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1.
Metabolomics ; 16(3): 29, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32095917

RESUMO

INTRODUCTION: Colorectal cancer (CRC) remains an incurable disease. Previous metabolomic studies show that metabolic signatures in plasma distinguish CRC patients from healthy controls. Chronic enteritis (CE) represents a risk factor for CRC, with a 20 fold greater incidence than in healthy individuals. However, no studies have performed metabolomic profiling to investigate CRC biomarkers in CE. OBJECTIVE: Our aims were to identify metabolomic signatures in CRC and CE and to search for blood-derived metabolite biomarkers distinguishing CRC from CE, especially early-stage biomarkers. METHODS: In this case-control study, 612 subjects were prospectively recruited between May 2015 and May 2016, and including 539 CRC patients (stage I, 102 cases; stage II, 259 cases; stage III, 178 cases) and 73 CE patients. Untargeted metabolomics was performed to identify CRC-related metabolic signatures in CE. RESULTS: Five pathways were significantly enriched based on 153 differential metabolites between CRC and CE. 16 biomarkers were identified for diagnosis of CRC from CE and for guiding CRC staging. The AUC value for CRC diagnosis in the external validation set was 0.85. Good diagnostic performances were also achieved for early-stage CRC (stage I and stage II), with an AUC value of 0.84. The biomarker panel could also stage CRC patients, with an AUC of 0.72 distinguishing stage I from stage II CRC and AUC of 0.74 distinguishing stage II from stage III CRC. CONCLUSIONS: The identified metabolic biomarkers exhibit promising properties for CRC monitoring in CE patients and are superior to commonly used clinical biomarkers (CEA and CA19-9).

2.
Anal Chem ; 91(18): 11897-11904, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31436405

RESUMO

SWATH-MS-based data-independent acquisition mass spectrometry (DIA-MS) technology has been recently developed for untargeted metabolomics due to its capability to acquire all MS2 spectra with high quantitative accuracy. However, software tools for deconvolving multiplexed MS/MS spectra from SWATH-MS with high efficiency and high quality are still lacking in untargeted metabolomics. Here, we developed a new software tool, namely, DecoMetDIA, to deconvolve multiplexed MS/MS spectra for metabolite identification and support the SWATH-based untargeted metabolomics. In DecoMetDIA, multiple model peaks are selected to model the coeluted and unresolved chromatographic peaks of fragment ions in multiplexed spectra and decompose them into a linear combination of the model peaks. DecoMetDIA enabled us to reconstruct the MS2 spectra of metabolites from a variety of different biological samples with high coverages. We also demonstrated that the deconvolved MS2 spectra from DecoMetDIA were of high accuracy through comparison to the experimental MS2 spectra from data-dependent acquisition (DDA). Finally, about 90% of deconvolved MS2 spectra in various biological samples were successfully annotated using software tools such as MetDNA and Sirius. The results demonstrated that the deconvolved MS2 spectra obtained from DecoMetDIA were accurate and valid for metabolite identification and structural elucidation. The comparison of DecoMetDIA to other deconvolution software such as MS-DIAL demonstrated that it performs very well for small polar metabolites. DecoMetDIA software is freely available at https://github.com/ZhuMSLab/DecoMetDIA .

3.
Ultraschall Med ; 40(6): 764-770, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30253431

RESUMO

PURPOSE: To analyze the ultrasonographic findings of invasive lobular carcinoma (ILC) of the breast in 360 women and the correlations between the characteristics and the intrinsic subtypes. MATERIALS AND METHODS: We evaluated the imaging findings according to the lexicon of the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS). The included ultrasonographic features were shape, orientation, margin, echo pattern, posterior features, calcifications, the vascularity of the masses and the presence of architectural distortions. The associations between those features and the intrinsic ILC subtypes were investigated. RESULTS: The most common manifestations of ILC on ultrasound (US) were hypoechoic masses with irregular shape, parallel orientation, spiculated margin, posterior acoustic shadowing, no calcification and blood vessels in the rim. The patients in the luminal A subtype were the youngest, and the patients in the HER2 overexpression subtype were the oldest (p = 0.01). On US, the HER2 overexpression subtype was characterized by microlobulated margins (p = 0.002), while the luminal A subtype and the luminal B subtype mostly had spiculated margins. The basal-like subtype was distinctive in that it had no posterior features (p = 0.041), rather than acoustic shadowing, and the masses in the HER2 and basal-like subtypes were larger than in the other two groups (p = 0.03). CONCLUSION: There were significant differences and several trends in the ultrasonographic characteristics of different intrinsic subtypes, which may supply accurate imaging diagnostic criteria to assist in the management of individuals with ILC.


Assuntos
Neoplasias da Mama , Carcinoma Lobular , Mama , Neoplasias da Mama/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Carcinoma Lobular/diagnóstico por imagem , Feminino , Humanos , Mamografia , Estudos Retrospectivos , Ultrassonografia , Ultrassonografia Mamária
4.
Anal Chem ; 91(3): 2401-2408, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30580524

RESUMO

The metabolic profiling of biofluids using untargeted metabolomics provides a promising choice to discover metabolite biomarkers for clinical cancer diagnosis. However, metabolite biomarkers discovered in biofluids may not necessarily reflect the pathological status of tumor tissue, which makes these biomarkers difficult to reproduce. In this study, we developed a new analysis strategy by integrating the univariate and multivariate correlation analysis approach to discover tumor tissue derived (TTD) metabolites in plasma samples. Specifically, untargeted metabolomics was first used to profile a set of paired tissue and plasma samples from 34 colorectal cancer (CRC) patients. Next, univariate correlation analysis was used to select correlative metabolite pairs between tissue and plasma, and a random forest regression model was utilized to define 243 TTD metabolites in plasma samples. The TTD metabolites in CRC plasma were demonstrated to accurately reflect the pathological status of tumor tissue and have great potential for metabolite biomarker discovery. Accordingly, we conducted a clinical study using a set of 146 plasma samples from CRC patients and gender-matched polyp controls to discover metabolite biomarkers from TTD metabolites. As a result, eight metabolites were selected as potential biomarkers for CRC diagnosis with high sensitivity and specificity. For CRC patients after surgery, the survival risk score defined by metabolite biomarkers also performed well in predicting overall survival time ( p = 0.022) and progression-free survival time ( p = 0.002). In conclusion, we developed a new analysis strategy which effectively discovers tumor tissue related metabolite biomarkers in plasma for cancer diagnosis and prognosis.

5.
Clin Chim Acta ; 487: 357-362, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30296444

RESUMO

BACKGROUND: Many studies have demonstrated that right-sided colon cancer (RCC) has a higher mortality rate and worse prognosis than left-sided colon cancer (LCC). However, the underlying biological mechanism that can account for these differences is unclear. METHODS: In this study, plasma metabolic profiles in 147 LCC patients and 105 RCC patients were systematically analyzed by the ultra high performance liquid chromatography quadruple time-of-flight mass spectrometry (UHPLC-QTOF/MS) platform in conjunction with univariate and multivariate statistical analysis. RESULTS: Metabolic signatures revealed considerable differences between patients with RCC and LCC, and clear separations were observed between the two groups in partial least-squares discriminant analysis score plots. In total, six metabolites were identified as potential metabolite markers for tumor location in RCC compared with LCC, including upregulated trimethylamine N-oxide and indoxyl sulfate, and downregulated anserine, L-targinine, gamma-glutamyl-gamma-aminobutyraldehyde and pyridoxal 5'-phosphate. These differences highlight that significant alternations occur in the pathways of methane metabolism, arginine and proline metabolism, histidine metabolism, beta-alanine metabolism and vitamin B6 metabolism in RCC compared with LCC. CONCLUSIONS: Identified biomarkers and metabolic pathways may facilate our understanding of the different mortality rates and prognoses between RCC and LCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Metabolômica , Biomarcadores Tumorais/sangue , Cromatografia Líquida de Alta Pressão , Neoplasias do Colo/sangue , Neoplasias do Colo/diagnóstico , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Análise Multivariada
6.
Anal Chem ; 90(6): 4062-4070, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-29485856

RESUMO

The complexity of metabolome presents a great analytical challenge for quantitative metabolite profiling, and restricts the application of metabolomics in biomarker discovery. Targeted metabolomics using multiple-reaction monitoring (MRM) technique has excellent capability for quantitative analysis, but suffers from the limited metabolite coverage. To address this challenge, we developed a new strategy, namely, SWATHtoMRM, which utilizes the broad coverage of SWATH-MS technology to develop high-coverage targeted metabolomics method. Specifically, SWATH-MS technique was first utilized to untargeted profile one pooled biological sample and to acquire the MS2 spectra for all metabolites. Then, SWATHtoMRM was used to extract the large-scale MRM transitions for targeted analysis with coverage as high as 1000-2000 metabolites. Then, we demonstrated the advantages of SWATHtoMRM method in quantitative analysis such as coverage, reproducibility, sensitivity, and dynamic range. Finally, we applied our SWATHtoMRM approach to discover potential metabolite biomarkers for colorectal cancer (CRC) diagnosis. A high-coverage targeted metabolomics method with 1303 metabolites in one injection was developed to profile colorectal cancer tissues from CRC patients. A total of 20 potential metabolite biomarkers were discovered and validated for CRC diagnosis. In plasma samples from CRC patients, 17 out of 20 potential biomarkers were further validated to be associated with tumor resection, which may have a great potential in assessing the prognosis of CRC patients after tumor resection. Together, the SWATHtoMRM strategy provides a new way to develop high-coverage targeted metabolomics method, and facilitates the application of targeted metabolomics in disease biomarker discovery. The SWATHtoMRM program is freely available on the Internet ( http://www.zhulab.cn/software.php ).


Assuntos
Espectrometria de Massas/métodos , Metaboloma , Metabolômica/métodos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Humanos , Células Jurkat , Reprodutibilidade dos Testes , Fluxo de Trabalho
7.
Exp Ther Med ; 15(3): 3088-3095, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29456712

RESUMO

Gastric cancer (GC) poses a serious public health threat and the 5-year survival rate of patients with GC is low. MicroRNAs (miRNAs/miRs) may serve oncogenic or tumor suppressor functions during tumorigenesis by regulating cell proliferation, apoptosis, migration and invasion and it has been demonstrated that they may be dysregulated in various types of cancer. The present study demonstrated that miR-144 and GATA4 were downregulated in GC tissues and cell lines and suggested that this may be due to hypermethylation. Additionally, miR-144 and GATA4 had synergistic effects on GC cells by repressing cell proliferation and inducing cell cycle arrest and apoptosis. The results of bioinformatics and a luciferase reporter assay indicated that cyclooxygenase-2 (COX-2) is a direct target of miR-144 and that miR-144 negatively regulated the expression of COX-2, which inhibits the viability of GC cells. GATA4 also induced a similar effect on COX-2. Taken together, the results of the present study may improve understanding of the underlying mechanism of miR-144 and GATA4 in GC.

8.
Metabolomics ; 14(9): 110, 2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30830371

RESUMO

INTRODUCTION: Colorectal cancer (CRC) is a clinically heterogeneous disease, which necessitates a variety of treatments and leads to different outcomes. Only some CRC patients will benefit from neoadjuvant chemotherapy (NACT). OBJECTIVES: An accurate prediction of response to NACT in CRC patients would greatly facilitate optimal personalized management, which could improve their long-term survival and clinical outcomes. METHODS: In this study, plasma metabolite profiling was performed to identify potential biomarker candidates that can predict response to NACT for CRC. Metabolic profiles of plasma from non-response (n = 30) and response (n = 27) patients to NACT were studied using UHPLC-quadruple time-of-flight)/mass spectrometry analyses and statistical analysis methods. RESULTS: The concentrations of nine metabolites were significantly different when comparing response to NACT. The area under the receiver operating characteristic curve value of the potential biomarkers was up to 0.83 discriminating the non-response and response group to NACT, superior to the clinical parameters (carcinoembryonic antigen and carbohydrate antigen 199). CONCLUSION: These results show promise for larger studies that could result in more personalized treatment protocols for CRC patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Metabolômica , Biomarcadores Tumorais/sangue , Cromatografia Líquida de Alta Pressão , Neoplasias Colorretais/sangue , Feminino , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Terapia Neoadjuvante
9.
Minerva Med ; 109(2): 141-149, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28398026

RESUMO

INTRODUCTION: Controversies persist between associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) and conventional staged hepatectomy. This meta-analysis aims to compare completion, regeneration capacity, and surgical outcomes between the two strategies. EVIDENCE ACQUISITION: We systematically searched PubMed, EMBASE, Cochrane Library, Medline. The main endpoints consisted of completion rate, future liver remnant (FLR) hypertrophy ratio, morbidity, major complication, minor complication, post-hepatectomy liver failure (PHLF) and mortality. Pooled data was assessed by the use of a random-effects model. Odds ratios (OR) were calculated for dichotomous outcomes and mean differences (MD) for continuous outcomes. EVIDENCE SYNTHESIS: Of the 124 identified studies, 7 were eligible and were included in our analysis (N.=525 participants). In the two groups, there was no statistical difference in morbidity (OR=1.62; 95% CI: 0.81-3.20; Z=1.37; P=0.17), minor complication rate (OR=1.27; 95% CI: 0.50-3.21; Z=0.51; P=0.61), PHLF rate (OR=0.87; 95% CI: 0.34-2.22; Z=0.30; P=0.76), mortality (OR=1.68; 95% CI: 0.59-4.83; Z=0.97; P=0.33). Meanwhile, statistical significance was showed in the completion rate (OR=8.29; 95% CI: 2.49-27.53; Z=3.45; P=0.0006), FLR hypertrophy ratio (MD=28.00; 95% CI: 16.06-39.93; Z=4.60; P<0.00001) and major complication rate (OR=1.83; 95% CI: 1.08-3.10; Z=2.26; P=0.02). CONCLUSIONS: Compared with conventional staged hepatectomy, ALPPS provides a higher completion rate and FLR hypertrophy ratio. However, it results in more major complications. Conventional staged hepatectomy is not better than ALPPS in the aspects of minor complication, PHLF, morbidity and mortality.


Assuntos
Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Veia Porta/cirurgia , Humanos , Ligadura , Regeneração Hepática , Resultado do Tratamento
10.
Sci Rep ; 7(1): 6069, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28729678

RESUMO

There are limited therapeutic methods for triple negative breast cancer in the clinic, which is easy to progress into the brain to form metastatic lesions and evolve into the terminal stage. Because both the primary cancer and the brain metastasis have high glycolysis, we hypothesize that lactate dehydrogenase (LDH), which catalyzes the final step of glycolysis, may be a predictor, as well as a treatment target, for breast cancer brain metastasis. Therefore, the expression of LDH-A was detected on 119 triple negative breast cancer tissues with immunohistochemistry, and the serum LDH levels were also measured. Our results showed that the LDH-A expression inside the tumor was significantly higher than the matched normal tissues. Tumor LDH-A expression, serum LDH status, and the slope of serum LDH status were closely associated with triple negative breast cancer brain metastasis and brain metastasis free survival. This study indicates that tumor LDH and serum LDH status are two predictors for triple negative breast cancer brain metastasis.


Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , L-Lactato Desidrogenase/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Isoenzimas/sangue , Isoenzimas/metabolismo , Estimativa de Kaplan-Meier , L-Lactato Desidrogenase/sangue , Metaboloma , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Neoplasias de Mama Triplo Negativas/sangue , Neoplasias de Mama Triplo Negativas/mortalidade
11.
Oncotarget ; 8(21): 35460-35472, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28389626

RESUMO

Colorectal cancer (CRC) remains an incurable disease. There are no effective noninvasive techniques that have achieved colorectal cancer (CRC) diagnosis, prognosis, survival and recurrence in clinic. To investigate colorectal cancer metabolism, we perform an electronic literature search, from 1998 to January 2016, for studies evaluating the metabolomic profile of patients with CRC regarding the diagnosis, recurrence, prognosis/survival, and systematically review the twenty-three literatures included. QUADOMICS tool was used to assess the quality of them. We highlighted the metabolism perturbations based on metabolites and pathway. Metabolites related to cellular respiration, carbohydrate, lipid, protein and nucleotide metabolism were significantly altered in CRC. Altered metabolites were also related to prognosis, survival and recurrence of CRC. This review could represent the most comprehensive information and summary about CRC metabolism to date. It certificates that metabolomics had great potential on both discovering clinical biomarkers and elucidating previously unknown mechanisms of CRC pathogenesis.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Metabolômica/métodos , Recidiva Local de Neoplasia/diagnóstico , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Análise de Sobrevida
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