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1.
J Card Surg ; 35(10): 2469-2476, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32789962

RESUMO

BACKGROUND: Pulmonary artery perfusion during cardiopulmonary bypass (CPB) is a known but rarely used technique in adult cardiac surgery. In this study, we aimed to investigate biochemical and histopathological effects of pulmonary artery perfusion during CPB on lung functions. METHODS: Between May 2014 and August 2014, all patients (n = 24) who gave informed consent for participating this study with inclusion criteria were included. Patients undergoing isolated coronary artery bypass grafting were sequentially randomized to conventional CPB (control group, n = 12) and conventional CPB with selective pulmonary artery perfusion (study group, n = 12). Lung functions were monitored using PF ratio, alveolar-arterial oxygen gradient, and lactate levels. A small sample tissue from the left lung was excised for histopathologic examination. Immunocytochemistry analysis was performed using anti-rabbit polyclonal vascular endothelial growth factor (VEGF), rabbit polyclonal inducible nitric oxide synthase (i-NOS), and BCL-2 antibodies. RESULTS: Postoperative course of the patients were uneventful without any clinical outcome differences in terms of cardiopulmonary complications, ventilation time and hospital stay. Pulmonary perfusion group had significantly better oxygenation values after extubation and at postoperative 24-hour. Electron microscopy examinations revealed better preservation of the alveolar wall integrity with pulmonary perfusion. The intensity of VEGF, i-NOS, and BCL-2 antibody expressions in bronchial epithelial cells were more prominent in the pulmonary perfusion group. CONCLUSIONS: Pulmonary artery perfusion during aortic cross-clamping provides better oxygenation and preservation of the wall alveolar integrity after coronary artery bypass grafting surgery. This technique can be used as a protective strategy to minimize CPB-induced lung injury in adult cardiac surgery.


Assuntos
Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/prevenção & controle , Ponte Cardiopulmonar/efeitos adversos , Perfusão/métodos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Artéria Pulmonar , Lesão Pulmonar Aguda/diagnóstico , Lesão Pulmonar Aguda/patologia , Adulto , Idoso , Biomarcadores/análise , Biomarcadores/sangue , Contagem de Células Sanguíneas , Proteína C-Reativa , Ponte de Artéria Coronária/métodos , Feminino , Hemoglobinas , Humanos , Inflamação , Pulmão/patologia , Pulmão/ultraestrutura , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/análise , Recuperação de Função Fisiológica , Esternotomia , Fator A de Crescimento do Endotélio Vascular/análise
2.
Life Sci ; 260: 118299, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32827542

RESUMO

AIMS: The most typical pathological manifestation of retinopathy of prematurity (ROP) is Retinal neovascularization (RNV). Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been reported to mediate angiogenesis. Our experiment aimed to research the effect and mechanism of the MALAT1 on RNV in ROP. MAIN METHODS: C57 mice was used to establish oxygen-introduced retinopathy (OIR), and divided into control, hyperoxia, hyperoxia control siRNA, and hyperoxia MALAT1 siRNA groups. KEY FINDINGS: It was shown that MALAT1 mRNA was high expressed in the retinas of OIR mice. Further studies revealed that after intravitreal injection of MALAT1 siRNA, the degree of retinopathy was significantly reduced compared with OIR group. In addition, the protein and mRNA expression levels of CCN1, AKT and VEGF were significantly decreased. This was accompanied by a decrease in inflammatory genes including IL-1ß, IL-6, and TNF-α compared with the hyperoxia control siRNA mice. SIGNIFICANCE: The result suggested that MALAT1 may be involved in the process of RNV in ROP and MALAT1 siRNA may be a promising agent for the treatment of ROP by inhibiting RNV.


Assuntos
RNA Longo não Codificante/fisiologia , Neovascularização Retiniana/fisiopatologia , Retinopatia da Prematuridade/fisiopatologia , Animais , Animais Recém-Nascidos , Proteína Rica em Cisteína 61/análise , Proteína Rica em Cisteína 61/genética , Modelos Animais de Doenças , Feminino , Hiperóxia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/análise , Proteínas Proto-Oncogênicas c-akt/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/farmacologia , RNA Mensageiro/análise , RNA Interferente Pequeno/administração & dosagem , Retina/química , Retinopatia da Prematuridade/etiologia , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/genética , Corpo Vítreo/efeitos dos fármacos
3.
PLoS One ; 15(7): e0235859, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687494

RESUMO

In our work, we aim to identify new candidate host biomarkers to discriminate between active TB patients (n = 28), latent infection (LTBI; n = 27) and uninfected (NoTBI; n = 42) individuals. For that, active TB patients and their contacts were recruited that donated serum and saliva samples. A multiplex assay was performed to study the concentration of different cytokines, chemokines and growth factors. Proteins with significant differences between groups were selected and logistic regression and the area under the ROC curve (AUC) was used to assess the diagnostic accuracy. The best marker combinations that discriminate active TB from NoTBI contacts were [IP-10 + IL-7] in serum and [Fractalkine + IP-10 + IL-1α + VEGF] in saliva. Best discrimination between active TB and LTBI was achieved using [IP-10 + BCA-1] in serum (AUC = 0.83) and IP-10 in saliva (p = 0.0007; AUC = 0.78). The levels of TNFα (p = 0.003; AUC = 0.73) in serum and the combination of [Fractalkine+IL-12p40] (AUC = 0.83) in saliva, were able to differentiate between NoTBI and LTBI contacts. In conclusion, different individual and combined protein markers could help to discriminate between active TB and both uninfected and latently-infected contacts. The most promising ones include [IP-10 + IL-7], [IP-10 + BCA-1] and TNFα in serum and [Fractalkine + IP-10 + IL-1α + VEGF], IP-10 and [Fractalkine+IL-12p40] in saliva.


Assuntos
Quimiocina CX3CL1/sangue , Quimiocina CXCL10/sangue , Interleucinas/sangue , Tuberculose Latente/sangue , Tuberculose Pulmonar/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/metabolismo , Quimiocina CX3CL1/análise , Quimiocina CXCL10/análise , Feminino , Humanos , Interleucinas/análise , Tuberculose Latente/diagnóstico , Tuberculose Latente/metabolismo , Masculino , Pessoa de Meia-Idade , Saliva/química , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/metabolismo , Fator A de Crescimento do Endotélio Vascular/análise
4.
Medicine (Baltimore) ; 99(19): e20011, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384458

RESUMO

BACKGROUND: Glioblastoma is the most common malignant primary brain tumor which has highly expressed vascular endothelial growth factor. To date, various antiangiogenic drugs have been investigated in clinical trials but with no overall conclusion, especially for newly diagnosed glioblastoma (nGBM). In this study, Bayesian network meta-analysis will be used to conduct a comprehensive analysis of the results of different clinical trials, and assess the efficacy of different antiangiogenic drugs on nGBM. METHODS: In order to find more comprehensive information about the application of antiangiogenic drugs in nGBM patients, we searched the MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials for relevant randomized controlled trials. We also reviewed their reference lists to avoid omissions. Cochrane risk of bias tool (V.1.4.3) and Stata (V.15.0) will be used to assess the methodological quality of this review. RESULTS: This study will provide reliable evidence for different antiangiogenic therapies in nGBM patients. CONCLUSION: We will evaluate the relative effectiveness of different antiangiogenic drugs and rank each intervention in nGBM patients through prognosis to provide decision-making reference on which method to choose for clinicians. PROTOCOL REGISTRATION NUMBER: CRD42019146537.


Assuntos
Inibidores da Angiogênese , Glioblastoma , Inibidores da Angiogênese/classificação , Inibidores da Angiogênese/farmacologia , Protocolos Clínicos , Glioblastoma/diagnóstico , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Metanálise em Rede , Seleção de Pacientes , Prognóstico , Revisões Sistemáticas como Assunto , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/análise
5.
Rev Assoc Med Bras (1992) ; 66(2): 174-179, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32428152

RESUMO

OBJECTIVE: Although estrogen therapy is widely used against post-menopausal symptoms, it can present adverse effects, including endometrial cancer. Soy isoflavones are considered a possible alternative to estrogen therapy. However, there are still concerns whether isoflavones exert trophic effects on the uterine cervix. To evaluate the histomorphometric and immunohistochemical alterations in the uterine cervix of ovariectomized rats treated with soy isoflavones (Iso). METHODS: Fifteen adult Wistar rats were ovariectomized (Ovx) and divided into three groups: Group I (Ovx), administered with vehicle solution; Group II (OVX-Iso), administered with concentrated extract of Iso (150 mg/kg) by gavage; and Group III (OVX-E2), treated with 17ß-estradiol (10 µg/kg), subcutaneously. After 30 days of treatments, the uterine cervix was fixed in 10% formaldehyde and processed for paraffin-embedding. Sections were stained with Hematoxylin and eosin for morphological and morphometric studies or subjected to immunohistochemistry for detections of Ki-67 and vascular endothelial growth factor-A (Vegf-A). The data obtained were subjected to statistical analysis (p ≤ 0.05). RESULTS: We noted an atrophic uterine cervix in GI, whereas it was more voluminous in GII and even more voluminous in GIII. The thickness of the cervical mucosa was significantly higher in GIII, as compared to GI and GII. The cell proliferation (Ki-67) was significantly elevated in the estradiol and isoflavones treated groups, whereas Vegf-A immunoexpression was significantly higher in GIII, as compared to groups GII and GI. CONCLUSIONS: Soy isoflavones cause less trophic and proliferative effects in the uterine cervix of rats as compared to estrogen.


Assuntos
Colo do Útero/efeitos dos fármacos , Estrogênios/farmacologia , Isoflavonas/farmacologia , Fitoestrógenos/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Colo do Útero/patologia , Epitélio/efeitos dos fármacos , Feminino , Imuno-Histoquímica , Antígeno Ki-67/análise , Membrana Mucosa/efeitos dos fármacos , Ovariectomia , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/análise
6.
Nucleic Acids Res ; 48(12): 6431-6444, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32442276

RESUMO

While many methods are available to measure the concentrations of proteins in solution, the development of a method to quantitatively report both increases and decreases in different protein concentrations in real-time using changes in the concentrations of other molecules, such as DNA outputs, has remained a challenge. Here, we present a biomolecular reaction process that reports the concentration of an input protein in situ as the concentration of an output DNA oligonucleotide strand. This method uses DNA oligonucleotide aptamers that bind either to a specific protein selectively or to a complementary DNA oligonucleotide reversibly using toehold-mediated DNA strand-displacement. It is possible to choose the sequence of output strand almost independent of the sensing protein. Using this strategy, we implemented four different exchange processes to report the concentrations of clinically relevant human α-thrombin and vascular endothelial growth factor using changes in concentrations of DNA oligonucleotide outputs. These exchange processes can operate in tandem such that the same or different output signals can indicate changes in concentration of distinct or identical input proteins. The simplicity of our approach suggests a pathway to build devices that can direct diverse output responses in response to changes in concentrations of specific proteins.


Assuntos
Aptâmeros de Nucleotídeos/química , Trombina/química , Fator A de Crescimento do Endotélio Vascular/química , Técnicas Biossensoriais/métodos , Humanos , Ligação Proteica , Trombina/análise , Fator A de Crescimento do Endotélio Vascular/análise
7.
Hum Pathol ; 99: 88-97, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32246989

RESUMO

Combined anti-VEGF/anti-programmed death ligand 1 (PD-L1) therapy synergistically improves treatment outcomes in advanced renal cell carcinoma (RCC) compared with anti-PD-L1 or anti-vascular endothelial growth factor (VEGF) monotherapy. Here, we analyzed the expression of VEGF and PD-L1 (SP142) in a retrospective cohort of 513 patients with clear-cell (cc) RCC. PD-L1 expression on tumor cells (TCs) and immune cells (ICs) was evaluated by immunohistochemistry (IHC) with a positive threshold value of ≥1%. Positive staining for PD-L1 on ICs and TCs was found in 115 (22.4%) and 7 (1.4%) cases, respectively. Moderate or strong staining for VEGF on TCs was found in 217 (42.3%) patients. PD-L1 expression on ICs and TCs was positively associated with VEGF expression on TCs. Both VEGF and PD-L1 (IC) positivity (VEGF/PD-L1 [IC]: +/+) was observed in 65 (12.7%) cases. Patients in this subgroup exhibited more aggressive clinicopathologic features, including older age, higher World Health Organization/International Society of Urological Pathology (ISUP) grade, angiolymphatic invasion, tumor necrosis, and sarcomatoid differentiation (P < 0.05). Kaplan-Meier analysis indicated that expression of VEGF and PD-L1 on ICs was positively correlated with tumor recurrence (P < 0.001), whereas expression of PD-L1 on TCs was not (P = 0.554). Tumors with positivity for both antibodies (VEGF/PD-L1 [IC]: +/+) exhibited the worst recurrence-free survival (P < 0.001), and double positivity independently predicted tumor recurrence in ccRCC. The present study provides comprehensive and basic information about VEGF and PD-L1 expression for new combined therapy in primary ccRCC.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/química , Neoplasias Renais/química , Fator A de Crescimento do Endotélio Vascular/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Nefrectomia , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Adulto Jovem
8.
PLoS One ; 15(3): e0230344, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214330

RESUMO

In age-related macular degeneration (AMD) or diabetic retinopathy (DR), hypoxia and inflammatory processes lead to an upregulation of the vascular endothelial growth factor (VEGF) expression and thereby to pathological neovascularisation with incorrectly formed vessels prone to damage, thus increasing the vascular permeability and the risk of bleeding and oedema in the retina. State of the art treatment is the repeated intraocular injection of anti-VEGF molecules. For developing improved individualized treatment approaches, a minimally invasive, repeatable method for in vivo quantification of VEGF in the eye is necessary. Therefore, we designed single molecule eBRET2 VEGF biosensors by directly fusing a Renilla luciferase mutant (Rluc8) N-terminal and a green fluorescent protein (GFP2) C-terminal to a VEGF binding domain. In total, 10 different VEGF biosensors (Re01- Re10) were generated based on either single domains or full length of VEGF receptor 1 or 2 extracellular regions as VEGF binding domains. Full length expression of the biosensors in HEK293-T cells was verified via Western Blot employing an anti-Rluc8-IgG. Expression of alternative splice variants was eliminated through the deletion of the donor splice site by introduction of a silent point mutation. In all ten biosensors the energy transfer from the Rluc8 to the GFP2 occurs and generates a measurable eBRET2 ratio. Four biosensors show a relevant change of the BRET ratio (ΔBR) after VEGF binding. Furthermore, each biosensor shows a unique detection range for VEGF quantification and especially Re06 and Re07 have a high sensitivity in the range of in vivo VEGF concentrations in the eye, previously measured by invasive methods. In conclusion, we generated several eBRET2 biosensors that are suitable for VEGF quantification in vitro and could identify two eBRET2 biosensors, which may be suitable for non-invasive in vivo VEGF quantification with an implantable device.


Assuntos
Técnicas Biossensoriais/instrumentação , Medições Luminescentes/instrumentação , Proteínas Recombinantes de Fusão/química , Fator A de Crescimento do Endotélio Vascular/análise , Animais , Córnea/patologia , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/patologia , Transferência de Energia , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Células HEK293 , Células Endoteliais da Veia Umbilical Humana , Humanos , Luciferases de Renilla/química , Luciferases de Renilla/genética , Degeneração Macular/diagnóstico , Degeneração Macular/patologia , Ligação Proteica , Domínios Proteicos , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Retina/patologia , Transfecção , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
Arq Neuropsiquiatr ; 78(1): 34-38, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32074192

RESUMO

OBJECTIVE: Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). METHODS: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. RESULTS: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. CONCLUSIONS: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.


Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Glioblastoma/genética , Glioma/genética , Neovascularização Patológica/genética , Expressão Gênica , Glioblastoma/patologia , Glioma/patologia , Humanos , Interleucina-8/análise , Mutação Puntual/genética , Receptores de Interleucina-8A/análise , Receptores de Interleucina-8B/análise , Valores de Referência , Fator A de Crescimento do Endotélio Vascular/análise , Fator B de Crescimento do Endotélio Vascular/análise , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análise
10.
J Pharmacol Exp Ther ; 373(2): 184-192, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32098861

RESUMO

Abicipar pegol (abicipar) is a novel DARPin therapeutic and highly potent vascular endothelial growth factor (VEGF) inhibitor intended for the treatment of neovascular age-related macular degeneration (nAMD). Here we develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for abicipar to guide dosing regimens in the clinic. The model incorporated abicipar-VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe the ocular and systemic PK data collected from the vitreous, aqueous humor (AH), choroid, retina, and serum of rabbits after a 1-mg abicipar intravitreal (IVT) dose. The model was translated to humans using human-specific mechanistic parameters and refitted to human serum and AH concentrations from patients with diabetic macular edema and nAMD. The model was then used to simulate 8-, 12- (quarterly), and 16-week dosing intervals in the clinic. Simulations of 2 mg abicipar IVT at 8-week or quarterly dosing in humans indicates minimum steady-state vitreal concentrations are maintained above both in vitro IC50 and in vivo human IC50 values. The model predicted virtually complete VEGF inhibition for the 8-week and quarterly dosing schedule during the 52-week treatment period. In the 16-week schedule, clinically significant VEGF inhibition was maintained during the 52-week period. The model quantitatively described abicipar-VEGF target engagement leading to rapid reduction of VEGF and a long duration of VEGF inhibition demonstrating the clinical feasibility of up to a 16-week dosing interval. Abicipar is predicted to reduce IVT dosing compared with other anti-VEGF therapies with the potential to lessen patient treatment burden. SIGNIFICANCE STATEMENT: Current anti-VEGF treatments for neovascular age-related macular degeneration require frequent (monthly) intravitreal injections and monitoring, which increases patient burden. We developed a mechanistic pharmakinetic/pharmadynamic model to describe the interaction between abicipar (a novel VEGF inhibitor) and VEGF to evaluate the duration of action. The model demonstrates extended abicipar-VEGF target engagement leading to clinical feasibility of up to a 16-week dosing interval. Our model predicted that abicipar 8-week and quarterly dosing schedules maintain virtually complete VEGF inhibition during the 52-week period.


Assuntos
Proteínas Recombinantes de Fusão/farmacologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Humanos , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Modelos Biológicos , Coelhos , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacocinética , Fator A de Crescimento do Endotélio Vascular/análise
11.
Clin Exp Metastasis ; 37(2): 293-304, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32008138

RESUMO

Most women with epithelial ovarian cancer (EOC) suffer from peritoneal carcinomatosis upon first clinical presentation. Extensive peritoneal carcinomatosis has a poor prognosis and its pathophysiology is not well understood. Although treatment with systemic intravenous chemotherapy is often initially successful, peritoneal recurrences occur regularly. We hypothesized that insufficient or poorly-perfused microvasculature may impair the therapeutic efficacy of systemic intravenous chemotherapy but may also limit expansive and invasive growth characteristic of peritoneal EOC metastases. In 23 patients with advanced EOC or suspicion thereof, we determined the angioarchitecture and perfusion of the microvasculature in peritoneum and in peritoneal metastases using incident dark field (IDF) imaging. Additionally, we performed immunohistochemical analysis and 3-dimensional (3D) whole tumor imaging using light sheet fluorescence microscopy of IDF-imaged tissue sites. In all metastases, microvasculature was present but the angioarchitecture was chaotic and the vessel density and perfusion of vessels was significantly lower than in unaffected peritoneum. Immunohistochemical analysis showed expression of vascular endothelial growth factor and hypoxia inducible factor 1α, and 3D imaging demonstrated vascular continuity between metastases and the vascular network of the peritoneum beneath the elastic lamina of the peritoneum. We conclude that perfusion of the microvasculature within metastases is limited, which may cause hypoxia, affect the behavior of EOC metastases on the peritoneum and limit the response of EOC metastases to systemic treatment.


Assuntos
Carcinoma Epitelial do Ovário/irrigação sanguínea , Microvasos/diagnóstico por imagem , Neoplasias Ovarianas/terapia , Neoplasias Peritoneais/irrigação sanguínea , Peritônio/patologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/secundário , Carcinoma Epitelial do Ovário/terapia , Hipóxia Celular , Quimioterapia Adjuvante , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imageamento Tridimensional , Imuno-Histoquímica , Microvasos/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Ovarianas/patologia , Ovariectomia , Ovário/patologia , Ovário/cirurgia , Neoplasias Peritoneais/prevenção & controle , Neoplasias Peritoneais/secundário , Peritônio/irrigação sanguínea , Estudos Prospectivos , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/metabolismo
13.
J Appl Oral Sci ; 28: e20190215, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31939521

RESUMO

OBJECTIVE: This study evaluated the angiogenesis-enhancing potential of a tricalcium silicate-based mineral trioxide aggregate (ProRoot MTA), Biodentine, and a novel bioceramic root canal sealer (Well-Root ST) in human dental pulp stem cells (hDPSCs), human periodontal ligament stem cells (hPLSCs), and human tooth germ stem cells (hTGSCs). METHODOLOGY: Dulbecco's modified Eagle's medium was conditioned for 24 h by exposure to ProRoot MTA, Biodentine, or Well-Root ST specimens (prepared according to the manufacturers' instructions). The cells were cultured in these conditioned media and their viability was assessed with 3-(4,5-dimethyl-thiazol-2-yl)-5-(3-carboxy-methoxy-phenyl)-2-(4-sulfo-phenyl)-2H tetrazolium (MTS) on days 1, 3, 7, 10, and 14. Angiogenic growth factors [platelet-derived growth factor (PDGF), basic fibroblast growth factor (FGF-2), and vascular endothelial growth factor (VEGF)] were assayed by sandwich enzyme-linked immunosorbent assay (ELISA) on days 1, 7, and 14. Human umbilical vein endothelial cell (HUVEC) migration assays were used to evaluate the vascular effects of the tested materials at 6-8 h. Statistical analyses included Kruskal-Wallis, Mann-Whitney U, and Friedman and Wilcoxon signed rank tests. RESULTS: None of tricalcium silicate-based materials were cytotoxic and all induced a similar release of angiogenic growth factors (PDGF, FGF-2, and VEGF) (p>0.05). The best cell viability was observed for hDPSCs (p<0.05) with all tricalcium silicate-based materials at day 14. Tube formation by HUVECs showed a significant increase with all tested materials (p<0.05). CONCLUSION: The tricalcium silicate-based materials showed potential for angiogenic stimulation of all stem cell types and significantly enhanced tube formation by HUVECs.


Assuntos
Indutores da Angiogênese/farmacologia , Compostos de Cálcio/farmacologia , Cerâmica/farmacologia , Materiais Restauradores do Canal Radicular/farmacologia , Silicatos/farmacologia , Células-Tronco/efeitos dos fármacos , Materiais Biocompatíveis/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Polpa Dentária/citologia , Polpa Dentária/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Fator 2 de Crescimento de Fibroblastos/análise , Fator 2 de Crescimento de Fibroblastos/efeitos dos fármacos , Citometria de Fluxo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Teste de Materiais , Neovascularização Fisiológica/efeitos dos fármacos , Ligamento Periodontal/citologia , Ligamento Periodontal/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/análise , Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Reprodutibilidade dos Testes , Estatísticas não Paramétricas , Germe de Dente/citologia , Germe de Dente/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos
14.
J Gynecol Obstet Hum Reprod ; 49(1): 101642, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31563698

RESUMO

OBJECTIVE: To investigate the effects of ginsenoside Rg3 on human ectopic endometriotic stromal cells in vitro. MATERIALS AND METHODS: Ectopic endometrial tissue specimens were obtained from 6 female patients with ovarian endometriosis who underwent laparoscopic surgical procedures. Endometrial stromal cells derived from isolated ectopic endometriotic lesions were cultured, and the purity and homogeneity of cells were verified by Immunocytochemistry. The effect of Rg3 on cell proliferation was detected by Cell Counting Kit-8 (CCK8). After treatment with Rg3, the protein expression of NF-κB p65 subunit, VEGF, and caspases3 were measured by western blot analysis. Meanwhile, the mRNA expression of NF-κB p65 subunit was determined by Quantitative real-time polymerase chain reaction (RT-PCR). RESULTS: Rg3 inhibited the proliferation of ectopic endometriotic cells in a time- and dose-dependent manner. The treatment with Rg3 significantly diminished the level of NF-κB p65 subunit as well as TNF-α induced nuclear translocation of NF-κB p65 subunit in ectopic endometriotic cells. Moreover, Rg3 upregulated the expression of caspases3 but suppressed the expression of VEGF. CONCLUSION: Our results indicate that Ginsenoside Rg3 suppresses endometriosis by reducing the viability of human ectopic endometrial stromal cells involving the nuclear factor-kappaB signaling pathway in vitro.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Endometriose/patologia , Ginsenosídeos/farmacologia , Células Estromais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Adulto , Caspase 3/análise , Proliferação de Células/efeitos dos fármacos , Endometriose/tratamento farmacológico , Endometriose/metabolismo , Feminino , Humanos , Técnicas In Vitro , Doenças Ovarianas/metabolismo , Doenças Ovarianas/patologia , RNA Mensageiro/análise , Transdução de Sinais , Células Estromais/metabolismo , Fator de Transcrição RelA/análise , Fator de Transcrição RelA/genética , Fator de Necrose Tumoral alfa/farmacologia , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Vet Dermatol ; 31(2): 102-105, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31696573

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF) is a cytokine involved primarily in angiogenesis. In human atopic dermatitis (AD), VEGF has been detected in the stratum corneum and blood. OBJECTIVE: To evaluate VEGF-A expression in the serum and stratum corneum of healthy and atopic dogs, and its possible correlation with disease severity in atopic dogs. ANIMAL: Fifteen atopic and 15 healthy, privately owned dogs. METHODS AND MATERIALS: The severity of clinical signs associated with AD was evaluated with the Canine Atopic Dermatitis Extent and Severity Index (CADESI-04). For all dogs, a single blood sample was performed and serum collected. Tape stripping (15 times) was performed on the left periocular area (lesional skin). A commercially available canine-specific VEGF-A enzyme-linked immunosorbent assay was performed with all samples. RESULTS: Vascular endothelial growth factor-A was undetectable in the serum. In the stratum corneum, there was no significant difference in VEGF-A concentrations between healthy (mean 89.4 ± 59.5 pg/ml) and atopic dogs (mean 100.3 ± 77.1pg/ml) (P = 0.71). There was no correlation between stratum corneum VEGF-A concentrations and CADESI-04 scores. CONCLUSIONS AND CLINICAL IMPORTANCE: The role of VEGF in canine AD is unclear. Because of many variants, VEGF-C and VEGF-D or VEGF-A isotopes should be explored in the skin to better evaluate the role of VEGF in canine atopy. Full-thickness skin biopsy, molecular biology and histopathological investigation may be necessary to further assess cutaneous VEGF expression.


Assuntos
Dermatite Atópica/veterinária , Doenças do Cão/imunologia , Pele/química , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/sangue , Animais , Dermatite Atópica/imunologia , Cães , Epiderme/patologia , Feminino , Masculino , Índice de Gravidade de Doença , Pele/patologia
16.
Support Care Cancer ; 28(1): 177-184, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31001696

RESUMO

PURPOSE: Crevicular fluid was used to assess interleukin-17 (IL-17) and vascular endothelial growth factor (VEGF) in cancer patients receiving zoledronic acid and/or bevacizumab. The markers were also assessed in the serum. METHODS: Twenty-five patients were included and comprised three groups: patients who received zoledronic acid (n = 9), patients who received bevacizumab (n = 9), and patients who received zoledronic acid combined with bevacizumab (n = 5). One patient received zoledronic acid and everolimus and another received zoledronic acid, bevacizumab, and temsirolimus. IL-17 and VEGF were measured by standard quantitative ELISA kits and assessed in two study points. RESULTS: Twenty-four patients maintained good periodontal health; one had asymptomatic osteonecrosis of the jaw. First assessment: 44 samples were collected; 21 from serum and 23 from crevicular fluid. Second assessment, 6 months later: 11 samples were collected; 6 from serum and 5 from crevicular fluid. IL-17 was detected in all samples, in serum and crevicular fluid, and remained unchanged at both time points. Serum VEGF in patients with bevacizumab alone or combined with zoledronic acid was significantly lower compared with that of patients who received zoledronic acid alone. VEGF was not detected in the crevicular fluid. CONCLUSIONS: Crevicular fluid might be an easy, non-invasive means to assess IL-17. The stable values of IL-17 in crevicular fluid and serum and the lack of VEGF in the crevicular fluid could be related to the good periodontal health of our patients. Further studies are needed to assess IL-17 and VEGF in the crevicular fluid in patients with and without periodontal disease.


Assuntos
Bevacizumab/administração & dosagem , Líquido do Sulco Gengival/química , Interleucina-17/análise , Neoplasias/tratamento farmacológico , Doenças Periodontais/diagnóstico , Fator A de Crescimento do Endotélio Vascular/análise , Ácido Zoledrônico/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/efeitos adversos , Biomarcadores/análise , Biomarcadores/metabolismo , Quimioterapia Combinada/efeitos adversos , Feminino , Líquido do Sulco Gengival/metabolismo , Humanos , Inflamação/diagnóstico , Inflamação/metabolismo , Interleucina-17/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/irrigação sanguínea , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/diagnóstico , Neovascularização Patológica/metabolismo , Osteonecrose/induzido quimicamente , Osteonecrose/diagnóstico , Osteonecrose/metabolismo , Doenças Periodontais/induzido quimicamente , Doenças Periodontais/etiologia , Bolsa Periodontal/induzido quimicamente , Bolsa Periodontal/diagnóstico , Bolsa Periodontal/metabolismo , Valor Preditivo dos Testes , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ácido Zoledrônico/efeitos adversos
17.
Nephrology (Carlton) ; 25(2): 125-134, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31264312

RESUMO

AIM: Renal thrombotic microangiopathy (TMA) is a common pathological manifestation of Castleman's disease (CD)-associated renal lesions. Increased level of plasma vascular endothelial growth factor (VEGF) has been shown in single-case reports. We aimed to investigate the dysregulation of VEGF in the pathogenesis of CD-associated TMA-like lesions (CD-TMA) in a larger cohort. METHODS: Nineteen patients with clinico-pathologically diagnosed CD with renal involvement were enrolled. Ten patients with pregnancy TMA or TMA of unknown reasons were enrolled as TMA control group. The plasma levels of VEGF, soluble Flt-1 and interleukin-6 (IL-6) were detected using enzyme-linked immunosorbent assay kits. The expression of VEGF in the kidney biopsied tissue sections and the lymph node specimens were detected by immunostaining. RESULTS: The plasma levels of VEGF and IL-6 levels were the highest in CD-TMA group compared to TMA control group and healthy controls. The levels of plasma VEGF was positively correlated with that of IL-6, and increased expression of VEGF and IL-6 was also observed in the lymph nodes from CD-TMA patients. However, the expression of VEGF in the glomerular podocytes was significantly decreased in CD-TMA group as well as in the TMA control. CONCLUSION: Our findings suggest that renal VEGF expression might be important in the pathogenetic mechanism of CD-associated TMA-like lesions.


Assuntos
Hiperplasia do Linfonodo Gigante , Interleucina-6 , Rim , Linfonodos , Podócitos/imunologia , Microangiopatias Trombóticas , Fator A de Crescimento do Endotélio Vascular , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Adulto , Biópsia/métodos , Hiperplasia do Linfonodo Gigante/imunologia , Hiperplasia do Linfonodo Gigante/patologia , Feminino , Humanos , Imuno-Histoquímica , Interleucina-6/análise , Interleucina-6/sangue , Rim/imunologia , Rim/patologia , Linfonodos/imunologia , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Microangiopatias Trombóticas/imunologia , Microangiopatias Trombóticas/patologia , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/análise , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue
18.
Transplantation ; 104(1): 79-89, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31283675

RESUMO

BACKGROUND: Predicting the development of early allograft dysfunction (EAD) following liver transplantation (LT) remains challenging for transplant clinicians. The objectives of this study are to investigate the potential relationship between the protein profiles of pretransplant grafts and the onset of EAD, and then combine with clinical parameters to construct a mathematically predictive model. METHODS: Clinical data of 121 LT procedures from donation after circulatory death at the authors' center were analyzed. The expression levels of 7 studied proteins were determined by immunohistochemistry. Another independent cohort of 37 subjects was designed for further validation of the predictive model. RESULTS: With an incidence of 43.0% (52/121), EAD was linked to significantly increased risk of acute kidney injury and renal replacement therapy, as well as reduced 6-month patient and liver graft survival. Allograft weight and high intrahepatic vascular endothelial growth factor (VEGF) expression were identified as independent risk factors of EAD and survival outcomes. Liver grafts with high VEGF expression exhibited delayed functional recovery within the first postoperative week. The combination of VEGF overexpression and EAD yielded the highest frequency of renal dysfunction and the worst survival. Based on allograft weight and intrahepatic VEGF expression, an EAD risk assessment model was developed. The incidence of EAD differed significantly between grafts with risk scores ≥-1.72 and <-1.72. The model functioned well in the validation cohort. CONCLUSIONS: Pretransplant intrahepatic protein profiling contributes to the estimation of early graft performance and recipient outcomes following LT. The predictive model could allow for an accurate prediction of EAD.


Assuntos
Lesão Renal Aguda/epidemiologia , Aloenxertos/metabolismo , Doença Hepática Terminal/cirurgia , Transplante de Fígado/efeitos adversos , Fígado/metabolismo , Disfunção Primária do Enxerto/epidemiologia , Lesão Renal Aguda/etnologia , Lesão Renal Aguda/terapia , Adulto , Estudos de Coortes , Doença Hepática Terminal/mortalidade , Feminino , Sobrevivência de Enxerto , Humanos , Imuno-Histoquímica , Incidência , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Período Pré-Operatório , Disfunção Primária do Enxerto/complicações , Terapia de Substituição Renal/estatística & dados numéricos , Medição de Risco/métodos , Fatores de Risco , Análise de Sobrevida , Transplante Homólogo/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
JAMA Ophthalmol ; 138(2): 136-146, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31830238

RESUMO

Importance: Radiation retinopathy following plaque radiotherapy for uveal melanoma can lead to vision loss that might be avoided with prophylactic anti-vascular endothelial growth factor treatment. Objective: To determine visual outcome following prophylactic intravitreal bevacizumab in patients with plaque-irradiated uveal melanoma. Design, Setting, and Participants: Retrospective, nonrandomized, interventional cohort study at Wills Eye Hospital, Philadelphia, Pennsylvania. Prophylactic bevacizumab was administered between 2008 and 2018 to 1131 eyes with irradiated uveal melanoma (bevacizumab group) and compared with 117 eyes with irradiated uveal melanoma between 2007 and 2009 (no bevacizumab [historical control] group). Interventions: Prophylactic intravitreal bevacizumab was provided at the time of plaque removal as well as 6 subsequent injections at 4-month intervals over 2 years. Main Outcomes and Measures: Visual acuity. Results: The median patient age was 61 years, 1195 of 1248 patients were white (96%), and 632 of 1248 were women (51%). The median tumor thickness was 4.0 mm, and median distance to foveola was 3.0 mm. A difference was not identified (bevacizumab vs control group) in demographic features, clinical features, or radiation parameters. The mean follow-up was 40 months vs 56 months (mean difference, -18; 95% CI, -24 to -13; P < .001). By survival analysis, the bevacizumab group demonstrated less optical coherence tomography evidence of cystoid macular edema at 24 months (28% vs 37%; hazard ratio [HR], 1.5; 95% CI, 1.1-2.2; P = .02) and 36 months (44% vs 54%; HR, 1.5; 95% CI, 1.1-2.1; P = .01), less clinical evidence of radiation maculopathy at 24 months (27% vs 36%; HR, 1.5; 95% CI, 1.0-2.2; P = .03), 36 months (44% vs 55%; HR, 1.50; 95% CI, 1.1-2.0; P = .01), and 48 months (61% vs 66%; HR, 1.4; 95% CI, 1.0-1.9; P = .03), and less clinical evidence of radiation papillopathy at 18 months (6% vs 12%; HR, 2.0; 95% CI, 1.1-3.9; P = .04). Nonparametric analysis documented better visual acuity outcomes in the bevacizumab group at all points, including 12 months (median logMAR visual acuity [Snellen equivalent]: 0.30 [20/40] vs 0.48 [20/60]; mean difference, -0.28; 95% CI, -0.48 to -0.07; P = .02), 24 months (0.40 [20/50] vs 0.70 [20/100]; mean difference, -0.52; 95% CI, -0.75 to -0.29; P < .001), 36 months (0.48 [20/60] vs 1.00 [20/200]; mean difference, -0.49; 95% CI, -0.76 to -0.21; P = .003), and 48 months (0.54 [20/70] vs 2.00 [counting fingers]; mean difference, -0.71; 95% CI, -1.03 to -0.38; P < .001). Conclusions and Relevance: These findings from a retrospective cohort of plaque radiotherapy and prophylactic intravitreal bevacizumab in patients with uveal melanoma suggest better visual outcomes when compared with nonrandomized historical control individuals through 4 years.


Assuntos
Bevacizumab/administração & dosagem , Melanoma/radioterapia , Neoplasias Uveais/radioterapia , Acuidade Visual , Terapia Combinada , Feminino , Humanos , Injeções Intravítreas , Masculino , Melanoma/mortalidade , Melanoma/patologia , Melanoma/fisiopatologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologia , Neoplasias Uveais/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/análise , Acuidade Visual/efeitos dos fármacos
20.
Spectrochim Acta A Mol Biomol Spectrosc ; 226: 117622, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31606672

RESUMO

Early detection of cancer is of great significance for disease prevention and diagnosis. However, the levels of most cancer markers are quite low in the early stages of disease, so it is urgent to develop a highly sensitive detection method. In this study, a label-free and highly sensitive colorimetric strategy was developed for the detection of the vascular endothelial growth factor165 (VEGF165) in human serum. First, a convenient biosensor was constructed by immobilizing VEGF165 on a microplate, where aptamers bound with VEGF165 to form a complex. Then, streptavidin labeled-horseradish peroxidase (HRP-SA) combined with the complex via the interaction between streptavidin and biotin, thus catalyzing the 3,3',5,5'-tetramethylbenzidine (TMB) and H2O2 system to produce colored products. In the presence of target, immobilized VEGF165 and target competitively bound with the aptamers, resulting in a reduction of the colorimetric signal. Moreover, the optical density (OD) signal decreased with the increase of target concentration. The strategy showed a broad linear range (0.1-100 ng/mL) and a rather low detection limit of 10 pg/mL with good precision and selectivity. Further, the proposed method was successfully applied in detecting VEGF165 in human serum. The detection results of serum samples showed that the proposed assay had a high correlation with CLEIA kits (r = 0.971, P = 0.001). It has potential for application in clinical research and diagnosis.


Assuntos
Técnicas Biossensoriais/métodos , Análise Química do Sangue/métodos , Soro/química , Fator A de Crescimento do Endotélio Vascular/análise , Aptâmeros de Nucleotídeos/química , Colorimetria/métodos , Estudos de Viabilidade , Humanos , Limite de Detecção , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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