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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.
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
3.
BMC Cancer ; 19(1): 741, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31357969

RESUMO

BACKGROUND: The overall prognosis of non-small cell lung cancer (NSCLC) is poor, and currently only patients with localized disease are potentially curable. Therefore, preferably non-invasively determined biomarkers that detect NSCLC patients at early stages of the disease are of high clinical relevance. The aim of this study was to identify and validate novel protein markers in plasma using the highly sensitive DNA-assisted multiplex proximity extension assay (PEA) to discriminate NSCLC from other lung diseases. METHODS: Plasma samples were collected from a total of 343 patients who underwent surgical resection for different lung diseases, including 144 patients with lung adenocarcinoma (LAC), 68 patients with non-malignant lung disease, 83 patients with lung metastasis of colorectal cancers and 48 patients with typical carcinoid. One microliter of plasma was analyzed using PEA, allowing detection and quantification of 92 established cancer related proteins. The concentrations of the plasma proteins were compared between disease groups. RESULTS: The comparison between LAC and benign samples revealed significantly different plasma levels for four proteins; CXCL17, CEACAM5, VEGFR2 and ERBB3 (adjusted p-value < 0.05). A multi-parameter classifier was developed to discriminate between samples from LAC patients and from patients with non-malignant lung conditions. With a bootstrap aggregated decision tree algorithm (TreeBagger), a sensitivity of 93% and specificity of 64% was achieved to detect LAC in this risk population. CONCLUSIONS: By applying the highly sensitive PEA, reliable protein profiles could be determined in microliter amounts of plasma. We further identified proteins that demonstrated different plasma concentration in defined disease groups and developed a signature that holds potential to be included in a screening assay for early lung cancer detection.


Assuntos
Adenocarcinoma de Pulmão/sangue , Proteínas Sanguíneas/análise , Carcinoma Pulmonar de Células não Pequenas/sangue , Detecção Precoce de Câncer/métodos , Neoplasias Pulmonares/sangue , Programas de Rastreamento/métodos , Idoso , Antígeno Carcinoembrionário/sangue , Quimiocinas CXC/sangue , Estudos de Coortes , Confiabilidade dos Dados , Feminino , Proteínas Ligadas por GPI/sangue , Humanos , Imunoensaio/métodos , Masculino , Modelos Biológicos , Curva ROC , Receptor ErbB-3/sangue , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
4.
Clin Lab ; 65(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775874

RESUMO

BACKGROUND: Biomarkers for early diagnosis and follow-up of cancers are still underutilized in clinical management. Thus, seeking new biomarkers with better sensitivity and specificity is still a challenge. VEGF, VEGFR2, and OPN are newly emerging biomarkers with clinical potential. METHODS: ELISA was used to analyze serum VEGF, VEGFR2, and OPN from 75 gastrointestinal cancer patients and 75 control subjects. The correlation of pre-operative serum VEGF, VEGFR2, and OPN levels with CEA, Ki-67 as well as clinical features (age, gender, tumor size, TNM stage, tumor stage, lymph node involvement, metastasis, and histological grading) in these patients. RESULTS: The pre-operative and post-operative serum VEGF and VEGFR2 levels and the post-operative OPN level in patients were significantly higher than in controls (p = 0.000, for all mentioned). The post-operative VEGF and OPN levels were significantly higher than that of pre-operative (p = 0.000 and 0.007, respectively). There was no correlation between pre-operative serum VEGF, VEGFR2, and OPN levels and serum CEA concentration. The pre-operative serum VEGF level was significantly correlated with the tumor Ki-67 scores; however, there was no correlation between serum VEGFR2 and OPN and Ki-67 scores. Univariate logistic regression analysis revealed that serum VEGF level was significantly higher in patients with advanced TNM (III - IV) stage and with lymph node involvement than in patients with low TNM stage (I - II) and with no lymph node involvement. High OPN level was correlated with metastasis. Multivariate logistic regression analysis results showed that serum VEGF and VEGFR2 were the two most important factors for the diagnosis of gastrointestinal cancers in this study (p = 0.000, for both). Combinatorial analysis of the biomarkers improved the performance of the assays. CONCLUSIONS: Serum VEGF and VEGFR2 are potential biomarkers for the diagnosis and prognosis evaluation of gastrointestinal cancers, while serum OPN is a potential biomarker for the prognostication of gastrointestinal cancers.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Gastrointestinais/sangue , Osteopontina/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/cirurgia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico
5.
J Cardiothorac Surg ; 14(1): 27, 2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696477

RESUMO

BACKGROUND: Graft function may be affected if the organ is exposed to hypoxia. We hypothesized that bronchiolitis obliterans (BO) after lung transplantation is associated with hypoxia-inducible factor-1α (HIF-1α). This study compares the expression of HIF-1α and its downstream proteins in allograft and isograft to explore the relationship between this pathway and BO in rats. MATERIAL AND METHODS: We performed an orthotopic left pulmonary transplant model using the tri-cuff vascular anastomosis method and evaluated the histopathology, including the severity of fibrosis (SF). The expression of HIF-1α, VEGF-A, and VEGFR-2 was accessed by immunohistochemistry. RESULTS: The imageology and pathology showed that the allogenic model developed BO 90 days after the operation. The percentages of a high expression of HIF-1α, VEGF-A, and VEGFR-2 in the allogeneic group were 77.27, 63.64, and 68.18% higher than in the isogeneic group, respectively. The SF score was highest in the allograft and was positively correlated with the expression of the proteins. CONCLUSION: This model can simulate human BO after lung transplantation. The expression of HIF-1α and its downstream proteins in post-transplantation was up-regulated, suggesting that activation of the HIF-1α-VEGF pathway might be involved in the occurrence and prognosis of BO.


Assuntos
Bronquiolite Obliterante/etiologia , Hipóxia/complicações , Transplante de Pulmão , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Bronquiolite Obliterante/sangue , Modelos Animais de Doenças , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Imuno-Histoquímica , Masculino , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Ratos , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
6.
Med Sci Monit ; 25: 492-499, 2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30652694

RESUMO

BACKGROUND Retinopathy of prematurity (ROP), or retrolental fibroplasia, affects premature infants who have undergone intensive care with oxygen therapy. This study aimed to investigate the inhibitory effect of the gamma-secretase inhibitor, DAPT, on neovascularization and its mechanism in a rat model of ROP. MATERIAL AND METHODS Sixty neonatal Sprague-Dawley (SD) rats included the control group (n=20), the model group (n=20), and the DAPT-treated group (n=20). The rat model of ROP was established using repeat cycles of oxygen inhalation. Enzyme-linked immunosorbent assay (ELISA) measured serum levels of vascular endothelial growth factor (VEGF), VEGF receptor-1 (VEGFR-1), and VEGFR-2. Histology of the retinal tissue included immunohistochemistry for the expression of Notch homolog-1 (Notch-1) and delta-like ligand 4 (DLL4). Retinal mRNA levels of DLL4, Notch-1, VEGF, VEGFR-1, and VEGFR-2 were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS The rat model of ROP showed increased serum levels of VEGF, VEGFR-1, and VEGFR-2 compared with the control group, which were decreased in the DAPT group. Histology of the retinal tissue in the model group showed degeneration of the retinal ganglion cells, and immunohistochemistry showed increased expression of Notch-1 and DLL4 compared with the control group and DAPT group. Retinal tissue in the model group had increased mRNA levels of DLL4, Notch-1, VEGF, VEGFR-1, and VEGFR-2 compared with the control group, and the DAPT group. CONCLUSIONS In a rat model, treatment with DAPT reduced the retinal changes associated with ROP with a mechanism that involved VEGF and its receptors through the DLL4/Notch-1 pathway.


Assuntos
Dipeptídeos/farmacologia , Retinopatia da Prematuridade/prevenção & controle , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Neovascularização Patológica/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Notch1/metabolismo , Retinopatia da Prematuridade/sangue , Retinopatia da Prematuridade/enzimologia , Retinopatia da Prematuridade/metabolismo , Transdução de Sinais/efeitos dos fármacos , 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
7.
J Infect Dis ; 219(7): 1076-1083, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30239747

RESUMO

BACKGROUND: Human immunodeficiency virus (HIV) may be related to cardiovascular disease through monocyte activation-associated endothelial dysfunction. METHODS: Blood samples from 15 HIV-negative participants (the uninfected group), 8 HIV-positive participants who were not receiving antiretroviral therapy (ART) (the infected, untreated group), and 15 HIV-positive participants who were receiving ART (the infected, treated group) underwent flow cytometry of endothelial colony-forming cells (ECFCs) and monocyte proportions. IncuCyte live cell imaging of 8 capillary proliferative capacity parameters were obtained from cord blood ECFCs treated with participant plasma. RESULTS: The ECFC percentage determined by flow cytometry was not different between the study groups; however, values of the majority of capillary proliferative capacity parameters (ie, cell area, network length, network branch points, number of networks, and average tube width uniformity) were significantly lower in infected, untreated participants as compared to values for uninfected participants or infected, treated participants (P < .00625 for all comparisons). CD14+CD16+ intermediate monocytes and soluble CD163 were significantly and negatively correlated with several plasma-treated, cord blood ECFC proliferative capacity parameters in the combined HIV-positive groups but not in the uninfected group. CONCLUSIONS: Cord blood ECFC proliferative capacity was significantly impaired by plasma from infected, untreated patients, compared with plasma from uninfected participants and from infected, treated participants. Several ECFC functional parameters were adversely associated with monocyte activation in the HIV-positive groups, thereby suggesting a mechanism by which HIV-related inflammation may impair vascular reparative potential and consequently increase the risk of cardiovascular disease during HIV infection.


Assuntos
Endotélio/imunologia , Soronegatividade para HIV/imunologia , Soropositividade para HIV/imunologia , Monócitos , Células-Tronco , Adulto , Fármacos Anti-HIV/uso terapêutico , Benzoxazinas/uso terapêutico , Proliferação de Células , Quimiocina CCL5/sangue , Endotélio/patologia , Feminino , Sangue Fetal , Citometria de Fluxo , Proteínas Ligadas por GPI/metabolismo , Soropositividade para HIV/sangue , Soropositividade para HIV/tratamento farmacológico , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Neovascularização Fisiológica , Plasma/imunologia , Estudos Prospectivos , Receptores de IgG/metabolismo , Células-Tronco/fisiologia , Molécula 1 de Adesão de Célula Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
8.
Biomed Pharmacother ; 108: 1328-1337, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30372835

RESUMO

Metformin is commonly prescribed as a hypoglycemic agent following the onset of type 2 diabetes mellitus. This study aimed to investigate pro- and/or anti-angiogenic effects of Metformin on human bone marrow mesenchymal stem cells. Cells were incubated with different doses of Metformin including 0.5, 1, 10, 50, 100, 200 and 500 µM for 14 days. Cell viability and total fatty acids profile were examined by MTT and gas chromatography methods. Differentiation of cells to endothelial lineage was studied by monitoring the expression of VEGFR-2 and Tie-2 receptors and VE-cadherin via real-time PCR and western blotting. Angiogenic potential and migration of cells were assessed by tubulogenesis and Transwell migration assays. PCR array was performed to analyze mTOR signaling. CD133+ and VEGFR-2+ cells were detected in blood samples of non-diabetic control, diabetic subjects and diabetics received Metformin. Metformin dose-dependently reduced cell survival. Decreased content of palmitate and oleate coincided increased level of stearate, palmitoleate, and linoleate (p < 0.05). Metformin decreased the angiogenic potential of cells by decreasing VEGFR-2 and Tie-2 expression (p < 0.05). The protein level of VE-cadherin decreased in cells received Metformin. Compared to the control, Metformin blunted the expression of VEGF subtypes and directed cells to energy status by induction of PRKAA1, PRKAB2, and PRKAG1 genes (p < 0.05). Non-significant differences were observed regarding the number of CD133 and VEGFR-2 cells in blood samples (p > 0.05). These data support a notion that Metformin could blunt the angiogenic behavior of human mesenchymal stem cells by modulating mTOR signaling pathway.


Assuntos
Células-Tronco Mesenquimais/efeitos dos fármacos , Metformina/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Antígeno AC133/sangue , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ácidos Graxos/análise , Humanos , Imunofenotipagem , Células-Tronco Mesenquimais/citologia , Serina-Treonina Quinases TOR/fisiologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
9.
Cancer ; 124(22): 4332-4341, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30303516

RESUMO

BACKGROUND: Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2. METHODS: NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in favor of arm A, with a median of 6.9 months (95% confidence interval [95% CI], 4.1-8.7 months) versus 2.3 months (95% CI, 1.6-3.5 months) (P<.001). No significant difference was noted with regard to overall survival, with a median of 26.9 months (95% CI, 14.4-63.6 months) for arm A and 24.2 months (95% CI, 11.3-36.4 months) for arm B. The response rate (according to Response Evaluation Criteria In Solid Tumors [RECIST]) was 22% in arm A (4 complete responses [CRs] and 8 partial responses [PRs]) and 17% in arm B (1 CR and 4 PRs). Stable disease or PR or CR was noted in 65% of patients in arm A and 48% of patients in arm B. The combination was found to be superior to monotherapy in patients with high and low levels of serum VEGF and VEGF receptor 2. Adverse events were consistent with the expected profiles of monotherapy with IL-2 and ziv-aflibercept. CONCLUSIONS: Ziv-aflibercept and IL-2 were found to significantly improve PFS compared with IL-2 alone, thereby meeting the primary endpoint of the current study. These findings support further study of immunotherapeutic combination strategies involving VEGF inhibitors.


Assuntos
Interleucina-2/administração & dosagem , Melanoma/tratamento farmacológico , Melanoma/patologia , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Proteínas Recombinantes de Fusão/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Interleucina-2/efeitos adversos , Masculino , Melanoma/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Proteínas Recombinantes de Fusão/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
10.
Ophthalmic Genet ; 39(6): 684-698, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30289322

RESUMO

BACKGROUND: Age-related macular degeneration is a progressive eye disease affecting the macula and causing acute visual loss particularly in elder people. The aim of the study was an attempt to discern an influence of expression levels and functional genetic polymorphisms of selected genes related to the extracellular matrix turnover or neovascularization on age-related macular degeneration occurrence and progression. METHODS: We conducted a case-control study of 200 polish patients with recognized age-related macular degeneration (dry and wet) and compared the results with those obtained from matched 100 healthy control subjects. TaqMan Genotyping Assays were employed to examine the following single nucleotide polymorphisms: matrix metalloproteinase (MMP)-2 -735C/T, MMP-7 -181A/G, MMP-9 -1702T/A, and -1562C/T; tissue inhibitors of metalloproteinase (TIMP)-2 -418G/C; vascular endothelial growth factor (VEGF) +405 G/C and +936 C/T, VEGFR-2 +1719 T/A and -271 G/A. Real-time polymerase chain reaction was assessed to determine the mRNA quantity. Serum levels of proteins were measured using enzyme-linked immunosorbent assay. RESULTS: The single nucleotide polymorphism genotyping showed that TT genotype for MMP-9 -1702T/A and CC genotype for VEGF +936C/T increase markedly the risk of age-related macular degeneration but do not influence on its progression. Additionally, the possible protective effect of CC genetic variant in MMP-9 -1562C/T polymorphism against progression of age-related macular degeneration was observed. We also found significant differences in systemic expression levels of MMP-2, -7, -9, TIMP-2, vascular endothelial growth factor, VEGFR-2, and pigment epithelium-derived factor between studied group. The research demonstrated evident differences in serum levels of MMP-2, -7, -9, TIMP-2, vascular endothelial growth factor, and pigment epithelium-derived factor between wet and dry age-related macular degeneration patients. CONCLUSIONS: We can conclude that disturbances in angiogenic homeostasis and processes of extracellular matrix turnover occurring in age-related macular degeneration-affected ocular tissues may be reflected in changes in systemic expression levels of the investigated genes.


Assuntos
Matriz Extracelular/enzimologia , Degeneração Macular/genética , Metaloproteinases da Matriz/genética , Polimorfismo de Nucleotídeo Único , Neovascularização Retiniana/genética , Inibidor Tecidual de Metaloproteinase-2/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Regulação Enzimológica da Expressão Gênica/fisiologia , Técnicas de Genotipagem , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/enzimologia , Masculino , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 7 da Matriz/sangue , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/genética , Metaloproteinases da Matriz/sangue , Pessoa de Meia-Idade , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Neovascularização Retiniana/diagnóstico , Neovascularização Retiniana/enzimologia , Inibidor Tecidual de Metaloproteinase-2/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
11.
J Vasc Interv Radiol ; 29(12): 1646-1653.e5, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30337148

RESUMO

PURPOSE: The primary end point of this trial was to determine the feasibility and safety of transarterial chemoembolization with the use of 75-150-µm drug-eluting embolics loaded with irinotecan (DEE-IRI) for the treatment of metastatic colorectal cancer (CRC) refractory to systemic chemotherapy. MATERIALS AND METHODS: Fourteen patients (mean age 57.9 years) with liver-dominant metastatic disease (14.3% unilobar, 85.7% bilobar), who had failed at least 1 line of chemotherapy, were enrolled and received up to 4 (mean 2.3) cycles of DEE-IRI lobar transarterial chemoembolization. Technical complications and adverse events were recorded, and response was assessed by means of imaging-based criteria. Levels of irinotecan and angiogenesis biomarkers in the serum were measured at multiple time points. RESULTS: Thirty-two DEE-IRI transarterial chemoembolizations were successfully performed, and the full dose (100 mg) was delivered in all cases. The only grade 3-4 toxicity was abdominal pain (29%). One patient had objective response according to the Response Evaluation Criteria in Solid Tumors and World Health Organization, and 3 patients had objective response according to the European Association for the Study of the Liver. The median overall survival was 18.14 months, and the 1-year survival was 65%. The average plasma Cmax of the active metabolite was 41.5 ± 26.1 ng/mL, with average Tmax of 1.3 ± 0.5 hours. The treatment significantly reduced levels of vascular endothelial growth factor receptor 1 (VEGFR1) at 24 hours. CONCLUSIONS: Lobar transarterial chemoembolization with the use of DEE-IRI is a technically feasible and well tolerated palliative treatment for patients with refractory liver-predominant CRC metastatic disease and has acceptable pharmacokinetics. VEGFR1 is a potential biomarker for predicting treatment efficacy and risk of adverse events.


Assuntos
Antineoplásicos/administração & dosagem , Quimioembolização Terapêutica/métodos , Neoplasias Colorretais/patologia , Portadores de Fármacos , Irinotecano/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Biomarcadores Tumorais/sangue , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/mortalidade , Neoplasias Colorretais/mortalidade , Connecticut , Estudos de Viabilidade , Feminino , Humanos , Irinotecano/efeitos adversos , Irinotecano/sangue , Irinotecano/farmacocinética , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Masculino , Microesferas , Pessoa de Meia-Idade , Cuidados Paliativos , Estudos Prospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , 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
12.
BMC Cardiovasc Disord ; 18(1): 169, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111293

RESUMO

BACKGROUND: Development of collateral circulation in coronary artery disease is cardio-protective. A key process in forming new blood vessels is attraction to occluded arteries of monocytes with their subsequent activation as macrophages. In patients from a prospectively recruited post-acute coronary syndromes cohort we investigated the prognostic performance of three products of activated macrophages, soluble vascular endothelial growth factor (VEGF) receptors (sFlt-1 and sKDR) and pterins, alongside genetic variants in VEGF receptor genes, VEGFR-1 and VEGFR-2. METHODS: Baseline levels of sFlt-1 (VEGFR1), sKDR (VEGFR2) and pterins were measured in plasma samples from subgroups (n = 513; 211; 144, respectively) of the Coronary Disease Cohort Study (CDCS, n = 2067). DNA samples from the cohort were genotyped for polymorphisms from the VEGFR-1 gene SNPs (rs748252 n = 2027, rs9513070 n = 2048) and VEGFR-2 gene SNPs (rs2071559 n = 2050, rs2305948 n = 2066, rs1870377 n = 2042). RESULTS: At baseline, levels of sFlt-1 were significantly correlated with age, alcohol consumption, NTproBNP, BNP and other covariates relevant to cardiovascular pathophysiology. Total neopterin levels were associated with alcohol consumption at baseline. 7,8 dihydroneopterin was associated with BMI. The A allele of VEGFR-2 variant rs1870377 was associated with higher plasma sFlt-1 and lower levels of sKDR at baseline. Baseline plasma sFlt-1 was univariately associated with all cause mortality with (p < 0.001) and in a Cox's proportional hazards regression model sFlt-1 and pterins were both associated with mortality independent of established predictors (p < 0.027). CONCLUSIONS: sFlt-1 and pterins may have potential as prognostic biomarkers in acute coronary syndromes patients. Genetic markers from VEGF system genes warrant further investigation as markers of levels of VEGF system components in these patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. ACTRN12605000431628 . 16 September 2005, Retrospectively registered.


Assuntos
Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/genética , Polimorfismo de Nucleotídeo Único , Pterinas/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/mortalidade , Fatores Etários , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Angiografia Coronária , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco
13.
Br J Cancer ; 119(1): 27-35, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29925934

RESUMO

BACKGROUND: Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib, in addition to cisplatin/gemcitabine [CisGem], improved the response rate, but did not improve the progression-free survival (PFS) in the ABC-03 study. Minimally invasive biomarkers predictive of cediranib benefit may improve patient outcomes. METHODS: Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC). RESULTS: Samples were available from n = 117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of the therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P < 0.001 and P = 0.02, respectively). CONCLUSIONS: Rising circulating VEGFA levels in patients with ABC, treated with CisGem, are associated with worse PFS and OS, not seen in patients receiving cediranib. Rising levels of markers of tumour burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation.


Assuntos
Neoplasias do Sistema Biliar/tratamento farmacológico , Queratina-18/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Sistema Biliar/sangue , Neoplasias do Sistema Biliar/patologia , Biomarcadores Tumorais/sangue , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Quinazolinas/administração & dosagem , Resultado do Tratamento , Reino Unido
14.
Emerg Microbes Infect ; 7(1): 89, 2018 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-29765019

RESUMO

Hemorrhagic fever with renal syndrome (HFRS) is characterized by endothelial dysfunction with capillary leakage without obvious cytopathology in the capillary endothelium. The aim of the study was to analyze the kinetics of vascular endothelial growth factor (VEGF) and its soluble receptor (sVEGFR-2) in HFRS patients infected with Dobrava (DOBV) or Puumala virus (PUUV). VEGF and sVEGFR-2 levels were measured in daily plasma and urine samples of 73 patients with HFRS (58 with PUUV, 15 with DOBV) and evaluated in relation to clinical and laboratory variables. In comparison with the healthy controls, initial samples (obtained in the first week of illness) from patients with HFRS had higher plasma and urine VEGF levels, whereas sVEGFR-2 levels were lower in plasma but higher in urine. VEGF levels did not differ in relation to hantavirus species, viral load, or the severity of HFRS. The comparison of VEGF dynamics in plasma and urine showed the pronounced secretion of VEGF in urine. Significant correlations were found between daily VEGF/sVEGFR-2 levels and platelet counts, as well as with diuresis: the correlations were positive for plasma VEGF/sVEGFR-2 levels and negative for urine levels. In addition, patients with hemorrhagic manifestations had very high plasma and urine VEGF, together with high urine sVEGFR-2. Measuring the local secretion of sVEGFR-2 in urine might be a useful biomarker for identifying HFRS patients who will progress to severe disease.


Assuntos
Hantavirus/isolamento & purificação , Febre Hemorrágica com Síndrome Renal/sangue , Febre Hemorrágica com Síndrome Renal/urina , Virus Puumala/isolamento & purificação , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/urina , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/urina , Adulto , Anticorpos Antivirais/sangue , Biomarcadores/sangue , Biomarcadores/urina , Progressão da Doença , Feminino , Hantavirus/imunologia , Febre Hemorrágica com Síndrome Renal/patologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Virus Puumala/imunologia , Carga Viral , Adulto Jovem
15.
Toxicol Ind Health ; 34(8): 555-562, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29759036

RESUMO

The present study was designed to evaluate soluble receptors as potential targets for lead (Pb). Analyses included the serum levels of soluble Vascular Endothelial Growth Factor Receptors 2 (sVEGFR-2), soluble Epidermal Growth Factor Receptor (sEGFR), soluble Human Epidermal Growth Factor 2 (sHER-2/neu), and soluble Interleukin 6 Receptors (sIL-6R) in the groups of chronically and subchronically occupationally exposed workers. The first group consisted of 56 male workers chronically exposed to Pb. The second group (control) comprised 24 male administrative workers. The third group included 36 male workers exposed to Pb for 40 ± 3 days. Examined subjects were employed in the Pb-zinc works to perform periodic maintenance of blast furnaces and production lines. The serum levels of sHER-2/neu and sIL-6R were significantly lower in the group of workers chronically exposed to Pb compared to control values by 45% ( p < 0.05) and 44% ( p < 0.05), respectively. The values of sVEGFR-2 and sEGFR decreased after a subchronic exposure to Pb compared to baseline by 14% ( p < 0.05) and 21% ( p < 0.05), respectively. At the same time, the levels of sIL-6R also decreased by 14% ( p < 0.05). Results of the present study indicated that both chronic and subchronic occupational Pb exposures resulted in decreased levels of several soluble receptors (sVEGFR-2, sEGFR, sHER-2/neu, and sIL-6R), probably due to Pb-induced modulations of the transcription factors and metalloprotease activities, that are necessary for soluble receptor synthesis.


Assuntos
Receptores ErbB/sangue , Intoxicação por Chumbo/etiologia , Exposição Ocupacional/efeitos adversos , Receptor ErbB-2/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Humanos , Intoxicação por Chumbo/sangue , Masculino , Metalurgia , Pessoa de Meia-Idade , Adulto Jovem
16.
Microvasc Res ; 119: 1-6, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29604296

RESUMO

BACKGROUND: KLOTHO is a regulator of endothelial cells activity and integrity. It has been described for the first time because of its anti-aging properties. KLOTHO encoding gene is present in many functional variants in humans, including "KL-VS" variant that has been connected with longevity and cardiovascular disease development. Few mechanisms have been proposed to explain these associations, but none of them focused on cells from CD34+ population. The aim of our study was to investigate influence of KLOTHO KL-VS polymorphism on populations of CD34+ and CD34+VEGFR2+ cells. METHODS AND RESULTS: We examined 167 Polish subjects from Pomeranian region. The analysis concerned KL-VS polymorphism, flow cytometry evaluation of whole blood cells and determination of endothelium-associated serum/plasma factors. Our results indicate that individuals possessing at least one KL-VS allele are characterized by greater number of CD34+ and CD34+VEGFR2+ and their various subpopulations (CD34+CD133+, CD34+c-Kit+, CD34+CXCR4+ and CD34+VEGFR2+c-Kit+) than wild-type volunteers. This group also exhibited more favorable lipid profile and statistically insignificant decrease of vWF and angiotensin II in their blood, whereas VEGF levels were elevated. CONCLUSION: One of the mechanisms that are responsible for previously described KL-VS heterozygote advantage may be connected with maintaining greater size of hematopoietic and endothelial progenitor cells population.


Assuntos
Antígenos CD34/sangue , Células Progenitoras Endoteliais/metabolismo , Proteínas de Membrana/genética , Polimorfismo Genético , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Idoso , Biomarcadores/sangue , Contagem de Células , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polônia
17.
Indian J Ophthalmol ; 66(4): 535-540, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29582815

RESUMO

Purpose: Despite the disease having similar glycemic status and duration microangiopathy in some patients develop within few years whereas it doesn't appear as a health complication in some diabetics for a considerable period. This study is undertaken to assess the hyperglycemia-induced biochemical background behind the development of diabetic retinopathy (DR) in type 2 diabetes mellitus (DM). Methods: Following proper diagnosis, 100 patients of type 2 DM of 10-12 years duration having no DR, and 42 patients of type 2 DM of the same duration and glycemic status as the second group, with mild retinopathy were recruited in the study. Lactic acid, glutamate, malondialdehyde (MDA), nitrate, advanced glycation end-products (AGEs), peripheral blood mononuclear cell reactive oxygen species (ROS), vascular endothelial growth factor (VEGF), and its receptor 2 (VEGFR2) in these two groups were produced in an assay following standard methodology. Results: Biochemical markers of anaerobic glycolysis, lipid peroxidation, AGEs, glutamate concentration, oxidative stress, and expression of VEGF and its VEGFR2 with significantly elevated markings were found in them who developed earliest stage of DR rather than them who had not. Conclusion: Hyperglycemia-induced anomalous glucose metabolism, lipid peroxidation, advanced glycation, glutamate toxicity, and oxidative stress create a background where apoptosis of retinal capillary endothelial cells invite increased expression of VEGF and VEGFR2, these being the crucial factors behind the development of diabetic microangiopathy.


Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Retinopatia Diabética/sangue , Adulto , Glicemia/metabolismo , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Ácido Glutâmico/sangue , Produtos Finais de Glicação Avançada/sangue , Índice Glicêmico , Humanos , Ácido Láctico/sangue , Masculino , Malondialdeído/sangue , Nitratos/sangue , Espécies Reativas de Oxigênio/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
18.
Clin Cancer Res ; 24(15): 3550-3559, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29588308

RESUMO

Purpose: Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown.Experimental Design: We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts.Results: WES-cfDNA yielded a 77% concordance rate with tumor exome sequencing and enabled the identification of the KDR/VEGFR2 L840F clonal, somatic mutation as the cause of therapy refractoriness in our patient. In addition, we found that 1% to 3% of samples from cancer sequencing projects harbor KDR somatic mutations located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK. Our in vitro and in vivo functional assays confirmed that L840F causes strong resistance to antiangiogenic drugs, whereas the KDR hot-spot mutant R1032Q confers sensitivity to strong VEGFR2 inhibitors. Moreover, we showed that the D717V, G800D, G800R, L840F, G843D, S925F, R1022Q, R1032Q, and S1100F VEGFR2 mutants promote tumor growth in mice.Conclusions: Our study supports WES-cfDNA as a powerful platform for portraying the somatic mutation landscape of cancer and discovery of new resistance mechanisms to cancer therapies. Importantly, we discovered that VEGFR2 is somatically mutated across tumor types and that VEGFR2 mutants can be oncogenic and control sensitivity/resistance to antiangiogenic drugs. Clin Cancer Res; 24(15); 3550-9. ©2018 AACR.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias Colorretais/genética , Neovascularização Patológica/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Quinase do Linfoma Anaplásico/genética , Inibidores da Angiogênese/efeitos adversos , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Receptores ErbB/genética , Exoma/genética , Feminino , Xenoenxertos , Humanos , Camundongos , Mutação , Neovascularização Patológica/sangue , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Conformação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-abl/genética , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Sequenciamento Completo do Exoma
20.
Eur J Surg Oncol ; 44(4): 496-501, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29397265

RESUMO

INTRODUCTION: Neovascularisation is a critical step in the progression of malignant tumors. Circulating endothelial progenitor cells (cEPC) have been proposed as surrogate markers of vasculogenesis in malignancies. In this project, we studied the impact of tumor-specific therapy on cEPC and associated angiogenic factors in patients with soft tissue tumors. MATERIALS AND METHODS: Fifty-three patients with soft tissue tumors (25 soft tissue sarcomas, 19 GIST, 9 desmoids) and 15 healthy controls were included. Blood samples were obtained at two time points, before and 8 weeks after start of tumor-specific therapy. Peripheral blood mononuclear cells (PBMCs) were isolated. cEPCs were characterised as CD34+, CD133+, CD45dim, CD31+ and vascular endothelial growth factor 2 (VEGFR-2) positive cells. Serum concentrations of VEGF-A and angiopoetin-2 were determined by enzyme-linked immunosorbent assay. RESULTS: VEGF-A and Ang-2 concentrations were significantly higher in tumor patients than in healthy controls in both samples (p < .01). Sarcoma patients with progressive disease developed a significant increase in cEPC levels between the two blood samples compared to those with stable disease (p = .002). GIST patients with progressive tumor or metastatic disease showed significant increase in VEGF-A values (p = .01). DISCUSSION: The pre-treatment values of the angiogenic markers did not correlate with the clinical course of the disease. However, cEPCs levels were significantly higher in sarcoma patients with progressive disease compared to those with stable disease and should be further evaluated as early markers of disease progression in sarcoma patients. VEGF-A and angiopoetin-2 clearly play a role as mediators of the vasculogenesis contributing to tumor progression.


Assuntos
Biomarcadores Tumorais/sangue , Células Progenitoras Endoteliais/patologia , Neovascularização Patológica/sangue , Neovascularização Patológica/patologia , Neoplasias de Tecidos Moles/sangue , Neoplasias de Tecidos Moles/patologia , Antígeno AC133/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiopoietina-2/sangue , Antígenos CD34/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Antígenos Comuns de Leucócito/sangue , Masculino , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/sangue , Prognóstico , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
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