.7% CI). Prediction confidence and endoscopist experience alone did not significantly improve any technology. The only subgroup to demonstrate a negative predictive value for adenoma above 90% was digital chromoendoscopy, making high confidence predictions of diminutive recto-sigmoid polyps. Chronologic meta-analyses show a

Journal article

Poynter L, Mirnezami R, Galea D, Veselkov K, Nicholson J, Takats Z, Darzi A, Kinross J, Mirnezami Aet al., 2019, Network mapping of molecular biomarkers influencing radiation response in rectal cancer, Clinical Colorectal Cancer, ISSN: 1533-0028

IntroductionPre-operative radiotherapy (RT) has an important role in the management of locally advanced rectal cancer (RC). Tumour regression following RT shows marked variability and robust molecular methods are needed with which to predict likely response. The aim of this study was to review the current published literature and employ Gene Ontology (GO) analysis to define key molecular biomarkers governing radiation response in RC.MethodsA systematic review of electronic bibliographic databases (MEDLINE, Embase) was performed for original articles published between 2000 and 2015. Biomarkers were then classified according to biological function and incorporated into a hierarchical GO tree. Both significant and non-significant results were included in the analysis. Significance was binarized based on uni- and multivariate statistics. Significance scores were calculated for each biological domain (or node), and a direct acyclic graph was generated for intuitive mapping of biological pathways and markers involved in rectal cancer radiation response.Results72 individual biomarkers, across 74 studies, were identified through review. On highest order classification, molecular biomarkers falling within the domains of response to stress, cellular metabolism and pathways inhibiting apoptosis were found to be the most influential in predicting radiosensitivity.ConclusionsHomogenising biomarker data from original articles using controlled GO terminology demonstrates that cellular mechanisms of response to radiotherapy in RC - in particular the metabolic response to radiotherapy - may hold promise in developing radiotherapeutic biomarkers with which to predict, and in the future modulate, radiation response.

Journal article

McGill D, Chekmeneva E, Lindon J, Takats Z, Nicholson Jet al., 2019, Application of novel Solid Phase Extraction-NMR protocols for metabolic profiling of human urine, Faraday Discussions, ISSN: 1359-6640

Metabolite identification and annotation procedures are necessary for the discovery of biomarkers indicative of phenotypes or disease states, but these processes can be bottlenecked by the sheer complexity of biofluids containing thousands of different compounds. Here we describe low-cost novel SPE-NMR protocols utilising different cartridges and conditions, on both natural and artifical urine mixtures, which produce unique retention profiles useful to metabolic profiling. We find that different SPE methods applied to biofluids such as urine can be used to selectively retain metabolites based on compound taxonomy or other key functional groups, reducing peak overlap through concentration and fractionation of unknowns and hence promising greater control over the metabolite annotation/identification process.

Journal article

Inglese P, Correia G, Takats Z, Nicholson JK, Glen RCet al., 2019, SPUTNIK: an R package for filtering of spatially related peaks in mass spectrometry imaging data, Bioinformatics, Vol: 35, Pages: 178-180, ISSN: 1367-4803

Summary: SPUTNIK is an R package consisting of a series of tools to filter mass spectrometry imaging peaks characterized by a noisy or unlikely spatial distribution. SPUTNIK can produce mass spectrometry imaging datasets characterized by a smaller but more informative set of peaks, reduce the complexity of subsequent multi-variate analysis and increase the interpretability of the statistical results. Availability: SPUTNIK is freely available online from CRAN repository and at https://github.com/paoloinglese/SPUTNIK. The package is distributed under the GNU General Public License version 3 and is accompanied by example files and data. Supplementary information: Supplementary data are available at Bioinformatics online.

Journal article

Antonowicz S, Hanna GB, Takats Z, Bodai Zet al., 2018, Pragmatic and rapid analysis of carbonyl, oxidation and chlorination nucleoside-adducts in murine tissue by UPLC-ESI-MS/MS, TALANTA, Vol: 190, Pages: 436-442, ISSN: 0039-9140

Journal article

Saudemont P, Quanico J, Robin Y-M, Baud A, Balog J, Fatou B, Tierny D, Pascal Q, Minier K, Pottier M, Focsa C, Ziskind M, Takats Z, Salzet M, Fournier Iet al., 2018, Real-Time Molecular Diagnosis of Tumors Using Water-Assisted Laser Desorption/lonization Mass Spectrometry Technology, CANCER CELL, Vol: 34, Pages: 840-+, ISSN: 1535-6108

Journal article

Inglese P, Dos Santos Correia G, Pruski P, Glen R, Takats Zet al., 2018, Co-localization features for classification of tumors using mass spectrometry imaging

Statistical modeling of mass spectrometry imaging (MSI) data is a crucial component for the understanding of the molecular characteristics of cancerous tissues. Quantification of the abundances of metabolites or batch effect between multiple spectral acquisitions represents only a few of the challenges associated with this type of data analysis. Here we introduce a method based on ion co-localization features that allows the classification of whole tissue specimens using MSI data, which overcomes the possible batch effect issues and generates data-driven hypotheses on the underlying mechanisms associated with the different classes of analyzed samples.

Working paper

Cameron SJ, Takáts Z, 2018, Mass spectrometry approaches to metabolic profiling of microbial communities within the human gastrointestinal tract, Methods, Vol: 149, Pages: 13-24, ISSN: 1046-2023

The interaction between microbial communities and their environment, such as the human gastrointestinal tract, has been an area of microbiology rapidly advanced, by developments in sequencing technology. However, these techniques are largely limited to the detection of the taxonomic composition of a microbial community and/or its genetic functional capacity. Here, we discuss a range of mass spectrometry-based approaches which researchers can employ to explore the host-microbiome interactions at the metabolic level. Traditional approaches to mass spectrometry are detailed, alongside new developments in the field, namely ambient ionisation mass spectrometry and imaging mass spectrometry, which we believe will prove to be important to future work in this field. We further discuss considerations for experimental workflows, data analysis options and propose a methodology for the establishment of causal relationships between functional host-microbiome interactions with regards to health and disease in the human gastrointestinal tract.

Journal article

Pruski P, Lewis H, Lee Y, Marchesi JR, Bennett P, Takats Z, MacIntyre DAet al., 2018, Assessment of microbiota:host interactions at the vaginal mucosa interface, Methods, Vol: 149, Pages: 74-84, ISSN: 1046-2023

There is increasing appreciation of the role that vaginal microbiota play in health and disease throughout a woman’s lifespan. This has been driven partly by molecular techniques that enable detailed identification and characterisation of microbial community structures. However, these methods do not enable assessment of the biochemical and immunological interactions between host and vaginal microbiota involved in pathophysiology. This review examines our current knowledge of the relationships that exist between vaginal microbiota and the host at the level of the vaginal mucosal interface. We also consider methodological approaches to microbiomic, immunologic and metabolic profiling that permit assessment of these interactions. Integration of information derived from these platforms brings the potential for biomarker discovery, disease risk stratification and improved understanding of the mechanisms regulating vaginal microbial community dynamics in health and disease.

Journal article

Bardin EE, Cameron SJS, Perdones-Montero A, Hardiman K, Bolt F, Alton EWFW, Bush A, Davies JC, Takats Zet al., 2018, Metabolic phenotyping and strain characterisation of pseudomonas aeruginosa Isolates from cystic fibrosis patients using rapid evaporative ionisation mass spectrometry, Scientific Reports, Vol: 8, ISSN: 2045-2322

Rapid evaporative ionisation mass spectrometry (REIMS) is a novel technique for the real-time analysis of biological material. It works by conducting an electrical current through a sample, causing it to rapidly heat and evaporate, with the analyte containing vapour channelled to a mass spectrometer. It was used to characterise the metabolome of 45 Pseudomonas aeruginosa (P. aeruginosa) isolates from cystic fibrosis (CF) patients and compared to 80 non-CF P. aeruginosa. Phospholipids gave the highest signal intensity; 17 rhamnolipids and 18 quorum sensing molecules were detected, demonstrating that REIMS has potential for the study of virulence-related metabolites. P. aeruginosa isolates obtained from respiratory samples showed a higher diversity, which was attributed to the chronic nature of most respiratory infections. The analytical sensitivity of REIMS allowed the detection of a metabolome that could be used to classify individual P. aeruginosa isolates after repeated culturing with 81% accuracy, and an average 83% concordance with multilocus sequence typing. This study underpins the capacities of REIMS as a tool with clinical applications, such as metabolic phenotyping of the important CF pathogen P. aeruginosa, and highlights the potential of metabolic fingerprinting for fine scale characterisation at a sub-species level.

Journal article

Phelps DL, Balog J, Gildea LF, Bodai Z, El-Bahrawy MA, Speller AVM, Rosini F, Kudo H, McKenzie JS, Brown R, Takats Z, Ghaem-Maghami Set al., 2018, The surgical intelligent knife distinguishes normal, borderline and malignant gynaecological tissues using rapid evaporative ionisation mass spectrometry (REIMS), British Journal of Cancer, Vol: 118, Pages: 1349-1358, ISSN: 0007-0920

BackgroundSurvival from ovarian cancer (OC) is improved with surgery, but surgery can be complex and tumour identification, especially for borderline ovarian tumours (BOT), is challenging. The Rapid Evaporative Ionisation Mass Spectrometric (REIMS) technique reports tissue histology in real-time by analysing aerosolised tissue during electrosurgical dissection.MethodsAerosol produced during diathermy of tissues was sampled with the REIMS interface. Histological diagnosis and mass spectra featuring complex lipid species populated a reference database on which principal component, linear discriminant and leave-one-patient-out cross-validation analyses were performed.ResultsA total of 198 patients provided 335 tissue samples, yielding 3384 spectra. Cross-validated OC classification vs separate normal tissues was high (97·4% sensitivity, 100% specificity). BOT were readily distinguishable from OC (sensitivity 90.5%, specificity 89.7%). Validation with fresh tissue lead to excellent OC detection (100% accuracy). Histological agreement between iKnife and histopathologist was very good (kappa 0.84, P < 0.001, z = 3.3). Five predominantly phosphatidic acid (PA(36:2)) and phosphatidyl-ethanolamine (PE(34:2)) lipid species were identified as being significantly more abundant in OC compared to normal tissue or BOT (P < 0.001, q < 0.001).ConclusionsThe REIMS iKnife distinguishes gynaecological tissues by analysing mass-spectrometry-derived lipidomes from tissue diathermy aerosols. Rapid intra-operative gynaecological tissue diagnosis may improve surgical care when histology is unknown, leading to personalised operations tailored to the individual.

Journal article

Varshavi D, Scott FH, Varshavi D, Veeravalli S, Phillips IR, Veselkov K, Strittmatter N, Takats Z, Shephard EA, Everett JRet al., 2018, Metabolic biomarkers of ageing in C57BL/6J wild-type and flavin-containing monooxygenase 5 (FMO5)-knockout mice, Frontiers in Molecular Biosciences, Vol: 5, ISSN: 2296-889X

It was recently demonstrated in mice that knockout of the flavin-containing monooxygenase 5 gene, Fmo5, slows metabolic ageing via pleiotropic effects. We have now used an NMR-based metabonomics approach to study the effects of ageing directly on the metabolic profiles of urine and plasma from male, wild-type C57BL/6J and Fmo5-/- (FMO5 KO) mice back-crossed onto the C57BL/6J background. The aim of this study was to identify metabolic signatures that are associated with ageing in both these mouse lines and to characterize the age-related differences in the metabolite profiles between the FMO5 KO mice and their wild-type counterparts at equivalent time points. We identified a range of age-related biomarkers in both urine and plasma. Some metabolites, including urinary 6-hydroxy-6-methylheptan-3-one (6H6MH3O), a mouse sex pheromone, showed similar patterns of changes with age, regardless of genetic background. Others, however, were altered only in the FMO5 KO, or only in the wild-type mice, indicating the impact of genetic modifications on mouse ageing. Elevated concentrations of urinary taurine represent a distinctive, ageing-related change observed only in wild-type mice.

Journal article

Veselkov KA, Sleeman J, Claude E, Vissers J, Galea D, Mroz A, Laponogov I, Towers M, Tonge R, Mirnezami R, Takats Z, Nicholson J, Langridge Jet al., 2018, BASIS: High-performance bioinformatics platform for processing of large-scale mass spectrometry imaging data in chemically augmented histology, Scientific Reports, Vol: 8, ISSN: 2045-2322

Mass Spectrometry Imaging (MSI) holds significant promise in augmenting digital histopathologic analysis by generating highly robust big data about the metabolic, lipidomic and proteomic molecular content of the samples. In the process, a vast quantity of unrefined data, that can amount to several hundred gigabytes per tissue section, is produced. Managing, analysing and interpreting this data is a significant challenge and represents a major barrier to the translational application of MSI. Existing data analysis solutions for MSI rely on a set of heterogeneous bioinformatics packages that are not scalable for the reproducible processing of large-scale (hundreds to thousands) biological sample sets. Here, we present a computational platform (pyBASIS) capable of optimized and scalable processing of MSI data for improved information recovery and comparative analysis across tissue specimens using machine learning and related pattern recognition approaches. The proposed solution also provides a means of seamlessly integrating experimental laboratory data with downstream bioinformatics interpretation/analyses, resulting in a truly integrated system for translational MSI.

Journal article

Lewis H, Pruski P, Brown R, Bennett P, Takats Z, MacIntyre Det al., 2018, Rapid mucosal metabolome profiling by desorption electrospray ionization MS (DESI-MS) for prediction of preterm pre-labour rupture of membranes (PPROM), RCOG World Congress 2018, Publisher: Wiley, Pages: 24-24, ISSN: 1470-0328

Conference paper

Guitton Y, Dervilly-Pinel G, Jandova R, Stead S, Takats Z, Le Bizec Bet al., 2018, Rapid evaporative ionisation mass spectrometry and chemometrics for high-throughput screening of growth promoters in meat producing animals, FOOD ADDITIVES AND CONTAMINANTS PART A-CHEMISTRY ANALYSIS CONTROL EXPOSURE & RISK ASSESSMENT, Vol: 35, Pages: 900-910, ISSN: 1944-0049

Journal article

Bodai Z, Cameron S, Bolt F, Simon D, Schaffer R, Karancsi T, Balog J, Rickards T, Burke A, Hardiman K, Abda J, Rebec M, Takats Zet al., 2018, Effect of electrode geometry on the classification performance of Rapid Evaporative Ionization Mass Spectrometric (REIMS) bacterial identification, Journal of The American Society for Mass Spectrometry, Vol: 29, Pages: 26-33, ISSN: 1044-0305

The recently developed automated, high-throughput monopolar REIMS platform is suited for the identification of clinically important microorganisms. Although already comparable to the previously reported bipolar forceps method, optimization of the geometry of monopolar electrodes, at the heart of the system, holds the most scope for further improvements to be made. For this, sharp tip and round shaped electrodes were optimized to maximize species-level classification accuracy. Following optimization of the distance between the sample contact point and tube inlet with the sharp tip electrodes, the overall cross-validation accuracy improved from 77% to 93% in negative and from 33% to 63% in positive ion detection modes, compared with the original 4 mm distance electrode. As an alternative geometry, round tube shaped electrodes were developed. Geometry optimization of these included hole size, number, and position, which were also required to prevent plate pick-up due to vacuum formation. Additional features, namely a metal “X”-shaped insert and a pin in the middle were included to increase the contact surface with a microbial biomass to maximize aerosol production. Following optimization, cross-validation scores showed improvement in classification accuracy from 77% to 93% in negative and from 33% to 91% in positive ion detection modes. Supervised models were also built, and after the leave 20% out cross-validation, the overall classification accuracy was 98.5% in negative and 99% in positive ion detection modes. This suggests that the new generation of monopolar REIMS electrodes could provide substantially improved species level identification accuracies in both polarity detection modes.

Journal article

Bergholt MS, Serio A, McKenzie JS, Boyd A, Soares RF, Tillner J, Chiappini C, Wu V, Dannhorn A, Takats Z, Williams A, Stevens MMet al., 2017, Correlated heterospectral lipidomics for biomolecular profiling of remyelination in multiple sclerosis, ACS Central Science, Vol: 4, Pages: 39-51, ISSN: 2374-7943

Analyzing lipid composition and distribution within the brain is important to study white matter pathologies that present focal demyelination lesions, such as multiple sclerosis. Some lesions can endogenously re-form myelin sheaths. Therapies aim to enhance this repair process in order to reduce neurodegeneration and disability progression in patients. In this context, a lipidomic analysis providing both precise molecular classification and well-defined localization is crucial to detect changes in myelin lipid content. Here we develop a correlated heterospectral lipidomic (HSL) approach based on coregistered Raman spectroscopy, desorption electrospray ionization mass spectrometry (DESI-MS), and immunofluorescence imaging. We employ HSL to study the structural and compositional lipid profile of demyelination and remyelination in an induced focal demyelination mouse model and in multiple sclerosis lesions from patients ex vivo. Pixelwise coregistration of Raman spectroscopy and DESI-MS imaging generated a heterospectral map used to interrelate biomolecular structure and composition of myelin. Multivariate regression analysis enabled Raman-based assessment of highly specific lipid subtypes in complex tissue for the first time. This method revealed the temporal dynamics of remyelination and provided the first indication that newly formed myelin has a different lipid composition compared to normal myelin. HSL enables detailed molecular myelin characterization that can substantially improve upon the current understanding of remyelination in multiple sclerosis and provides a strategy to assess remyelination treatments in animal models.

Journal article

Inglese P, Strittmatter N, Doria L, Mroz A, Speller A, Poynter L, Dannhorn A, Kudo H, Mirnezami R, Goldin RD, Nicholson JK, Takats Z, Glen RCet al., 2017, Network analysis of mass spectrometry imaging data from colorectal cancer identifies key metabolites common to metastatic development, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:p>A deeper understanding of inter-tumor and intra-tumor heterogeneity is a critical factor for the advancement of next generation strategies against cancer. The heterogeneous morphology exhibited by solid tumors is mirrored by their metabolic heterogeneity. Defining the basic biological mechanisms that underlie tumor cell variability will be fundamental to the development of personalized cancer treatments. Variability in the molecular signatures found in local regions of cancer tissues can be captured through an untargeted analysis of their metabolic constituents. Here we demonstrate that DESI mass spectrometry imaging (MSI) combined with network analysis can provide detailed insight into the metabolic heterogeneity of colorectal cancer (CRC). We show that network modules capture signatures which differentiate tumor metabolism in the core and in the surrounding region. Moreover, module preservation analysis of network modules between patients with and without metastatic recurrence explains the inter-subject metabolic differences associated with diverse clinical outcomes such as metastatic recurrence.</jats:p><jats:sec><jats:title>Significance</jats:title><jats:p>Network analysis of DESI-MSI data from CRC human tissue reveals clinically relevant co-expression ion patterns associated with metastatic susceptibility. This delineates a more complex picture of tumor heterogeneity than conventional hard segmentation algorithms. Using tissue sections from central regions and at a distance from the tumor center, ion co-expression patterns reveal common features among patients who developed metastases (up of &gt; 5 years) not preserved in patients who did not develop metastases. This offers insight into the nature of the complex molecular interactions associated with cancer recurrence. Presently, predicting CRC relapse is challenging, and histopathologically like-for-like cancers freque

Working paper

Galea D, Inglese P, Cammack L, Strittmatter N, Rebec M, Mirnezami R, Laponogov I, Kinross J, Nicholson J, Takats Z, Veselkov KAet al., 2017, Translational utility of a hierarchical classification strategy in biomolecular data analytics., Scientific Reports, Vol: 7, ISSN: 2045-2322

Hierarchical classification (HC) stratifies and classifies data from broad classes into more specific classes. Unlike commonly used data classification strategies, this enables the probabilistic prediction of unknown classes at different levels, minimizing the burden of incomplete databases. Despite these advantages, its translational application in biomedical sciences has been limited. We describe and demonstrate the implementation of a HC approach for "omics-driven" classification of 15 bacterial species at various taxonomic levels achieving 90-100% accuracy, and 9 cancer types into morphological types and 35 subtypes with 99% and 76% accuracy, respectively. Unknown bacterial species were probabilistically assigned with 100% accuracy to their respective genus or family using mass spectra (n = 284). Cancer types were predicted by mRNA data (n = 1960) for most subtypes with 95-100% accuracy. This has high relevance in clinical practice where complete datasets are difficult to compile with the continuous evolution of diseases and emergence of new strains, yet prediction of unknown classes, such as bacterial species, at upper hierarchy levels may be sufficient to initiate antimicrobial therapy. The algorithms presented here can be directly translated into clinical-use with any quantitative data, and have broad application potential, from unlabeled sample identification, to hierarchical feature selection, and discovery of new taxonomic variants.

Journal article

Black C, Chevallier OP, Haughey SA, Balog J, Stead S, Pringle SD, Riina MV, Martucci F, Acutis PL, Morris M, Nikolopoulos DS, Takats Z, Elliott CTet al., 2017, A real time metabolomic profiling approach to detecting fish fraud using rapid evaporative ionisation mass spectrometry, METABOLOMICS, Vol: 13, ISSN: 1573-3882

Journal article

Inglese P, Alexander JL, Mroz A, Takats Z, Glen Ret al., 2017, Variational autoencoders for tissue heterogeneity exploration from (almost) no preprocessed mass spectrometry imaging data, arXiv

The paper presents the application of Variational Autoencoders (VAE) for datadimensionality reduction and explorative analysis of mass spectrometry imagingdata (MSI). The results confirm that VAEs are capable of detecting the patternsassociated with the different tissue sub-types with performance than standardapproaches.

Journal article

Verplanken K, Stead S, Jandova R, Van Poucke C, Claereboudt J, Vanden Bussche J, De Saeger S, Takats Z, Wauters J, Vanhaecke Let al., 2017, Rapid evaporative ionization mass spectrometry for high-throughput screening in food analysis: The case of boar taint, TALANTA, Vol: 169, Pages: 30-36, ISSN: 0039-9140

Journal article

Smith WD, Bardin E, Cameron L, Edmondson CL, Farrant KV, Martin I, Murphy RA, Soren O, Turnbull AR, Wierre-Gore N, Alton EW, Bundy JG, Bush A, Connett GJ, Faust SN, Filloux A, Freemont PS, Jones AL, Takats Z, Webb JS, Williams HD, Davies JCet al., 2017, Current and future therapies for Pseudomonas aeruginosa infection in patients with cystic fibrosis, FEMS Microbiology Letters, Vol: 364, ISSN: 0378-1097

Pseudomonas aeruginosa opportunistically infects the airways of patients with cystic fibrosis and causes significant morbidity and mortality. Initial infection can often be eradicated though requires prompt detection and adequate treatment. Intermittent and then chronic infection occurs in the majority of patients. Better detection of P. aeruginosa infection using biomarkers may enable more successful eradication before chronic infection is established. In chronic infection P. aeruginosa adapts to avoid immune clearance and resist antibiotics via efflux pumps, β-lactamase expression, reduced porins and switching to a biofilm lifestyle. The optimal treatment strategies for P. aeruginosa infection are still being established, and new antibiotic formulations such as liposomal amikacin, fosfomycin in combination with tobramycin and inhaled levofloxacin are being explored. Novel agents such as the alginate oligosaccharide OligoG, cysteamine, bacteriophage, nitric oxide, garlic oil and gallium may be useful as anti-pseudomonal strategies, and immunotherapy to prevent infection may have a role in the future. New treatments that target the primary defect in cystic fibrosis, recently licensed for use, have been associated with a fall in P. aeruginosa infection prevalence. Understanding the mechanisms for this could add further strategies for treating P. aeruginosa in future.

Journal article

Tillner J, Wu V, Jones EA, Pringle SD, Karancsi T, Dannhorn A, Veselkov K, McKenzie JS, Takats Zet al., 2017, Faster, more reproducible DESI-MS for biological tissue imaging, Journal of The American Society for Mass Spectrometry, Vol: 28, Pages: 2090-2098, ISSN: 1044-0305

A new, more robust sprayer for desorption electrospray ionization (DESI) mass spectrometry imaging is presented. The main source of variability in DESI is thought to be the uncontrolled variability of various geometric parameters of the sprayer, primarily the position of the solvent capillary, or more specifically, its positioning within the gas capillary or nozzle. If the solvent capillary is off-center, the sprayer becomes asymmetrical, making the geometry difficult to control and compromising reproducibility. If the stiffness, tip quality, and positioning of the capillary are improved, sprayer reproducibility can be improved by an order of magnitude. The quality of the improved sprayer and its potential for high spatial resolution imaging are demonstrated on human colorectal tissue samples by acquisition of images at pixel sizes of 100, 50, and 20 μm, which corresponds to a lateral resolution of 40-60 μm, similar to the best values published in the literature. The high sensitivity of the sprayer also allows combination with a fast scanning quadrupole time-of-flight mass spectrometer. This provides up to 30 times faster DESI acquisition, reducing the overall acquisition time for a 10 mm × 10 mm rat brain sample to approximately 1 h. Although some spectral information is lost with increasing analysis speed, the resulting data can still be used to classify tissue types on the basis of a previously constructed model. This is particularly interesting for clinical applications, where fast, reliable diagnosis is required. Graphical Abstract ᅟ.

Journal article

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