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
to

165 results found

Capece D, D'Andrea D, Begalli F, Goracci L, Tornatore L, Alexander JL, Di Veroli A, Leow S-C, Vaiyapuri TS, Ellis JK, Verzella D, Bennett J, Savino L, Ma Y, McKenzie JS, Doria ML, Mason SE, Chng KR, Keun HC, Frost G, Tergaonkar V, Broniowska K, Stunkel W, Takats Z, Kinross JM, Cruciani G, Franzoso Get al., 2021, Enhanced triacylglycerol catabolism by Carboxylesterase 1 promotes aggressive colorectal carcinoma., Journal of Clinical Investigation, ISSN: 0021-9738

The ability to adapt to low-nutrient microenvironments is essential for tumor-cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription-factor pathway associates with advanced disease stages and shorter survival in CRC patients. NF-κB has been shown to drive tumor-promoting inflammation, cancer-cell survival and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in CRC patients is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC-cell survival via cell-autonomous mechanisms that fuel fatty-acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight CRC patients. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype (CMS)4, associated with obesity, stemness and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator, HNF4A, in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavourable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.

Journal article

Manoli E, Mason S, Ford L, Adebesin A, Bodai Z, Darzi A, Kinross J, Takats Zet al., 2021, Validation of ultrasonic harmonic scalpel for real-time tissue identification using rapid evaporative ionization mass spectrometry, Analytical Chemistry, Vol: 93, Pages: 5906-5916, ISSN: 0003-2700

In this study, we integrate rapid evaporative ionization mass spectrometry (REIMS) with the Harmonic scalpel, an advanced laparoscopic surgical instrument that utilizes ultrasound energy to dissect and coagulate tissues. It provides unparalleled manipulation capability to surgeons and has superseded traditional electrosurgical tools particularly in abdominal surgery, but is yet to be validated with REIMS. The REIMS platform coupled with the Harmonic device was shown to produce tissue-specific lipid profiles through the analysis of porcine tissues in both negative and positive ionization modes. Comparison with other methods of electrosurgical dissection, such as monopolar electrosurgery and CO2 laser, showed spectral differences in the profile dependent on the energy device used. The Harmonic device demonstrated major spectral differences in the phospholipid region of m/z 600–1000 compared with the monopolar electrosurgical and CO2 laser-generated spectra. Within the Harmonic REIMS spectra, high intensities of diglycerides and triglycerides were observed. In contrast, monopolar electrosurgical and laser spectra demonstrated high abundances of glycerophospholipids. The Harmonic scalpel was able to differentiate between the liver, muscle, colon, and small intestine, demonstrating 100% diagnostic accuracy. The validation of the Harmonic device–mass spectrometry combination will allow the platform to be used safely and robustly for real-time in vivo surgical tissue identification in a variety of clinical applications.

Journal article

Dannhorn A, Ling S, Powell S, McCall E, Maglennon G, Jones GN, Pierce AJ, Strittmatter N, Hamm G, Barry ST, Bunch J, Goodwin RJA, Takats Zet al., 2021, Evaluation of UV-C Decontamination of Clinical Tissue Sections for Spatially Resolved Analysis by Mass Spectrometry Imaging (MSI), ANALYTICAL CHEMISTRY, Vol: 93, Pages: 2767-2775, ISSN: 0003-2700

Journal article

Sands CJ, Gómez-Romero M, Correia G, Chekmeneva E, Camuzeaux S, Izzi-Engbeaya C, Dhillo WS, Takats Z, Lewis MRet al., 2021, Representing the metabolome with high fidelity: range and response as quality control factors in LC-MS-based global profiling., Analytical Chemistry, Vol: 93, Pages: 1924-1933, ISSN: 0003-2700

Liquid chromatography-mass spectrometry (LC-MS) is a powerful and widely used technique for measuring the abundance of chemical species in living systems. Its sensitivity, analytical specificity, and direct applicability to biofluids and tissue extracts impart great promise for the discovery and mechanistic characterization of biomarker panels for disease detection, health monitoring, patient stratification, and treatment personalization. Global metabolic profiling applications yield complex data sets consisting of multiple feature measurements for each chemical species observed. While this multiplicity can be useful in deriving enhanced analytical specificity and chemical identities from LC-MS data, data set inflation and quantitative imprecision among related features is problematic for statistical analyses and interpretation. This Perspective provides a critical evaluation of global profiling data fidelity with respect to measurement linearity and the quantitative response variation observed among components of the spectra. These elements of data quality are widely overlooked in untargeted metabolomics yet essential for the generation of data that accurately reflect the metabolome. Advanced feature filtering informed by linear range estimation and analyte response factor assessment is advocated as an attainable means of controlling LC-MS data quality in global profiling studies and exemplified herein at both the feature and data set level.

Journal article

Paraskevaidi M, Cameron SJS, Whelan E, Bowden S, Tzafetas M, Mitra A, Semertzidou A, Athanasiou A, Bennett P, MacIntyre D, Takats Z, Kyrgiou Met al., 2020, Laser-assisted rapid evaporative ionisation mass spectrometry (LA-REIMS) as a metabolomics platform in cervical cancer screening, EBioMedicine, Vol: 60, ISSN: 2352-3964

BackgroundThe introduction of high-risk human papillomavirus (hrHPV) testing as part of primary cervical screening is anticipated to improve sensitivity, but also the number of women who will screen positive. Reflex cytology is the preferred triage test in most settings but has limitations including moderate diagnostic accuracy, lack of automation, inter-observer variability and the need for clinician-collected sample. Novel, objective and cost-effective approaches are needed.MethodsIn this study, we assessed the potential use of an automated metabolomic robotic platform, employing the principle of laser-assisted Rapid Evaporative Ionisation Mass Spectrometry (LA-REIMS) in cervical cancer screening.FindingsIn a population of 130 women, LA-REIMS achieved 94% sensitivity and 83% specificity (AUC: 91.6%) in distinguishing women testing positive (n = 65) or negative (n = 65) for hrHPV. We performed further analysis according to disease severity with LA-REIMS achieving sensitivity and specificity of 91% and 73% respectively (AUC: 86.7%) in discriminating normal from high-grade pre-invasive disease.InterpretationThis automated high-throughput technology holds promise as a low-cost and rapid test for cervical cancer screening and triage. The use of platforms like LA-REIMS has the potential to further improve the accuracy and efficiency of the current national screening programme.

Journal article

Van Meulebroek L, Cameron S, Plekhova V, De Spiegeleer M, Wijnant K, Michels N, De Henauw S, Lapauw B, Takats Z, Vanhaecke Let al., 2020, Rapid LA-REIMS and comprehensive UHPLC-HRMS for metabolic phenotyping of feces, TALANTA, Vol: 217, ISSN: 0039-9140

Journal article

Dannhorn A, Kazanc E, Ling S, Nikula C, Karali E, Serra MP, Vorng J-L, Inglese P, Maglennon G, Hamm G, Swales J, Strittmatter N, Barry ST, Sansom OJ, Poulogiannis G, Bunch J, Goodwin RJA, Takats Zet al., 2020, Universal Sample Preparation Unlocking Multimodal Molecular Tissue Imaging, ANALYTICAL CHEMISTRY, Vol: 92, Pages: 11080-11088, ISSN: 0003-2700

Journal article

Tzafetas M, Mitra A, Paraskevaidi M, Bodai Z, Kalliala I, Bowden S, Lathouras K, Rosini F, Szasz M, Savage A, Manoli E, Balog J, McKenzie J, Lyons D, Bennett P, MacIntyre D, Ghaem-Maghami S, Takats Z, Kyrgiou Met al., 2020, The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease (vol 117, pg 7338, 2020), PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 18892-18892, ISSN: 0027-8424

Journal article

Koundouros N, Karali E, Tripp A, Valle A, Inglese P, Perry NJS, Magee DJ, Virmouni SA, Elder GA, Tyson AL, Doria ML, van Weverwijk A, Soares RF, Isacke CM, Nicholson JK, Glen RC, Takats Z, Poulogiannis Get al., 2020, Metabolic fingerprinting links oncogenic PIK3CA with enhanced arachidonic acid-derived eicosanoids, Cell, Vol: 181, Pages: 1596-1611.e27, ISSN: 0092-8674

Oncogenic transformation is associated with profound changes in cellular metabolism, but whether tracking these can improve disease stratification or influence therapy decision-making is largely unknown. Using the iKnife to sample the aerosol of cauterized specimens, we demonstrate a new mode of real-time diagnosis, coupling metabolic phenotype to mutant PIK3CA genotype. Oncogenic PIK3CA results in an increase in arachidonic acid and a concomitant overproduction of eicosanoids, acting to promote cell proliferation beyond a cell-autonomous manner. Mechanistically, mutant PIK3CA drives a multimodal signaling network involving mTORC2-PKCζ-mediated activation of the calcium-dependent phospholipase A2 (cPLA2). Notably, inhibiting cPLA2 synergizes with fatty acid-free diet to restore immunogenicity and selectively reduce mutant PIK3CA-induced tumorigenicity. Besides highlighting the potential for metabolic phenotyping in stratified medicine, this study reveals an important role for activated PI3K signaling in regulating arachidonic acid metabolism, uncovering a targetable metabolic vulnerability that largely depends on dietary fat restriction.

Journal article

Abbassi-Ghadi N, Antonowicz S, McKenzie J, Kumar S, Huang J, Jones E, Strittmatter N, Petts G, Kudo H, court S, Hoare J, Veselkov K, Goldin R, Takats Z, Hanna Get al., 2020, De novo lipogenesis alters the phospholipidome of esophageal adenocarcinoma, Cancer Research, Vol: 80, Pages: 2764-2774, ISSN: 0008-5472

The incidence of esophageal adenocarcinoma is rising, survival remains poor, and new tools to improve early diagnosis and precise treatment are needed. Cancer phospholipidomes quantified with mass spectrometry imaging can support objective diagnosis in minutes using a routine frozen tissue section. However, whether mass spectrometry imaging can objectively identify primary esophageal adenocarcinoma is currently unknown and represents a significant challenge, as this microenvironment is complex with phenotypically similar tissue-types. Here we used desorption electrospray ionisation mass spectrometry imaging (DESI-MSI) and bespoke chemometrics to assess the phospholipidomes of esophageal adenocarcinoma and relevant control tissues. Multivariable models derived from phospholipid profiles of 117 patients were highly discriminant for esophageal adenocarcinoma both in discovery (area-under-curve = 0.97) and validation cohorts (AUC = 1). Among many other changes, esophageal adenocarcinoma samples were markedly enriched for polyunsaturated phosphatidylglycerols with longer acyl chains, with stepwise enrichment in pre-malignant tissues. Expression of fatty acid and glycerophospholipid synthesis genes was significantly upregulated, and characteristics of fatty acid acyls matched glycerophospholipid acyls. Mechanistically, silencing the carbon switch ACLY in esophageal adenocarcinoma cells shortened GPL chains, linking de novo lipogenesis to the phospholipidome. Thus, DESI-MSI can objectively identify invasive esophageal adenocarcinoma from a number of pre-malignant tissues and unveils mechanisms of phospholipidomic reprogramming. These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite as well as functional studies to determine how polyunsaturated phosphatidylglycerols contribute to esophageal carcinogenesis.

Journal article

Tzafetas M, Mitra A, Paraskevaidi M, Bodai Z, Kalliala I, Bowden S, Lathouras K, Rosini F, Szasz M, Savage A, Balog J, McKenzie J, Lyons D, Bennett P, MacIntyre D, Ghaem-Maghami S, Takats Z, Kyrgiou Met al., 2020, The intelligent-Knife (i-Knife) and its intraoperative diagnostic advantage for the treatment of cervical disease, Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 7338-7346, ISSN: 0027-8424

Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory m/z features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings.

Journal article

Gowers G-OF, Cameron SJS, Perdones-Montero A, Bell D, Chee SM, Kern M, Tew D, Ellis T, Takats Zet al., 2019, Off-colony screening of biosynthetic libraries by rapid laser-enabled mass spectrometry, ACS Synthetic Biology, Vol: 8, Pages: 2566-2575, ISSN: 2161-5063

Leveraging advances in DNA synthesis and molecular cloning techniques, synthetic biology increasingly makes use of large construct libraries to explore large design spaces. For biosynthetic pathway engineering the ability to screen these libraries for a variety of metabolites of interest is essential. If the metabolite of interest or the metabolic phenotype is not easily measurable, screening soon becomes a major bottleneck involving time-consuming culturing, sample preparation, and extraction. To address this, we demonstrate the use of automated Laser-Assisted Rapid Evaporative Ionisation Mass Spectrometry (LA-REIMS) - a form of ambient laser desorption ionisation mass spectrometry - to perform rapid mass spectrometry analysis direct from agar plate yeast colonies without sample preparation or extraction. We use LA-REIMS to assess production levels of violacein and betulinic acid directly from yeast colonies at a rate of 6 colonies per minute. We then demonstrate the throughput enabled by LA-REIMS by screening over 450 yeast colonies in under 4 hours, while simultaneously generating recoverable glycerol stocks of each colony in real-time. This showcases LA-REIMS as a pre-screening tool to complement downstream quantification methods such as LCMS. Through pre-screening several hundred colonies with LA-REIMS, we successfully isolate and verify a strain with a 2.5-fold improvement in betulinic acid production. Finally, we show that LA-REIMS can detect 20 out of a panel of 27 diverse biological molecules, demonstrating the broad applicability of LA-REIMS to metabolite detection. The rapid and automated nature of LA-REIMS makes this a valuable new technology to complement existing screening technologies currently employed in academic and industrial workflows.

Journal article

Cameron SJS, Alexander JL, Bolt F, Burke A, Ashrafian H, Teare J, Marchesi JR, Kinross J, Li JV, Takats Zet al., 2019, Evaluation of direct from sample metabolomics of human feces using rapid evaporative ionization mass spectrometry, Analytical Chemistry, Vol: 91, Pages: 13448-13457, ISSN: 0003-2700

Mass spectrometry is a powerful tool in the investigation of the human fecal metabolome. However, current approaches require time-consuming sample preparation, chromatographic separations, and consequently long analytical run times. Rapid evaporative ionization mass spectrometry (REIMS) is a method of ambient ionization mass spectrometry and has been utilized in the metabolic profiling of a diverse range of biological materials, including human tissue, cell culture lines, and microorganisms. Here, we describe the use of an automated, high-throughput REIMS robotic platform for direct analysis of human feces. Through the analysis of fecal samples from five healthy male participants, REIMS analytical parameters were optimized and used to assess the chemical information obtainable using REIMS. Within the fecal samples analyzed, bile acids, including primary, secondary, and conjugate species, were identified, and phospholipids of possible bacterial origin were detected. In addition, the effect of storage conditions and consecutive freeze/thaw cycles was determined. Within the REIMS mass spectra, the lower molecular weight metabolites, such as fatty acids, were shown to be significantly affected by storage conditions for prolonged periods at temperatures above −80 °C and consecutive freeze/thaw cycles. However, the complex lipid region was shown to be unaffected by these conditions. A further cohort of 50 fecal samples, collected from patients undergoing bariatric surgery, were analyzed using the optimized REIMS parameters and the complex lipid region mass spectra used for multivariate modeling. This analysis showed a predicted separation between pre- and post-surgery specimens, suggesting that REIMS analysis can detect biological differences, such as microbiome-level differences, which have traditionally been reliant upon methods utilizing extensive sample preparations and chromatographic separations and/or DNA sequencing.

Journal article

Ogrinc N, Saudemont P, Balog J, Robin Y-M, Gimeno J-P, Pascal Q, Tierny D, Takats Z, Salzet M, Fournier Iet al., 2019, Water-assisted laser desorption/ionization mass spectrometry for minimally invasive in vivo and real-time surface analysis using SpiderMass, NATURE PROTOCOLS, Vol: 14, Pages: 3162-3182, ISSN: 1754-2189

Journal article

Tzafetas M, Mitra A, Kalliala I, Lever S, Bodai Z, Rosini F, Savage A, McKenzie J, MacIntyre D, Ghaem-Maghami S, Takats Z, Kyrgiou Met al., 2019, THE IKNIFE AND ITS APPLICATION FOR THE TREATMENT OF CERVICAL ABNORMALITIES, Publisher: BMJ PUBLISHING GROUP, Pages: A589-A589, ISSN: 1048-891X

Conference paper

Marcus D, Savage A, Balog J, Kudo H, Abda J, Dina R, Takats Z, Ghaem-Maghami Set al., 2019, ENDOMETRIAL CANCER: CAN THE IKNIFE DIAGNOSE ENDOMETRIAL CANCER?, Publisher: BMJ PUBLISHING GROUP, Pages: A100-A101, ISSN: 1048-891X

Conference paper

Mason S, Manoli E, Poynter L, Alexander J, Paizs P, Adebesin A, Goldin R, Darzi A, Takats Z, Kinross Jet al., 2019, Mass spectrometry transanal minimally invasive surgery (MS-TAMIS) to promote organ preservation in rectal cancer, Surgical Endoscopy: surgical and interventional techniques, Vol: 34, Pages: 3618-3625, ISSN: 0930-2794

BACKGROUND: Transanal minimally invasive surgery (TAMIS) is deployed for organ preservation in early rectal cancer and significant rectal polyps. Rapid evaporative ionisation mass spectrometry (REIMS) provides biochemical tissue analysis, which could be applied intraoperatively to give real-time tissue feedback to the surgeon and decrease the risk of an involved margin. However, the accuracy and feasibility of this approach have not been established. METHODS: In this prospective observational study, patients undergoing resection of rectal adenomas or carcinomas were recruited. An electrosurgical handpiece analysed tissues ex vivo using diathermy, with the aerosol aspirated into a Xevo G2-S ToF mass spectrometer. The relative abundance of lipids underwent predictive statistical modelling and leave-one-patient-out cross-validation. The outcomes of interest were the ability of REIMS to differentiate normal, adenomatous and cancerous tissue, or any disease subtype from normal. REIMS was coupled with TAMIS for in vivo sampling, assessing the accuracy of tissue recognition and distinguishing bowel wall layers. RESULTS: Forty-seven patients were included, yielding 266 spectra (121 normal, 109 tumour and 36 adenoma). REIMS differentiates normal, adenomatous and cancerous rectal tissues with 86.8% accuracy, and normal and adenomatous tissue with 92.4% accuracy and 91.4% accuracy when differentiating disease from normal. We have performed the first five in-man mass spectrometry augmented TAMIS (MS-TAMIS). In real time, MS-TAMIS can differentiate rectal mucosa and submucosa based on their relative abundance of triglycerides and glycerophospholipids. The ex vivo accuracy distinguishing diseased and normal tissues is maintained in vivo at 90%, with negative predictive value of 95%. The system identified a deep and lateral involved tumour margin during TAMIS. CONCLUSIONS: REIMS distinguishes rectal tissue types based on underlying lipid biology, and this can be translated in vivo

Journal article

Smith WD, Cameron SJ, Fletcher OL, Bardin E, Takats Z, Hogg C, Filloux A, Bush A, Davies JCet al., 2019, PSEUDOMONAS AERUGINOSA METABOLOME DIFFERENCES BETWEEN CF AND NON-CF BRONCHIECTASIS DETECTED USING DIRECT-FROM-SAMPLE MASS SPECTROMETRY, Pediatric Pulmonology, Publisher: WILEY, Pages: S313-S313, ISSN: 8755-6863

Conference paper

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

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, Vol: 218, Pages: 395-416, 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

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, Vol: 114, Pages: 1219-1230, 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

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, Vol: 91, Pages: 8873-8882, 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

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, Vol: 18, Pages: e210-e222, 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

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, Pages: 1-9, ISSN: 2045-2322

The morphological transformation of beef tissues after various processing treatments facilitates the addition of cheap offal products. Undetectable to the naked eye, analytical techniques are required to identify such scenarios within minced and processed products. DNA methodologies are ill-equipped to detect adulteration of offal cuts from the same species and vibrational spectroscopic studies, although rapid and non-destructive, have proved inconclusive as to whether the specific adulterant can be identified. For the first time we present a mass spectrometric approach employing an ambient ionisation process to eliminate sample preparation and provide near-instantaneous results. Rapid evaporative ionisation mass spectrometry (REIMS) was used to assess its capabilities of detecting minced beef adulteration with beef brain, heart, kidney, large intestine and liver tissues and chemometric analysis enabled unique or significant markers to be identified. The adulteration levels detected with the REIMS technology when analysing raw adulterated beef burgers were; brain (5%); heart (1–10%); kidney (1–5%); large intestine (1–10%) and liver (5–10%). For boiled adulterated samples; brain (5–10%); heart (1–10%); kidney (1–5%); large intestine (1–10%) and liver (5–10%). REIMS allows rapid and specific identification of offal cuts within adulterated beef burgers and could provide a paradigm shift across many authenticity applications.

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

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

Nucleoside-adduct analysis by liquid chromatography mass spectrometry is a powerful tool in genotoxicity studies. Efforts to date have quantified an impressive array of DNA damage products, although methodological diversity suggests quantification is still a challenging task. For example, inadequate co-examination of normal nucleosides, cumbersome sample preparation and large DNA requirements were identified to be recurring issues. A six-minute ultra-performance liquid chromatography method is presented which adequately separates seven candidate nucleoside-adducts from the four unmodified nucleosides. The method was sensitive to 1 adduct per 108 normal bases with 20 µg DNA input for most targets. The method was shown to be accurate (81–119% across quintuplets of six tissue types) and precise (relative standard deviation 4–13%). The fast method time facilitated a second quantitation for normal nucleosides at an appropriate dilution, allowing DNA damage concentrations to be contextualised accurately sample-to-sample. From DNA samples, the analytical processing time was < 8 h, and 96 samples can easily be prepared in a day. The method was used to quantify carbonyl, chloro- and oxo- adducts in murine tissue samples.

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/ionization mass spectrometry technology, Cancer Cell, Vol: 34, Pages: 840-851.e4, ISSN: 1535-6108

Histopathological diagnosis of biopsy samples and margin assessment of surgical specimens are challenging aspects in sarcoma. Using dog patient tissues, we assessed the performance of a recently developed technology for fast ex vivo molecular lipid-based diagnosis of sarcomas. The instrument is based on mass spectrometry (MS) molecular analysis through a laser microprobe operating under ambient conditions using excitation of endogenous water molecules. Classification models based on cancer/normal/necrotic, tumor grade, and subtypes showed a minimum of 97.63% correct classification. Specific markers of normal, cancer, and necrotic regions were identified by tandem MS and validated by MS imaging. Real-time detection capabilities were demonstrated by ex vivo analysis with direct interrogation of classification models.

Journal article

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