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1.
Klin Lab Diagn ; 64(10): 588-593, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31742950

RESUMO

At some works, it has been shown there are signs of damage and endothelium dysfunction in patients with chronic viral hepatitis (CVH) and liver cirrhosis of viral etiology the severity of these conditions depends on the severity of the pathological process. Evaluation of the role of angiogenic factors and endothelial dysfunction in persistent of CVH in children and adolescents. 35 patients were examined: of which 11 with chronic hepatitis B (CHB) and 24 with chronic hepatitis C (CHC). The reference group consisted of 120 practically healthy persons of the corresponding age and sex. VEGF-A, angiotensin (ANG), soluble receptors of VEGF-A (sVEGF-R1 и sVEGF-R2) and trombomodulin (TM) have been investigated in serum by enzyme immunoassay using special kits (BCM Diagnostics, USA). Other endothelial dysfunction markers as von Willebrand factor (vWf) was determined in blood plasma by immunoturbidimetry (Siemens, Germany), plasminogen (PLG) was investigated due to extended coagulation. In children with CVH, regardless of etiology, the concentration of VEGF-A was significantly lower, and sVEGF-R2, sVEGF-R1 and TM was higher than in children without liver disease (p <0.001, p <0.05, p <0.01, p <0.001, respectively). The concentration of TM and the level of PLG activity in patients with CHC were slightly higher than in CHB. Decreased level of VEGF-A and increased expression of its soluble receptors indicate enhanced inhibition of angiogenesis in CVH, which may indicate the pathogenetic role of this phenomenon in the development of liver damage in CHC.


Assuntos
Hepatite B Crônica/sangue , Hepatite C Crônica/sangue , Cirrose Hepática/virologia , Neovascularização Patológica/sangue , Adolescente , Angiotensinas/sangue , Biomarcadores/sangue , Criança , Humanos , Plasminogênio/análise , Trombomodulina/sangue , 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 , Fator de von Willebrand/análise
2.
In Vivo ; 33(2): 581-586, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30804145

RESUMO

BACKGROUND: Endothelial microparticles (EMPs) released from activated or apoptotic endothelial cells may play a role in coagulation and thrombus formation. However, there is insufficient evidence regarding the impact of EMPs on angiogenesis in patients with cancer. MATERIALS AND METHODS: Sixteen patients with head and neck cancer (HNC) undergoing radiotherapy/radiochemotherapy (RT/RCT) and 10 healthy controls were studied. Serum EMPs were counted by flow cytometry, and vascular endothelial growth factor (VEGF) was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean EMP level was significantly higher in patients with HNC before RT/RCT (1,601±1,479 EMP/µl) compared to the control group (782±698 EMP/µl). The number of EMPs was not notably increased after RT/RCT (1,629±769 EMP/µl). There was no significant correlation between the plasma EMP number and concentration of VEGF before (r=0.131; p=0.625), 1 day after (r=-0.042, p=0.874), nor 3 months after RT/RCT (r=0.454, p=0.076). CONCLUSION: Released EMPs may not influence promotion of neovascularization in patients with HNC.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Neovascularização Patológica/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/efeitos da radiação , Micropartículas Derivadas de Células/metabolismo , Micropartículas Derivadas de Células/patologia , Quimiorradioterapia/efeitos adversos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Citometria de Fluxo , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia
3.
Oncogene ; 38(6): 868-880, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30177842

RESUMO

Perihilar cholangiocarcinoma (PHCCA) is the most common type of cholangiocarcinoma with low resection rate and high morbidity. The study of PHCCA biomarkers made progresses slowly compared with intrahepatic cholangiocarcinoma because of surgical complexity and low possibility of radical surgery, which resulted in the difficulty of specimen obtainment. To screen and identify new biomarkers in PHCCA, we constructed a retrospective cohort with 121 PHCCA patients and a prospective cohort consisting of 64 PHCCA patients, and screened the candidate biomarkers by immunohistochemistry and quantified PCR. In our study, expression of high mobility group box 1 (HMGB1) was demonstrated to be significantly associated with microvascular density (MVD) and unfavorable prognosis of PHCCA in both retrospective and prospective study. Moreover, HMGB1 concentrations in bile and serum of PHCCA patients and healthy controls were detected and compared. Postoperative serum HMGB1 and reflux cholangitis indicated recurrence and unfavorable prognosis of PHCCA. With experiments in vitro and in vivo, we demonstrated that intracellular HMGB1 could be released from PHCCA cells and induce invasion and angiogenesis with LPS stimulation. VEGFR2 expression in vessel endothelial cells was upregulated by the released HMGB1 from PHCCA, resulting in the ectopic angiogenesis. In conclusion, intracellular HMGB1 could be released from PHCCA cells and promote angiogenesis via elevating VEGFR2 in vessel endothelial cells. High expression of HMGB1 was associated with MVD and poor prognosis in clinical analyzation. Postoperative serum HMGB1 and cholangitis could predict high recurrence and unfavorable prognosis.


Assuntos
Neoplasias dos Ductos Biliares , Proteína HMGB1/sangue , Tumor de Klatskin , Proteínas de Neoplasias/sangue , Neovascularização Patológica , Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Intervalo Livre de Doença , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Tumor de Klatskin/sangue , Tumor de Klatskin/mortalidade , Tumor de Klatskin/cirurgia , Masculino , Neovascularização Patológica/sangue , Neovascularização Patológica/mortalidade , Neovascularização Patológica/cirurgia , Estudos Prospectivos , Taxa de Sobrevida
4.
J Obstet Gynaecol Res ; 45(3): 729-733, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30520542

RESUMO

A 41-year-old woman (gravida 2, para 1) underwent elective termination of pregnancy at approximately 7 weeks of gestation. At 1 month after the elective abortion, she was referred due to abnormal results in a cervical cytological examination. Transvaginal ultrasonography showed a heterogeneous mass of 16 mm in diameter in the left adnexal region. At 3 months after her referral, the asymptomatic left adnexal mass had increased to 55 mm in diameter. Prominent vascular flow was detected in the solid portion by color Doppler ultrasonography. Magnetic resonance imaging showed suspected hemorrhage in the left adnexal cystic mass. Three-dimensional computerized tomographic angiography showed the prominent development of tortuous blood vessels in the left adnexal region, which originated from the left ovarian artery. The patient had a negative ß-human chorionic gonadotropin (hCG) level. Left salpingectomy was performed by a single-port laparoscopic approach. A pathological examination revealed degenerated villous tissue with ß-hCG-positive syncytiotrophoblasts.


Assuntos
Doenças dos Anexos/diagnóstico por imagem , Gonadotropina Coriônica Humana Subunidade beta/sangue , Neovascularização Patológica/diagnóstico por imagem , Gravidez Tubária/diagnóstico por imagem , Doenças dos Anexos/sangue , Doenças dos Anexos/cirurgia , Adulto , Feminino , Humanos , Neovascularização Patológica/sangue , Neovascularização Patológica/cirurgia , Gravidez , Gravidez Tubária/sangue , Gravidez Tubária/cirurgia , Salpingectomia
5.
Cancer Sci ; 110(2): 771-783, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30520543

RESUMO

Nonalcoholic steatohepatitis (NASH) is a common cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapeutic strategies for preventing and treating NASH-mediated liver cirrhosis and HCC are lacking. Cholesterol is closely associated with vascular endothelial growth factor (VEGF), a key factor that promotes HCC. Recent reports have demonstrated that statins could prevent HCC development. In contrast, we have little information on ezetimibe, an inhibitor of cholesterol absorption, in regards to the prevention of NASH-related liver cirrhosis and HCC. In the present study, a steatohepatitis-related HCC model, hepatocyte-specific phosphatase and tensin homolog (Pten)-deficient (PtenΔhep ) mice were fed a high-fat (HF) diet with/without ezetimibe. In the standard-diet group, ezetimibe did not reduce the development of liver tumors in PtenΔhep mice, in which the increase of serum cholesterol levels was mild. Feeding of a HF diet increased serum cholesterol levels markedly and subsequently increased serum levels of VEGF, a crucial component of angiogenesis. The HF diet increased the number of VEGF-positive cells and vascular endothelial cells in the tumors of PtenΔhep mice. Kupffer cells, macrophages in the liver, increased VEGF expression in response to fat overload. Ezetimibe treatment lowered cholesterol levels and these angiogenetic processes. As a result, ezetimibe also suppressed inflammation, liver fibrosis and tumor growth in PtenΔhep mice on the HF diet. Tumor cells were highly proliferative with HF-diet feeding, which was inhibited by ezetimibe. In conclusion, ezetimibe suppressed development of liver tumors by inhibiting angiogenesis in PtenΔhep mice with hypercholesterolemia.


Assuntos
Inibidores da Angiogênese/farmacologia , Dieta Hiperlipídica/efeitos adversos , Ezetimiba/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Animais , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/sangue , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/sangue , Neovascularização Patológica/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue
6.
Nat Commun ; 9(1): 4672, 2018 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-30405103

RESUMO

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/secundário , Receptor TIE-2/sangue , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adulto , Idoso , Angiopoietina-2/metabolismo , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/tratamento farmacológico , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neovascularização Patológica/sangue , Prognóstico , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Nutr Res ; 59: 72-79, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30442235

RESUMO

Erratic eating behavior disrupts the daily feeding and fasting pattern and leads to metabolic dysfunction and chronic diseases including cancer. In the present study, we tested the hypothesis that time-restricted feeding of a high-fat diet (HFD) to the dark phase does not enhance mammary tumorigenesis in MMTV-PyMT mice. Female mice were assigned to 3 groups and fed the standard AIN93G diet or an HFD with or without dark phase restricted feeding (12 hours). The duration of restricted feeding was 8 weeks. The HFD group had 24% more body fat mass than the AIN93G group; the body fat mass of the restricted group remained similar to that of the AIN93G group. Energy intake of the restricted group was similar to that of the HFD and AIN93G groups. The median mammary tumor latency was 5.8, 7.0, and 6.4 weeks for the AIN93G, HFD, and restricted groups, respectively. Mammary tumor progression was 241% higher in the HFD group than that in the AIN93G group; there was no significant difference in tumor progression between the restricted and AIN93G groups. Plasma concentrations of leptin, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, angiopoietin-2, vascular endothelial growth factor, and hepatocyte growth factor were significantly higher in the HFD group than those in the control group; these measurements were similar between the restricted and control groups. In conclusion, feeding restricted to the dark phase mitigates the HFD-enhanced mammary tumorigenesis; this may be related to the lower body adiposity and associated inflammatory and angiogenic signals.


Assuntos
Neoplasias da Mama/prevenção & controle , Carcinogênese , Dieta Hiperlipídica/efeitos adversos , Jejum , Comportamento Alimentar , Obesidade/complicações , Tecido Adiposo/metabolismo , Adiposidade , Angiopoietina-2/sangue , Animais , Neoplasias da Mama/sangue , Neoplasias da Mama/etiologia , Quimiocina CCL2/sangue , Escuridão , Feminino , Fator de Crescimento de Hepatócito/sangue , Inflamação/sangue , Inflamação/prevenção & controle , Leptina/sangue , Camundongos Endogâmicos , Neovascularização Patológica/sangue , Neovascularização Patológica/prevenção & controle , Obesidade/sangue , Obesidade/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Fator A de Crescimento do Endotélio Vascular/sangue
8.
Mol Cancer ; 17(1): 148, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30309369

RESUMO

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer related to asbestos exposure. The discovery of soluble biomarkers with diagnostic/prognostic and/or therapeutic properties would improve therapeutic care of MPM patients. Currently, soluble biomarkers described present weaknesses preventing their use in clinic. This study aimed at evaluating brain-derived neurotrophic factor (BDNF), we previously identified using transcriptomic approach, in MPM. We observed that high BDNF expression, at the mRNA level in tumors or at the protein level in pleural effusions (PE), was a specific hallmark of MPM samples. This protein presented significant but limited diagnostic properties (area under the curve (AUC) = 0.6972, p < 0.0001). Interestingly, high BDNF gene expression and PE concentration were predictive of shorter MPM patient survival (13.0 vs 8.3 months, p < 0.0001, in PE). Finally, BDNF did not affect MPM cell oncogenic properties but was implicated in PE-induced angiogenesis. In conclusion, BDNF appears to be a new interesting biomarker for MPM and could also be a new therapeutic target regarding its implication in angiogenesis.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Mesotelioma/sangue , Mesotelioma/patologia , Neovascularização Patológica/sangue , Neoplasias Pleurais/sangue , Neoplasias Pleurais/patologia , Biomarcadores Tumorais , Fator Neurotrófico Derivado do Encéfalo/genética , Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mesotelioma/genética , Mesotelioma/mortalidade , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/metabolismo , Neoplasias Pleurais/genética , Neoplasias Pleurais/mortalidade , Prognóstico , RNA Mensageiro/genética , Curva ROC
9.
Biochim Biophys Acta Mol Basis Dis ; 1864(12): 3759-3770, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30292634

RESUMO

Liver inflammation after chronic hepatitis B virus (HBV) infection is essential for hepatocellular carcinoma (HCC) development. We did a nested case-control study based on QBC chronic HBV infection cohort to identify HCC-related inflammatory cytokines. Serum levels of distinct Th-cell representative cytokines at varied periods before HCC diagnosis were determined in 50 HCC cases and 150 age- and gender-matched controls who did not develop HCC in 8-10 years. The individuals with HCC outcome had statistically higher serum levels of IL-23 than controls (P < 0.01). Further analysis in HCC tissues showed that CD14+ inflammatory macrophages were the major IL-23 producers. Monocytes-derived macrophages generated more amount of IL-23 after being stimulated with cell-associated HBV core antigen from damaged HBV-infected hepatocytes than the cells being stimulated with HBV-S and HBV e antigen, which are secreted from infected hepatocytes. IL-23 upregulated IL-23 receptor expressions on macrophages, enhanced macrophage-mediated angiogenesis. In HBV-transgenic (Alb1HBV) mice, administration of diethylnitrosamine induced more liver tumors than in wild-type mice. The livers of Alb1HBV mice had higher concentrations of IL-23 and vascular endothelial growth factor (VEGF) than the wild-type mice. Neutralizing IL-23 activity, diethylnitrosamine-treated Alb1HBV mice developed significantly less tumors and produced less VEGF, tumor angiogenesis was inhibited with dramatically decreased CD31+ cells within tumor mass (all P < 0.01). CONCLUSION: Persistent IL-23 generation of liver inflammatory macrophages responding to damaged hepatocytes after chronic HBV infection altered macrophage function for HCC promotion. Blocking IL-23 activity might be helpful for the intervention in chronic hepatitis B patients who had high risk to HCC.


Assuntos
Carcinoma Hepatocelular/etiologia , Hepatite B Crônica/complicações , Hepatócitos/imunologia , Inflamação/etiologia , Interleucina-23/imunologia , Neoplasias Hepáticas/etiologia , Macrófagos/imunologia , Animais , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Hepatite B Crônica/sangue , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatócitos/patologia , Humanos , Inflamação/sangue , Inflamação/imunologia , Inflamação/patologia , Interleucina-23/sangue , Fígado/imunologia , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Neovascularização Patológica/sangue , Neovascularização Patológica/etiologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/patologia
10.
Biosci Rep ; 38(6)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30254101

RESUMO

Background: Increasing evidences reveal that inflammation plays a critical role in tumorigenesis and progression. We aimed to develop the nomograms based on inflammatory biomarkers to predict micro-vascular invasion (MVI) and tumor grade in stage I/II hepatocellular carcinoma (HCC).Methods: A retrospective cohort of 627 patients with stage I/II HCC between January 2007 and December 2014 was included in the study. Logistic regression was performed to identify the independent risk factors of tumor grade and MVI. The significant predictors including neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), lymphocyte-to-monocyte ratio (LMR), tumor volume age, and tumor size were subsequently incorporated to build the nomograms. The prediction accuracies of the nomograms were evaluated using the area under the receiver operating characteristic (ROC) curve.Results: The independent risk factors for tumor grade were NLR, dNLR, and tumor volume (P<0.001, P=0.001, and P<0.001, respectively), which were assembled into tumor grade nomogram. MVI nomogram was developed by dNLR, LMR, age, and tumor size (P<0.001, P<0.001, P<0.001, and P=0.001, respectively) which were the independent predictors for MVI. The area under the ROC curve of nomograms for predicting tumor grade and MVI were 0.727 (95% confidence intervals [CI]: 0.690-0.761) and 0.839 (95% CI: 0.808-0.867), respectively. Patients who had a nomogram score of less than 100 and 79 were considered to have high possibility of moderate grade and have low risks of MVI presence, respectively.Conclusion: We successfully developed nomograms predicting tumor grade and MVI based on inflammatory biomarkers with high accuracy, leading to a rational therapeutic choice for stage I/II HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Inflamação/sangue , Neoplasias Hepáticas/sangue , Neovascularização Patológica/sangue , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Carcinogênese/genética , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Feminino , Humanos , Inflamação/diagnóstico por imagem , Inflamação/patologia , Contagem de Leucócitos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Invasividade Neoplásica/diagnóstico por imagem , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/patologia , Neutrófilos/patologia , Nomogramas , Fatores de Risco , Carga Tumoral
11.
Life Sci ; 211: 25-30, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30195618

RESUMO

AIMS: Gestational trophoblastic neoplasms (GTN) exemplify a rare, mostly curable but highly aggressive disease. It is often associated with a rapid formation of distant metastases and most likely with an intense neoangiogenesis processes. The aim of the study was to analyze markers in serum of patients with GTN before chemotherapy compared to healthy pregnant women. MAIN METHODS: In this study sixteen protein angiogenesis markers were evaluated in serum of 21 patients with GTN before chemotherapy and compared with healthy pregnant women. Markers were measured using BioPlex Pro Human Cancer Biomarker Panel 1 immunoassay. t-Tests and receiver operating characteristic curves were used for statistical analysis. KEY FINDINGS: Receiver operator curve analysis identified six proteins (sTIE-2, osteopontin, sIL-6α, sVEGFR-2, sEGFR, PECAM-1) which had sufficient sensitivity and specificity (AUC > 0,70) to distinguish GTN patients before the treatment from pregnant controls. The levels of three proteins (sTIE-2, osteopontin and sIL-6α) were altered in GTN patients before the treatment as compared to healthy controls (p = 0,0112; p = 0,0442; p = 0,0488, respectively) and thereby may serve as potential disease markers. SIGNIFICANCE: Serum concentration of proteins related to angiogenesis changes in the course of GTN and may appear useful in the diagnostic process of this disease.


Assuntos
Indutores da Angiogênese/sangue , Biomarcadores Tumorais/sangue , Doença Trofoblástica Gestacional/diagnóstico , Imunoensaio/métodos , Neovascularização Patológica/diagnóstico , Adulto , Estudos de Casos e Controles , Feminino , Doença Trofoblástica Gestacional/sangue , Humanos , Neovascularização Patológica/sangue , Gravidez , Curva ROC
12.
Proc Natl Acad Sci U S A ; 115(38): E8948-E8957, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30158168

RESUMO

Angiogenesis is essential in the early stage of solid tumor recurrence, but how a suspensive tumor is reactivated before angiogenesis is mostly unknown. Herein, we stumble across an interesting phenomenon that s.c. xenografting human lung cancer tissues can awaken the s.c. suspensive tumor in nude mice. We further found that a high level of insulin-like growth factor 1 (IGF1) was mainly responsible for triggering the transition from suspensive tumor to progressive tumor in this model. The s.c. suspensive tumor is characterized with growth arrest, avascularity, and a steady-state level of proliferating and apoptotic cells. Intriguingly, CD133+ lung cancer stem cells (LCSCs) are highly enriched in suspensive tumor compared with progressive tumor. Mechanistically, high IGF1 initiates LCSCs self-renewal from asymmetry to symmetry via the activation of a PI3K/Akt/ß-catenin axis. Next, the expansion of LCSC pool promotes angiogenesis by increasing the production of CXCL1 and PlGF in CD133+ LCSCs, which results in lung cancer recurrence. Clinically, a high level of serum IGF1 in lung cancer patients after orthotopic lung cancer resection as an unfavorable factor is strongly correlated with the high rate of recurrence and indicates an adverse progression-free survival. Vice versa, blocking IGF1 or CXCL1/PlGF with neutralizing antibodies can prevent the reactivation of a suspensive tumor induced by IGF1 stimulation in the mouse model. Collectively, the expansion of LCSC pool before angiogenesis induced by IGF1 is a key checkpoint during the initiation of cancer relapse, and targeting serum IGF1 may be a promising treatment for preventing recurrence in lung cancer patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Antígeno AC133/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/sangue , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CXCL1/antagonistas & inibidores , Quimiocina CXCL1/metabolismo , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Neoplasias Pulmonares/sangue , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia/sangue , Neovascularização Patológica/sangue , Fosfatidilinositol 3-Quinases/metabolismo , Fator de Crescimento Placentário/antagonistas & inibidores , Fator de Crescimento Placentário/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/metabolismo
13.
Bull Exp Biol Med ; 165(4): 521-525, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30121924

RESUMO

The study demonstrates significant variety of neovascularization degree and vessel diameter in the carotid atherosclerotic plaque. It is suggested that the increase in the number of vessels with a diameter <20 µ can be indicative of increased atherosclerosis activity, while the increase in the number of vessels with a diameter ≥40 µ indicates "reparative potential" of plaques. Duplex contrast-enhanced ultrasound scanning allows characterization of the localization and number of vessels with a diameter of ≥30 µ in the plaque, while even slight elevation of plasma concentration of basic fibroblast growth factor attests, first of all, to increased content of small vessels <30 µ in the plaque. The level of fibroblast growth factor >1.5 pg/ml is a reliable marker of increased number of both small and large vessels in the plaque.


Assuntos
Artérias Carótidas/patologia , Neovascularização Patológica/patologia , Placa Aterosclerótica/patologia , Idoso , Meios de Contraste , Feminino , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/sangue , Placa Aterosclerótica/sangue
14.
Future Oncol ; 14(19): 1953-1963, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30043623

RESUMO

AIM: The study aimed to elucidate the value of multislice spiral computed tomography (MSCT) perfusion for the early prediction of gastric cancer (GC) recurrence. METHODS: MSCT perfusion scans were performed to obtain values pertaining to blood flow (BF), blood volume (BV), mean transit time (MTT) and permeability surface (PS). Logistic regression analysis was employed to evaluate the risk factors of postoperative recurrence in GC. RESULTS: The maximum diameter of GC has a positive relationship with PS. The maximum enhancement of GC was positively correlated with BF, blood volume and PS. PS, BF, vascular thrombus and Tumor, Node, Metastasis staging were found to be significant risk factors in relation to the recurrence of GC (p = 0.006, p = 0.002, p < 0.001). CONCLUSION: MSCT perfusion is strongly correlated with postoperative recurrence of GC, and PS and BF values, vascular thrombus and Tumor, Node, Metastasis staging were discovered as being prominent factors influencing the recurrence of GC.


Assuntos
Recidiva Local de Neoplasia/sangue , Complicações Pós-Operatórias/sangue , Neoplasias Gástricas/sangue , Tomografia Computadorizada Espiral , Idoso , Velocidade do Fluxo Sanguíneo , Determinação do Volume Sanguíneo , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/complicações , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/cirurgia , Neovascularização Patológica/sangue , Neovascularização Patológica/diagnóstico por imagem , Neovascularização Patológica/patologia , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/patologia , Fatores de Risco , Neoplasias Gástricas/complicações , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/cirurgia
15.
Ann Rheum Dis ; 77(11): 1665-1674, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30021803

RESUMO

OBJECTIVE: In systemic sclerosis (SSc), early microvascular injury is followed by impaired angiogenesis and peripheral capillary loss. Here, we investigated the possible contribution of the neurovascular guidance molecule Slit2 and its Roundabout (Robo) receptors to SSc-related endothelial cell dysfunction. METHODS: Circulating Slit2 levels were measured in patients with SSc and healthy controls. Slit2, Robo1 and Robo4 expression was investigated in SSc and healthy skin biopsies and explanted dermal microvascular endothelial cells (MVECs). Slit2/Robo4 function in MVEC angiogenesis was studied by cell viability, wound healing and capillary-like tube formation assays. RESULTS: Circulating Slit2 was significantly increased in either SSc or patients with a very early diagnosis of SSc (VEDOSS) compared with controls. Interestingly, serum Slit2 levels were raised in patients with VEDOSS with nailfold videocapillaroscopy (NVC) abnormalities, while they were similar in VEDOSS with normal NVC and controls. In SSc, Slit2 and Robo4 expression was upregulated in clinically affected skin and explanted MVECs in respect to controls. The angiogenic performance of healthy MVECs was significantly reduced after challenge with recombinant human Slit2 or SSc sera. These inhibitory effects were significantly attenuated when SSc sera were preincubated with an anti-Slit2 blocking antibody. In vitro angiogenesis was severely compromised in SSc-MVECs and could be significantly ameliorated by Slit2 neutralisation or ROBO4 gene silencing. Slit2/Robo4 axis interfered with angiogenesis through the inhibition of Src kinase phosphorylation. CONCLUSIONS: In SSc, increased circulating levels of Slit2 and activation of the Slit2/Robo4 antiangiogenic axis may contribute to peripheral microangiopathy since the very early phase of the disease.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Neovascularização Patológica/sangue , Proteínas do Tecido Nervoso/fisiologia , Receptores de Superfície Celular/fisiologia , Escleroderma Sistêmico/patologia , Adulto , Idoso , Sobrevivência Celular/fisiologia , Células Cultivadas , Células Endoteliais/fisiologia , Endotélio Vascular/patologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Proteínas do Tecido Nervoso/sangue , Receptores de Superfície Celular/sangue , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/fisiopatologia , Pele/irrigação sanguínea , Cicatrização/fisiologia
16.
Cancer Gene Ther ; 25(9-10): 248-259, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29983418

RESUMO

Esophageal cancer related gene-4 (Ecrg4) has been shown to be a tumor suppressor in many organs. Exosomes are naturally secreted nanosized particles that carry signal molecules including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs) among others. Upon internalization, exosomes unload their cargos that in turn modulate the biology of the recipient cells. Mounting evidence has shown that exosomal miRNAs are functional. However, reports that exosomes carry functional mRNAs remain scarce. We found that serum exosomes contain ECRG4 open reading frame. To simulate serum exosomal ECRG4, stable cell line expressing ECRG4 was created, from which exosomes were isolated and characterized, and the internalization and the resulting biological effects of exosomal ECRG4 were evaluated. Results showed that serum exosomes contain higher levels of ECRG4 mRNA in healthy individuals than their cancer counterparts. Exosomal ECRG4 can be internalized and unload the encapsulated ECRG4 into recipient cells, which subsequently suppressed cell proliferation in vitro, and inhibited tumor growth in a xenograft mouse model. Mechanistically, ECRG4-containing exosomes, when internalized, suppressed the expression of genes commonly implicated in inflammation, cell proliferation, and angiogenesis. Given that exosome is an ideal vehicle for therapeutics delivery and that ECRG4 is a tumor suppressor gene, the exosomal ECRG4 can be exploited as a formulation for cancer gene therapy.


Assuntos
Proliferação de Células , Exossomos/metabolismo , Genes Supressores de Tumor , Proteínas de Neoplasias/sangue , Neoplasias , Neovascularização Patológica/sangue , RNA Mensageiro/sangue , RNA Neoplásico/sangue , Células A549 , Animais , Exossomos/patologia , Feminino , Células HEK293 , Humanos , Inflamação/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/sangue , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica/patologia , Proteínas Supressoras de Tumor
17.
Cancer Med ; 7(8): 3773-3791, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30003708

RESUMO

This study aimed to explore the correlation of circulating pro-angiogenic miRNAs' expressions with risk, clinicopathological features, and survival profiles in gastric cancer (GC). Three hundred and thirty-three GC patients underwent radical resection and 117 health controls (HCs) were recruited for this study. Plasma samples were obtained from GC patients before the operation and from HCs after enrollment. Fourteen pro-angiogenic miRNAs were asseassed by quantitative polymerase chain reaction (qPCR). Disease-free survival (DFS) and overall survival (OS) of GC patients were calculated and the median follow-up duration was 36.0 months. Seven out of 14 pro-angiogenic miRNAs including let-7f, miR-17-5p, miR-18a, miR-19b-1, miR-20a, miR-210, and miR-296 were observed to be elevated in GC patients compared with HCs. MiR-18a, miR-20a, and miR-210 disclosed good predictive values of GC risk. Six pro-angiogenic miRNAs including miR-17-5p, miR-92a, miR-210, miR-20a, miR-18a, and miR-296 expressions were positively while 1 pro-angiogenic miRNA (miR-130a) was negatively correlated with tumor malignancy degree in GC patients. K-M curve disclosed that 5 pro-angiogenic miRNAs including miR-17-5p, miR-18a, miR-20a, miR-92a, and miR-210 correlated with worse DFS, while 4 pro-angiogenic miRNAs including miR-17-5p, miR-18a, miR-20a, and miR-210 associated with shorter OS. Further multivariate Cox's analysis revealed that miR-17-5p, miR-18a, miR-20a, and miR-210 were independent predictive factors for unfavorable DFS and OS. In conclusion, circulating pro-angiogenic miRNAs could serve as novel noninvasive biomarkers for disease risk and malignancy degree, and miR-17-5p, miR-18a, miR-20a, and miR-210 are independent factors predicting poor prognosis in GC patients.


Assuntos
Biomarcadores Tumorais , MicroRNA Circulante/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Idoso , MicroRNA Circulante/sangue , Terapia Combinada , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neovascularização Patológica/sangue , Prognóstico , Curva ROC , Medição de Risco , Fatores de Risco , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia
19.
Sci Rep ; 8(1): 8849, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29892086

RESUMO

Inflammatory activity plays a central role in the development of carotid rupture-vulnerable atherosclerotic plaques, which is one of the major contributors to acute ischemic stroke. Our objective was to characterize carotid intraplaque neovascularizations (INP) using contrast-enhanced ultrasound (CEUS) and evaluate plaque burden through exploring the relationship between INP and cell count of peripheral leukocytes. Sixty-two patients with large artery atherosclerosis (LAA) were enrolled in this study. CEUS was performed to characterize the carotid artery plaques. The correlations between the CEUS imaging features of carotid plaques and leukocyte counts were investigated. The results showed that the characteristic parameters derived from CEUS, including peak of time-intensity curve (TIC-P), mean of time-intensity curve (TIC-M), peak (FC-P), sharpness (FC-S) and area under the curve (FC-AUC) compared with the control group, were all increased in the stroke group. TIC-P, TIC-M and FC-P were negatively related to lymphocytes, respectively. FC-S and FC-AUC were positively correlated with neutrophils, respectively. Our study indicated carotid INP was closely related to the peripheral leukocytes count. CEUS may serve as a useful tool to predict vulnerability of plaque.


Assuntos
Isquemia Encefálica , Encéfalo/irrigação sanguínea , Estenose das Carótidas , Placa Aterosclerótica/sangue , Acidente Vascular Cerebral , Ultrassonografia/métodos , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/sangue , Isquemia Encefálica/patologia , Estenose das Carótidas/sangue , Estenose das Carótidas/diagnóstico por imagem , Meios de Contraste/química , Feminino , Humanos , Contagem de Leucócitos/métodos , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/patologia
20.
J Cancer Res Ther ; 14(3): 570-573, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29893319

RESUMO

Objective: Survivin is one of the apoptosis inhibitor proteins, and it plays a key role in tumor angiogenesis and cancer progression. This study was conducted to investigate the serum level of survivin to determine its diagnostic value in cancer patients. Materials and Methods: Blood samples were taken from cancer patients (n = 67) prior to surgery or chemo/radiotherapy and age-matched healthy volunteers (n = 23). The serum levels of survivin were analyzed by enzyme-linked immunosorbent assays. The difference in serum levels between patients and control was evaluated by using statistical methods. Correlation between the serum levels of survivin and clinicopathological features of cancer patients were also evaluated. Results: The diagnoses of patients were breast cancer (49.3%), colon cancer (25.4%), ovarian cancer (14.9%), and other cancers (10.4%). Serum survivin levels were significantly higher in cancer patients than healthy subjects (196.23 pg/ml vs. 117.73 pg/ml, respectively, P = 0.019). No significant relations were found between serum survivin level and demographic characteristics of cancer. The optimal cut-off value of serum survivin was determined at >120.8 pg/ml, and its serum levels above this cut-off value were associated with 4.198 times increased risk of cancer. Conclusion: Our study results may suggest that high serum survivin levels can show 4 times increased risk of cancer in a subject with a high suspicion of cancer. Furthermore, survivin level was not influenced with demographic characteristics of breast, gastric, colorectal, prostate, ovarian cancer, and glioblastome multiforme.


Assuntos
Biomarcadores Tumorais/sangue , Detecção Precoce de Câncer , Proteínas Inibidoras de Apoptose/sangue , Neoplasias/sangue , Adulto , Idoso , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/classificação , Neoplasias/patologia , Neovascularização Patológica/sangue , Neovascularização Patológica/patologia , Fatores de Risco , Survivina
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