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1.
Anticancer Res ; 39(11): 6403-6412, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704874

RESUMO

BACKGROUND: Cytokines, metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) take part in many processes involved in tumor progression and invasion such as degradation of the extracellular matrix, influence on immune cells associated with tumor tissue, and angiogenesis. Thus, the aim of this study was to compare the concentration of plasma levels and tissue expression of macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-2 and MMP9, and their tissue inhibitors TIMP1 and TIMP2 in patients with cervical cancer, patients with high-grade cervical intraepithelial dysplasia (CIN3) and patients with ectropion. PATIENTS AND METHODS: Concentration and expression of all tested parameters was measured in serum with enzyme-linked immunosorbent assay (ELISA) and in tissue with immunohistochemistry method. RESULTS: The epithelial expression of M-CSF and TIMP1 in cancer tissue was much stronger as compared to that in ectropion and CIN3. In the case of MMP2, lack of or weak expression in epithelial cells was observed in all tested groups. Our studies showed statistical differences of tested parameters in tissue expression and in plasma concentrations in patients with cervical cancer, patients with CIN3 and patients with ectropion. Moreover, data revealed positive correlation between plasma level and cervical cancer cell expression of VEGF. CONCLUSION: Our findings indicate a potential role of all the proteins tested here in cervical cancer diagnosis, especially VEGF. However, further studies will show whether they play a role in the progression of cancerous changes in epithelial tissue of the cervix.


Assuntos
Fator Estimulador de Colônias de Macrófagos/análise , Metaloproteases/análise , Inibidores Teciduais de Metaloproteinases/análise , Displasia do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/química , Fator A de Crescimento do Endotélio Vascular/análise , Adenocarcinoma/sangue , Adenocarcinoma/química , Adulto , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/química , Citocinas/análise , Citocinas/sangue , Feminino , Humanos , Fator Estimulador de Colônias de Macrófagos/sangue , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/análise , Metaloproteinase 9 da Matriz/sangue , Metaloproteases/sangue , Pessoa de Meia-Idade , Inibidor Tecidual de Metaloproteinase-1/análise , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/análise , Inibidor Tecidual de Metaloproteinase-2/sangue , Inibidores Teciduais de Metaloproteinases/sangue , Displasia do Colo do Útero/sangue , Neoplasias do Colo do Útero/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto Jovem
2.
Cancer Sci ; 110(11): 3565-3572, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520559

RESUMO

Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Camptotecina/análogos & derivados , Neoplasias do Colo/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Grupo com Ancestrais do Continente Asiático , Camptotecina/uso terapêutico , Neoplasias do Colo/sangue , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Fluoruracila/uso terapêutico , Humanos , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Interleucina-8/sangue , Japão , Calicreínas/sangue , Leucovorina/uso terapêutico , Fator de Crescimento Placentário/sangue , Prognóstico , Intervalo Livre de Progressão , Estudos Prospectivos , Proteína D Associada a Surfactante Pulmonar/sangue , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Neoplasias Retais/sangue , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Análise de Regressão , Tenascina/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
3.
BMC Neurol ; 19(1): 167, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319804

RESUMO

BACKGROUND: Higher circulating levels of tissue inhibitor of matrix metalloproteinases (TIMP)-1 early after ischemic stroke have been associated with lower survival. The objectives of this study were to determine serum TIMP-1 levels during the first week of a severe cerebral infarction in surviving and non-surviving patients, and whether those levels during the first week could be used as a mortality biomarker for these patients. METHODS: We included patients with severe malignant middle cerebral artery infarction (MMCAI) defined as computer tomography showing ischaemic changes in more than 50% of the middle cerebral artery territory and Glasgow Coma Scale (GCS) ≤ 8. We measured serum levels of matrix metalloproteinases (MMP)-9 and TIMP-1. End-point study was 30-day mortality. RESULTS: We found higher TIMP-1 concentrations at days 1 (p < 0.001), 4 (p = 0.001), and 8 (p = 0.03) of MMCAI in non- urviving (n = 34) than in surviving (n = 34) patients. We found lower serum MMP-9 concentrations at day 1 (p = 0.03) of MMCAI and no significant differences at days 4 and 8. ROC curve analysis of TIMP-1 concentrations performed at days 1, 4, and 8 of MMCAI showed an area under curve to predict 30-day mortality of 81% (p < 0.001), 80% (p < 0.001) and 72% (p = 0.07) respectively. CONCLUSIONS: The new findings of our study were that non-surviving MMCAI patients showed higher serum TIMP-1 levels during the first week of MMCAI that surviving patients, and those levels during the first week of MMCAI could be used as mortality biomarkers.


Assuntos
Infarto da Artéria Cerebral Média/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Idoso , Biomarcadores/sangue , Feminino , Escala de Coma de Glasgow , Humanos , Infarto da Artéria Cerebral Média/mortalidade , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Acidente Vascular Cerebral/sangue
4.
J Zhejiang Univ Sci B ; 20(8): 687-692, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31273966

RESUMO

The objective of this study was to assess the angiogenic potential expressed as a quotient of vascular endothelial growth factor A (VEGF-A), as an indicator of proangiogenic activity, and the circulating receptors (soluble VEGF receptor protein R1 (sVEGFR-1) and sVEGFR-2), as indicators of the effect of angiogenic inhibition, depending on the concentrations of matrix metalloproteinase 2 (MMP-2) and MMP-9 and their tissue inhibitor 1 (TIMP-1) and TIMP-2 in the plasma of patients with lower extremity artery disease (LEAD). These blood parameters in patients with intermittent claudication (IC) and critical limb ischemia (CLI) were compared for select clinical and biochemical features. Stimulation of angiogenesis in the plasma of individuals with LEAD was evident as indicated by the significant increase in VEGF-A concentration along with reduced inhibition depending on circulating receptors sVEGFR-1 and sVEGFR-2. Critical ischemia was associated with higher VEGF-A, MMP-9, TIMP-1, and TIMP-2 concentrations than in the case of IC.


Assuntos
Claudicação Intermitente/sangue , Isquemia/sangue , Extremidade Inferior/irrigação sanguínea , Metaloproteinase 9 da Matriz/sangue , Neovascularização Patológica , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/sangue , Idoso , Inibidores da Angiogênese/farmacologia , Feminino , Regulação da Expressão Gênica , Humanos , Claudicação Intermitente/tratamento farmacológico , Isquemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
5.
Cancer Immunol Immunother ; 68(8): 1263-1272, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31240326

RESUMO

BACKGROUND: An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC. MATERIALS AND METHODS: A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8-117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3-57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels. CONCLUSION: Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Orofaríngeas/diagnóstico , Papillomaviridae/fisiologia , Infecções por Papillomavirus/diagnóstico , Inibidor Tecidual de Metaloproteinase-1/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/mortalidade , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Metaloproteinase 8 da Matriz/sangue , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/epidemiologia , Neoplasias Orofaríngeas/mortalidade , Infecções por Papillomavirus/epidemiologia , Infecções por Papillomavirus/mortalidade , Prognóstico , Análise de Sobrevida
6.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141909

RESUMO

BACKGROUND: Cardiac collagen remodeling is important in the progression of heart failure. Estimation of cardiac collagen turnover by serum levels of serological markers is used for monitoring cardiac tissue repair and fibrosis. Peritoneal dialysis (PD) is used for the long-term management of refractory congestive heart failure (CHF). In this study, we investigated the effect of PD treatment on circulating fibrosis markers levels in patients with refractory CHF and fluid overload. METHODS: Twenty-five patients with refractory CHF treated with PD were prospectively enrolled in the study. Circulating fibrosis markers procollagen type III C-peptide (PIIINP), matrix metalloproteinase 2 (MMP-2), and tissue inhibitor of metalloproteinases I (TIMP-1) levels were checked at baseline and after three and six months of treatment. RESULTS: The clinical benefit of PD manifested by improved NYHA functional class and reduced hospitalization rate. Serum brain natriuretic peptide (BNP) levels decreased significantly during the treatment. Serum MMP-2 and TIMP-1 decreased significantly on PD. Circulating PIIINP showed two patterns of change, either decreased or increased following PD treatment. Patients in whom circulating PIIINP decreased had significantly lower baseline serum albumin, lower baseline mean arterial blood pressure, higher serum CRP, and a less significant improvement in hospitalization rate compared to the patients in whom circulating PIIINP increased. Patients in whom all three markers decreased demonstrated a trend to longer survival compared to patients whose markers increased or did not change. CONCLUSION: In refractory CHF patients PD treatment was associated with a reduction in circulating fibrosis markers.


Assuntos
Insuficiência Cardíaca/sangue , Metaloproteinase 2 da Matriz/sangue , Fragmentos de Peptídeos/sangue , Diálise Peritoneal/efeitos adversos , Pró-Colágeno/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Idoso , Biomarcadores/sangue , Feminino , Insuficiência Cardíaca/terapia , Humanos , Masculino , Pessoa de Meia-Idade
7.
Immunopharmacol Immunotoxicol ; 41(2): 224-230, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31046512

RESUMO

Objective: The aim of this work was to compare matrix metalloproteinase-9 and -12, tissue inhibitor of metalloproteinase-1 and -4, and neutrophil elastase in exhaled breath condensate (EBC) and peripheral blood of patients with COPD. Methods: Peripheral blood and EBC samples from COPD patients and healthy donors were collected. In serum and EBC, MMP-9, MMP-12, NE, TIMP-1, and TIMP-4 proteins were detected by ELISA. The mRNA expression levels of MMP-9, MMP-12, NE, TIMP-1, and TIMP-4 in peripheral blood mononuclear cells (PBMCs) were analyzed by qRT-PCR. Results: The protein levels of MMP-9 (p=.034) and MMP-12 (p=.041) in the EBC of COPD smokers were higher than those of COPD never-smokers. The concentrations of TIMP-1 (p=.072) and TIMP-4 (p=.084) in the EBC of COPD smokers were higher than those of COPD never-smokers; however, the difference was not statistically significant. MMP-9 (r=-0.78, p<.0001) and TIMP-1 (r=-0.71, p<.0001) levels in EBC were significantly negatively correlated with pulmonary function FEV1%pred. The protein levels of MMP-12 (r=-0.37, p=.034) and TIMP-4 (r=-0.34, p=.041) were also negatively correlated with FEV1%pred. The expression of MMP-9, MMP-12, NE, TIMP-1, and TIMP-4 in PBMCs and serum of COPD smokers were significantly higher than those of control never-smokers (p<.05). Conclusions: Exhaled MMP-9, MMP-12, TIMP-1, and TIMP-4 levels increased in stable COPD patients and were negatively correlated with FEV1%pred, which suggests the usefulness of their measurement in EBC for the monitoring of airway inflammation. However, to better assess their diagnostic or prognostic value, larger studies are necessary.


Assuntos
Expiração , Mediadores da Inflamação/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Idoso , Biomarcadores/sangue , Testes Respiratórios , Estudos Transversais , Feminino , Humanos , Masculino , Metaloproteinase 12 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidores Teciduais de Metaloproteinases/sangue
8.
Horm Metab Res ; 51(6): 389-395, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31075797

RESUMO

The association between obesity and cardiovascular diseases has a multifactorial pathogenesis, including the synthesis of inflammatory molecules, the increase in oxidative stress and the dysregulation of the matrix metalloprotease (MMP) concentration and activity. In a group of adults with obesity, divided in 2 subgroups according to the body mass index (BMI), we examined lipid peroxidation, expressed as thiobarbituric acid-reactive substances (TBARS), protein oxidation, expressed as protein carbonyl groups (PCs), plasma gelatinases (MMP-2 and MMP-9), and their tissue inhibitors (TIMP-1 and TIMP-2). In the whole group, as well as in the 2 subgroups (with BMI 30-35 or BMI>35) of obese subjects, we observed an increase in TBARS, PCs, MMP-2, and MMP-9, and also TIMP-1 and TIMP-2 in comparison with the control group. A positive correlation between TBARS and PCs emerged in obese subjects and persisted after dividing obese subjects according to BMI. The correlation between MMP-2 and TIMP-2 was not statistically significant, while a significant correlation was present between MMP-9 and TIMP-1. The correlations between the markers of oxidative stress (TBARS and PCs) and those of the MMP/TIMP profile indicated a more marked influence of protein oxidation on MMPs and TIMPs in comparison with TBARS. The innovative aspect of our study was the simultaneous evaluation of oxidative stress markers and MMP/TIMP profile in adult obese subjects. We observed significant alterations and correlations that may negatively influence the clinical course of the disease.


Assuntos
Peroxidação de Lipídeos , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Obesidade/fisiopatologia , Proteínas/química , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/sangue , Adulto , Biomarcadores/análise , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Oxirredução , Estresse Oxidativo , Proteólise
9.
Dis Markers ; 2019: 3136792, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143300

RESUMO

The aim of this study was to assess the expression of MMP-9 and TIMP-1 in cancerous tissue as well as in the serum and plasma concentrations of these proteins in patients with laryngeal cancer and compare the results to the inflammatory reaction in healthy subjects. Twenty-seven patients who were diagnosed with laryngeal carcinoma and selected for total laryngectomy were included in the study group. MMP-9 and TIMP-1 expression in tissues was assessed using immunohistochemical assays. Immunoenzymatic ELISA methods were used to measure MMP-9 and TIMP-1 concentrations in serum and plasma. MMP-9 and TIMP-1 were identified in tumor cells and in the tumor stroma compartment, as well as in macroscopically healthy mucous membrane. MMP-9 expression was more significant in tumor stroma than in the perimatrix of the mucous membrane (p = 0.047). TIMP-1 expression was significantly higher in the matrix and perimatrix of the mucous membrane than in cancer tissue (p = 0.0093) and the tumor stroma compartment (p < 0.0001). Expression of TIMP-1 was observed more frequently in tumors without infiltrated lymph nodes (p = 0.009). Serum concentrations of MMP-9 and TIMP-1 as well as plasma TIMP-1 concentration were significantly higher in the study group than in the control group (p = 0.0004, p = 0.002, and p = 0.0001, respectively). A significantly higher TIMP-1 level in plasma was found in patients with poorly differentiated tumors compared to G1 and G2 (p = 0.046). MMP-9/TIMP-1 rate in serum was significantly higher in the study group than in the control group. The balance between the level of MMP-9 and TIMP-1 is disrupted in laryngeal cancer. The significant correlation between TIMP-1 expression and the presence of lymph node metastases, as well as that between TIMP-1 plasma concentration and stage of cancer histological differentiation, might indicate the importance of this molecule as a prognostic factor during carcinogenesis.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias Laríngeas/metabolismo , Metaloproteinase 9 da Matriz/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Idoso , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Neoplasias Laríngeas/sangue , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Metástase Linfática , Masculino , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-1/metabolismo
10.
PLoS One ; 14(3): e0214084, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30883599

RESUMO

BACKGROUND: Biomarkers that reflect progression of dilatation of the aorta in patients with aortic conditions are needed as surrogate tools to assist in monitoring the condition in a non-invasive manner in combination with imaging procedures. This study aimed to investigate whether biomarkers are associated with aortic dimensions in patients enrolled in the Genetically-Triggered Thoracic Aortic Conditions (GenTAC) registry. METHODS: Plasma samples of 159 patients enrolled in the GenTAC registry were assessed for circulating biomarkers [interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), tissue inhibitor of metalloproteinase-2 (TIMP-2) and transforming growth factor-ß1 (TGFß1)]. Association of circulating biomarker levels with aortic dimensions was investigated. RESULTS: IL-6 showed significant positive correlations with aortic dimensions at each segment of the aorta, with the correlation increasing in more distal aortic regions (ascending aorta, R = 0.26, p = 0.004; proximal arch, R = 0.35, p<0.0001; transverse arch, R = 0.30, p = 0.0005; mid-descending thoracic aorta, R = 0.40, p<0.0001; thoracoabdominal aorta, R = 0.38, p<0.0001; suprarenal abdominal aorta, R = 0.42, p<0.0001; and infrarenal aorta, R = 0.43, p<0.0001). TIMP-1 showed a significant correlation albeit weaker than IL-6, and also showed increasing correlation towards the distal areas of the aorta. CONCLUSIONS: Circulating IL-6 and TIMP-1 were associated with aortic dimensions in patients with aortopathies enrolled in the GenTAC cohort.


Assuntos
Aorta , Doenças da Aorta/sangue , Interleucina-6/sangue , Sistema de Registros , Adulto , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/sangue , Fator de Crescimento Transformador beta1/sangue
11.
Biomolecules ; 9(2)2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30781876

RESUMO

Chronic obstructive pulmonary disease (COPD) is influenced by genetic and environmental factors. A protease-antiprotease imbalance has been suggested as a possible pathogenic mechanism for COPD. Here, we examined the relationship between circulating serpina3g, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 and -2 (TIMP-1 and -2, respectively) and severity of COPD. We included 150 stable COPD patients and 35 control subjects in the study. The COPD patients were classified into four groups (I, II, III, and IV), according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines based on the severity of symptoms and the exacerbation risk. Plasma serpina3g, MMP-9, and TIMP-1 and -2 concentrations were significantly higher in the all patients than in control subjects. Plasma serpina3g, MMP-9, and TIMP-1 and -2 concentrations were significantly higher in groups III and IV than in groups I and II. A negative correlation between serpina3g, MMP-9, and TIMP-1 and -2 levels and the forced expiratory volume in 1 s (FEV1) was observed. MMP-9 concentration and the MMP-9/TIMP-1 ratio were higher in patients with emphysema than in other phenotypes (both with p < 0.01). The findings of this study suggest that circulating serpina3g, MMP-9, and TIMP-1 and -2 levels may play an important role in airway remodeling in COPD pathogenesis. Disrupted protease-antiprotease imbalance in patients with COPD is related to the presence of airway injury. MMP-9 concentration and the MMP-9/TIMP-1 ratio are the best predictors of emphysema in COPD patients.


Assuntos
Metaloproteinase 9 da Matriz/sangue , Doença Pulmonar Obstrutiva Crônica/sangue , Serpinas/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/sangue , Idoso , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/metabolismo , Serpinas/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo
12.
Nutrients ; 11(1)2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30658483

RESUMO

Polycystic ovary syndrome (PCOS) increases the risk of metabolic syndrome and non-alcoholic-fatty-liver disease (NAFLD). Vitamin D supplementation may exert positive effects on liver biochemistry in patients with NAFLD; however, its effects on PCOS are unknown. This randomized, double-blind, placebo-controlled study explored the effect of vitamin D supplementation on cardiovascular risk factors (high-sensitivity C-reactive protein (hs-CRP), weight, body mass index (BMI), lipid profile, glucose levels, insulin levels, the homeostatic model assessment-insulin resistance (HOMA-IR), hormones (free androgen index (FAI), testosterone, sex hormone binding globulin (SHBG), and liver markers (alanine aminotransferase (ALT), hyaluronic acid (HA), N-terminal pro-peptide of type III procollagen (PIIINP), tissue inhibitor of metallo-proteinases-1 (TIMP-1), and the enhanced liver fibrosis (ELF) score). Forty women with PCOS were recruited and randomized to vitamin D (3200 IU) or placebo daily for 3 months. All outcomes were measured at baseline and 3 months follow-up (FU). Greater increases in vitamin D levels were shown in the supplementation group (vitamin D, baseline: 25.6 ± 11.4 nmol/L, FU: 90.4 ± 19.5 nmol/L vs. placebo, baseline: 30.9 ± 11.1 nmol/L, FU: 47.6 ± 20.5 nmol/L, p < 0.001). Between groups comparisons (% baseline change) revealed significant differences in ALT (p = 0.042) and a weak effect indicating a greater reduction in the HOMA-IR in the vitamin D group (p = 0.051). No further between group differences were seen in other cardiovascular risk factor, liver markers, or hormones. This study supports beneficial effects of vitamin D supplementation on liver markers and modest improvements in insulin sensitivity in vitamin D deficient women with PCOS.


Assuntos
Biomarcadores/sangue , Doenças Cardiovasculares/prevenção & controle , Suplementos Nutricionais , Síndrome do Ovário Policístico/sangue , Vitamina D/administração & dosagem , Adolescente , Adulto , Alanina Transaminase/metabolismo , Glicemia/metabolismo , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Colesterol/sangue , Método Duplo-Cego , Feminino , Humanos , Ácido Hialurônico/sangue , Insulina/sangue , Resistência à Insulina , Fígado/metabolismo , Pessoa de Meia-Idade , Fatores de Risco , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Triglicerídeos/sangue , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/tratamento farmacológico , Adulto Jovem
13.
PLoS One ; 14(1): e0209158, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30650075

RESUMO

INTRODUCTION: Epoxyeicosatrienoic acids (EETs) are able to enhance angiogenesis and regulate inflammation that is especially important in wound healing under ischemic conditions. Thus, we evaluated the effect of local EET application on ischemic wounds in mice. METHODS: Ischemia was induced by cautherization of two of the three supplying vessels to the mouse ear. Wounding was performed on the ear three days later. Wounds were treated either with 11,12 or 14,15 EET and compared to untreated control and normal wounds. Epithelialization was measured every second day. VEGF, TNF-α, TGF-ß, matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP), Ki67, and SDF-1α were evaluated immunohistochemically in wounds on day 3, 6, and 9. RESULTS: Ischemia delayed wound closure (12.8 days ± 1.9 standard deviation (SD) for ischemia and 8.0 days ± 0.94 SD for control). 11,12 and14,15 EET application ameliorated deteriorated wound healing on ischemic ears (7.6 ± 1.3 SD for 11,12 EET and 9.2 ± 1.4 SD for 14,15 EET). Ischemia did not change VEGF, TNF-α, TGF-ß, SDF-1α, TIMP, MMP7 or MMP9 level significantly compared to control. Local application of 11,12 as well as 14,15 EET induced a significant elevation of VEGF, TGF-ß, and SDF-1α expression as well as proliferation during the whole phase of wound healing compared to control and ischemia alone. CONCLUSION: In summary, EET improve impaired wound healing caused by ischemia as they enhance neovascularization and alter inflammatory response in wounds. Thus elevating lipid mediator level as 11,12 and 14,15 EET in wounds might be a successful strategy for amelioration of deranged wound healing under ischemia.


Assuntos
Eicosanoides/uso terapêutico , Isquemia/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Quimiocina CXCL12/sangue , Modelos Animais de Doenças , Isquemia/sangue , Metaloproteinase 7 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Camundongos , Inibidor Tecidual de Metaloproteinase-1/sangue , Fator de Crescimento Transformador beta/sangue , Fator de Necrose Tumoral alfa/sangue , Fator A de Crescimento do Endotélio Vascular/sangue
14.
Drug Dev Res ; 80(3): 360-367, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30609097

RESUMO

Hit, Lead & Candidate Discovery This study investigated the effects of a natural phenolic compound quercetin on surgical-induced osteoarthritis (OA) in rabbits. Forty-eight New Zealand White rabbits were used to establish OA model by Hulth modified method, and subsequently randomized into untreated OA group (treatment was drinking water), celecoxib treated group (celecoxib 100 mg kg-1 by gavage), and quercetin treated group (25 mg kg-1 by gavage). Sixteen nonoperated rabbits served as the normal controls (drinking water was given). The treatment (length: 4 weeks) started on the 5th week postoperation when the OA pathological changes were manifested. Expressions of superoxide dismutase (SOD), matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in serum, synovial fluid, and synovial tissue were measured at 8 and 12 weeks postoperation. Pathological analysis was performed with synovial tissue section and Osteoarthritis Research Society International histopathology grading and staging scores were determined. The quercetin treated group showed higher SOD and TIMP-1 expressions but lower MMP-13 expression than untreated OA group in the serum, synovial fluid and synovial tissues (p < .05). There was no significant difference in the SOD, MMP-13 and TIMP-1 expressions between the quercetin-treated and celecoxib-treated groups. The MMP-13/TIMP-1 ratio of the quercetin treated group was significantly lower than that of the untreated OA group (p < .05). Quercetin can up-regulate SOD and TIMP-1, down-regulate MMP-13, and improve the degeneration of OA through weakening the oxidative stress responses and inhibiting the degradation of cartilage extracellular matrix.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Osteoartrite do Joelho/tratamento farmacológico , Quercetina/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Modelos Animais de Doenças , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/patologia , Metaloproteinase 13 da Matriz/sangue , Metaloproteinase 13 da Matriz/metabolismo , Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Estresse Oxidativo/efeitos dos fármacos , Quercetina/farmacologia , Coelhos , Superóxido Dismutase/sangue , Superóxido Dismutase/metabolismo , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/metabolismo , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-1/metabolismo
15.
Curr Med Chem ; 26(42): 7694-7713, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30182835

RESUMO

BACKGROUND AND OBJECTIVES: Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) is a multifunctional natural matrixin inhibitor that is generally considered a negative regulator of cancer metastasis. Clinical studies reporting the prognostic value of TIMP-1 in Non-small Cell Lung Cancer (NSCLC) are inconsistent. Therefore, the present study aimed to determine the prognostic impact of TIMP-1 expression in NSCLC. METHODS: Appropriate studies with full-text articles were identified in searches of the China National Knowledge Infrastructure (CNKI), Cochrane Library, PubMed, and Web of Science databases up to March 7, 2018. The pooled Hazard Ratio (HR) of overall survival with a 95% confidence interval (95% CI) was employed to assess the relationship between the expression of TIMP-1 and NSCLC patient survival. RESULTS: The meta-analysis comprised 40 studies including 3,194 patients. Study outcomes indicated that high TIMP-1 expression is independently associated with poor overall survival (HR: 1.60; 95% CI: 1.50, 1.69; P < 0.00001) with 61% of heterogeneity. In addition, we analyzed subgroups, including ethnicities, histological types, percentage of TIMP-1 expression levels, specimens, and tumor stage. All results were statistically significant. The outcome of our meta-analysis indicates that high expression levels of TIMP-1 are correlated with poor prognosis in patients with NSCLC. CONCLUSION: Expression levels of TIMP-1 represent a potential prognostic biomarker in NSCLC patients in addition to being a possible therapeutic target.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Prognóstico , Inibidor Tecidual de Metaloproteinase-1/sangue
16.
Nefrologia ; 39(2): 184-191, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30509751

RESUMO

BACKGROUND AND OBJECTIVE: Matrix metalloproteinases (MMPs) are involved in deleterious tissue remodeling associated with target organ damage in renal disease. The aim of this study was to study the association between renal dysfunction and activity of the inflammatory metalloproteinase MMP-9 in hypertensive patients with mild-moderate chronic kidney disease (CKD). MATERIAL AND METHODS: Plasmatic active MMP-9, total MMP-9, tissue inhibitor of MMP-9 (TIMP-1), MMP-9/TIMP-1 ratio and MMP-9-TIMP-1 interaction were analyzed in 37 hypertensive patients distributed by estimated glomerular filtration rate (eGFR) in 3 groups:>90, 90-60 y 60-30mL/min/1.73 m2. RESULTS: Total MMP-9 was not different as eGFR declines. TIMP-1 was significantly increased in hypertensive patients with eGFR 60-30mL/min/1.73 m2 (P<.01 versus>90mL/min/1.73 m2). This relates to the significant decrease in the interaction between MMP-9-TIMP-1 observed in patients with eGFR 60-30mL/min/1.73 m2 (P<.01 versus>90mL/min/1.73 m2). Despite the systemic elevation of TIMP-1, active MMP-9 was significantly increased in hypertensive patients with eGFR 60-30mL/min/1.73 m2 (P<.05 and P<0.01 versus>90 and 90-60mL/min/1.73 m2, respectively). TIMP-1, active MMP-9 and MMP-9-TIMP-1 interaction significantly correlate with the decline in renal function, which was not observed with total MMP-9. CONCLUSIONS: The progression of CKD, even in stages where the decline of renal function is still moderate, is associated with an increase in MMP-9 activity, which could be considered as a potential therapeutic target.


Assuntos
Hipertensão/enzimologia , Metaloproteinase 9 da Matriz/sangue , Insuficiência Renal Crônica/enzimologia , Inibidor Tecidual de Metaloproteinase-1/sangue , Idoso , Análise de Variância , Biomarcadores/metabolismo , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão/complicações , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Fatores de Tempo
17.
Transl Stroke Res ; 10(1): 44-51, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29687301

RESUMO

Small vessel disease (SVD) is frequent in aging and stroke patients. Inflammation and remodeling of extracellular matrix have been suggested as concurrent mechanisms of SVD. We investigated the relationship between imaging features of SVD and circulating metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in patients with ischaemic stroke. In patients treated with intravenous thrombolysis, we took blood samples before intravenous thrombolysis and 90 days after the acute stroke and analysed levels of MMPs and TIMPs. We assessed leukoaraiosis, number of lacunes and brain atrophy on pre-treatment CT scan and graded global SVD burden combining such features. We investigated associations between single features, global SVD and MMPs and TIMPs at baseline and at follow-up, retaining univariate statistically significant associations in multivariate linear regression analysis and adjusting for clinical confounders. A total of 255 patients [mean (±SD) = 68.6 (± 12.7) years, 154 (59%) males] were included, 107 (42%) had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. A total of 107 (42%) patients had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. After adjustment, only TIMP-4 proved associations with SVD features. Brain atrophy was associated with baseline TIMP-4 (ß = 0.20;p = 0.019) and leukoaraiosis with 90 days TIMP-4 (ß = 0.19; p = 0.013). Global SVD score was not associated with baseline TIMP-4 levels (ß = 0.10; p = 0.072), whereas was associated with 90 days TIMP-4 levels (ß = 0.21; p = 0.003). Total SVD burden was associated with higher TIMP-4 levels 90 days after stroke, whereas was not during the acute phase. Our results support a biological relationship between SVD grade and TIMP-4.


Assuntos
Doenças de Pequenos Vasos Cerebrais/sangue , Doenças de Pequenos Vasos Cerebrais/etiologia , Acidente Vascular Cerebral/complicações , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidores Teciduais de Metaloproteinases/sangue , Ativador de Plasminogênio Tecidual/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Isquemia Encefálica/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , Tomógrafos Computadorizados , Tomografia Computadorizada por Raios X
18.
Acta Oncol ; 58(sup1): S42-S48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30523734

RESUMO

BACKGROUND: Blood-based, cancer-associated biomarkers may detect subjects at risk of having neoplastic diseases. The aim of the present study was to evaluate whether elevated serological protein biomarker levels may identify adenoma patients, who are at increased risk of being diagnosed with subsequent primary malignancy. METHODS: Levels of CEA, CA19-9, TIMP-1 and YKL-40 were determined in blood samples collected prior to diagnostic bowel endoscopy due to symptoms of colorectal neoplasia. Follow-up time was ten years, and identified adenoma patients, who were diagnosed with subsequent primary intra- or extra-colonic malignant diseases. The biomarker levels were also determined in 400 subjects, who underwent diagnostic colonoscopy, had clean colorectum and were without apparent co-morbidity; these levels were used as reference levels. In the present study, biomarkers were interpreted as elevated when levels were above the reference intervals adjusting for age and gender. The 1-year and 5-years cumulative incidences were calculated. RESULTS: Primary malignancies were identified in 175 (19%) of the 923 subjects diagnosed with adenomas at the primary bowel endoscopy. In detail, 20 of the 175 subjects were diagnosed with colorectal cancer (CRC) and 155 subjects with extra-colonic cancers. Thirty patients were diagnosed with malignancy within the first year. Three groups were established: 0: no elevated biomarkers; 1: 1 of the 4 biomarkers elevated; and 2: ≥2 biomarkers elevated. The cumulative 5-years incidence of malignancy was: 0: 6.9%; 1: 11.8%; and 2: 17.5% (p = .0009). CONCLUSION: Elevated blood-based, cancer-associated protein biomarker levels in subjects diagnosed with adenomas at large bowel endoscopy identifies subjects at increased risk of being diagnosed with subsequent primary malignancy.


Assuntos
Adenoma/diagnóstico , Antígeno CA-19-9/sangue , Antígeno Carcinoembrionário/análise , Proteína 1 Semelhante à Quitinase-3/sangue , Neoplasias Colorretais/diagnóstico , Neoplasias Intestinais/diagnóstico , Inibidor Tecidual de Metaloproteinase-1/sangue , Adenoma/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/epidemiologia , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Neoplasias Intestinais/sangue , Neoplasias Intestinais/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Adulto Jovem
19.
Rheumatology (Oxford) ; 58(2): 254-259, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30239834

RESUMO

Objectives: To validate enhanced liver fibrosis (ELF) test and its components-amino-terminal propeptide of procollagen type III (PIIINP), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and HA-as biomarkers of fibrosis in SSc in an independent, international, multicentre cohort. Methods: Two hundred and fifty-four SSc patients from six Rheumatology Centres were included. Sera were collected and stored according to EUSTAR biobanking recommendations and analysed through automated high throughput diagnostics. Statistical analysis was performed with SPSS software. Results: Two hundred and forty-seven SSc patients (mean age 55.7 ± 13.9 years, 202 F) were analysed. ELF score, TIMP-1 and PIIINP levels were higher in males (P = 0.0197, P = 0.0107, P = 0.0108 respectively) and in dcSSc (P = 0.001, P = 0.0008, P < 0.0001 respectively). ELF score and the single markers significantly correlated with modified Rodnan skin score (r = 0.37, P < 0.0001), disease activity and severity (P < 0.0001 for all markers, except for HA P = 0.0001) and inversely with forced vital capacity, (FVC) % (TIMP-1, r = -0.21, P = 0.0012; PIIINP, r = -0.26, P = 0.0001), TLC% (ELF score, r = -0.20, P = 0.0036; TIMP-1, r = -0.32, P < 0.0001; PIIINP, r = -0.28, P < 0.0001), diffusion capacity of the lung for carbon monoxide (DLCO) % (P < 0.0001 for all markers, except for HA P = 0.0115). Multivariate analysis indicated that age (P < 0.001), modified Rodnan skin score (P < 0.001) and DLCO% (P = 0.005) were independently associated with ELF score. Conclusion: Between the first and this validation studies, the value of the ELF score as independent marker of skin and lung involvement in SSc is confirmed in 457 patients. A longitudinal study is on-going to identify an SSc specific algorithm with predictive value for skin and lung progression.


Assuntos
Cirrose Hepática/etiologia , Escleroderma Sistêmico/complicações , Adulto , Idoso , Bancos de Espécimes Biológicos , Biomarcadores/sangue , Feminino , Fibrose , Humanos , Ácido Hialurônico/sangue , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Fibrose Pulmonar/diagnóstico , Fibrose Pulmonar/etiologia , Escleroderma Sistêmico/diagnóstico , Índice de Gravidade de Doença , Pele/patologia , Inibidor Tecidual de Metaloproteinase-1/sangue
20.
Blood Cells Mol Dis ; 74: 5-12, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30344086

RESUMO

Predictive biomarkers for acute graft-versus-host disease (aGVHD) is currently lacking. In this study, we employed an unbiased proteome profiling method to prospectively collected plasma samples from allogeneic hematopoietic stem cell transplantation (alloHSCT) recipients to identify protein biomarkers that predict the risk of aGVHD and non-relapse mortality (NRM). In the discovery set, including five aGVHD patients and five controls, we identified seven candidate proteins. Patients with high levels of these proteins tended to exhibit a higher risk of aGVHD and NRM compared to patients with low levels in post-engraftment plasma samples from an independent validation set (n = 89). Tissue inhibitor of metalloproteinase 1, plastin-2, and regenerating islet-derived protein 3-α were selected as the most-predictive biomarkers via an exhaustive variable screening algorithm and were collectively used to develop a biomarker panel score ranging from 0 to 3. The biomarker panel score correlated significantly with aGVHD and NRM risk in univariable and multivariable Cox models. Furthermore, using the biomarker panel score in conjunction with clinical predictors significantly improved the discriminatory performance of the Cox model in predicting aGVHD and NRM risk. Our findings suggest that plasma-derived protein biomarkers can be used to predict aGVHD and NRM before the onset of clinical manifestations.


Assuntos
Biomarcadores/sangue , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Doença Aguda , Adulto , Estudos de Casos e Controles , Doença Enxerto-Hospedeiro/diagnóstico , Humanos , Glicoproteínas de Membrana/sangue , Proteínas dos Microfilamentos/sangue , Proteínas/análise , Proteômica , Risco , Inibidor Tecidual de Metaloproteinase-1/sangue , Transplante Homólogo
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