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Metabolomics for the diagnosis of bladder cancer: A systematic review |
Herney Andrés García-Perdomoa,b,*( ),Angélica María Dávila-Raigozab,Fernando Korkesc
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aDivision of Urology/Urooncology, Department of Surgery, School of Medicine, Universidad del Valle, Cali, Colombia bUROGIV Research Group, School of Medicine, Universidad del Valle, Cali, Colombia cUrologic Oncology, Division of Urology, ABC Medical School, Sao Paulo, Brazil |
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Abstract Objective: Metabolomics has been extensively utilized in bladder cancer (BCa) research, employing mass spectrometry and nuclear magnetic resonance spectroscopy to compare various variables (tissues, serum, blood, and urine). This study aimed to identify potential biomarkers for early BCa diagnosis. Methods: A search strategy was designed to identify clinical trials, descriptive and analytical observational studies from databases such as Medline, Embase, Cochrane Central Register of Controlled Trials, and Latin American and Caribbean Literature in Health Sciences. Inclusion criteria comprised studies involving BCa tissue, serum, blood, or urine profiling using widely adopted metabolomics techniques like mass spectrometry and nuclear magnetic resonance. Primary outcomes included description of metabolites and metabolomics profiling in BCa patients and the association of metabolites and metabolomics profiling with BCa diagnosis compared to control patients. The risk of bias was assessed using the Quality Assessment of Studies of Diagnostic Accuracy. Results: The search strategy yielded 2832 studies, of which 30 case-control studies were included. Urine was predominantly used as the primary sample for metabolite identification. Risk of bias was often unclear inpatient selection, blinding of the index test, and reference standard assessment, but no applicability concerns were observed. Metabolites and metabolomics profiles associated with BCa diagnosis were identified in glucose, amino acids, nucleotides, lipids, and aldehydes metabolism. Conclusion: The identified metabolites in urine included citric acid, valine, tryptophan, taurine, aspartic acid, uridine, ribose, phosphocholine, and carnitine. Tissue samples exhibited elevated levels of lactic acid, amino acids, and lipids. Consistent findings across tissue, urine, and serum samples revealed downregulation of citric acid and upregulation of lactic acid, valine, tryptophan, taurine, glutamine, aspartic acid, uridine, ribose, and phosphocholine.
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Received: 14 January 2022
Available online: 20 April 2024
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Corresponding Authors:
* Division of Urology/Urooncology, Department of Surgery, School of Medicine, Universidad del Valle, Cali, Colombia. E-mail address: herney.garcia@correounivalle.edu.co (H.A. García-Perdomo).
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Metabolomics technique | Advantage | Disadvantage | Applicable substance | NMR spectroscopy | -High reproducibility, straightforward sample preparation, preservation of molecular integrity, potential sample reuse, cost-effectiveness, and greater ease of identification compared to MS [14] | -Lower detectable metabolites in urine sample and lower sensitivity compared to MS [14] | -Body fluids, in vivo and in situ studies [13] | GC-MS | -Higher specificity and sensitivity, available for comparison with a standard, and can be used for both targeted and nontargeted analyses compared to NMR spectroscopy [12] | -The manipulation of low volatile molecules can present difficulties [12] | -Heat stable, volatile, medium, and low polar molecules [14] | LC-MS | -Higher specificity and sensitivity, available for comparison with a standard, and can be used for both targeted and nontargeted analyses compared to NMR spectroscopy [12,14] | -Low retention for hydrophilic molecules and no complete database to compare with a standard [14] | -Most compounds, including those that exhibit heat-lability, nonvolatility, and resistance to derivatization [12] |
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Advantages and limitations of NMR compared to MS in metabolomics applications.
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Flowchart of selected studies.
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Study | Country | Participant, n | Gender | Age, year | Analytical platform | Sample type | Cancer Pt, n | Control, n | Metabolite up-regulated in BCa | Metabolite down-regulated in BCa | Srivastava et al., 2010 [21] | India | 103 | ? Male and female | ? BCa: 45±25a (range 20-70) ? Control: 35±15a (range 20-50) | ? H-NMR | Urine | 33 | ? 70 o- HC: 37 o- UTI: 31 o- BS: 2 | ? Tau | ? Hippuric acid, citrate, and Phe | Kim et al., 2010 [23] | Republic of Korea | 19 | ? Male | ? BCa: range 47-78 ? Control: range 42-78 | ? GC-MS | Urine | 11 | ? HC: 8 | ? Val, Leu, pyroglutamic acid, Thr, Phe, Asp, glutamic acid, asparagine, alpha-aminoadipic acid, Tyr, and Trp | ? Ala, Gly, a-aminobutyric acid, serine, ornithine, Gln, and Lys | Pasikanti et al., 2010 [22] | Singapore | 75 | ? Male and female | ? BCa: 67.2±12.3a ? Control: 61.3±12.4a | ? GC/TOFMS | Urine | 24 | ? Non-BCa Pts: 51 | ? Melibiose, uridine, and Val | ? Senecioic acid, 2-butenedioic acid, ribonic acid, 2,5-furandicarboxylic acid, sumiki’s acid, 2-propenoic acid, glycerol, gluconic acid, valerate, fructose, citric acid, and ribitol | Putluri et al., 2011 [24] | USA | 134 | ? Male and female | NR | ? LC-MS | Urine | 83 | ? HC: 51 | ? Val, carnitine, Tyr, creatine, histidine, Leu/Ile, kynurenine, Phe, Lys, serine, thymine, guanine, and uracil | ? Histamine and palmitic acid | Gamagedara et al., 2012 [26] | USA | 23 | ? NR | NR | ? LC-MS | Urine | 11 | ? Non-BCa Pts: 12 | ? Tau | ? NR | Huang et al, 2011 [25] | China | 59 | ? Male and female | ? BCa: mean 56 (range 42-71) ? Control: mean 53 (range 46-67) | ? LC-MS | Urine | 27 | ? HC: 32 | ? NR | ? Carnitine and hippuric acid | Cao et al., 2012 [27] | China | 110 | ? Male | ? HC: 67.43±8.75a ? Calculi: 55.04±11.34a ? LBC: 60.26±14.52a ? HBC: 70.27±11.0a ? Post-TURBT: 66.65±9.42a | ? H-NMR | Serum | 37 | ? 73 o- HC: 25 o- CP: 28 o- Post-TURBT: 20 | ? Glucose, acetoacetate, and very low-density lipoprotein | ? Ile, Leu, Tyr, Phe, choline, lactate, Gly, and citrate | Huang et al., 2013 [31] | China | 43 | ? Male and female | ? BCa: mean 60.5 (range 45-74) ? Control: mean 50.5 (range 26-65) | ? LC-MS | Urine | 19 | ? HC: 24 | ? Tau | ? Carnitine and hippuric acid | Jobu et al., 2012 [32] | Japan | 16 | ? NR | ? NR | ? GC-MS | Urine | 9 | ? HC: 7 | ? Ethylbenzene, nonanoyl chloride, dodecanal, (Z)-2-nonenal, and 5-dimethyl-3(2H)-isoxazolone | ? NR | Lin et al., 2012 [28] | China | 68 | ? Male and female | ? HC: mean 45 (range 21-68) ? Nephrolithiasis: mean 54; range (31-74) ? BPH: mean 70 (range 65-82) ? BCa: mean 61 (range 45-74) | ? LC-MS | Serum | 20 | ? 48 o- HC: 20 o- Nephrolithiasis: 18 o- BPH: 10 | ? Eicosatrienol, azaprostanoic acid, docosatrienol, retinol, and 14-apo-beta-carotenal | ? NR | Tripathi et al., 2013 [35] | USA | 59 | ? Male and female | ? HC: 69.4±10.6a (range 51?87) ? BCa: o- Ta-T1: 60.1±11.5a (range 33?78) o- ≥T2: 68.8±11.7a (range 43?87) | ? HR-MAS-NMR GC-MS | Tissue | 33 | ? HC: 26 | ? Triglycerides, Leu, Ile, Val, lactate, Ala, acetate, Lys, glutamate, glutathione, Gln, aspartate, creatine, choline, phosphocholine, glycerophosphocholine, Tau, Gly, inositol, uridine diphosphate sugars, Phe, and Tyr | ? NR | Bansal et al., 2013 [30] | India | 99 | ? Male | ? >40 | ? H-NMR | Serum | 67 | ? HC: 32 | ? Dimethylamine, malonate, lactate, histidine, Val, and Gln | ? NR | Pasikanti et al., 2013 [29] | Singapore | 99 | ? Male and female | ? BCa: 68.3±10.9a ? Control: 60.5±12.7a | ? GC×GC-TOFMS | Urine | 38 | ? Non-BCa Pts: 61 | ? Adipic acid, anthranilic acid, coumaric acid derivative, cyclopentane-1, 2-diamine, erythritol, erythro-pentonic acid, ethylmalonic acid, gluconic acid derivative, heptadecanoic acid, hydroxybutyric acid, itaconic acid, lactic acid, melibiose, N-acetylanthranilic acid, p-cresol, pseudouridine, uridine, vanillylmandelic acid, 2,3,4,5-tetrahydroxypentanoic acid-1,4-lactone, 2-aminoisobutyric acid, 2-hydroxymalonic acid, 2-pentadecanol, 3,4-dihydroxyphenyl pyruvate, 3-hydroxysebacic acid, 3-methyladipic acid, and 4-methoxycinnamic acid | ? Citric acid, dihydroxyacetone, ethyl tartrate, gluconic acid, glycerol, levulinic acid enol, pinene, ribitol, ribonic acid, sebacic acid, Sumiki’s acid, 2,5-furandicarboxylic acid, 2-butanedioic acid, and 2-hydroxyglutaric acid | Jin et al., 2014 [33] | Republic of Korea | 259 | ? Male and female | ? BCa: 65.64±12.65a ? Control: 64.31±9.18a | ? HPLC-QTOFMS | Urine | 138 | ? 121 o- HC: 69 o- HU: 52 | ? Succinate, pyruvate, oxoglutarate, carnitine, phosphoenolpyruvate, trimethyllysine, isovalerylcarnitine, octenoylcarnitine, acetyl coenzyme A, carnitine palmitoyltransferase, and carnitine acylcarnitine | ? Melatonin, glutarylcarnitine, decanoylcarnitine, and dihydrolipoyl dehydrogenase (pyruvate dehydrogenase complex) | Peng et al., 2014 [34] | China and Canada | 285 | ? Male and female | ? BCa: 68±14a ? Control: 61±5a | ? LC-MS | Urine | 135 | ? 150 o- Hernia: 82; o- UTI or HU: 68 | ? 5-hydroxyindoleacetic acid, phosphoethanolamine, and pyroglutamic acid | ? Uridine and histamine | Wittmann et al, 2014 [36] | USA | 440 | ? Male and female | ? BCa: mean 67.4 ? Control: mean 64.2 | ? UHPLC-MS/MS- GC-MS | Urine | 95 | ? Non-BCa Pts: 345 | ? Lactate, acetylcarnitine, palmitoyl sphingomyelin, adipate, Trp, gluconate, Ile, Val, Leu, phosphocholine, choline, aspartate, beta-hydroxypyruvate, and guanine | ? 3-hydroxyphenylaceate, fructose, pyridoxate, succinate, xanthurenate, itaconate, 2-methylbutyrylglycine, pyruvic acid, citrate, tyramine, guanidinoacetate, anserine, gamma-aminobutyrate, creatine, adenosine, and ethanolamine | Shen et al., 2015 [37] | China | 44 | ? Male and female | ? BCa: 65.14±13.27a ? Control: 53.76 ±19.47a | ? UPLC-HRMS | Urine | 23 | ? HC: 21 | ? Nicotinuric acid, Asp, Gly, Trp, and trehalose | ? Gly, Cys, Ala, Lys, inosinic acid, and ureidosuccinic acid | Zhou et al., 2016 [38] | China | 140 | ? Male and female | ? BCa: 66±12.6a ? Control: 65.6±6.8a | ? GC-MS-SIM | Plasma | 92 | ? HC: 48 | ? Hypotaurine, uridine, malic acid, fumaric acid, creatinine, ribose, glycolic acid, gluconic acid, kynurenine, erythritol, ribonic acid, and serine | ? Hippuric acid, hypoxanthine, lactose, xylitol, eicosenoic acid, and glyoxylic acid | Shao et al., 2017 [40] | China | 122 | ? Male and female | ? BCa: 68.2±14.5a ? Control: 64.6±13.2a | ? UPLCTOF-MS | Urine | 87 | ? Hernia: 65 | ? Imidazoleacetic acid | ? NR | Tan et al., 2017 [39] | China | 172 | ? Male and female | ? NR | ? UHPLC-Q-TOFMS | Serum | 120 | ? HC: 52 | ? 5-aminoimidazole ribonucleotide, hypoxanthine, inosine, acetyl-N-formyl-5-methoxykynurenamine, Indoleacetic acid, glycocholic acid, phytosphingosine, sphinganine, and linolenyl carnitine | ? 3-hydroxyoctanoyl carnitine and 3-hydroxydecanoyl carnitine | Cheng et al, 2018 [42] | China | 284 | ? Male and female | ? BCa: 62.2±13.2a ? Control: 59.5±11.2a | ? LC-HRMS | Urine | 167 | ? HC: 117 | ? Dopamine 4-sulfate, doxazosin, dihydroferulic acid 4-O-glucuronide, ofloxacin, 15-dehydro-prostaglandin E1(1-), 4-(ethoxymethyl) phenol, ovalicin, flunisolide, (Z)-13-hexadecenoic acid, and alpha-ionol O-[arabinosyl-(1->6)-glucoside] | ? Aspartyl-histidine, tyrosyl-methionine, 3-hydroxy-carbofuran, 1,2-dehydrosalsolinol, ecabet, gossyvertin, avocadyne 4-acetate, 13-hydroxy-9-methoxy-10-oxo-11-octadecenoic acid, fluoxymesterone, and 1-acetoxy-2-hydroxy-16-heptadecen-4-one | Yumba Mpanga et al., 2018 [41] | Poland | 80 | ? Male and female | ? BCa: median 62; ? Control: median 60 | ? RP-HPLC-QQQ/MS | Urine | 40 | ? HC: 40 | ? Trimethyllysine, Tau, citrulline, acetyllysine, glucuronic acid, gluconic acid, N-acetylneuraminic acid, pseudouridine, xanthine, uridine, 7-methylguanine, aconitic acid, and Trp | ? 3,7-dimethyluric acid, 2-furoyglycine, 1,7-dimethylxanthine, and hippuric acid | Wei et al., 2019 [44] | China | 30 | ? NR | ? NR | ? HS-GC-MS | Blood | 15 | ? HC: 15 | ? Formaldehyde, acetaldehyde, propanal, butanal, pentanal, hexanal, and heptanal | ? NR | Jacyna et al, 2019 [43] | Poland | 48 | ? Male | ? NR | ? HPLC-TOF/MS, GC-QQQ/MS, and HNMR | Urine | 24 | ? HC: 24 | ? 2-deoxy-ribonic acid, diacetylspermine, meso-erythritol, Gln, lactic acid, pentanedioic acid, phenylacetylglutamine, propanoic acid, threonic acid, Tyr, uric acid, and uridine | ? S-adenosylmethionine, benzenediol, glycolic acid, hippuric acid, and pipecolic acid | Loras et al., 2019 [45] | Spain | 34 | ? Male and female | ? NR | ? H-NMR | Tissue and urine | 21 | ? Non-BCa Pts: 13 | ? Ala, Gln, glutamate, Tau, Pro, Gly, Thr, Phe, Val, Lys, methanol, creanine, choline, glycerol, glycerophosphocholine, phosphocholine, citrate, succinate, hippuric acid, lactic acid, Tau, and sucrose | ? Ala, Gln, glutamate, Tau, Pro, Gly, Thr, Phe, Val, Lys, methanol, creanine, choline, glycerol, glycerophosphocholine, phosphocholine, citrate, succinate, hippuric acid, lactic acid, Tau, and sucrose | Lin et al, 2021 [46] | China | 124 | ? Male and female | ? BCa: 67.4±13.5a ? Control: 65±12a | ? GC-MS | Urine | 63 | ? Hernia: 61 | ? Desaminotyrosine, erythritol, d-ribose, ribitol, d-fructose, d-mannose, and d-galactose | ? NR | Luczykowski et al, 2021 [47] | Poland | 48 | ? Male and female | ? BCa: 65±12a ? Control: 64±10.4a | ? LC-MS | Urine | 24 | ? HC: 24 | ? 2-acetyl-1-alkyl-sn-glycero-3, phosphocholine, and adenine | ? 3-dehydroxycarnitine, 3-methylxanthine, 4-hydroxycinnamic acid, 5-hydroxyindoleacetic acid, benzoic acid, carnosine, epinephrine, hippuric acid, histidine, isoniazid, n-acetyl-Phe, p-aminobenzoic acid, retinol, theophylline, gluconic acid, and indolelactic acid | Pinto et al., 2021 [48] | Portugal | 109 | ? Male and female | ? BCa: 68.9±10.6a ? Control: 51±5.2a | ? HS-SPME-GC-MS | Urine | 53 | ? Non-BCa Pts: 56 | ? 2-methylnonane, 2,4-dimethylheptane, 2,6-dimethylnonane, 1-methylnaphthalene, 2-methylnaphthalene, 1,2,4-trimethylbenzene, and p-cresol | ? 2-furaldehyde, 2-methylbutanal, formaldehyde, hexanal, 2-butanone, 4-heptanone, carvone, piperitone, and 1,5-dimethyl-6,8-dioxabicycloctane | Li et al, 2022 [49] | China | 95 | ? Male and female | ? BCa: 65.8±3.5a ? Control: 61±4.1a | ? LC-MS | Urine | 57 | ? Non-BCa Pts: 38 | ? Isoleucyl-Phe, choline, 1-methylhistidine, n-undecanoylglycine, linoleyl carnitine, adenosine-monophosphate, niacinamide, phenylalanyl-asparagine, and Tau | ? Mesobilirubinogen, 2-hydroxycaproic acid, urobilin, 6-hydroxyhexanoic acid, cytidine, dihydrotestosterone, histidine, flavin mononucleotide, valyl-serine, 4-acetamidobutanoic acid, (5R)-5-hydroxyhexanoic acid, adenosine, arginine, 1,11-undeanedicarboxylic acid, ubiquinone-2, butenylcarnitine, sebacic acid, and alanyl-tyrosine | Jacyna et al., 2022 [50] | Poland | 48 | ? Male and female | ? 69.6±5.6a | ? HPLC-TOF/MS, GC-QqQ/MS and H-NMR | Urine | 24 | ? HC: 24 | ? Benzenediol, 2-deoxy-ribonic acid, diacetylspermine, meso-erythritol, Gln, hippuric acid, lactic acid, pentanedioic acid, phenylacetylglutamine, pipecolic acid, propanoic acid, threonic acid, Tyr, uric acid, and uridine | ? Benzenediol, 2-deoxy-ribonic acid, diacetylspermine, meso-erythritol, Gln, hippuric acid, lactic acid, pentanedioic acid, phenylacetylglutamine, pipecolic acid, propanoic acid, threonic acid, Tyr, uric acid, and uridine |
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Characteristics of the included studies.
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Risk of bias assessment within studies.
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Risk of bias assessment across studies.
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Study | Sample type | Analytical platform | Anaerobic oxidation (glycolysis) | Aerobic oxidation (the TCA cycle) | Glucose | Fructose | Pyruvic acid | Lactose | Lactic acid | Citrate or citric acid | Succinate | Malic acid | Fumaric acid | Itaconate | Srivastava et al., 2010 [21] | Urine | H-NMR | | | | | | ↓ | | | | | Kim et al., 2010 [23] | Urine | GC-MS | | | | | | | | | | | Pasikanti et al., 2010 [22] | Urine | GC/TOFMS | | ↓ | | | | ↓ | | | | | Cao et al., 2012 [27] | Serum | H-NMR | ↑ | | | | ↓ | ↓ | | | | | Bansal et al., 2013 [30] | Serum | H-NMR | | | | | ↑ | | | | | | Pasikanti et al., 2013 [29] | Urine | GC×GC-TOFMS | | | | | | ↓ | | | | | Tripathi et al., 2013 [35] | Tissue | HR-MAS-NMR GC-MS | | | | | ↑ | | | | | | Jin et al., 2014 [33] | Urine | HPLC-QTOFMS | | | ↑ | | | | ↑ | | | | Wittmann et al., 2014 [36] | Urine | UHPLC-MS/MS GC-MS | | ↓ | ↓ | | ↑ | ↓ | ↓ | | | ↓ | Zhou et al., 2016 [38] | Plasma | GC-MS-SIM | | | | ↓ | | | | ↑ | ↑ | | Jacyna et al., 2019 [43] | Urine | MS and H-NMR | | | | | ↑ | | | | | | Loras et al., 2019 [45] | Urine | NMR | | | | | ↓↑ | ↓↑ | ↓↑ | | | | Jacyna et al., 2022 [50] | Urine | MS and H-NMR | | | | | ↑ | | | | | |
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Glucose metabolism-related metabolites in bladder cancer.
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Study | Sample type | Analytical platform | Essential amino acid | Non-essential amino acid | Leu | Met | Lys | Val | Ile | Phe | Trp | Thr | Ser | Cys | Asp | Pro | Arg | Tyr | Asn | Glu | Gly | Ala | His | Tau | Gln | Srivastava et al., 2010 [21] | Urine | H-NMR | | | | | | ↓ | | | | | | | | | | | | | | ↑ | | Kim et al., 2010 [23] | Urine | GC-MS | ↑ | | ↓ | ↑ | | | ↑ | ↑ | ↓ | | ↑ | | | ↑ | ↑ | | ↓ | ↑ | | | ↓ | Pasikanti et al., 2010 [22] | Urine | GC/TOFMS | | | | ↑ | | | | | | | | | | | | | | | | | | Gamagedara et al., 2012 [26] | Urine | LC-MS | | | | | | | | | | | | | | | | | | | | ↑ | | Putluri et al., 2011 [24] | Urine | LC-MS | ↑ | | ↑ | ↑ | ↑ | | | | ↑ | | | | | ↑ | | | | | ↑ | | | Huang et al., 2011 [25] | Urine | LC-MS | | | | | | | | | | | | | | | | | | | | ↑ | | Cao et al., 2012 [27] | Serum | H-NMR | ↓ | | | | ↓ | ↓ | | | | | | | | ↓ | | | ↓ | | | | | Bansal et al., 2013 [30] | Serum | H-NMR | | | | ↑ | | | | | | | | | | | | | | | ↑ | | ↑ | Tripathi et al., 2013 [35] | Tissue | HR-MAS-NMR GC-MS | ↑ | | ↑ | ↑ | ↑ | ↑ | | | | | ↑ | | | ↑ | | ↑ | ↑ | ↑ | | ↑ | ↑ | Wittmann et al., 2014 [36] | Urine | UHPLC-MS/MS GC-MS | ↑ | | | ↑ | ↑ | | ↑ | | | | | | | | | | | | ↑ | | ↑ | Shen et al., 2015 [37] | Urine | UPLC-HRMS | | | ↓ | | | | ↑ | | | ↓ | ↑ | | | | | | ↑ | ↓ | | | | Yumba Mpanga et al., 2018 [41] | Urine | RP-HPLC-QQQ/MS | | | | | | | ↑ | | | | | | | | | | | | | ↑ | | Jacyna et al., 2019 [43] | Urine | MS and H-NMR | | | | | | | | | | | | | | ↑ | | | | | | | ↑ | Loras et al., 2019 [45] | Tissue and urine | H-NMR | | | ↑↓ | ↑↓ | | | | ↑↓ | | | | ↑↓ | | | | ↑↓ | | ↑↓ | | ↑↓ | ↑↓ | ?uczykowski et al., 2021 [47] | Urine | LC-MS | | | | | | ↓ | | | | | | | | | | | | | ↓ | | | Li et al., 2022 [49] | Urine | LC-MS | | | | | | | | | | | | | ↓ | | | | | | ↓ | ↑ | | Jacyna et al., 2022 [50] | Urine | MS and H-NMR | | | | | | | | | | | | | | ↑↓ | | | | | | | ↑↓ |
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Metabolites of amino acid metabolism in bladder cancer.
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Study | Sample type | Analytical platform | Purine | Pyrimidine | Adenine | Guanine | Cytosine | Thymine | Uridine | Uracil | Inosine | Hypoxanthine | Ribose | Pasikanti et al., 2010 [22] | Urine | GC/TOFMS | | | | | ↑ | | | | | Putluri et al., 2011 [24] | Urine | LC-MS | | ↑ | | ↑ | | ↑ | | | | Tripathi et al., 2013 [35] | Tissue | H-NMR, GC-MS | | | | | ↑ | | | | | Pasikanti et al., 2013 [29] | Urine | GC×GC-TOFMS | | | | | ↑ | | | | ↑ | Peng et al., 2014 [34] | Urine | LC-MS | | | | | ↓ | | | | | Wittmann et al., 2014 [36] | Urine | UHPLC-MS/MS GC-MS | ↓ | ↑ | | | | | | | | Zhou et al., 2016 [38] | Plasma | GC-MS-SIM | | | | | ↑ | | | ↓ | ↑ | Tan et al., 2017 [39] | Serum | UHPLC-Q-TOFMS | | | | | | | ↑ | ↑ | | Yumba Mpanga et al., 2018 [41] | Urine | RP-HPLC-QQQ/MS | | | | | ↑ | | | | | Jacyna et al., 2019 [43] | Urine | MS, H-NMR | | | | | ↑ | | | | | Lin et al., 2021 [46] | Urine | GC-MS | | | | | | | | | ↑ | Li et al., 2022 [49] | Urine | LC-MS | ↓ | | | | | | | | | Jacyna et al., 2022 [50] | Urine | MS, H-NMR | | | | | ↑↓ | | | | |
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Nucleotide metabolites in bladder cancer.
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