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Accurate diagnosis and classification of kidney cancer are crucial for high-quality healthcare services. However, the current diagnostic platforms remain challenges in the rapid and accurate analysis of large-scale clinical biosamples. Herein, we fabricated a bifunctional smart nanoplatform based on tannic acid-modified gold nanoflowers (TA@AuNFs), integrating nanozyme catalysis for colorimetric sensing and self-assembled nanoarray-assisted LDI-MS analysis. The TA@AuNFs presented peroxidase (POD)- and glucose oxidase-like activity owing to the abundant galloyl residues on the surface of AuNFs. Combined with the colorimetric assay, the TA@AuNF-based sensing nanoplatform was used to directly detect glucose in serum for kidney tumor diagnosis. On the other hand, TA@AuNFs could self-assemble into closely packed and homogeneous two-dimensional (2D) nanoarrays at liquid-liquid interfaces by using Fe3+ as a mediator. The self-assembled TA@AuNFs (SA-TA@AuNFs) arrays were applied to assist the LDI-MS analysis of metabolites, exhibiting high ionization efficiency and excellent MS signal reproducibility. Based on the SA-TA@AuNF array-assisted LDI-MS platform, we successfully extracted metabolic fingerprints from urine samples, achieving early-stage diagnosis of kidney tumor, subtype classification, and discrimination of benign from malignant tumors. Taken together, our developed TA@AuNF-based bifunctional smart nanoplatform showed distinguished potential in clinical disease diagnosis, point-of-care testing, and biomarker discovery.
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Renal cell carcinoma (RCC) is a substantial pathology of the urinary system with a growing prevalence rate. However, current clinical methods have limitations for managing RCC due to the heterogeneity manifestations of the disease. Metabolic analyses are regarded as a preferred noninvasive approach in clinics, which can substantially benefit the characterization of RCC. This study constructs a nanoparticle-enhanced laser desorption ionization mass spectrometry (NELDI MS) to analyze metabolic fingerprints of renal tumors (n = 456) and healthy controls (n = 200). The classification models yielded the areas under curves (AUC) of 0.938 (95% confidence interval (CI), 0.884-0.967) for distinguishing renal tumors from healthy controls, 0.850 for differentiating malignant from benign tumors (95% CI, 0.821-0.915), and 0.925-0.932 for classifying subtypes of RCC (95% CI, 0.821-0.915). For the early stage of RCC subtypes, the averaged diagnostic sensitivity of 90.5% and specificity of 91.3% in the test set is achieved. Metabolic biomarkers are identified as the potential indicator for subtype diagnosis (p < 0.05). To validate the prognostic performance, a predictive model for RCC participants and achieve the prediction of disease (p = 0.003) is constructed. The study provides a promising prospect for applying metabolic analytical tools for RCC characterization.
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BACKGROUND AND AIMS: Biliary tract cancers are aggressive gastrointestinal malignancies characterized by a dismal 5-year overall survival rate <20%. Current diagnostic modalities suffer from limitations regarding sensitivity and specificity. This study aimed to develop a bile metabolite-based platform for precise discrimination between malignant and benign biliary diseases. APPROACH AND RESULTS: Samples were collected from 336 patients with biliary tract cancer or benign biliary diseases across 3 independent cohorts. Untargeted metabolic fingerprinting was performed on 300 bile samples using novel nanoparticle-enhanced laser desorption/ionization mass spectrometry. Subsequently, a diagnostic assay was developed based on the exploratory cohort using a selected bile metabolic biomarker panel, with performance evaluated in the validation cohort. Further external validation of disease-specific metabolites from bile samples was conducted in a prospective cohort (n = 36) using quantitative analysis. As a result, we established a novel bile-based assay, BileMet, for the rapid and precise detection of malignancies in the biliary tract system with an AUC of 0.891. We identified 6-metabolite biomarker candidates and discovered the critical role of the chenodeoxycholic acid glycine conjugate as a protective metabolite associated with biliary tract cancer. CONCLUSIONS: Our findings confirmed the improved diagnostic capabilities of BileMet assay in a clinical setting. If applied, the BileMet assay enables intraoperative testing and fast medical decision-making for cases with suspected malignancy where brush cytology detection fails to support malignancy, ultimately reducing the economic burden by over 90%.
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Polyphenols with antioxidant properties are of significant interest in medical and pharmaceutical applications. Given the diverse range of activities of polyphenols in vivo, accurate detection of these compounds plays a crucial role in nutritional surveillance and pharmaceutical development. Yet, the efficient quantitation of polyphenol contents and qualification of monomer compositions present a notable challenge when studying polyphenol bioavailability. In this study, platinum-modified nickel-iron layered double hydroxide (Pt/NiFe-LDH hybrids) were designed to mimic peroxidases for colorimetric analysis and act as enhanced matrices for laser desorption/ionization mass spectrometry (LDI MS) to quantify and qualify polyphenols. The hybrids exhibited an enzymatic activity of 33.472 U/mg for colorimetric assays, facilitating the rapid and direct quantitation of total tea polyphenols within approximately 1 min. Additionally, the heterogeneous structure and exposed hydroxyl groups on the hybrid surface contributed to photoelectric enhancement and in-situ enrichment of polyphenols in LDI MS. This study introduces an innovative approach to detect polyphenols using advanced materials, potentially inspiring the future development and applications of other photoactive nanomaterials.
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Accurate diagnosis of chronic obstructive pulmonary disease (COPD) and exacerbations by metabolic biomarkers enables individualized treatment. Advanced metabolic detection platforms rely on designed materials. Here, we design mesoporous PdPt alloys to characterize metabolic fingerprints for diagnosing COPD and exacerbations. As a result, the optimized PdPt alloys enable the acquisition of metabolic fingerprints within seconds, requiring only 0.5 µL of native plasma by laser desorption/ionization mass spectrometry owing to the enhanced electric field, photothermal conversion, and photocurrent response. Machine learning decodes metabolic profiles acquired from 431 individuals, achieving a precise diagnosis of COPD with an area under the curve (AUC) of 0.904 and an accurate distinction between stable COPD and acute exacerbations of COPD (AECOPD) with an AUC of 0.951. Notably, eight metabolic biomarkers identified accurately discriminate AECOPD from stable COPD while providing valuable information on disease progress. Our platform will offer an advanced nanoplatform for the management of COPD, complementing standard clinical techniques.
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Effective detection of bio-molecules relies on the precise design and preparation of materials, particularly in laser desorption/ionization mass spectrometry (LDI-MS). Despite significant advancements in substrate materials, the performance of single-structured substrates remains suboptimal for LDI-MS analysis of complex systems. Herein, designer Au@SiO2@ZrO2 core-shell substrates are developed for LDI-MS-based early diagnosis and prognosis of pancreatic cancer (PC). Through controlling Au core size and ZrO2 shell crystallization, signal amplification of metabolites up to 3 orders is not only achieved, but also the synergistic mechanism of the LDI process is revealed. The optimized Au@SiO2@ZrO2 enables a direct record of serum metabolic fingerprints (SMFs) by LDI-MS. Subsequently, SMFs are employed to distinguish early PC (stage I/II) from controls, with an accuracy of 92%. Moreover, a prognostic prediction scoring system is established with enhanced efficacy in predicting PC survival compared to CA19-9 (p < 0.05). This work contributes to material-based cancer diagnosis and prognosis.
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Detección Precoz del Cáncer , Oro , Neoplasias Pancreáticas , Dióxido de Silicio , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Circonio , Neoplasias Pancreáticas/diagnóstico , Humanos , Circonio/química , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Pronóstico , Detección Precoz del Cáncer/métodos , Oro/química , Dióxido de Silicio/químicaRESUMEN
Prostate cancer (PCa) is the second most common cancer in males worldwide. The Gleason scoring system, which classifies the pathological growth pattern of cancer, is considered one of the most important prognostic factors for PCa. Compared to indolent PCa, PCa with high Gleason score (h-GS PCa, GS ≥ 8) has greater clinical significance due to its high aggressiveness and poor prognosis. It is crucial to establish a rapid, non-invasive diagnostic modality to decipher patients with h-GS PCa as early as possible. In this study, ferric nanoparticle-assisted laser desorption/ionization mass spectrometry (FeNPALDI-MS) to extract prostate fluid metabolic fingerprint (PSF-MF) is employed and combined with the clinical features of patients, such as prostate-specific antigen (PSA), to establish a multi-modal diagnosis assisted by machine learning. This approach yields an impressive area under the curve (AUC) of 0.87 to diagnose patients with h-GS, surpassing the results of single-modal diagnosis using only PSF-MF or PSA, respectively. Additionally, using various screening methods, six key metabolites that exhibit greater diagnostic efficacy (AUC = 0.96) are identified. These findings also provide insights into related metabolic pathways, which may provide valuable information for further elucidation of the pathological mechanisms underlying h-GS PCa.
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Serum united urine metabolic analysis comprehensively reveals the disease status for kidney diseases in particular. Thus, the precise and convenient acquisition of metabolic molecular information from united biofluids is vitally important for clinical disease diagnosis and biomarker discovery. Laser desorption/ionization mass spectrometry (LDI-MS) presents various advantages in metabolic analysis; however, there remain challenges in ionization efficiency and MS signal reproducibility. Herein, we constructed a self-assembled hyperbranched black gold nanoarray (HyBrAuNA) assisted LDI-MS platform to profile serum united urine metabolic fingerprints (S-UMFs) for diagnosis of early stage renal cell carcinoma (RCC). The closely packed HyBrAuNA afforded strong electromagnetic field enhancement and high photothermal conversion efficacy, enabling effective ionization of low abundant metabolites for S-UMF collection. With a uniform nanoarray, the platform presented excellent reproducibility to ensure the accuracy of S-UMFs obtained in seconds. When it was combined with automated machine learning analysis of S-UMFs, early stage RCC patients were discriminated from the healthy controls with an area under the curve (AUC) > 0.99. Furthermore, we screened out a panel of 9 metabolites (4 from serum and 5 from urine) and related pathways toward early stage kidney tumor. In view of its high-throughput, fast analytical speed, and low sample consumption, our platform possesses potential in metabolic profiling of united biofluids for disease diagnosis and pathogenic mechanism exploration.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/metabolismo , Reproducibilidad de los Resultados , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Neoplasias Renales/patología , Riñón/metabolismoRESUMEN
Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and aggressive malignancy, and timely diagnosis of ESCC contributes to an increased cancer survival rate. However, current detection methods for ESCC mainly rely on endoscopic examination, limited by a relatively low participation rate. Herein, ferric-particle-enhanced laser desorption/ionization mass spectrometry (FPELDI MS) is utilized to record the serum metabolic fingerprints (SMFs) from a retrospective cohort (523 non-ESCC participants and 462 ESCC patients) to build diagnostic models toward ESCC. The PFELDI MS achieved high speed (≈30 s per sample), desirable reproducibility (coefficients of variation < 15%), and high throughput (985 samples with ≈124â¯200 data points for each spectrum). Desirable diagnostic performance with area-under-the-curves (AUCs) of 0.925-0.966 is obtained through machine learning of SMFs. Further, a metabolic biomarker panel is constructed, exhibiting superior diagnostic sensitivity (72.2-79.4%, p < 0.05) as compared with clinical protein biomarker tests (4.3-22.9%). Notably, the biomarker panel afforded an AUC of 0.844 (95% confidence interval [CI]: 0.806-0.880) toward early ESCC diagnosis. This work highlighted the potential of metabolic analysis for accurate screening and early detection of ESCC and offered insights into the metabolic characterization of diseases including but not limited to ESCC.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/diagnóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Esofágicas/diagnóstico , Reproducibilidad de los Resultados , Biomarcadores de TumorRESUMEN
OBJECTIVE: Metabolic biomarkers are expected to decode the phenotype of gastric cancer (GC) and lead to high-performance blood tests towards GC diagnosis and prognosis. We attempted to develop diagnostic and prognostic models for GC based on plasma metabolic information. DESIGN: We conducted a large-scale, multicentre study comprising 1944 participants from 7 centres in retrospective cohort and 264 participants in prospective cohort. Discovery and verification phases of diagnostic and prognostic models were conducted in retrospective cohort through machine learning and Cox regression of plasma metabolic fingerprints (PMFs) obtained by nanoparticle-enhanced laser desorption/ionisation-mass spectrometry (NPELDI-MS). Furthermore, the developed diagnostic model was validated in prospective cohort by both NPELDI-MS and ultra-performance liquid chromatography-MS (UPLC-MS). RESULTS: We demonstrated the high throughput, desirable reproducibility and limited centre-specific effects of PMFs obtained through NPELDI-MS. In retrospective cohort, we achieved diagnostic performance with areas under curves (AUCs) of 0.862-0.988 in the discovery (n=1157 from 5 centres) and independent external verification dataset (n=787 from another 2 centres), through 5 different machine learning of PMFs, including neural network, ridge regression, lasso regression, support vector machine and random forest. Further, a metabolic panel consisting of 21 metabolites was constructed and identified for GC diagnosis with AUCs of 0.921-0.971 and 0.907-0.940 in the discovery and verification dataset, respectively. In the prospective study (n=264 from lead centre), both NPELDI-MS and UPLC-MS were applied to detect and validate the metabolic panel, and the diagnostic AUCs were 0.855-0.918 and 0.856-0.916, respectively. Moreover, we constructed a prognosis scoring system for GC in retrospective cohort, which can effectively predict the survival of GC patients. CONCLUSION: We developed and validated diagnostic and prognostic models for GC, which also contribute to advanced metabolic analysis towards diseases, including but not limited to GC.
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Biothiols participate in numerous physiological and pathological processes in an organism. Quantitative determination and reaction monitoring of biothiols have important implications for evaluating human health. Herein, we synthesized plasmonic alloys as the matrix to assist the laser desorption and ionization (LDI) process of biothiols in mass spectrometry (MS). Plasmonic alloys were constructed with mesoporous structures for LDI enhancement and trimetallic (PdPtAu) compositions for noble metal-thiol hybridization, toward enhanced detection sensitivity and selectivity, respectively. Plasmonic alloys enabled direct detection of biothiols from complex biosamples without any enrichment or separation. We introduced internal standards into the quantitative MS system, achieving accurate quantitation of methionine directly from serum samples with a recovery rate of 103.19% ± 6.52%. Moreover, we established a rapid monitoring platform for the oxidation-reduction reaction of glutathione, consuming trace samples down to 200 nL with an interval of seconds. This work contributes to the development of molecular tools based on plasmonic materials for biothiol detection toward real-case applications.
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Aleaciones , Compuestos de Sulfhidrilo , Humanos , Compuestos de Sulfhidrilo/química , Espectrometría de Masas , Glutatión/química , Oxidación-ReducciónRESUMEN
Accurate and rapid metabolic profiling of cerebrospinal fluid (CSF) is urgently needed but remains challenging for clinical diagnosis of central nervous system diseases and biomarker discovery. Matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) holds promise for metabolic analysis. Its low signal reproducibility, however, severely restricts acquisition of quantitative MS data in clinical practice. Herein, a multifunctional self-assembled AuNPs array (MSANA)-based LDI-MS platform for direct amino acids analysis and metabolic profiling in patient CSF samples is developed. MSANA featuring a highly ordered and closely packed two-dimensional nanostructure permits capture and direct analysis of aromatic amino acids by LDI-MS with high selectivity and micromolar sensitivity. Meanwhile, the MSANA-based LDI-MS platform exhibits excellent reproducibility (RSD < 10%), largely outperforming the direct matrix spotting approach widely used now (RSD < 44%). The platform is successfully used in metabolic profiling of CSF (1 µL) within minutes for discrimination of medulloblastoma patients from non-tumor controls. Taken together, the MSANA-based LDI-MS platform shows potential clinical values toward large-scale metabolic diagnostics and pathogenic mechanism study.
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Oro , Nanopartículas del Metal , Humanos , Reproducibilidad de los Resultados , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Metabolómica/métodosRESUMEN
Glucose is a source of energy for daily activities of the human body and is regarded as a clinical biomarker, due to the abnormal glucose level in the blood leading to many endocrine metabolic diseases. Thus, it is indispensable to develop simple, accurate, and sensitive methods for glucose detection. However, the current methods mainly depend on natural enzymes, which are unstable, hard to prepare, and expensive, limiting the extensive applications in clinics. Herein, we propose a dual-mode Cu2O nanoparticles (NPs) based biosensor for glucose analysis based on colorimetric assay and laser desorption/ionization mass spectrometry (LDI MS). Cu2O NPs exhibited excellent peroxidase-like activity and served as a matrix for LDI MS analysis, achieving visual and accurate quantitative analysis of glucose in serum. Our proposed method possesses promising application values in clinical disease diagnostics and monitoring.
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On-site screening of diabetes and precise diagnosis of diabetic complications may provide a conduit for early intervention and disease burden reduction. However, stratified metabolic analysis needs designed materials for colorimetric detection of targeted biomarkers and direct metabolic fingerprinting of the native blood. Here, an advanced dual-modal nanoplatform is constructed based on PdPtAu alloys, which serve both as the nanoenzymes in colorimetric sensing for targeted metabolite quantitation and as matrix in laser desorption/ionization mass spectrometry for untargeted metabolic fingerprinting. The platform achieved rapid glucose quantitation toward point-of-care testing of 27 participants and identified diabetic retinopathy from diabetic population with a sensitivity and specificity of 84.6%. We further assessed the generalizability of the nanoplatform for real-case applications, through the captured digital images and computing resources equipped in smartphones. The results advance the design of material-based platforms for stratified metabolic analysis and display promise to fit in the current hierarchical medical system in practice.
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Técnicas Biosensibles , Diabetes Mellitus , Retinopatía Diabética , Aleaciones , Colorimetría , Diabetes Mellitus/diagnóstico , Humanos , Teléfono InteligenteRESUMEN
Pathogenic bacteria have become a huge threat to social health and economy for their frighteningly infectious and lethal capacity. It is quite important to make a diagnosis in advance to prevent infection or allow a rapid treatment after infection. Noble metal nanoparticles, due to their unique physicochemical properties, especially optical properties, have drawn a great attention during the past decades and have been widely applied into all kinds of fields related to human health. By utilizing these noble metal nanoparticles, optical diagnosis platforms towards pathogenic bacteria have emerged continually, providing highly sensitive, selective, and particularly facile detection tools for clinic or point-of-care diagnosis. This review summarizes the recent development in this field. It begins with a brief introduction of pathogenic bacteria and noble metal nanoparticles. And then, optical detection methods are systematically discussed in three distinct aspects. In addition to these proof-of-concept methods, corresponding algorithms and point-of-care detection devices are also described. Finally, the review ends up with subjective views on present limitations and some appropriate advice for future research directions.
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Bacterias/aislamiento & purificación , Técnicas Bacteriológicas/métodos , Técnicas de Química Analítica/métodos , Nanopartículas del Metal/química , Técnicas Bacteriológicas/instrumentación , Técnicas de Química Analítica/instrumentación , Metales Pesados/química , Pruebas en el Punto de AtenciónRESUMEN
In this work, we reported a facile and highly sensitive strategy for colorimetric detection of cysteine (Cys) based on the inhibition of catalytic activity of bimetallic nanoclusters induced by Cys. Glutathione-modified gold-platinum nanoclusters (GSH-Au/Pt NCs) with different Au/Pt molar ratios were prepared via one-pot approach and utilized as peroxidase mimics to catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2. It has been found that Cys could inhibit the peroxidase-like activity of GSH-Au/Pt NCs efficiently, which leads to a decrease of the absorption intensity of the system at 652 nm with a fading of the blue color. These findings provide a worthy method for visualization and quantitative detection of Cys with different concentrations in the range from 0.5 to 30 µM, and the detection limit is 0.154 µM. Moreover, this method displays a promising application in colorimetric analysis of Cys in urine samples.
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Colorimetría , Nanopartículas del Metal , Cisteína , Glutatión , Oro , Peróxido de Hidrógeno , Límite de Detección , Peroxidasa , PeroxidasasRESUMEN
A novel construction of compactly supported orthogonal scaling functions and wavelets with spline functions is presented in this paper. Let [Formula: see text] be the center B-spline of order n, except for the case of order one, we know [Formula: see text] is not orthogonal. But by the formula of orthonormalization procedure, we can construct an orthogonal scaling function corresponding to [Formula: see text]. However, unlike [Formula: see text] itself, this scaling function no longer has compact support. To induce the orthogonality while keeping the compact support of [Formula: see text], we put forward a simple, yet efficient construction method that uses the formula of orthonormalization procedure and the weighted average method to construct the two-scale symbol of some compactly supported orthogonal scaling functions.