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2.
Gene ; 714: 143993, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31330238

RESUMO

BACKGROUND: Recently, disagreements remain in increasing evidence about the potential value of circulating cell-free DNA (cfDNA) as a noninvasive diagnostic biomarker for ovarian cancer (OC). Here, this update meta-analysis was performed to further assess the diagnostic performance of circulating cfDNA in discriminating OC from non-cancerous individuals. METHODS: We performed a systemic literature search of PubMed, Embase, Web of Science, Cochrane Library, OVID, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases to obtain 22 eligible articles including a total of 1125 patients and 1244 controls. The pooled sensitivity, specificity, diagnostic odds ratio (DOR) and area under receiver operating characteristics curves (AUROC) of the included studies for cfDNA in diagnosing OC patients were used to estimate the diagnostic value. The clinical utility of cfDNA was evaluated by Fagan nomogram. Heterogeneity was explored utilizing subgroup analysis and meta-regression. RESULTS: The pooled sensitivity and specificity were 73% and 90%, the DOR and AUROC were 25.29 and 0.90, respectively. Subgroup analyses and meta-regression, according to patients' region, study design, clinical stage, specimen types, detection indicators, simple size, publication year revealed there were no significant sources of heterogeneity. Additionally, subgroup analyses showed qualitative detection (methylation detection); TNM stage I-IV, publication year 2011-2018, serum-based cfDNA assays exhibited better diagnostic performance as compared to quantitative detection, TNM stage III-IV, publication year 2002-2010; plasma-based cfDNA assays, and more participants and prospective studies manifested superior diagnostic accuracy. The result of sensitivity analysis indicated no study exclusively contributed to the heterogeneity and Deeks' funnel plot suggested no evidence of significant publication bias. CONCLUSIONS: Our meta-analysis found the qualitative detection (methylation); TNM stage I-IV, publication year 2011-2018 were related to more effective diagnostic accuracy for OC. However, serum-based cell-free DNA detection should be cautiously interpreted due to unclear factors. Hence, further large-scale longitudinal studies are required to validate the diagnostic potential of cell-free DNA. The present study provides to accrue knowledge of cell-free DNA levels for future researches.


Assuntos
Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Razão de Chances , Sensibilidade e Especificidade
3.
Clin Biochem ; 71: 46-51, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278894

RESUMO

OBJECTIVE: To investigate the association between cfDNA levels measured during non-invasive prenatal testing (NIPT) and the risk of pregnancy complications in a Chinese population. METHODS: This was a retrospective cohort study of 831 pregnant women who underwent NIPT at 12-22 weeks of gestation. Maternal plasma cfDNA levels and pregnancy outcomes were obtained from NIPT Screening System and hospitalization records, respectively. Logistic regression analysis was performed to investigate the relationship between cfDNA levels and pregnancy complications (after adjusting for confounding factors). RESULTS: Maternal cfDNA levels were significantly higher in women diagnosed with intrahepatic cholestasis of pregnancy (ICP) and preeclampsia (PE) compared to pregnant women with non-pregnancy complications (NPC) (median cfDNA 7.07, 6.42 vs. 5.99 ng/mL). Increase in cfDNA levels were associated with an increased risk for ICP (adjusted-OR = 1.20, 95% CI: 1.07-1.34) and PE (adjusted-OR = 1.14, 95% CI: 1.02-1.26). In addition, increase in cfDNA levels were associated with risk of GDM, and was dependent on maternal age (maternal age ≥ 35 years: adjusted-OR = 1.16, 95% CI: 1.04-1.29; maternal age < 35 years: adjusted-OR = 0.85, 95% CI: 0.73-0.99). CONCLUSION: Maternal plasma cfDNA levels measured during NIPT are associated with pregnancy complications (ICP, PE and GDM). Maternal age may be an important effect modifier for the association between plasma cfDNA levels and GDM.


Assuntos
Ácidos Nucleicos Livres/sangue , Complicações na Gravidez/sangue , Segundo Trimestre da Gravidez , Adulto , Feminino , Humanos , Gravidez , Estudos Retrospectivos
4.
Acta Cytol ; 63(6): 449-455, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091522

RESUMO

Liquid biopsy provides the opportunity of detecting, analyzing and monitoring cancer in various body effluents such as blood or urine instead of a fragment of cancer tissue. It is composed of different biological matrices such as circulating tumor cells (CTCs), cell free nucleic acids, exosomes or tumors "educated platelets." In addition to representing a non- or minimally invasive procedure, it should represent a better view of tumor heterogeneity and allows for real-time monitoring of cancer evolution. Recent technological and molecular advances, greatly facilitated by the use of microfluidics in many cases, have permitted large progresses both in our ability to purify and analyze liquid biopsy components. In particular, the great developments of droplet-based digital PCR and the various optimizations of next generation sequencing technologies are central to the several validations of CTC-free DNA as a strong cancer biomarker. However, complete adoption of liquid biopsy in clinics will require pursuing recent efforts in the standardization of procedures both on the pre-analytical and analytical aspects.


Assuntos
Biomarcadores Tumorais/análise , DNA Tumoral Circulante/sangue , Biópsia Líquida/métodos , Recidiva Local de Neoplasia/diagnóstico , Neoplasias/diagnóstico , Células Neoplásicas Circulantes/química , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/isolamento & purificação , Biópsia por Agulha Fina , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/isolamento & purificação , DNA Tumoral Circulante/isolamento & purificação , Exossomos/química , Humanos , Biópsia Líquida/normas , Monitorização Fisiológica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Células Neoplásicas Circulantes/patologia
5.
J Coll Physicians Surg Pak ; 29(5): 483-485, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31036126

RESUMO

The aim of this study was to explore the feasibility of non-invasive prenatal genetic diagnosis of ß-thalassemia with small fragments of cell-free fetal DNA (cffDNA) in peripheral blood of pregnant women. It was an observational study carried out at Department of Obstetrics, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, China, from January 2016 to March 2018. A total of 40 pregnant women, who were likely to give birth to babies with severe ß-thalassemia, were selected, and ß-globin genotype of the fetus was non-invasively detected by cffDNA in peripheral blood of their mothers. Small fragments of cffDNA from all specimens were successfully amplified. Compared with the results of traumatic prenatal diagnosis, 37 cases (92.50%) were diagnosed and 3 cases (7.50%) were misdiagnosed. The cffDNA in maternal plasma can be used for non-invasive prenatal genetic diagnosis of ß-thalassemia, and is worthy of promotion.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA/sangue , DNA/genética , Amplificação de Genes/genética , Gravidez/sangue , Diagnóstico Pré-Natal/métodos , Globinas beta/genética , Talassemia beta/diagnóstico , Adulto , Ácidos Nucleicos Livres/genética , DNA/isolamento & purificação , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/genética , Feto/irrigação sanguínea , Testes Genéticos , Humanos , Gestantes , Talassemia beta/genética
6.
Int J Lab Hematol ; 41 Suppl 1: 102-116, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069972

RESUMO

INTRODUCTION: Rapid technological advancements in clinical molecular genetics have increased our diagnostic and prognostic capabilities in health care. Understanding these assays, as well as how they may change over time, is critical for pathologists, clinicians, and translational researchers alike. METHODS: This review provides a practical summary and basic reference for current molecular genetic technologies, as well as new testing methodologies that are in use, gaining momentum, or anticipated to contribute more broadly in the future. RESULTS: Here, we discuss DNA and RNA based methodologies including classic assays such as the polymerase chain reaction (PCR), Sanger sequencing, and microarrays, to more cutting-edge next-generation sequencing (NGS) based assays and emerging molecular technologies such as cell-free DNA (cfDNA) or circulating tumor DNA (ctDNA), and NGS-based detection of infectious disease organisms. CONCLUSION: This review serves as a basic foundation for knowledge in current and emerging clinical molecular genetic technologies.


Assuntos
Ácidos Nucleicos Livres/genética , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Reação em Cadeia da Polimerase/métodos , Ácidos Nucleicos Livres/sangue , Doenças Hematológicas/sangue , Humanos
7.
Crit Rev Oncol Hematol ; 139: 7-15, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31112884

RESUMO

Cell-free DNA (cfDNA), which is DNA released from cells into the circulation, is one of the most promising non-invasive biomarkers in cancer. This approach could be of interest for the management of Diffuse Large B-Cell Lymphoma (DLBCL) patients, which is the most common non-Hodgkin lymphoma. Then, the aim of this systematic review was to define the utility of cfDNA in this disease. Selected articles were classified in four groups, depending on the aspects of cfDNA studied, i.e. concentration, methylation, IgH gene rearrangements, and somatic mutations. While concentration and methylation of cfDNA need to be further analyzed, IgH gene rearrangements and somatic mutations seem to be the most promising biomarkers to date. Their detection has been shown to allow disease monitoring and early prediction of relapse. Although more efforts and standardization of techniques are needed, studying cfDNA in liquid biopsy may help improve the outcome of DLBCL patients.


Assuntos
Biomarcadores Tumorais/genética , Ácidos Nucleicos Livres/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Ácidos Nucleicos Livres/sangue , Humanos , Biópsia Líquida , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/genética , Prognóstico
8.
Int J Mol Sci ; 20(9)2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31052333

RESUMO

Circulating extracellular vesicles are small particles enclosed by a phospholipid bilayer. Vesicles deriving directly from the cellular membrane by an active budding process retain cell origin specific proteins and RNA. These vesicles carry pathophysiological information from their parental cell and hold the potential to allow analysis of organs without the need for a biopsy. We included in our study 27 patients undergoing bariatric surgery. Hepatic extracellular vesicles were determined by flow cytometry. mRNA specific for hepatic cellular origin was determined in the extracellular vesicle fraction using qPCR. Surgery led to a massive reduction of weight and overall hepatic stress as determined by alanine transaminase (ALT), aspartate transaminase (AST) and γ-glutamyltransferase (GGT). Total extracellular vesicle numbers were reduced after bariatric surgery. Liver specific vesicles identified by HepPar1 or asialoglycoprotein receptor (ASGPR) were significantly reduced after bariatric surgery in both AnnexinV+ and AnnexinV- subgroups. When analyzing circulating liver-specific mRNAs, we found reduced levels of these mRNAs after surgery even though total circulating RNA remained unchanged. We conclude that circulating hepatic extracellular vesicles are detectable in samples from patients undergoing gastric bypass surgery. These vesicles are reduced after a reduction of hepatic stress also observed with classic liver enzyme measurements. We conclude that ASGPR or HepPar positive vesicles hold the potential to serve as liver specific vesicle markers.


Assuntos
Vesículas Extracelulares/metabolismo , Derivação Gástrica , Fígado/metabolismo , Obesidade Mórbida/metabolismo , Adulto , Biomarcadores/sangue , Ácidos Nucleicos Livres/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/sangue , Obesidade Mórbida/cirurgia
9.
Transplant Proc ; 51(3): 820-822, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30979470

RESUMO

Graft-derived cell-free DNA (Gcf-DNA) is a non-invasive biomarker to monitor graft function. There are different methods to quantify Gcf-DNA, such as the classical Y-chromosome method and the latest digital droplet polymerase chain reaction method. In this study, we reported 2 patients genetically diagnosed with propionic acidemia (PA) went through living-donor liver transplantation (LDLT), and monitoring the change of Gcf-DNA examined by the amplification refractory mutation system polymerase chain reaction (ARMS-PCR) method. Two patients went through the operation successfully, and a 5 mL whole blood specimen was collected at 6 specific time points (day 0, day 1, day 7, day 14, day 30, day 60). The comparison of Gcf-DNA and the routine liver function showed that they have similar change-tendency curves, with the curves reaching the top at day 1 because of ischemia-reperfusion injury and generally declining from day 7-day 60 along with recovery of the patient. Applying the ARMS-PCR method to detect Gcf-DNA can be done without knowing the donor information and is not limited by donor-recipient-sex-mismatch condition. In conclusion, Gcf-DNA is a promising biomarker that can monitor graft function in LDLT, and we will apply it in more samples and observe it long term to validate its efficiency in the future.


Assuntos
Biomarcadores/sangue , Ácidos Nucleicos Livres/sangue , Transplante de Fígado , Doadores Vivos , Reação em Cadeia da Polimerase/métodos , Pré-Escolar , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Humanos , Masculino
10.
Cardiovasc Diabetol ; 18(1): 49, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992036

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with a hypercoagulable state and increased neutrophil extracellular traps formation (NETosis). We investigated predictors of NETosis and cell death markers in circulating blood and their association with a prothrombotic state in T2DM. METHODS: In a cross-sectional study involving 113 T2DM patients aged 63.7 ± 8.2 years, we investigated citrullinated histone H3 (H3Cit), cell-free deoxyribonucleic acid (cfDNA), myeloperoxidase, neutrophil elastase, and inflammation markers, along with thrombin generation (TG), plasma clot lysis time (CLT), clot permeability (Ks) and fibrinolysis inhibitors. RESULTS: On multivariate logistic regression analysis adjusted for age and gender, predictors of high H3Cit (≥ 7.36 ng/mL, upper quartile) were: glycated hemoglobin (HbA1c) ≥ 7.0% and interleukin-6. Interleukin-6 was also found to be a predictor of high cfDNA (≥ 2.84 µg/mL, upper quartile) along with glucose. Citrullinated histone H3 and cfDNA correlated positively with CLT and inversely with Ks, while TG associated solely with cfDNA. These associations were not seen with myeloperoxidase and neutrophil elastase. Patients with previous myocardial infarction (n = 21, 18.6%) had higher H3Cit (+108%, p < 0.001) and cfDNA (+45%, p = 0.022). On multivariable analysis adjusted for potential confounders, H3Cit and cfDNA, along with plasminogen activator inhibitor-1 and concomitant cardiovascular disease, were predictors of CLT. Citrullinated histone H3 alone was a predictor of Ks and only cfDNA was a predictor of peak thrombin generated. CONCLUSIONS: In T2DM, NETosis detectable in circulating blood is associated with inflammatory state and a prothrombotic state, especially hypofibrinolysis.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Armadilhas Extracelulares/metabolismo , Fibrinólise , Trombose/sangue , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Ácidos Nucleicos Livres/sangue , Citrulinação , Estudos Transversais , DNA/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Hemoglobina A Glicada/metabolismo , Histonas/sangue , Humanos , Mediadores da Inflamação/sangue , Elastase de Leucócito/sangue , Masculino , Pessoa de Meia-Idade , Peroxidase/sangue , Fatores de Risco , Trombina/metabolismo , Trombose/diagnóstico , Trombose/etiologia
11.
Reprod Biol Endocrinol ; 17(1): 34, 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953560

RESUMO

BACKGROUND: Women with Polycystic Ovary Syndrome (PCOS) present a heterogeneous reproductive and metabolic profile with an increased lifetime risk of Type 2 Diabetes (T2D). Early biomarkers of these metabolic disturbances in PCOS women have not been identified. The abundance of circulating insulin gene promotor cell-free DNA (INS cfDNA) was shown to be valuable as a predictive biomarker of ß-cell death in individuals with Type 1 diabetes (T1D) as well as with gestational diabetes. Since ß-cell death is common to the development of T1D as well as in T2D, we aimed to investigate if insulin-coding DNA is more abundant in circulation of PCOS women (vs Controls) and if their levels change after 6 yr. follow-up as a potential measure to predict future T2D. METHODS: A cohort of 40 women diagnosed with PCOS according to Rotterdam 2003 criteria and eight healthy controls were examined at baseline and 6 years follow-up. Clinical measurements for evaluation of glucose homeostasis as well as blood/serum samples were obtained at each visit. Methylated and unmethylated INS cfDNA were quantified using droplet digital PCR. Differences between groups were assessed using Kruskall-Wallis test and Wilcoxon Signed rank test. RESULTS: At baseline, there was no detectable difference in copy number (copies/µL) of methylated (p = 0.74) or unmethylated INS cfDNA (p = 0.34) between PCOS and Control groups. At follow up, neither methylated (p = 0.50) nor unmethylated INScfDNA levels (p = 0.48) differed significantly between these groups. Likewise, when pooling the groups, there was no difference between baseline and follow up, in terms of copies of methylated or unmethylated INS cfDNA (p = 0.38 and p = 0.52, respectively). There were no significant correlations between counts of unmethylated or methylated cfDNA and the clinical measurements of ß-cell function and pre-diabetes. CONCLUSION: The circulating level of unmethylated and methylated INScfDNA is similar between PCOS and Controls and cannot be used to predict islet ß-cell loss and progression to Type 2 diabetes in a 6-year follow-up. TRIAL REGISTRATION: The Danish Data Protection Agency (REG-31-2016. Approval: 01-12-2015) and by the Danish Scientific Ethical committee of Region Zealand (Journal no. SJ-525. Approval: 13-06-2016), Clinicaltrials.gov, ( NCT03142633 , registered 1. March, 2017, Retrospectively registered).


Assuntos
Ácidos Nucleicos Livres/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Insulina/genética , Síndrome do Ovário Policístico/metabolismo , Adulto , Biomarcadores/sangue , Metilação de DNA , Feminino , Humanos , Estudos Longitudinais
12.
Biomed Res Int ; 2019: 5028512, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949501

RESUMO

Objective: As cell-free DNA levels in the pleural fluid and serum of parapneumonic pleural effusion (PPE) patients have not been thoroughly explored, we evaluated their diagnostic potential. Methods: Twenty-two PPE and 16 non-PPE patients were evaluated. Serum and pleural fluids were collected, and cell-free DNA was quantified. All biomarkers were assessed for correlation with days after admission. Receiver operating characteristic (ROC) curve analysis was used to determine diagnostic accuracy and optimal cut-off point. Results: Nuclear and mitochondrial DNA levels in the pleural fluid and nuclear DNA levels in serum of PPE patients were significantly higher than in those of the non-PPE patients. However, only cell-free DNA levels in pleural fluid correlated with days after admission among PPE patients (r= 0.464, 0.538, respectively). ROC curve analysis showed that nuclear and mitochondrial DNA in pleural fluid had AUCs of 0.945 and 0.889, respectively. With cut-off values of 134.9 and 17.8 ng/ml for nuclear and mitochondrial DNA in pleural fluid, respectively, 96% sensitivity and 81% specificity were observed for PPE diagnosis. Conclusion: Nuclear and mitochondrial DNA in pleural fluid possess PPE diagnostic potential and correlated with disease severity. Serum nuclear DNA could also be used to distinguish freshly admitted PPE patients (Day 1) from non-PPE patients, but with less accuracy.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA Mitocondrial/sangue , Pleura/metabolismo , Derrame Pleural , Pneumonia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Derrame Pleural/sangue , Derrame Pleural/diagnóstico , Pneumonia/sangue , Pneumonia/diagnóstico
13.
J Biotechnol ; 298: 82-87, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-30986516

RESUMO

Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor with a 16-24 -months overall survival time (OS). Effective management is hindered by intratumoral heterogeneity, a characteristic trait of GBM which results in subpopulations of cells with altered therapeutic responsiveness, different invasiveness and growth potential. Correct initial molecular profiling of the tumor, as well as following its molecular biological changes are further impeded by the intracranial location of the tumors, hence the risks of surgical interventions. Radiological examination, the sole non-invasive method of obtaining information about the tumors, also has limitations. This review article aims to summarize the currently available information about the promising applicability of liquid biopsy, extracellular vesicles (EVs), and circulating cell-free nucleic acids (cf-NAs) in GBM patients. Liquid biopsy is a quick and inexpensive way of obtaining exceptionally relevant information about tumors, and can be performed multiple times during the clinical course of the disease. Furthermore, integrating analyses of EVs and related cf-NAs in clinical practice might also help to establish diagnosis in a non-invasive manner, and complex oncotherapy could be indicated in the future without high-risk neurosurgical interventions.


Assuntos
Biomarcadores Tumorais/sangue , Ácidos Nucleicos Livres/sangue , Glioblastoma/sangue , Biópsia Líquida , Idoso , Idoso de 80 Anos ou mais , Exossomos/genética , Exossomos/patologia , Vesículas Extracelulares/genética , Vesículas Extracelulares/patologia , Feminino , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Masculino
14.
J Biotechnol ; 298: 76-81, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31002856

RESUMO

Ovarian tumor is one of the leading causes of cancer among women. Patients are diagnosed at an advanced stage, usually. There is a need for new specific and sensitive biomarkers. Mitochondrial DNA copy number change was observed in various cancers. Our aim was to detect mitochondrial DNA copy number in whole blood (wb-mtDNA) and in plasma (cell-free and exosome encapsulated mtDNA) in patients with serous epithelial ovarian tumor. DNA was isolated from EDTA blood and plasma obtained from 24 patients and 24 healthy controls. Exosomes were isolated from cell-free plasma, and exosome encapsulated DNA (exoDNA) was extracted. Quantitative-real-time PCR was performed with Human Mitochondrial DNA (mtDNA) Monitoring Primer Set. Kruskall­Wallis and Mann­Whitney U test were used for data analysis. Wb-mtDNA copy number was significantly different among healthy controls and patients in multiple comparison (p = 0.0090 considering FIGO stage independently, and p = 0.0048 considering early- and late-stage cancers). There was a significant decrease among early-stage, all advanced stage and all cancer patients (FIGO I: 32.5 ± 8.3, p = 0.0061; FIGO III + IV: 37.2 ± 13.7 p = 0.0139; FIGO I + III + IV: 35.6 ± 12.2, p = 0.0017) or FIGO III patients alone (32.8 ± 5.6, p = 0.00089) compared to healthy controls. We found significant increase in copy number in exosomal mtDNA in cancer patients (236.0 ± 499.0, p = 0.0155), advanced-stage cancer patients (333.0 ± 575.0, p = 0.0095), of FIGO III (362.0 ± 609.2, p = 0.0494), and FIGO IV (304.0 ± 585.0, p = 0.0393) patients alone but not in samples of FIGO I patients (10.0 ± 3.5, p = 0.3907). In multiple comparison the increase was significant considering early- and late-stage cancers (p = 0.0253). Cell-free mtDNA copy numbers were not increased significantly. We found the highest copy number of mtDNA in exosomes, followed by plasma and peripheral blood in late-stage cancer patients. We observed significant difference in wb-mtDNA copy number between healthy controls and both early- and late-stage cancer patients.


Assuntos
Carcinoma Epitelial do Ovário/sangue , Ácidos Nucleicos Livres/sangue , DNA Mitocondrial/sangue , Mitocôndrias/genética , Idoso , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/patologia , Variações do Número de Cópias de DNA/genética , Exossomos/genética , Exossomos/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real
16.
BMC Cancer ; 19(1): 292, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935424

RESUMO

BACKGROUND: Although sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib. METHODS: This prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients. RESULTS: The cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/µL; P < 0.0001). Patients who did not achieve disease control with sorafenib had significantly higher cfDNA levels (0.82 vs. 0.63 ng/µL; P = 0.006) and I-scores (3405 vs. 1024; P = 0.0017) than those achieving disease control. The cfDNA-high group had significantly worse TTP (2.2 vs. 4.1 months; HR = 1.71; P = 0.002) and OS (4.1 vs. 14.8 months; HR = 3.50; P < 0.0001) than the cfDNA-low group. The I-score-high group had poorer TTP (2.2 vs. 4.1 months; HR = 2.09; P < 0.0001) and OS (4.6 vs. 14.8 months; HR = 3.35; P < 0.0001). In the multivariable analyses, the cfDNA remained an independent prognostic factor for OS (P < 0.0001), and the I-score for both TTP (P = 0.011) and OS (P = 0.010). The VEGFA ratio was not significantly associated with treatment outcomes. CONCLUSION: Pretreatment cfDNA concentration and genome-wide CNA in cfDNA are potential biomarkers predicting outcomes in advanced HCC patients receiving first-line sorafenib.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Variações do Número de Cópias de DNA , Amplificação de Genes , Neoplasias Hepáticas/tratamento farmacológico , Sorafenibe/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Ácidos Nucleicos Livres/sangue , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Sorafenibe/farmacologia , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangue
17.
J Biotechnol ; 297: 66-70, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30953676

RESUMO

The pathological diagnostics of cancer - based on the histological features - is today increasingly completed by molecular profiling at variable depth in an almost evident fashion. Predictive information should cover potential therapeutic targets and/or major resistance mechanisms the nature of which is subject of alteration during the course of the treatment. Mutational profiling recently became technically available by the analysis of circulating free DNA obtained following non-invasive peripheral blood or body fluid sampling. This "liquid biopsy" approach reflects the general status considering the actual tumor burden, irrespective of the intratumoral distribution and anatomical site. However, the dynamics of the liquid compartment relies on tissue-related processes reflected by histological variables. The amount and composition of free DNA seems to be influenced by many factors, including the stage and anatomical localization of the cancer, the relative mass of neoplastic subclones, the growth rate, the stromal and inflammatory component, the extent of tumor cell death and necrosis. The histopathological context should be considered also when analysis of cfDNA is about to replace repeated tumor sampling for molecular follow-up.


Assuntos
Biópsia Líquida/métodos , Mutação/genética , Neoplasias/genética , Neoplasias/patologia , Patologistas , Ácidos Nucleicos Livres/sangue , Humanos , Neoplasias/sangue , Células Neoplásicas Circulantes/patologia
19.
Nat Commun ; 10(1): 1299, 2019 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-30898996

RESUMO

Due to their rarity and diversity, sarcomas are difficult to diagnose. Consequently, there is an urgent demand for a novel diagnostic test for these cancers. In this study, we investigated serum miRNA profiles from 1002 patients with bone and soft tissue tumors representing more than 43 histological subtypes, including sarcomas, intermediate tumors, and benign tumors, to determine whether serum miRNA profiles could be used to specifically detect sarcomas. Circulating serum miRNA profiles in sarcoma patients were clearly distinct from those in patients with other types of tumors. Using the serum levels of seven miRNAs, we developed a molecular detector, Index VI, that could distinguish sarcoma patients from benign and healthy controls with remarkably high sensitivity (90%) and specificity (95%), regardless of histological subtype. Index VI provides an approach to the early and precise detection of sarcomas, potentially leading to curative treatment and longer survival.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/diagnóstico , Ácidos Nucleicos Livres/genética , MicroRNAs/genética , Neoplasias/diagnóstico , Sarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adulto , Idoso , Biomarcadores Tumorais/sangue , Neoplasias Ósseas/sangue , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Estudos de Casos e Controles , Ácidos Nucleicos Livres/sangue , Diagnóstico Diferencial , Feminino , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/genética , Neoplasias/patologia , Análise de Componente Principal , Reação em Cadeia da Polimerase em Tempo Real , Sarcoma/sangue , Sarcoma/genética , Sarcoma/patologia , Sensibilidade e Especificidade , Neoplasias de Tecidos Moles/sangue , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Transcriptoma
20.
Ann Clin Microbiol Antimicrob ; 18(1): 10, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30871553

RESUMO

BACKGROUND: Considerable progress has been made in dengue management, however the lack of appropriate predictors of severity has led to huge number of unwanted admissions mostly decided on the grounds of warning signs. Apoptosis related mediators, among others, are known to correlate with severe dengue (SD) although no predictive validity is established. The objective of this study was to investigate the association of plasma cell-free DNA (cfDNA) with SD, and evaluate its prognostic value in SD prediction at acute phase. METHODS: This was a hospital-based prospective cohort study conducted in Vietnam. All the recruited patients were required to be admitted to the hospital and were strictly monitored for various laboratory and clinical parameters (including progression to SD) until discharged. Plasma samples collected during acute phase (6-48 h before defervescence) were used to estimate the level of cfDNA. RESULTS: Of the 61 dengue patients, SD patients (n = 8) developed shock syndrome in 4.8 days (95% CI 3.7-5.4) after the fever onset. Plasma cfDNA levels before the defervescence of SD patients were significantly higher than the non-SD group (p = 0.0493). From the receiver operating characteristic (ROC) curve analysis, a cut-off of > 36.9 ng/mL was able to predict SD with a good sensitivity (87.5%), specificity (54.7%), and area under the curve (AUC) (0.72, 95% CI 0.55-0.88; p = 0.0493). CONCLUSIONS: Taken together, these findings suggest that cfDNA could serve as a potential prognostic biomarker of SD. Studies with cfDNA kinetics and its combination with other biomarkers and clinical parameters would further improve the diagnostic ability for SD.


Assuntos
Biomarcadores/sangue , Ácidos Nucleicos Livres/sangue , Testes Diagnósticos de Rotina/métodos , Dengue Grave/diagnóstico , Adolescente , Adulto , Criança , Feminino , Hospitalização , Humanos , Imunoglobulina M/sangue , Masculino , Prognóstico , Estudos Prospectivos , Curva ROC , Sensibilidade e Especificidade , Dengue Grave/fisiopatologia , Fatores de Tempo , Vietnã , Adulto Jovem
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