Elevated IGFIR expression regulating VEGF and VEGF-C predicts lymph node metastasis in human colorectal cancer

International Nuclear Information System (INIS)

Zhang, Chunhui; Hao, Li; Wang, Liang; Xiao, Yichuan; Ge, Hailiang; Zhu, Zhenya; Luo, Yunbao; Zhang, Yi; Zhang, Yanyun

2010-01-01

Insulin-like growth factor-I receptor (IGFIR) has been shown to regulate the tumor development. The objective of the current study is to determine the association of IGFIR with lymph node metastasis and to explore the related mechanism in human colorectal cancer in clinic. In a random series of 98 colorectal cancer patients, the expressions of IGFIR, vascular endothelial growth factor (VEGF) and VEGF-C were investigated by immunohistochemistry, and the association of these expressions with lymph node metastasis was statistically analyzed. The expressions of VEGF and VEGF-C in colorectal cancer cells stimulated with IGF-I were also examined by real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Higher rates of IGFIR (46%), VEGF (53%), and VEGF-C (46%) expression were found in colorectal cancer tissues than in normal and colorectal adenoma tissues. These expressions were significantly associated with clinicopathologic factors and lymph node status. We also found the concomitant high expressions of IGFIR/VEGF (P < 0.001) and IGFIR/VEGF-C (P = 0.001) had a stronger correlation with lymph node metastasis than did each alone or both low expressions. In addition, IGF-I could effectively induce the VEGF and VEGF-C mRNA expression and protein secretion in colorectal cancer cells expressing IGFIR molecules. Moreover, Patients who had strong staining for IGFIR, VEGF and VEGF-C showed significantly less favorable survival rates compared with patients who had low staining for these molecules (P < 0.001). The survival rates of patients who were both high expression of IGFIR/VEGF and IGFIR/VEGF-C also were significantly lower compared with patients who were negative or one of high expression of these molecules (P < 0.001). Together the findings indicated for the first time that simultaneous examination of the expressions of IGFIR, VEGF and VEGF-C will benefit the diagnosis of lymph node metastasis in order to assay the

OPTIMAL MANAGEMENT OF PIGMENT EPITHELIAL DETACHMENTS IN EYES WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

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Khanani, Arshad M; Eichenbaum, David; Schlottmann, Patricio G; Tuomi, Lisa; Sarraf, David

2018-04-24

This review aimed to determine the optimal management of retinal pigment epithelial detachments (PEDs) in neovascular age-related macular degeneration (nAMD) based on review of available evidence in the literature. A comprehensive literature review evaluates previous retrospective and prospective studies that assessed the treatment of PEDs in nAMD. Studies illustrated that anti-vascular endothelial growth factor (VEGF) therapy can be effective in eyes with PED secondary to nAMD. Similar visual outcomes are associated with different anti-VEGF treatments. Higher anti-VEGF doses may improve anatomical response, without correlation with vision improvement. Fibrovascular PEDs may be difficult to treat, but even these eyes can gain vision with anti-VEGF therapy. A retinal pigment epithelial tear may develop in 15% to 20% of eyes with PEDs after anti-VEGF therapy, especially in PEDs greater than 500 µm to 600 µm in height; however, vision may stabilize with continued therapy. Atrophy may complicate eyes with PED and nAMD after anti-VEGF therapy, especially in association with complete PED resolution. Available literature suggests that anti-VEGF therapy is safe and efficacious for PED and nAMD. Treatment should focus on vision gains rather than PED resolution because there is no apparent correlation between anatomical and functional improvement in most eyes with PED and nAMD.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

VEGF as a Survival Factor in Ex Vivo Models of Early Diabetic Retinopathy.

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Amato, Rosario; Biagioni, Martina; Cammalleri, Maurizio; Dal Monte, Massimo; Casini, Giovanni

2016-06-01

Growing evidence indicates neuroprotection as a therapeutic target in diabetic retinopathy (DR). We tested the hypothesis that VEGF is released and acts as a survival factor in the retina in early DR. Ex vivo mouse retinal explants were exposed to stressors similar to those characterizing DR, that is, high glucose (HG), oxidative stress (OS), or advanced glycation end-products (AGE). Neuroprotection was provided using octreotide (OCT), a somatostatin analog, and pituitary adenylate cyclase activating peptide (PACAP), two well-documented neuroprotectants. Data were obtained with real-time RT-PCR, Western blot, ELISA, and immunohistochemistry. Apoptosis was induced in the retinal explants by HG, OS, or AGE treatments. At the same time, explants also showed increased VEGF expression and release. The data revealed that VEGF is released shortly after exposure of the explants to stressors and before the level of cell death reaches its maximum. Retinal cell apoptosis was inhibited by OCT and PACAP. At the same time, OCT and PACAP also reduced VEGF expression and release. Vascular endothelial growth factor turned out to be a protective factor for the stressed retinal explants, because inhibiting VEGF with a VEGF trap further increased cell death. These data show that protecting retinal neurons from diabetic stress also reduces VEGF expression and release, while inhibiting VEGF leads to exacerbation of apoptosis. These observations suggest that the retina in early DR releases VEGF as a prosurvival factor. Neuroprotective agents may decrease the need of VEGF production by the retina, therefore limiting the risk, in the long term, of pathologic angiogenesis.

Effects of EG-VEGF, VEGF and TGF-β1 on pregnancy outcome in patients undergoing IVF-ET treatment.

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Gao, Min-zhi; Zhao, Xiao-ming; Lin, Yi; Sun, Zhao-gui; Zhang, Hui-qin

2012-10-01

To investigate the correlation of endocrine gland-derived vascular endothelial growth factor (EG-VEGF), vascular endothelial growth factor (VEGF) and transforming growth factor beta 1 (TGF-β1) with the corresponding reproductive outcome in patients who received in vitro fertilization-embryo transfer (IVF-ET). Sixty-seven women undergoing IVF-ET at a university tertiary hospital were recruited for a prospective study. Concentrations of EG-VEGF, VEGF and TGF-β1 were measured by enzyme-linked immunosorbent assay (ELISA) in follicular fluid (FF) collected during oocyte retrieval (OR) and in serum collected 2 days after OR. In FF, concentrations of both EG-VEGF and VEGF were negatively correlated with peak E2 and the number of MII oocytes retrieved, and positively correlated with each other. In serum, concentrations of all the three growth factors were positively correlated with the rate of good quality embryo, and with one another. Patients in the pregnancy group had lower peak E2 concentrations and higher serum EG-VEGF concentrations than those in the non-pregnancy group, but such tendency was not observed in the case of VEGF and TGF-β1. Both concentrations of EG-VEGF and VEGF in FF were negatively correlated with ovarian response and oocyte maturation. Concentrations of all the three growth factors in serum were positively correlated with embryo quality, but only serum concentrations of EG-VEGF were associated with the pregnancy outcome.

Expression of VEGF(xxx)b, the inhibitory isoforms of VEGF, in malignant melanoma.

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Pritchard-Jones, R O; Dunn, D B A; Qiu, Y; Varey, A H R; Orlando, A; Rigby, H; Harper, S J; Bates, D O

2007-07-16

Malignant melanoma is the most lethal of the skin cancers and the UK incidence is rising faster than that of any other cancer. Angiogenesis - the growth of new vessels from preexisting vasculature - is an absolute requirement for tumour survival and progression beyond a few hundred microns in diameter. We previously described a class of anti-angiogenic isoforms of VEGF, VEGF(xxx)b, that inhibit tumour growth in animal models, and are downregulated in some cancers, but have not been investigated in melanoma. To determine whether VEGF(xxx)b expression was altered in melanoma, PCR and immunohistochemistry of archived human tumour samples were used. In normal epidermis and in a proportion of melanoma samples, VEGF(xxx)b staining was seen. Some melanomas had much weaker staining. Subsequent examination revealed that expression was significantly reduced in primary melanoma samples (both horizontal and vertical growth phases) from patients who subsequently developed tumour metastasis compared with those who did not (analysis of variance (ANOVA) Pxxx)b expression appears to predict metastatic spread in patients with primary melanoma. These results suggest that there is a switch in splicing as part of the metastatic process, from anti-angiogenic to pro-angiogenic VEGF isoforms. This may form part of a wider metastatic splicing phenotype.

CXCL7-Mediated Stimulation of Lymphangiogenic Factors VEGF-C, VEGF-D in Human Breast Cancer Cells

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Minghuan Yu

2010-01-01

Full Text Available Increased expression of lymphangiogenesis factors VEGF-C/D and heparanase has been correlated with the invasion of cancer. Furthermore, chemokines may modify matrix to facilitate metastasis, and they are associated with VEGF-C and heparanase. The chemokine CXCL7 binds heparin and the G-protein-linked receptor CXCR2. We investigated the effect of CXCR2 blockade on the expression of VEGF-C/D, heparanase, and on invasion. CXCL7 siRNA and a specific antagonist of CXCR2 (SB225002 were used to treat CXCL7 stably transfected MCF10AT cells. Matrigel invasion assays were performed. VEGF-C/D expression and secretion were determined by real-time PCR and ELISA assay, and heparanase activity was quantified by ELISA. SB225002 blocked VEGF-C/D expression and secretion (P<.01. CXCL7 siRNA knockdown decreased heparanase (P<.01. Both SB225002 and CXCL7 siRNA reduced the Matrigel invasion (P<.01. The MAP kinase signaling pathway was not involved. The CXCL7/CXCR2 axis is important for cell invasion and the expression of VEGF-C/D and heparanase, all linked to invasion.

VEGF(121)b, a new member of the VEGF(xxx)b family of VEGF-A splice isoforms, inhibits neovascularisation and tumour growth in vivo.

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Rennel, E S; Varey, A H R; Churchill, A J; Wheatley, E R; Stewart, L; Mather, S; Bates, D O; Harper, S J

2009-10-06

The key mediator of new vessel formation in cancer and other diseases is VEGF-A. VEGF-A exists as alternatively spliced isoforms - the pro-angiogenic VEGF(xxx) family generated by exon 8 proximal splicing, and a sister family, termed VEGF(xxx)b, exemplified by VEGF(165)b, generated by distal splicing of exon 8. However, it is unknown whether this anti-angiogenic property of VEGF(165)b is a general property of the VEGF(xxx)b family of isoforms. The mRNA and protein expression of VEGF(121)b was studied in human tissue. The effect of VEGF(121)b was analysed by saturation binding to VEGF receptors, endothelial migration, apoptosis, xenograft tumour growth, pre-retinal neovascularisation and imaging of biodistribution in tumour-bearing mice with radioactive VEGF(121)b. The existence of VEGF(121)b was confirmed in normal human tissues. VEGF(121)b binds both VEGF receptors with similar affinity as other VEGF isoforms, but inhibits endothelial cell migration and is cytoprotective to endothelial cells through VEGFR-2 activation. Administration of VEGF(121)b normalised retinal vasculature by reducing both angiogenesis and ischaemia. VEGF(121)b reduced the growth of xenografted human colon tumours in association with reduced microvascular density, and an intravenous bolus of VEGF(121)b is taken up into colon tumour xenografts. Here we identify a second member of the family, VEGF(121)b, with similar properties to those of VEGF(165)b, and underline the importance of the six amino acids of exon 8b in the anti-angiogenic activity of the VEGF(xxx)b isoforms.

Granulocyte-Colony Stimulating Factor Receptor, Tissue Factor, and VEGF-R Bound VEGF in Human Breast Cancer In Loco.

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Wojtukiewicz, Marek Z; Sierko, Ewa; Skalij, Piotr; Kamińska, Magda; Zimnoch, Lech; Brekken, Ralf A; Thorpe, Philip E

2016-01-01

Doxorubicin and docetaxel-based chemotherapy regimens used in breast cancer patients are associated with high risk of febrile neutropenia (FN). Granulocyte colony-stimulating factors (G-CSF) are recommended for both treating and preventing chemotherapy-induced neutropenia. Increased thrombosis incidence in G-CSF treated patients was reported; however, the underlying mechanisms remain unclear. The principal activator of blood coagulation in cancer is tissue factor (TF). It additionally contributes to cancer progression and stimulates angiogenesis. The main proangiogenic factor is vascular endothelial growth factor (VEGF). The aim of the study was to evaluate granulocyte-colony stimulating factor receptor (G-CSFR), tissue factor (TF) expression and vascular endothelial growth factor receptor (VEGF-R) bound VEGF in human breast cancer in loco. G-CSFR, TF and VEGFR bound VEGF (VEGF: VEGFR) were assessed in 28 breast cancer tissue samples. Immunohistochemical (IHC) methodologies according to ABC technique and double staining IHC procedure were employed utilizing antibodies against G-CSFR, TF and VEGF associated with VEGFR (VEGF: VEGFR). Expression of G-CSFR was demonstrated in 20 breast cancer tissue specimens (71%). In 6 cases (21%) the expression was strong (IRS 9-12). Strong expression of TF was observed in all investigated cases (100%). Moreover, expression of VEGF: VEGFR was visualized in cancer cells (IRS 5-8). No presence of G-CSFR, TF or VEGF: VEGFR was detected on healthy breast cells. Double staining IHC studies revealed co-localization of G-CSFR and TF, G-CSFR and VEGF: VEGFR, as well as TF and VEGF: VEGFR on breast cancer cells and ECs. The results of the study indicate that GCSFR, TF and VEGF: VEGFR expression as well as their co-expression might influence breast cancer biology, and may increase thromboembolic adverse events incidence.

The prognosis was poorer in colorectal cancers that expressed both VEGF and PROK1 (No correlation coefficient between VEGF and PROK1).

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Goi, Takanori; Nakazawa, Toshiyuki; Hirono, Yasuo; Yamaguchi, Akio

2015-10-06

The angiogenic proteins vascular endothelial growth factor (VEGF) and prokineticin1 (PROK1) proteins are considered important in colorectal cancer, the relationship between their simultaneous expression and prognosis was investigated in the present study. VEGF and PROK1 expression in 620 primary human colorectal cancer lesions was confirmed via immunohistochemical staining with anti-VEGF and anti-PROK1 antibodies, and the correlation between the expression of these 2 proteins and recurrence/prognosis were investigated. VEGF protein was expressed in 329 (53.1%) and PROK1 protein was expressed in 223 (36.0%). PROK1 and VEGF were simultaneously expressed in 116 (18.7%) of the 620 cases. The correlation coefficient between VEGF expression and PROK1 expression was r = 0.11, and therefore correlation was not observed. Clinical pathology revealed that substantially lymphnode matastasis, hematogenous metastasis, or TMN advanced-stage IV was significantly more prevalent in cases that expressed both VEGF and PROK1 than in the cases negative for both proteins or those positive for only 1 of the proteins. Also the cases positive for both proteins exhibited the worst recurrence and prognosis. In the Cox proportional hazards model, VEGF and PROK1 expression was an independent prognostic factor. The prognosis was poorer in colorectal cancers that expressed both PROK1 and VEGF relative to the cases that expressed only 1 protein, and the expression of both proteins was found to be an independent prognostic factor.

The effects of anti-VEGF drugs on the retinal pigment epithelium and inner segment after intravitreal injection in the monkeys

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Nan Su

2016-06-01

Full Text Available AIM: To compare the effects on the retina inner segment and retinal pigment epithelium(RPEof intravitreally injecting bevacizumab, ranibizumab and aflibercept into monkey eyes.METHODS: Fourteen healthy cynomolgus monkeys(Macaca fascicularis, aged 3-8y,10 males,4 femaleswere raised at the Covance Laboratories under standard conditions. The 14 monkeys were grouped into 4 groups. Three of the groups with 4 monkeys each were injected intravitreally with one of the drugs, either bevacizumab, ranibizumab or aflibercept, while the 4th group with 2 monkeys served as a negative control. On 1d and 7d of injection, 2 monkeys from each drug treatment group were sacrificed under general anaesthesia and the 4 eyes were enucleated. All the enucleated eyes were fixed in formalin, embedded in paraffin wax, cut into 4.0 μm sections and deparaffinized according to standard procedures. Image-Pro Plus was used for all the photos to measure the content of vascular endothelial growth factor(VEGFin the inner segment and RPE. The ANOVA test from JMP10.0 statistical program was used to evaluate the results.RESULTS: Retinal sections were checked for their anti-VEGF immune reactivity. The untreated control samples had the highest level of VEGF in the RPE and inner segment. All of these three drugs can reduce the level of VEGF in the RPE and inner segment, but Avastin seems to be more effective than Eylea in this regard. Lucentis treatment at 1d seems to be more effective than Eylea at VEGF 1d. But at 7d, both Lucentis and Eylea have the same effect on reducing VEGF expression level in the RPE and inner segment.CONCLUSION: All of these three drugs can reduce the level of VEGF in the RPE and inner segment.

A Systematic Review and Meta-Analysis on the Safety of Vascular Endothelial Growth Factor (VEGF) Inhibitors for the Treatment of Retinopathy of Prematurity

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Pertl, Laura; Steinwender, Gernot; Mayer, Christoph; Hausberger, Silke; Pöschl, Eva-Maria; Wackernagel, Werner; Wedrich, Andreas; El-Shabrawi, Yosuf; Haas, Anton

2015-01-01

Introduction Laser photocoagulation is the current gold standard treatment for proliferative retinopathy of prematurity (ROP). However, it permanently reduces the visual field and might induce myopia. Vascular endothelial growth factor (VEGF) inhibitors for the treatment of ROP may enable continuing vascularization of the retina, potentially allowing the preservation of the visual field. However, for their use in infants concern remains. This meta-analysis explores the safety of VEGF inhibitors. Methods The Ovid Interface was used to perform a systematic review of the literature in the databases PubMed, EMBASE and the Cochrane Library. Results This meta-analysis included 24 original reports (including 1.457 eyes) on VEGF inhibitor treatment for ROP. The trials were solely observational except for one randomized and two case-control studies. We estimated a 6-month risk of retreatment per eye of 2.8%, and a 6-month risk of ocular complication without the need of retreatment of 1.6% per eye. Systemic complications were only reported as isolated incidents. Discussion VEGF inhibitors seem to be associated with low recurrence rates and ocular complication rates. They may have the benefit of potentially allowing the preservation of visual field and lower rates of myopia. Due to the lack of data, the risk of systemic side effects cannot be assessed. PMID:26083024

Xue-fu-Zhu-Yu decoction protects rats against retinal ischemia by downregulation of HIF-1α and VEGF via inhibition of RBP2 and PKM2.

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Tan, Shu-Qiu; Geng, Xue; Liu, Jorn-Hon; Pan, Wynn Hwai-Tzong; Wang, Li-Xiang; Liu, Hui-Kang; Hu, Lei; Chao, Hsiao-Ming

2017-07-14

Retinal ischemia-related eye diseases result in visual dysfunction. This study investigates the protective effects and mechanisms of Xue-Fu-Zhu-Yu decoction (XFZYD) with respect to retinal ischemia. Retinal ischemia (I) was induced in Wistar rats by a high intraocular pressure (HIOP) of 120 mmHg for 1 h, which was followed by reperfusion of the ischemic eye; the fellow untreated eye acted as a control. Electroretinogram (ERG), biochemistry and histopathology investigations were performed. Significant ischemic changes occurred after ischemia including decreased ERG b-wave ratios, less numerous retinal ganglion cells (RGCs), reduced inner retinal thickness, fewer choline acetyltransferase (ChAT) labeled amacrine cell bodies, increased glial fibrillary acidic protein (GFAP) immunoreactivity and increased vimentin Müller immunolabeling. These were accompanied by significant increases in the mRNA/protein concentrations of vascular endothelium growth factor, hypoxia-inducible factor-1α, pyruvate kinase M2 and retinoblastoma-binding protein 2. The ischemic changes were concentration-dependently and significantly altered when XFZYD was given for seven consecutive days before or after retina ischemia, compared to vehicle. These alterations included enhanced ERG b-wave amplitudes, more numerous RGCs, enhanced inner retinal thickness, a greater number of ChAT immunolabeled amacrine cell bodies and decreased GFAP/vimentin immunoreactivity. Furthermore, decreased mRNA levels of VEGF, HIF-1α, PKM2, and RBP2 were also found. Reduced protein concentrations of VEGF, HIF-1α, PKM2, and RBP2 were also demonstrated. Furthermore, there was an inhibition of the ischemia-associated increased ratios (target protein/β-actin) in the protein levels of VEGF, HIF-1α, PKM2, and RBP2, which were induced by Shikonin, JIB-04 or Avastin. XFZYD would seem to protect against well-known retinal ischemic changes via a synergistic inhibition of RBP2 and PKM2, as well as down-regulation of HIF-1�

Clinical significance of the VEGF level in urinary bladder carcinoma.

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Sankhwar, Monica; Sankhwar, Satya Narayan; Abhishek, Amar; Rajender, Singh

2015-01-01

To investigate the correlation of Vascular Endothelial Growth Factor (VEGF) and micro-vessel density (MVD) with urinary bladder tumor and its stage. The study was conducted between January 2010 and December 2012. The study included screening of 122 patients at elevated risk for bladder cancer, of which 35 patients were finally enrolled in the study. Diagnosis was made on the basis of urine cytology, radiological investigation (ultrasound KUB, and CT-scan) and histopathology. Thirty-five normal cancer-free individuals were enrolled as controls. Human VEGF levels were measured using an enzyme linked immunoassay and protein content (pg/mg protein) by Lowry method. SPSS for Windows version 10.0.7 (SPSS, Chicago, IL, USA) was used for statistical analysis of the data. Mean urine VEGF level in the cases was significantly higher in comparison to the control group. There was a direct correlation between VEGF level and tumor stage. Mean urine VEGF values were minimum in the control group (22.75 ± 15.41 pg/mg creatinine) and maximum in stage IV patients (180.15 ± 75.93 pg/mg creatinine). Tissue VEGF levels also showed a similar trend of increase with increase in stage. Urine VEGF level also showed a correlation with tissue VEGF level. Similarly, MVD showed a significant increase with increase in tumor stage. A correlation between bladder cancer and MVD and VEGF suggest that the latter can serve as markers for therapeutic guidance. This is the first study from India on clinical and pathological correlation among urine VEGF, tumor tissue VEGF levels, and Micro Vessel Density (MVD) in urinary bladder cancer patients.

Detection of VEGF-A(xxx)b isoforms in human tissues.

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Bates, David O; Mavrou, Athina; Qiu, Yan; Carter, James G; Hamdollah-Zadeh, Maryam; Barratt, Shaney; Gammons, Melissa V; Millar, Ann B; Salmon, Andrew H J; Oltean, Sebastian; Harper, Steven J

2013-01-01

Vascular Endothelial Growth Factor-A (VEGF-A) can be generated as multiple isoforms by alternative splicing. Two families of isoforms have been described in humans, pro-angiogenic isoforms typified by VEGF-A165a, and anti-angiogenic isoforms typified by VEGF-A165b. The practical determination of expression levels of alternative isoforms of the same gene may be complicated by experimental protocols that favour one isoform over another, and the use of specific positive and negative controls is essential for the interpretation of findings on expression of the isoforms. Here we address some of the difficulties in experimental design when investigating alternative splicing of VEGF isoforms, and discuss the use of appropriate control paradigms. We demonstrate why use of specific control experiments can prevent assumptions that VEGF-A165b is not present, when in fact it is. We reiterate, and confirm previously published experimental design protocols that demonstrate the importance of using positive controls. These include using known target sequences to show that the experimental conditions are suitable for PCR amplification of VEGF-A165b mRNA for both q-PCR and RT-PCR and to ensure that mispriming does not occur. We also provide evidence that demonstrates that detection of VEGF-A165b protein in mice needs to be tightly controlled to prevent detection of mouse IgG by a secondary antibody. We also show that human VEGF165b protein can be immunoprecipitated from cultured human cells and that immunoprecipitating VEGF-A results in protein that is detected by VEGF-A165b antibody. These findings support the conclusion that more information on the biology of VEGF-A165b isoforms is required, and confirm the importance of the experimental design in such investigations, including the use of specific positive and negative controls.

Targeting VEGF in canine oxygen-induced retinopathy - a model for human retinopathy of prematurity.

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McLeod, D Scott; Lutty, Gerard A

2016-01-01

Development of the dog superficial retinal vasculature is similar to the mechanism of human retinal vasculature development; they both develop by vasculogenesis, differentiation, and assembly of vascular precursors called angioblasts. Canine oxygen-induced retinopathy (OIR) was first developed by Arnall Patz in an effort to experimentally determine the effects of hyperoxia on the development of the retinal vasculature. The canine OIR model has many characteristics in common with human retinopathy of prematurity. Exposure of 1-day-old dogs to hyperoxia for 4 days causes a vaso-obliteration throughout the retina. Vasoproliferation, after the animals have returned to room air, is robust. The initial small preretinal neovascular formations anastomose to form large preretinal membranes that eventually cause tractional retinal folds. The end-stage pathology of the canine model is similar to stage IV human retinopathy of prematurity. Therefore, canine OIR is an excellent forum to evaluate the response to drugs targeting VEGF and its receptors. Evaluation of an antibody to VEGF-R2 and the VEGF-Trap demonstrated that doses should be titered down so that preretinal neovascularization is inhibited but retinal revascularization is able to proceed, vascularizing peripheral retina and preventing it from being a source of VEGF.

VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema

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Yoon, Young-sup; Murayama, Toshinori; Gravereaux, Edwin; Tkebuchava, Tengiz; Silver, Marcy; Curry, Cynthia; Wecker, Andrea; Kirchmair, Rudolf; Hu, Chun Song; Kearney, Marianne; Ashare, Alan; Jackson, David G.; Kubo, Hajime; Isner, Jeffrey M.; Losordo, Douglas W.

2003-01-01

Although lymphedema is a common clinical condition, treatment for this disabling condition remains limited and largely ineffective. Recently, it has been reported that overexpression of VEGF-C correlates with increased lymphatic vessel growth (lymphangiogenesis). However, the effect of VEGF-C–induced lymphangiogenesis on lymphedema has yet to be demonstrated. Here we investigated the impact of local transfer of naked plasmid DNA encoding human VEGF-C (phVEGF-C) on two animal models of lymphed...

VEGF-C Is a Thyroid Marker of Malignancy Superior to VEGF-A in the Differential Diagnostics of Thyroid Lesions.

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Kosma Woliński

Full Text Available Thyroid nodular goiter is one of the most common medical conditions affecting even over a half of adult population. The risk of malignancy is rather small but noticeable-estimated by numerous studies to be about 3-10%. The definite differentiation between benign and malignant ones is a vital issue in endocrine practice. The aim of the current study was to assess the expression of vascular endothelial growth factor A (VEGF-A and VEGF-C on the mRNA level in FNAB washouts in case of benign and malignant thyroid nodules and to evaluate the diagnostic value of these markers of malignancy.Patients undergoing fine-needle aspiration biopsy (FNAB in our department between January 2013 and May 2014 were included. In case of all patients who gave the written consent, after ultrasonography (US and fine-needle aspiration biopsy (FNAB performed as routine medical procedure the needle was flushed with RNA Later solution, the washouts were frozen in -80 Celsius degrees. Expression of VEGF-A and VEGF-C and GADPH (reference gene was assessed in washouts on the mRNA level using the real-time PCR technique. Probes of patients who underwent subsequent thyroidectomy and were diagnosed with differentiated thyroid cancer (DTC; proved by post-surgical histopathology were analyzed. Similar number of patients with benign cytology were randomly selected to be a control group.Thirty one DTCs and 28 benign thyroid lesions were analyzed. Expression of VEGF-A was insignificantly higher in patients with DTCs (p = 0.13. Expression of VEGF-C was significantly higher in patients with DTC. The relative expression of VEGF-C (in comparison with GAPDH was 0.0049 for DTCs and 0.00070 for benign lesions, medians - 0.0036 and 0.000024 respectively (p<0.0001.Measurement of expression VEGF-C on the mRNA level in washouts from FNAB is more useful than more commonly investigated VEGF-A. Measurement of VEGF-C in FNAB washouts do not allow for fully reliable differentiation of benign and

Genetics of VEGF serum variation in human isolated populations of cilento: importance of VEGF polymorphisms.

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Daniela Ruggiero

Full Text Available Vascular Endothelial Growth Factor (VEGF is the main player in angiogenesis. Because of its crucial role in this process, the study of the genetic factors controlling VEGF variability may be of particular interest for many angiogenesis-associated diseases. Although some polymorphisms in the VEGF gene have been associated with a susceptibility to several disorders, no genome-wide search on VEGF serum levels has been reported so far. We carried out a genome-wide linkage analysis in three isolated populations and we detected a strong linkage between VEGF serum levels and the 6p21.1 VEGF region in all samples. A new locus on chromosome 3p26.3 significantly linked to VEGF serum levels was also detected in a combined population sample. A sequencing of the gene followed by an association study identified three common single nucleotide polymorphisms (SNPs influencing VEGF serum levels in one population (Campora, two already reported in the literature (rs3025039, rs25648 and one new signal (rs3025020. A fourth SNP (rs41282644 was found to affect VEGF serum levels in another population (Cardile. All the identified SNPs contribute to the related population linkages (35% of the linkage explained in Campora and 15% in Cardile. Interestingly, none of the SNPs influencing VEGF serum levels in one population was found to be associated in the two other populations. These results allow us to exclude the hypothesis that the common variants located in the exons, intron-exon junctions, promoter and regulative regions of the VEGF gene may have a causal effect on the VEGF variation. The data support the alternative hypothesis of a multiple rare variant model, possibly consisting in distinct variants in different populations, influencing VEGF serum levels.

VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema

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Yoon, Young-sup; Murayama, Toshinori; Gravereaux, Edwin; Tkebuchava, Tengiz; Silver, Marcy; Curry, Cynthia; Wecker, Andrea; Kirchmair, Rudolf; Hu, Chun Song; Kearney, Marianne; Ashare, Alan; Jackson, David G.; Kubo, Hajime; Isner, Jeffrey M.; Losordo, Douglas W.

2003-01-01

Although lymphedema is a common clinical condition, treatment for this disabling condition remains limited and largely ineffective. Recently, it has been reported that overexpression of VEGF-C correlates with increased lymphatic vessel growth (lymphangiogenesis). However, the effect of VEGF-C–induced lymphangiogenesis on lymphedema has yet to be demonstrated. Here we investigated the impact of local transfer of naked plasmid DNA encoding human VEGF-C (phVEGF-C) on two animal models of lymphedema: one in the rabbit ear and the other in the mouse tail. In a rabbit model, following local phVEGF-C gene transfer, VEGFR-3 expression was significantly increased. This gene transfer led to a decrease in thickness and volume of lymphedema, improvement of lymphatic function demonstrated by serial lymphoscintigraphy, and finally, attenuation of the fibrofatty changes of the skin, the final consequences of lymphedema. The favorable effect of phVEGF-C on lymphedema was reconfirmed in a mouse tail model. Immunohistochemical analysis using lymphatic-specific markers: VEGFR-3, lymphatic endothelial hyaluronan receptor-1, together with the proliferation marker Ki-67 Ab revealed that phVEGF-C transfection potently induced new lymphatic vessel growth. This study, we believe for the first time, documents that gene transfer of phVEGF-C resolves lymphedema through direct augmentation of lymphangiogenesis. This novel therapeutic strategy may merit clinical investigation in patients with lymphedema. PMID:12618526

Clinicopathological and prognostic significance of HER-2/neu and VEGF expression in colon carcinomas

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Li Jing

2011-06-01

Full Text Available Abstract Background HER-2/neu and VEGF expression is correlated with disease behaviors in various cancers. However, evidence for their expression in colon cancer is rather contradictory both for the protein expression status and prognostic value. HER-2/neu is found to participate in VEGF regulation, and has known correlation with VEGF expression in some tumors. In this study, we investigated HER-2/neu and VEGF expression in Chinese colon patients and explored whether there was any correlation between their expression patterns. Methods HER-2/neu and VEGF were investigated immunohistochemically using tumor samples obtained from 317 colon cancer patients with all tumor stages. Correlation of the degree of staining with clinicopathological parameters and survival was investigated. Results Positive expression rates of HER-2/neu and VEGF in colon cancer were 15.5% and 55.5% respectively. HER-2/neu expression was significantly correlated with tumor size and distant metastases (P (P > 0.05. Expression of VEGF was significantly correlated with tumor size, tumor stage, lymph node metastases, and distant metastases (P (P = 0.146. No correlation between HER-2/neu and VEGF expression was detected (P = 0.151. Conclusions HER-2/neu and VEGF are not important prognostic markers of colon cancer. The present results do not support any association between HER2/neu and VEGF expression in this setting.

AKT increases VEGF expression in tumor cells by transactivating the proximal VEGF promoter

International Nuclear Information System (INIS)

Pore, N.; Bernhard, E.J.; Shu, H.-K.; Li, B.; O'Rourke, D.M.; Maity, A.; Haas-Kogan, D.

2003-01-01

Vascular endothelial growth factor (VEGF) is overexpressed in many cancers including glioblastomas and may contribute to their growth. Epidermal growth factor receptor (EGFR) amplification and loss of PTEN, commonly found in glioblastomas leading to increase phosphatidylinositol-3-kinase (PI3K) activity and VEGF expression. In the current study we show that AKT, which is downstream of PI3K, regulates VEGF expression. U87MG human glioblastoma cells lack wildtype PTEN and express high levels of phosphorylated AKT. Over expression of AKT either by stable expression in immortalized human astrocytes or by transduction with adenovirus containing activated myristoylated AKT in SF188 glioblastoma cells increases VEGF expression. Moreover the elevation of angiogenesis by constitutively expressed AKT is further confirmed by in vivo matrigel plug assay in nude mice. The upregulation of VEGF by AKT is mediated through a region in the proximal promoter located between -88 and -70 (+1 is transcription start site). In transient transfection activity of a luciferase reporter containing the -88/+54 region of the VEGF promoter is increased by cotransfection with myristoylated AKT and downregulated by a dominant negative AKT expression vector. Mutation of the putative Sp1 binding sites located in the -88/-70 region we show that AKT acts through Sp1 to transactivate the VEGF promoter. Cotransfection of the VEGF promoter reporter with both Sp1 and myristoylated AKT expression vectors increases promoter activity to a greater extent than either Sp1 or Akt by itself. In vivo phosphate labeling of proteins reveals that AKT leads to increased Sp1 phosphorylation. Gel shift assays using a radio labeled probe corresponding to nucleotides -88 through -66 in the promoter show increased binding with nuclear extracts from cells transduced with adenovirus expressing myristoylated AKT. In conclusion, our results suggest that loss of PTEN leads to increased VEGF expression by increasing AKT

Interaction between VEGF and Calcium-Independent Phospholipase A(2) in Proliferation and Migration of Retinal Pigment Epithelium

DEFF Research Database (Denmark)

Toft-Kehler, Anne Katrine; Andersen, Emelie Cammilla; Andreasen, Jens Rovelt

2012-01-01

Purpose: Inhibition of VEGF in the eye is an important treatment modality for reducing proliferation and migration of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD). Additionally, previous studies suggest calcium-independent phospholipase A2 group VIA (iPLA2-VIA) to be...

Theoretical investigation of aberrations upon ametropic human eyes

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Tan, Bo; Chen, Ying-Ling; Lewis, J. W. L.; Baker, Kevin

2003-11-01

The human eye aberrations are important for visual acuity and ophthalmic diagnostics and surgical procedures. Reported monochromatic aberration data of the normal 20/20 human eyes are scarce. There exist even fewer reports of the relation between ametropic conditions and aberrations. We theoretically investigate the monochromatic and chromatic aberrations of human eyes for refractive errors of -10 to +10 diopters. Schematic human eye models are employed using optical design software for axial, index, and refractive types of ametropia.

VEGF Signaling in Neurological Disorders

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Joon W. Shim

2018-01-01

Full Text Available Vascular endothelial growth factor (VEGF is a potent growth factor playing diverse roles in vasculogenesis and angiogenesis. In the brain, VEGF mediates angiogenesis, neural migration and neuroprotection. As a permeability factor, excessive VEGF disrupts intracellular barriers, increases leakage of the choroid plexus endothelia, evokes edema, and activates the inflammatory pathway. Recently, we discovered that a heparin binding epidermal growth factor like growth factor (HB-EGF—a class of EGF receptor (EGFR family ligands—contributes to the development of hydrocephalus with subarachnoid hemorrhage through activation of VEGF signaling. The objective of this review is to entail a recent update on causes of death due to neurological disorders involving cerebrovascular and age-related neurological conditions and to understand the mechanism by which angiogenesis-dependent pathological events can be treated with VEGF antagonisms. The Global Burden of Disease study indicates that cancer and cardiovascular disease including ischemic and hemorrhagic stroke are two leading causes of death worldwide. The literature suggests that VEGF signaling in ischemic brains highlights the importance of concentration, timing, and alternate route of modulating VEGF signaling pathway. Molecular targets distinguishing two distinct pathways of VEGF signaling may provide novel therapies for the treatment of neurological disorders and for maintaining lower mortality due to these conditions.

Age, sex, and type of medication predict the effect of anti-VEGF treatment on central retinal thickness in wet age-related macular degeneration

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Bek T

2018-03-01

Full Text Available Toke Bek, Sidsel Ehlers Klug Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark Purpose: Randomized clinical trials studying the effects of VEGF inhibition on wet age-related macular degeneration (wAMD are designed so that the effects of individually varying risk factors on the treatment response are eliminated. The influence of these risk factors can be studied in large data sets from real-life experience.Patients and methods: All 2,255 patients diagnosed with wAMD requiring anti-VEGF treatment in at least one eye over more than 9 years in a defined Danish population with 0.9 million inhabitants were studied. The predictive value of eye laterality, sex, current smoking status, type of anti-VEGF compound, membrane position, membrane type, leakage area, number of injections, number of visits, age, time to follow-up, visual acuity, and central retinal thickness (CRT at baseline on change in CRT after three monthly injections with anti-VEGF compound followed by treatment pro re nata for up to 12 months was assessed.Results: After 12 months, 67 patients had died, 903 had had stable CRT for at least 6 months, and 1,285 patients had not achieved stable CRT. The reduction in CRT was -84.8±118.3 µm, whereas the increase in visual acuity was 2.2±14.7 Early Treatment Diabetic Retinopathy Study letters. The risk factors included contributed to 64% of the variation in CRT reduction. High age and high CRT at baseline predicted high CRT reduction, whereas more injections, treatment with ranibizumab, and male sex predicted a low CRT reduction.Conclusion: Age, sex, and type of anti-VEGF medication can be used to plan treatment and inform patients about the expected response of anti-VEGF treatment in wAMD. Keywords: wet AMD, anti-VEGF treatment, risk factors, real-life experience 

Endogenous Vascular Endothelial Growth Factor-A (VEGF-A) Maintains Endothelial Cell Homeostasis by Regulating VEGF Receptor-2 Transcription*

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E, Guangqi; Cao, Ying; Bhattacharya, Santanu; Dutta, Shamit; Wang, Enfeng; Mukhopadhyay, Debabrata

2012-01-01

Vascular endothelial growth factor A (VEGF-A) is one of the most important factors controlling angiogenesis. Although the functions of exogenous VEGF-A have been widely studied, the roles of endogenous VEGF-A remain unclear. Here we focused on the mechanistic functions of endogenous VEGF-A in endothelial cells. We found that it is complexed with VEGF receptor 2 (VEGFR-2) and maintains a basal expression level for VEGFR-2 and its downstream signaling activation. Endogenous VEGF-A also controls expression of key endothelial specific genes including VEGFR-2, Tie-2, and vascular endothelial cadherin. Of importance, endogenous VEGF-A differs from exogenous VEGF-A by regulating VEGFR-2 transcription through mediation of FoxC2 binding to the FOX:ETS motif, and the complex formed by endogenous VEGF-A with VEGFR-2 is localized within the EEA1 (early endosome antigen 1) endosomal compartment. Taken together, our results emphasize the importance of endogenous VEGF-A in endothelial cells by regulating key vascular proteins and maintaining the endothelial homeostasis. PMID:22167188

One year results of anti-VEGF treatment in pigment epithelial detachment secondary to macular degeneration

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Harun Yüksel

2013-08-01

Full Text Available PURPOSE:Pigment epithelial detachment (PED may be seen in all stages of age-related macular degeneration (ARMD and may lead to poor prognosis. In this study, we retrospectively examined the effect of anti-VEGF treatments in ARMD patients with vascularized PED. METHODS:Medical records of 15 patients with PED secondary to ARMD were reviewed retrospectively. The diagnosis of PED was made with fundoscopy, fundus fluorescein angiography and optical coherence tomography. Patients were treated with intravitreal ranibizumab or/and bevacizumab and followed up for a minimum of one year. PED height and best corrected visual acuity (BCVA was obtained before the first intravitreal anti-VEGF injection and again at the 1st, 3rd, 6th and 12th month after the injection. RESULTS: The mean baseline BCVA was 0.71 ± 0.48 logarithm of the minimal angle of resolution (logMAR unit and the mean baseline PED height was 361 ± 153 µ. The mean injection count per eye was 3.9 ± 2.9. There was a significant reduce in mean PED height (247 ± 177 µ also in 2 eyes PED completely resolved at the end of the follow up period. The mean BCVA at 12th month (0,69 ± 0,37 were not different from the baseline record. CONCLUSIONS: This retrospective case series showed that intravitreal anti-VEGF therapy preserved vision and reduced PED height in PED patients in a one-year follow-up period.

Construction of special eye models for investigation of chromatic and higher-order aberrations of eyes.

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Zhai, Yi; Wang, Yan; Wang, Zhaoqi; Liu, Yongji; Zhang, Lin; He, Yuanqing; Chang, Shengjiang

2014-01-01

An achromatic element eliminating only longitudinal chromatic aberration (LCA) while maintaining transverse chromatic aberration (TCA) is established for the eye model, which involves the angle formed by the visual and optical axis. To investigate the impacts of higher-order aberrations on vision, the actual data of higher-order aberrations of human eyes with three typical levels are introduced into the eye model along visual axis. Moreover, three kinds of individual eye models are established to investigate the impacts of higher-order aberrations, chromatic aberration (LCA+TCA), LCA and TCA on vision under the photopic condition, respectively. Results show that for most human eyes, the impact of chromatic aberration on vision is much stronger than that of higher-order aberrations, and the impact of LCA in chromatic aberration dominates. The impact of TCA is approximately equal to that of normal level higher-order aberrations and it can be ignored when LCA exists.

Refractive errors in premature infants with retinopathy of prematurity after anti-vascular endothelial growth factor (anti-VEGF therapy

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Vujanović Milena S.

2017-01-01

Full Text Available Background/Aim. Retinopathy of prematurity (ROP is a vasoproliferative retinopathy which affects the blood vessels of the retina during its development. The aim of this study was to evaluate the incidence and the degree of refractive errors in premature infants with severe ROP treated with antivascular endothelial growth factor (anti-VEGF (bevacizumab. Methods. This prospective study included 21 patients (42 eyes nine months old who received intravitreal injection of anti-VEGF therapy. The control group consisted of 45 patients (90 eyes who were subjected to laser treatment. In cycloplegia each patient underwent retinoscopy, keratorefractometry, and A-scan ultrasonography. Results. Myopia was present in 47.62% of the eyes in the study group and in 33.33% of the eyes in the control group, but there were no statistically significant differences between these groups. Seven (16.67% eyes in the study group and 17 (18.89% eyes in the control group were discovered to have high myopia (SE– spherical equivalents < -3.0 D – dioptre. Clinically significant hypermetropia was higher in the study group (47.62% than in the control group (34.44%, but with no statistically significant difference. In addition, high hypermetropia was significantly greater in the control group (15.56% than in the study group (11.90% (p < 0.001. Astigmatism was more common in the control group than in the study group (81.11% vs 71.43%, respectively, especially high astigmatism (56% vs 43%, respectively. Also the more common form of astigmatism was with the rule (WTR both in the study and the control group (42.86% vs 55.56%, respectively. Anisometropia was significantly greater in the control group (24.44% than in the study group (9.52% (p < 0.05. The children from the study group had significantly greater lens thickness, and a shorter anterior chamber depth than children from the control group (p < 0.01. There was no significant difference in the axial length of the eye between

Novel VEGF decoy receptor fusion protein conbercept targeting multiple VEGF isoforms provide remarkable anti-angiogenesis effect in vivo.

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Qin Wang

Full Text Available VEGF family factors are known to be the principal stimulators of abnormal angiogenesis, which play a fundamental role in tumor and various ocular diseases. Inhibition of VEGF is widely applied in antiangiogenic therapy. Conbercept is a novel decoy receptor protein constructed by fusing VEGF receptor 1 and VEGF receptor 2 extracellular domains with the Fc region of human immunoglobulin. In this study, we systematically evaluated the binding affinity of conbercept with VEGF isoforms and PlGF by using anti-VEGF antibody (Avastin as reference. BIACORE and ELISA assay results indicated that conbercept could bind different VEGF-A isoforms with higher affinity than reference. Furthermore, conbercept could also bind VEGF-B and PlGF, whereas Avastin showed no binding. Oxygen-induced retinopathy model showed that conbercept could inhibit the formation of neovasularizations. In tumor-bearing nude mice, conbercept could also suppress tumor growth very effectively in vivo. Overall, our study have demonstrated that conbercept could bind with high affinity to multiple VEGF isoforms and consequently provide remarkable anti-angiogenic effect, suggesting the possibility to treat angiogenesis-related diseases such as cancer and wet AMD etc.

Vascular endothelial growth factors and angiogenesis in eye disease

NARCIS (Netherlands)

Witmer, A. N.; Vrensen, G. F. J. M.; van Noorden, C. J. F.; Schlingemann, R. O.

2003-01-01

The vascular endothelial growth factor (VEGF) family of growth factors controls pathological angiogenesis and increased vascular permeability in important eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). The purpose of this review is to develop new insights

Long-term results of repeated anti-vascular endothelial growth factor therapy in eyes with retinal pigment epithelial tears.

Science.gov (United States)

Moreira, Carlos A; Arana, Luis A; Zago, Rommel J

2013-02-01

To evaluate the long-term results of retinal pigment epithelium tears in eyes treated with repeated anti-vascular endothelial growth factor (VEGF) therapy. Five patients with retinal pigment epithelial tears (without foveal center involvement) after anti-VEGF injection were studied retrospectively. Mean follow-up time was 52 months, with measurements of visual acuity and evaluation of macular findings by angiography and optical coherence tomography during this period. All eyes had a persistent submacular neovascular membrane 30 days after the tear. An anti-VEGF drug was reinjected until the membranes stopped leaking. The mean initial visual acuity immediately after the tear was 20/160, and the mean final visual acuity was 20/60. The number of anti-VEGF reinjections varied from two to eight during the follow-up period. Long-term optical coherence tomography analysis showed reduced fluid and remodeling of the torn retinal pigment epithelium. Long-term visual results with repeated anti-VEGF therapy are not as devastating as suggested previously. Visual acuity and metamorphopsia improve with time as long as the neovascular membrane is inactive. Optical coherence tomography changes in the macular area reflect the visual acuity improvement.

VEGF Correlates with Inflammation and Fibrosis in Tuberculous Pleural Effusion

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Bien, Mauo-Ying; Wu, Ming-Ping; Chen, Wei-Lin; Chung, Chi-Li

2015-01-01

Objective. To investigate the relationship among angiogenic cytokines, inflammatory markers, and fibrinolytic activity in tuberculous pleural effusion (TBPE) and their clinical importance. Methods. Forty-two patients diagnosed with TBPE were studied. Based on chest ultrasonography, there were 26 loculated and 16 nonloculated TBPE patients. The effusion size radiological scores and effusion vascular endothelial growth factor (VEGF), interleukin- (IL-) 8, plasminogen activator inhibitor type-1 (PAI-1), and tissue type plasminogen activator (tPA) were measured. Treatment outcome and pleural fibrosis, defined as radiological residual pleural thickening (RPT), were assessed at 6-month follow-up. Results. The effusion size and effusion lactate dehydrogenase (LDH), VEGF, IL-8, PAI-1, and PAI-1/tPA ratio were significantly higher, while effusion glucose, pH value, and tPA were significantly lower, in loculated than in nonloculated TBPE. VEGF and IL-8 correlated positively with LDH and PAI-1/tPA ratio and negatively with tPA in both loculated and nonloculated TBPE. Patients with higher VEGF or greater effusion size were prone to develop RPT (n = 14; VEGF, odds ratio 1.28, P = 0.01; effusion size, odds ratio 1.01, P = 0.02), and VEGF was an independent predictor of RPT in TBPE (receiver operating characteristic curve AUC = 0.985, P Effusion VEGF correlates with pleural inflammation and fibrosis and may be targeted for adjunct therapy for TBPE. PMID:25884029

VEGF correlates with inflammation and fibrosis in tuberculous pleural effusion.

Science.gov (United States)

Bien, Mauo-Ying; Wu, Ming-Ping; Chen, Wei-Lin; Chung, Chi-Li

2015-01-01

To investigate the relationship among angiogenic cytokines, inflammatory markers, and fibrinolytic activity in tuberculous pleural effusion (TBPE) and their clinical importance. Forty-two patients diagnosed with TBPE were studied. Based on chest ultrasonography, there were 26 loculated and 16 nonloculated TBPE patients. The effusion size radiological scores and effusion vascular endothelial growth factor (VEGF), interleukin- (IL-) 8, plasminogen activator inhibitor type-1 (PAI-1), and tissue type plasminogen activator (tPA) were measured. Treatment outcome and pleural fibrosis, defined as radiological residual pleural thickening (RPT), were assessed at 6-month follow-up. The effusion size and effusion lactate dehydrogenase (LDH), VEGF, IL-8, PAI-1, and PAI-1/tPA ratio were significantly higher, while effusion glucose, pH value, and tPA were significantly lower, in loculated than in nonloculated TBPE. VEGF and IL-8 correlated positively with LDH and PAI-1/tPA ratio and negatively with tPA in both loculated and nonloculated TBPE. Patients with higher VEGF or greater effusion size were prone to develop RPT (n=14; VEGF, odds ratio 1.28, P=0.01; effusion size, odds ratio 1.01, P=0.02), and VEGF was an independent predictor of RPT in TBPE (receiver operating characteristic curve AUC=0.985, PEffusion VEGF correlates with pleural inflammation and fibrosis and may be targeted for adjunct therapy for TBPE.

Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase

Science.gov (United States)

Yum, Soohwan; Jeong, Seongkeun; Kim, Dohoon; Lee, Sunyoung; Kim, Wooseong; Yoo, Jin-Wook; Kwon, Oh Sang; Kim, Dae-Duk; Min, Do Sik; Jung, Yunjin

2017-01-01

The topical application of minoxidil may achieve millimolar concentrations in the skin. We investigated whether millimolar minoxidil could induce vascular endothelial growth factor (VEGF), a possible effector for minoxidil-mediated hair growth, and how it occurred at the molecular level. Cell-based experiments were performed to investigate a molecular mechanism underlying the millimolar minoxidil induction of VEGF. The inhibitory effect of minoxidil on hypoxia-inducible factor (HIF) prolyl hydroxylase-2 (PHD-2) was tested by an in vitro von Hippel–Lindau protein (VHL) binding assay. To examine the angiogenic potential of millimolar minoxidil, a chorioallantoic membrane (CAM) assay was used. In human keratinocytes and dermal papilla cells, millimolar minoxidil increased the secretion of VEGF, which was not attenuated by a specific adenosine receptor antagonist that inhibits the micromolar minoxidil induction of VEGF. Millimolar minoxidil induced hypoxia-inducible factor-1α (HIF-1α), and the induction of VEGF was dependent on HIF-1. Moreover, minoxidil applied to the dorsal area of mice increased HIF-1α and VEGF in the skin. In an in vitro VHL binding assay, minoxidil directly inhibited PHD-2, thus preventing the hydroxylation of cellular HIF-1α and VHL-dependent proteasome degradation and resulting in the stabilization of HIF-1α protein. Minoxidil inhibition of PHD-2 was reversed by ascorbate, a cofactor of PHD-2, and the minoxidil induction of cellular HIF-1α was abrogated by the cofactor. Millimolar minoxidil promoted angiogenesis in the CAM assay, an in vivo angiogenic test, and this was nullified by the specific inhibition of VEGF. Our data demonstrate that PHD may be the molecular target for millimolar minoxidil-mediated VEGF induction via HIF-1. PMID:29295567

Targeting VEGF in canine oxygen-induced retinopathy - a model for human retinopathy of prematurity

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McLeod DS

2016-05-01

Full Text Available D Scott McLeod, Gerard A Lutty Department of Ophthalmology, Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, MD, USA Abstract: Development of the dog superficial retinal vasculature is similar to the mechanism of human retinal vasculature development; they both develop by vasculogenesis, differentiation, and assembly of vascular precursors called angioblasts. Canine oxygen-induced retinopathy (OIR was first developed by Arnall Patz in an effort to experimentally determine the effects of hyperoxia on the development of the retinal vasculature. The canine OIR model has many characteristics in common with human retinopathy of prematurity. Exposure of 1-day-old dogs to hyperoxia for 4 days causes a vaso-obliteration throughout the retina. Vasoproliferation, after the animals have returned to room air, is robust. The initial small preretinal neovascular formations anastomose to form large preretinal membranes that eventually cause tractional retinal folds. The end-stage pathology of the canine model is similar to stage IV human retinopathy of prematurity. Therefore, canine OIR is an excellent forum to evaluate the response to drugs targeting VEGF and its receptors. Evaluation of an antibody to VEGF-R2 and the VEGF-Trap demonstrated that doses should be titered down so that preretinal neovascularization is inhibited but retinal revascularization is able to proceed, vascularizing peripheral retina and preventing it from being a source of VEGF. Keywords: angioblasts, blood vessels, endothelial cells, oxygen, retinopathy, retina, vascular endothelial cell growth factor

Anti-VEGF therapy in the management of retinopathy of prematurity: what we learn from representative animal models of oxygen-induced retinopathy

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Wang H

2016-05-01

Full Text Available Haibo Wang Department of Ophthalmology, John A Moran Eye Center, The University of Utah, Salt Lake City, UT, USA Abstract: Retinopathy of prematurity (ROP remains a leading cause of childhood blindness, affecting infants born prematurely. ROP is characterized by the onset of delayed physiological retinal vascular development (PRVD and followed by pathologic neovascularization into the vitreous instead of the retina, called intravitreal neovascularization (IVNV. Therefore, the therapeutic strategy for treating ROP is to promote PRVD and inhibit or prevent IVNV. Vascular endothelial growth factor (VEGF plays an important role in the pathogenesis of ROP. There is a growing body of studies testing the use of anti-VEGF agents as a treatment for ROP. Intravitreal anti-VEGF treatment for ROP has potential advantages compared with laser photocoagulation, the gold standard for the treatment of severe ROP; however, intravitreal anti-VEGF treatment has been associated with reactivation of ROP and suppression of systemic VEGF that may affect body growth and organ development in preterm infants. Therefore, it is important to understand the role of VEGF in PRVD and IVNV. This review includes the current knowledge of anti-VEGF treatment for ROP from animal models of oxygen-induced retinopathy (OIR, highlighting the importance of VEGF inhibition by targeting retinal Müller cells, which inhibits IVNV and permits PRVD. The signaling events involved in mediating VEGF expression and promoting VEGF-mediated angiogenesis, including hypoxia-dependent signaling, erythropoietin/erythropoietin receptor-, oxidative stress-, beta-adrenergic receptor-, integrin-, Notch/Delta-like ligand 4- and exon guidance molecules-mediated signaling pathways, are also discussed. Keywords: vascular endothelial growth factor, retinopathy of prematurity, intravitreal neovascularization, oxygen-induced retinopathy model, physiological retinal vascular development

Soluble vascular endothelial growth factor (VEGF) receptor-1 inhibits migration of human monocytic THP-1 cells in response to VEGF.

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Zhu, Cansheng; Xiong, Zhaojun; Chen, Xiaohong; Lu, Zhengqi; Zhou, Guoyu; Wang, Dunjing; Bao, Jian; Hu, Xueqiang

2011-08-01

We aimed to investigate the regulation and contribution of vascular endothelial growth factor (VEGF) and sFlt-1(1-3) to human monocytic THP-1 migration. Ad-sFlt-1/FLAG, a recombinant adenovirus carrying the human sFlt-1(1-3) (the first three extracellular domains of FLT-1, the hVEGF receptor-1) gene, was constructed. L929 cells were infected with Ad-sFlt-1/FLAG and the expression of sFlt-1 was detected by immunofluorescent assay and ELISA. Corning(®) Transwell(®) Filter Inserts containing polyethylene terephthalate (PET) membranes with pore sizes of 3 μm were used as an experimental model to simulate THP-1 migration. Five VEGF concentrations (0, 0.1, 1, 10 and 100 ng/ml), four concentrations of sFlt-1(1-3)/FLAG expression supernatants (0.1, 1, 10 and 100 ng/ml), and monocyte chemoattractant protein-1 (MCP-1, 10 ng/ml) were used to test the ability of THP-1 cells to migrate through PET membranes. The sFlt-1(1-3) gene was successfully recombined into Ad-sFlt-1/FLAG. sFlt-1(1-3) was expressed in L929 cells transfected with Ad-sFlt-1/FLAG. THP-1 cell migration increased with increasing concentrations of VEGF, while cell migration decreased with increasing concentrations of sFlt1(1-3)/FLAG. sFlt1(1-3)/FLAG had no effect on MCP-1-induced cell migration. This study demonstrated that VEGF is able to elicit a migratory response in THP-1 cells, and that sFlt-1(1-3) is an effective inhibitor of THP-1 migration towards VEGF.

Ovarian hyperstimulation syndrome is correlated with a reduction of soluble VEGF receptor protein level and a higher amount of VEGF-A.

Science.gov (United States)

Pietrowski, D; Szabo, L; Sator, M; Just, A; Egarter, C

2012-01-01

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threatening condition associated with increased vascular permeability. The vascular endothelial growth factor (VEGF) system and its receptors have been identified as the main angiogenic factors responsible for increased capillary permeability and are therefore discussed as crucial for the occurrence of OHSS. Recently, a number of soluble receptors for the VEGFs have been detected (sVEGF-Rs) and it has been shown that these sVEGF-Rs compete with the membrane-standing VEGF-R to bind VEGFs. We analyzed the serum levels of soluble VEGF-R1, -R2 and -R3 in 34 patients suffering from OHSS and in 34 controls without this disease. In a subgroup analysis, we correlated the severity of the OHSS with the detected amounts of VEGF-R1, -R2 and -R3. In addition, we determined the amount of total VEGF-A in the samples. All the three soluble VEGF receptors tended to be higher in the control group compared with that in the OHSS group but this difference only reached significance for sVEGF-R2 (mean ± SEM: 15.5 ± 0.6 versus 13.8 ± 0.5 ng/ml, respectively, P< 0.05). In the subgroup analysis, sVEGF-R2 levels decreased as the severity of OHSS increased (OHSS-I: 16.8 ± 1.9 ng/ml and OHSS-III: 12.7 ± 1.0 ng/ml, P< 0.05) Moreover, the serum levels of total VEGF-A were higher in the OHSS group than those in the controls (537.7 ± 38.9 versus 351 ± 53.4 pg/ml, respectively P< 0.05). We propose that VEGF-A plays a role in the occurrence of OHSS, that the amount of biologically available VEGF-A is modulated by sVEGF-Rs and that different combinations of VEGF-A and sVEGF-R levels might contribute to the severity of OHSS.

Contraction induced secretion of VEGF from skeletal muscle cells is mediated by adenosine

DEFF Research Database (Denmark)

Høier, Birgitte; Olsen, Karina; Nyberg, Michael Permin

2010-01-01

and that the contraction induced secretion of VEGF is partially mediated via adenosine acting on A(2B) adenosine receptors. Moreover, the contraction induced secretion of VEGF protein from muscle is dependent on both PKA and MAPK activation, but only the MAPK pathway appears to be adenosine dependent.......The role of adenosine and contraction for secretion of VEGF in skeletal muscle was investigated in human subjects and rat primary skeletal muscle cells. Microdialysis probes were inserted into the thigh muscle of seven male subjects and dialysate was collected at rest, during infusion of adenosine...... and contraction caused secretion of VEGF (pcontraction induced secretion of VEGF protein was abolished by the A(2B) antagonist enprofyllin and markedly reduced by inhibition of PKA or MAPK. The results demonstrate that adenosine causes secretion of VEGF from human skeletal muscle cells...

Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells

International Nuclear Information System (INIS)

Yamagishi, Naoko; Teshima-Kondo, Shigetada; Masuda, Kiyoshi; Nishida, Kensei; Kuwano, Yuki; Dang, Duyen T; Dang, Long H; Nikawa, Takeshi; Rokutan, Kazuhito

2013-01-01

Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells. To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system. Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function(s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines. Our findings suggest that chronic inhibition of tumor cell-derived VEGF

VEGF Correlates with Inflammation and Fibrosis in Tuberculous Pleural Effusion

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Mauo-Ying Bien

2015-01-01

Full Text Available Objective. To investigate the relationship among angiogenic cytokines, inflammatory markers, and fibrinolytic activity in tuberculous pleural effusion (TBPE and their clinical importance. Methods. Forty-two patients diagnosed with TBPE were studied. Based on chest ultrasonography, there were 26 loculated and 16 nonloculated TBPE patients. The effusion size radiological scores and effusion vascular endothelial growth factor (VEGF, interleukin- (IL- 8, plasminogen activator inhibitor type-1 (PAI-1, and tissue type plasminogen activator (tPA were measured. Treatment outcome and pleural fibrosis, defined as radiological residual pleural thickening (RPT, were assessed at 6-month follow-up. Results. The effusion size and effusion lactate dehydrogenase (LDH, VEGF, IL-8, PAI-1, and PAI-1/tPA ratio were significantly higher, while effusion glucose, pH value, and tPA were significantly lower, in loculated than in nonloculated TBPE. VEGF and IL-8 correlated positively with LDH and PAI-1/tPA ratio and negatively with tPA in both loculated and nonloculated TBPE. Patients with higher VEGF or greater effusion size were prone to develop RPT (n=14; VEGF, odds ratio 1.28, P=0.01; effusion size, odds ratio 1.01, P=0.02, and VEGF was an independent predictor of RPT in TBPE (receiver operating characteristic curve AUC=0.985, P<0.001. Conclusions. Effusion VEGF correlates with pleural inflammation and fibrosis and may be targeted for adjunct therapy for TBPE.

Subthreshold micropulse laser reduces anti-VEGF injection burden in patients with diabetic macular edema.

Science.gov (United States)

Moisseiev, Elad; Abbassi, Sam; Thinda, Sumeer; Yoon, Joseph; Yiu, Glenn; Morse, Lawrence S

2018-01-01

To evaluate the efficacy of micropulse laser in the early treatment of diabetic macular edema (DME) and its associated burden of anti-vascular endothelial growth factor (VEGF) injections. This retrospective comparative study compared a group of 19 eyes with DME treated with micropulse laser to a matched control group of 19 eyes with DME treated with ranibizumab injections without micropulse laser. Recorded parameters included previous medical and ocular history, previous and subsequent ranibizumab injections administered for DME, visual acuity (VA), central macular thickness throughout the follow-up period, and the occurrence of any complications. The improvement in VA was comparable in both groups, at 12 months and at the final follow-up. Patients treated with micropulse laser required significantly fewer ranibizumab injections than their controls, both at 12 months (1.7 ± 2.3 vs 5.6 ± 2.1) and by the end of the follow-up (2.6 ± 3.3 vs 9.3 ± 5.1) (plaser were encountered. Micropulse laser is a safe and effective treatment for DME, which may achieve comparable improvement in VA along with a significant reduction in the burden of anti-VEGF injections. We suggest a treatment approach for its inclusion in the early stages of DME.

Regulation of human feto-placental endothelial barrier integrity by vascular endothelial growth factors: competitive interplay between VEGF-A165a, VEGF-A165b, PIGF and VE-cadherin.

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Pang, Vincent; Bates, David O; Leach, Lopa

2017-12-01

The human placenta nourishes and protects the developing foetus whilst influencing maternal physiology for fetal advantage. It expresses several members of the vascular endothelial growth factor (VEGF) family including the pro-angiogenic/pro-permeability VEGF-A 165 a isoform, the anti-angiogenic VEGF-A 165 b, placental growth factor (PIGF) and their receptors, VEGFR1 and VEGFR2. Alterations in the ratio of these factors during gestation and in complicated pregnancies have been reported; however, the impact of this on feto-placental endothelial barrier integrity is unknown. The present study investigated the interplay of these factors on junctional occupancy of VE-cadherin and macromolecular leakage in human endothelial monolayers and the perfused placental microvascular bed. Whilst VEGF-A 165 a (50 ng/ml) increased endothelial monolayer albumin permeability ( P 0.05) or PlGF ( P >0.05) did not. Moreover, VEGF-A 165 b (100 ng/ml; P 0.05) inhibited VEGF-A 165 a-induced permeability when added singly. PlGF abolished the VEGF-A 165 b-induced reduction in VEGF-A 165 a-mediated permeability ( P >0.05); PlGF was found to compete with VEGF-A 165 b for binding to Flt-1 at equimolar affinity. Junctional occupancy of VE-cadherin matched alterations in permeability. In the perfused microvascular bed, VEGF-A 165 b did not induce microvascular leakage but inhibited and reversed VEGF-A 165 a-induced loss of junctional VE-cadherin and tracer leakage. These results indicate that the anti-angiogenic VEGF-A 165 b isoform does not increase permeability in human placental microvessels or HUVEC primary cells and can interrupt VEGF-A 165 a-induced permeability. Moreover, the interplay of these isoforms with PIGF (and s-flt1) suggests that the ratio of these three factors may be important in determining the placental and endothelial barrier in normal and complicated pregnancies. © 2017 The Author(s).

Well-Controlled Cell-Trapping Systems for Investigating Heterogeneous Cell-Cell Interactions.

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Kamiya, Koki; Abe, Yuta; Inoue, Kosuke; Osaki, Toshihisa; Kawano, Ryuji; Miki, Norihisa; Takeuchi, Shoji

2018-03-01

Microfluidic systems have been developed for patterning single cells to study cell-cell interactions. However, patterning multiple types of cells to understand heterogeneous cell-cell interactions remains difficult. Here, it is aimed to develop a cell-trapping device to assemble multiple types of cells in the well-controlled order and morphology. This device mainly comprises a parylene sheet for assembling cells and a microcomb for controlling the cell-trapping area. The cell-trapping area is controlled by moving the parylene sheet on an SU-8 microcomb using tweezers. Gentle downward flow is used as a driving force for the cell-trapping. The assembly of cells on a parylene sheet with round and line-shaped apertures is demonstrated. The cell-cell contacts of the trapped cells are then investigated by direct cell-cell transfer of calcein via connexin nanopores. Finally, using the device with a system for controlling the cell-trapping area, three different types of cells in the well-controlled order are assembled. The correct cell order rate obtained using the device is 27.9%, which is higher than that obtained without the sliding parylene system (0.74%). Furthermore, the occurrence of cell-cell contact between the three cell types assembled is verified. This cell-patterning device will be a useful tool for investigating heterogeneous cell-cell interactions. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase

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Soohwan Yum

2017-12-01

Full Text Available The topical application of minoxidil may achieve millimolar concentrations in the skin. We investigated whether millimolar minoxidil could induce vascular endothelial growth factor (VEGF, a possible effector for minoxidil-mediated hair growth, and how it occurred at the molecular level. Cell-based experiments were performed to investigate a molecular mechanism underlying the millimolar minoxidil induction of VEGF. The inhibitory effect of minoxidil on hypoxia-inducible factor (HIF prolyl hydroxylase-2 (PHD-2 was tested by an in vitro von Hippel–Lindau protein (VHL binding assay. To examine the angiogenic potential of millimolar minoxidil, a chorioallantoic membrane (CAM assay was used. In human keratinocytes and dermal papilla cells, millimolar minoxidil increased the secretion of VEGF, which was not attenuated by a specific adenosine receptor antagonist that inhibits the micromolar minoxidil induction of VEGF. Millimolar minoxidil induced hypoxia-inducible factor-1α (HIF-1α, and the induction of VEGF was dependent on HIF-1. Moreover, minoxidil applied to the dorsal area of mice increased HIF-1α and VEGF in the skin. In an in vitro VHL binding assay, minoxidil directly inhibited PHD-2, thus preventing the hydroxylation of cellular HIF-1α and VHL-dependent proteasome degradation and resulting in the stabilization of HIF-1α protein. Minoxidil inhibition of PHD-2 was reversed by ascorbate, a cofactor of PHD-2, and the minoxidil induction of cellular HIF-1α was abrogated by the cofactor. Millimolar minoxidil promoted angiogenesis in the CAM assay, an in vivo angiogenic test, and this was nullified by the specific inhibition of VEGF. Our data demonstrate that PHD may be the molecular target for millimolar minoxidil-mediated VEGF induction via HIF-1.

Endocrine gland derived-VEGF is down-regulated in human pituitary adenoma.

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Raica, Marius; Coculescu, Mihail; Cimpean, Anca Maria; Ribatti, Domenico

2010-10-01

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic molecule restricted to endocrine glands and, particularly, to steroid-secreting cells. The expression of EG-VEGF and its significance in human adenohypophysis in physiological and pathological conditions is still unknown. In this study, we investigated by immunohistochemistry the expression of EG-VEGF in 2 samples of normal adenohypophysis and 43 bioptic samples of pituitary adenoma. Moreover, the expression of growth hormone (GH), prolactin (PRL), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH) and adrenocorticoprophic hormone (ACTH) were also estimated. The results of this study for the first time demonstrate a down-regulation of EG-VEGF expression in human pituitary adenoma as compared to normal adenohypophysis, suggesting an impaired function of the neoplastic cells in terms of hormone release in the blood stream, as a consequence of impaired tumor angiogenesis in the tumor. On the basis of our data showing a marked decrease in the expression of EG-VEGF in pituitary adenoma, with the exception of LH-secreting adenomas, we suggest that LH might be involved in the induction of EG-VEGF secretion.

The immunohistochemical expression of endocrine gland-derived-VEGF (EG-VEGF) as a prognostic marker in ovarian cancer.

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Bălu, Sevilla; Pirtea, L; Gaje, Puşa; Cîmpean, Anca Maria; Raica, M

2012-01-01

Ovarian cancer-related angiogenesis is a complex process orchestrated by many positive and negative regulators. Many growth factors are involved in the development of the tumor-associated vasculature, and from these, endocrine gland-derived vascular endothelial growth factor (EG-VEGF) seems to play a crucial role. EG-VEGF is the first organ-specific angiogenic factor and its effects are restricted to the endothelial cells of the endocrine glands. Although EG-VEGF was detected in both normal and neoplastic ovaries, its clinical significance remains controversial. In the present study, we analyzed 30 patients with epithelial ovarian cancer, and the immunohistochemical expression of EG-VEGF was compared with the conventional clinico-pathological parameters of prognosis. Neoplastic cells of the ovarian carcinoma expressed EG-VEGF in 73.33% of the cases, as a cytoplasmic granular product of reaction. We found a strong correlation between the expression of EG-VEGF at protein level and tumor stage, grade, and microscopic type. The expression of EG-VEGF was found in patients with stage III and IV, but not in stage II. The majority of serous adenocarcinoma, half of the cases with clear cell carcinoma and two cases with endometrioid carcinoma showed definite expression in tumor cells. No positive reaction was found in the cases with mucinous carcinoma. Our results showed that EG-VEGF expression is an indicator not only of the advanced stage, but also of ovarian cancer progression. Based on these data, we concluded that EG-VEGF expression in tumor cells of the epithelial ovarian cancer is a good marker of unfavorable prognosis and could be an attractive therapeutic target in patients with advanced-stage tumors, refractory conventional chemotherapy.

Study on the correlation between VEGF and peritumoral edema and tumor border in astrocytoma by CT

International Nuclear Information System (INIS)

Ye Yuxiang; Tan Siping; Liu Bo; Liu Guorui; Zhen Zhichao; Fan Miao

2004-01-01

Objective: To study the correlation between VEGF and peritumoral edema and tumor border in human astrocytoma, investigate the significance of its CT features in molecular-biology. Methods: The VEGF was examined by means of SP immunohistochemical technique in 52 cases of astrocytoma proved by pathology. The correlation of tumor VEGF with peritumoral edema, and tumor border was analyzed. Results: The peritumoral edema, tumor border and mass effect of astrocytoma was positively correlated with its VEGF. The VEGF increased with peritumoral edema and mass effect (P<0.01). VEGF were significantly higher in uncertain border group than those the clear border group (P<0.05), which VEGF were 69.2 ± 19.0. Conclusion: The over expression of VEGF obviously effect CT features in astrocytoma, such as peritumoral edema and tumor border

Impact of VEGF and VEGF receptor 1 (FLT1) expression on the prognosis of stage III esophageal cancer patients after radiochemotherapy

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Rades, D. [Dept. of Radiation Oncology, Univ. Medical Center Hamburg-Eppendorf (Germany); Dept. of Radiation Oncology, Univ. Hospital Schleswig-Holstein, Luebeck (Germany); Golke, H. [Dept. of Radiation Oncology, Univ. Medical Center Hamburg-Eppendorf (Germany); Inst. of Pathology, Univ. Medical Center Hamburg-Eppendorf (Germany); Schild, S.E. [Dept. of Radiation Oncology, Mayo Clinic, Scottsdale, AZ (United States); Kilic, E. [Inst. of Pathology, Univ. Medical Center Hamburg-Eppendorf (Germany); Inst. of Pathology, Univ. Hospital Basel-Stadt (Switzerland)

2008-08-15

Background and purpose: high expression of vascular endothelial growth factor (VEGF) is negatively associated with clinical outcome. The prognostic value of VEGF receptor 1 (FLT1) is unclear. This retrospective study investigated the impact of tumor expression of VEGF and FLT1 on outcome in 68 stage III esophageal cancer patients. Material and methods: the impact of tumor VEGF and FLT expression (< 10% vs. > 10%) and five additional potential prognostic factors on overall survival (OS) and locoregional control (LC) was retrospectively evaluated. These factors included T-stage (T3 vs. T4), N-stage (NO vs. N1), treatment (radiochemotherapy plus resection vs. radiochemotherapy alone), erythropoietin (ERYPO {sup registered} 10000, Janssen-Cilag, Neuss, Germany) administration during radiotherapy, and majority of hemoglobin levels during radiotherapy (< 12 vs. {>=} 12 g/dl). Subgroup analyses were performed for patients receiving resection (R0 vs. R1/2 resection). The factors found to be significant on univariate analyses (Kaplan-Meier method, log-rank test) were included in multivariate analyses performed with the Cox proportional hazard model. Results: on univariate analysis, improved OS was associated with T3 stage (p = 0.011), surgery (p = 0.019), and hemoglobin {>=} 12 g/dl (p < 0.001). Improved LC was associated with T3 stage (p = 0.025), hemoglobin {>=} 12 g/dl (p < 0.001), and VEGF negativity (p = 0.045). On multivariate analyses, only hemoglobin maintained significance. In patients having surgery, R0 resection was significantly better than R1/2 resection for OS (p < 0.001) and LC (p < 0.001). Conclusion: preradiotherapy tumor VEGF expression appears negatively correlated with outcomes, whereas FLT1 expression appears to have no significant impact on OS and LC. (orig.)

Impact of VEGF and VEGF receptor 1 (FLT1) expression on the prognosis of stage III esophageal cancer patients after radiochemotherapy

International Nuclear Information System (INIS)

Rades, D.; Golke, H.; Schild, S.E.; Kilic, E.

2008-01-01

Background and purpose: high expression of vascular endothelial growth factor (VEGF) is negatively associated with clinical outcome. The prognostic value of VEGF receptor 1 (FLT1) is unclear. This retrospective study investigated the impact of tumor expression of VEGF and FLT1 on outcome in 68 stage III esophageal cancer patients. Material and methods: the impact of tumor VEGF and FLT expression ( 10%) and five additional potential prognostic factors on overall survival (OS) and locoregional control (LC) was retrospectively evaluated. These factors included T-stage (T3 vs. T4), N-stage (NO vs. N1), treatment (radiochemotherapy plus resection vs. radiochemotherapy alone), erythropoietin (ERYPO registered 10000, Janssen-Cilag, Neuss, Germany) administration during radiotherapy, and majority of hemoglobin levels during radiotherapy (< 12 vs. ≥ 12 g/dl). Subgroup analyses were performed for patients receiving resection (R0 vs. R1/2 resection). The factors found to be significant on univariate analyses (Kaplan-Meier method, log-rank test) were included in multivariate analyses performed with the Cox proportional hazard model. Results: on univariate analysis, improved OS was associated with T3 stage (p = 0.011), surgery (p = 0.019), and hemoglobin ≥ 12 g/dl (p < 0.001). Improved LC was associated with T3 stage (p = 0.025), hemoglobin ≥ 12 g/dl (p < 0.001), and VEGF negativity (p = 0.045). On multivariate analyses, only hemoglobin maintained significance. In patients having surgery, R0 resection was significantly better than R1/2 resection for OS (p < 0.001) and LC (p < 0.001). Conclusion: preradiotherapy tumor VEGF expression appears negatively correlated with outcomes, whereas FLT1 expression appears to have no significant impact on OS and LC. (orig.)

Targeting the VEGF pathway: antiangiogenic strategies in the treatment of non-small cell lung cancer.

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Aita, Marianna; Fasola, Gianpiero; Defferrari, Carlotta; Brianti, Annalisa; Bello, Maria Giovanna Dal; Follador, Alessandro; Sinaccio, Graziella; Pronzato, Paolo; Grossi, Francesco

2008-12-01

The management of advanced non-small cell lung cancer (NSCLC) has evolved considerably in recent years, due to a progressive understanding of tumour biology and the identification of promising molecular targets. Several agents have been developed so far inhibiting vascular endothelial growth factor (VEGF) - a key protein in tumour neoangiogenesis, growth and dissemination - or its receptor signalling system. The finding in study E4599 of a survival benefit for carboplatin-paclitaxel plus bevacizumab - a humanised anti-VEGF monoclonal antibody - over chemotherapy (CT) alone led the U.S. Food and Drug Administration (FDA) to approve the novel combination for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. In a randomised phase III trial presented at the American Society of Clinical Oncology (ASCO) 2007 Annual Meeting, patients receiving cisplatin-gemcitabine plus bevacizumab experienced a significantly longer progression-free survival (PFS) compared to the standard arm. Based on these data, the European Medicines Agency (EMEA) has granted marketing authorisation for bevacizumab in addition to any platinum-based CT for first-line treatment of advanced NSCLC other than predominantly squamous histology. Aim of this report is to provide an overview on bevacizumab in NSCLC, with special emphasis on clinical results presented at ASCO last meeting. Multitargeted tyrosine kinase inhibitors (TKIs), sharing a focus on both the angiogenesis process and additional cell-surface receptors, and VEGF Trap, a novel fusion protein with markedly higher affinity for VEGF than bevacizumab, will be briefly discussed as well.

Comparison of efficacy between anti-vascular endothelial growth factor (VEGF) and laser treatment in Type-1 and threshold retinopathy of prematurity (ROP).

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Li, Zijing; Zhang, Yichi; Liao, Yunru; Zeng, Rui; Zeng, Peng; Lan, Yuqing

2018-01-30

Retinopathy of Prematurity (ROP) is one of the most common causes of childhood blindness worldwide. Comparisons of anti-VEGF and laser treatments in ROP are relatively lacking, and the data are scattered and limited. The objective of this meta-analysis is to compare the efficacy of both treatments in type-1 and threshold ROP. A comprehensive literature search on ROP treatment was conducted using PubMed and Embase up to March 2017 in all languages. Major evaluation indexes were extracted from the included studies by two authors. The fixed-effects and random-effects models were used to measure the pooled estimates. The test of heterogeneity was performed using the Q statistic. Ten studies were included in this meta-analysis. Retreatment incidence was significantly increased for anti-VEGF (OR 2.52; 95% CI 1.37 to 4.66; P = 0.003) compared to the laser treatment, while the incidences of eye complications (OR 0.29; 95% CI 0.10 to 0.82; P = 0.02) and myopia were significantly decreased with anti-VEGF compared to the laser treatment. However, there was no difference in the recurrence incidence (OR 1.86; 95% CI 0.37 to 9.40; P = 0.45) and time between treatment and retreatment (WMD 7.54 weeks; 95% CI 2.00 to 17.08; P = 0.12). This meta-analysis indicates that laser treatment may be more efficacious than anti-VEGF treatment. However, the results of this meta-analysis also suggest that laser treatment may cause more eye complications and increase myopia. Large-scale prospective RCTs should be performed to assess the efficacy and safety of anti-VEGF versus laser treatment in the future.

Human Adipose-Derived Stem Cells Delay Retinal Degeneration in Royal College of Surgeons Rats Through Anti-Apoptotic and VEGF-Mediated Neuroprotective Effects.

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Li, Z; Wang, J; Gao, F; Zhang, J; Tian, H; Shi, X; Lian, C; Sun, Y; Li, W; Xu, J-Y; Li, P; Zhang, J; Gao, Z; Xu, J; Wang, F; Lu, L; Xu, G-T

2016-01-01

Stem cell therapy is a promising therapeutic approach for retinal degeneration (RD). Our study investigated the effects of human adipose derived stem cell (hADSCs) on Royal College of Surgeons (RCS) rats. Green fluorescent protein (GFP)-labeled hADSCs were transplanted subretinally into RCS rats at postnatal (PN) 21 days to explore potential therapeutic effects, while adeno-associated viral vector (AAV2)-vascular endothelial growth factor (VEGF) and siVEGF-hADSCs were used to aid the mechanistic dissections. Visual function was evaluated by Electroretinogram (ERG) recording. Potential transdifferentiations were examined by Immunofluorescence (IF) and gene expressions were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Apoptotic retinal cells were detected by Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) assay and the cytokines secreted by hADSCs were measured by Enzyme-linked Immunosorbent Assay (ELISA). The visual function of RCS rats began to decrease one week after their eyes opened at PN week 3 and almost lost in PN 5 weeks, accompanied by the loss of retinal outer nuclear layer (ONL). Subretinal transplantation of hADSCs significantly improved the visual function 2 weeks after the transplantation and such therapeutic effect persisted up to 8 weeks after the treatment (PN 11 weeks), with 3-4 rows of photoreceptors remained in the ONL and reduced apoptosis. Consistent with these phenotypic changes, the gene expression of rod photoreceptor markers Rhodopsin (Rho), Crx and Opsin (Opn1) in RCS rats showed obvious decreasing trends over time after PN 3 weeks, but were elevated with hADSC treatment. hADSC transplantation also repressed the expressions of Bax, Bak and Caspase 3, but not the expression of anti-apoptotic genes, including Bcl-2 and Bcl-XL. Finally, substantial VEGF, hepatocyte growth factor (HGF) and pigment epithelium-derived factor (PEDF) secretions from hADSCs were detected, while endogenous

DNA methylation regulates expression of VEGF-C, and S-adenosylmethionine is effective for VEGF-C methylation and for inhibiting cancer growth

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Da, M.X. [Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou (China); Zhang, Y.B. [Department of Surgery, Ningxia Medical University, Yinchuan (China); Yao, J.B. [Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou (China); Duan, Y.X. [Department of Surgery, Ningxia Medical University, Yinchuan (China)

2014-09-30

DNA hypomethylation may activate oncogene transcription, thus promoting carcinogenesis and tumor development. S-adenosylmethionine (SAM) is a methyl donor in numerous methylation reactions and acts as an inhibitor of intracellular demethylase activity, which results in hypermethylation of DNA. The main objectives of this study were to determine whether DNA hypomethylation correlated with vascular endothelial growth factor-C (VEGF-C) expression, and the effect of SAM on VEGF-C methylation and gastric cancer growth inhibition. VEGF-C expression was assayed by Western blotting and RT-qPCR in gastric cancer cells, and by immunohistochemistry in tumor xenografts. VEGF-C methylation was assayed by bisulfite DNA sequencing. The effect of SAM on cell apoptosis was assayed by flow cytometry analyses and its effect on cancer growth was assessed in nude mice. The VEGF-C promoters of MGC-803, BGC-823, and SGC-7901 gastric cancer cells, which normally express VEGF-C, were nearly unmethylated. After SAM treatment, the VEGF-C promoters in these cells were highly methylated and VEGF-C expression was downregulated. SAM also significantly inhibited tumor growth in vitro and in vivo. DNA methylation regulates expression of VEGF-C. SAM can effectively induce VEGF-C methylation, reduce the expression of VEGF-C, and inhibit tumor growth. SAM has potential as a drug therapy to silence oncogenes and block the progression of gastric cancer.

Treatment of Corneal Neovascularization Using Anti-VEGF Bevacizumab

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Deli Krizova

2014-01-01

Full Text Available Purpose. To evaluate antiangiogenic effect of local use of bevacizumab (anti-VEGF antibody in patients with corneal neovascularization. Methods. Patients were divided into two groups. All patients suffered from some form of corneal neovascularization (NV. Patients in group A received 0.2–0.5 mL of bevacizumab solution subconjunctivally (concentration 25 mg/mL in a single dose. Group A included 28 eyes from 27. Patients in group B applied bevacizumab eye drops twice daily (concentration 2.5 mg/mL for two weeks. Group B included 38 eyes from 35 patients. We evaluated the number of corneal segments affected by NV, CDVA, and the incidence of complications and subjective complaints related to the treatment. The minimum follow-up period was six months. Results. By the 6-month follow-up, in group A the percentage reduction of the affected peripheral segments was 21.6% and of the central segments was 9.6%; in group B the percentage reduction of the central segments was 22.7% and of the central segments was 38.04%. In both groups we noticed a statistically significant reduction in the extent of NV. Conclusion. The use of bevacizumab seems to be an effective and safe method in the treatment of corneal neovascularization, either in the subconjunctival or topical application form.

VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis

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Zhang, Fan; Tang, Zhongshu; Hou, Xu; Lennartsson, Johan; Li, Yang; Koch, Alexander W.; Scotney, Pierre; Lee, Chunsik; Arjunan, Pachiappan; Dong, Lijin; Kumar, Anil; Rissanen, Tuomas T.; Wang, Bin; Nagai, Nobuo; Fons, Pierre; Fariss, Robert; Zhang, Yongqing; Wawrousek, Eric; Tansey, Ginger; Raber, James; Fong, Guo-Hua; Ding, Hao; Greenberg, David A.; Becker, Kevin G.; Herbert, Jean-Marc; Nash, Andrew; Yla-Herttuala, Seppo; Cao, Yihai; Watts, Ryan J.; Li, Xuri

2009-01-01

VEGF-B, a homolog of VEGF discovered a long time ago, has not been considered an important target in antiangiogenic therapy. Instead, it has received little attention from the field. In this study, using different animal models and multiple types of vascular cells, we revealed that although VEGF-B is dispensable for blood vessel growth, it is critical for their survival. Importantly, the survival effect of VEGF-B is not only on vascular endothelial cells, but also on pericytes, smooth muscle cells, and vascular stem/progenitor cells. In vivo, VEGF-B targeting inhibited both choroidal and retinal neovascularization. Mechanistically, we found that the vascular survival effect of VEGF-B is achieved by regulating the expression of many vascular prosurvival genes via both NP-1 and VEGFR-1. Our work thus indicates that the function of VEGF-B in the vascular system is to act as a “survival,” rather than an “angiogenic” factor and that VEGF-B inhibition may offer new therapeutic opportunities to treat neovascular diseases. PMID:19369214

Interplay between VEGF and Nrf2 regulates angiogenesis due to intracranial venous hypertension.

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Li, Liwen; Pan, Hao; Wang, Handong; Li, Xiang; Bu, Xiaomin; Wang, Qiang; Gao, Yongyue; Wen, Guodao; Zhou, Yali; Cong, Zixiang; Yang, Youqing; Tang, Chao; Liu, Zhengwei

2016-11-21

Venous hypertension(VH) plays an important role in the pathogenesis of cerebral arteriovenous malformations (AVMs) and is closely associated with the HIF-1α/VEGF signaling pathway. Nuclear factor erythroid 2-related factor 2(Nrf2) significantly influences angiogenesis; however, the interplay between Nrf2 and VEGF under VH in brain AVMs remains unclear. Therefore, our study aimed to investigate the interplay between Nrf2 and VEGF due to VH in brain AVMs. Immunohistochemistry indicated that Nrf2 and VEGF were highly expressed in human brain AVM tissues. In vivo, we established a VH model in both wild-type (WT) and siRNA-mediated Nrf2 knockdown rats. VH significantly increased the expression of Nrf2 and VEGF. Loss of Nrf2 markedly inhibited the upregulation of VEGF, as determined by Western blot analysis and qRT-PCR. In vitro, primary brain microvascular endothelial cells (BMECs) were isolated from WT and Nrf2 -/- mice, and a VEGF-Nrf2 positive feed-back loop was observed in BMECs. By trans well assay and angiogenesis assay, Nrf2 knockout significantly inhibited the migration and vascular tube formation of BMECs. These findings suggest that the interplay between Nrf2 and VEGF can contribute to VH-induced angiogenesis in brain AVMs pathogenesis.

Anemia and elevated systemic levels of vascular endothelial growth factor (VEGF)

International Nuclear Information System (INIS)

Dunst, J.; Becker, A.; Lautenschlaeger, C.; Markau, S.; Becker, H.; Fischer, K.; Haensgen, G.

2002-01-01

Background: Tissue hypoxia is a major stimulus for the up-regulation of vascular endothelial growth factor (VEGF). Anemia might theoretically impact on angiogenesis via impairment of tissue oxygenation. We have investigated this hypothesis in patients with solid cancers and benign diseases. Patients and methods: 49 patients with untreated locoregionally confined solid cancers of the head and neck, cervix, rectum and lung and 59 additional patients with non-malignant diseases (36 normemic patients without serious diseases and 23 patients with renal anemia) were enrolled and the impact of anemia on plasma VEGF levels were determined. VEGF was measured with a commercially available sandwich enzyme immunoassay technique. Results: Plasma levels of VEGF were 16.2±12.7 pg/ml in 36 normemic patients without malignant disease, 49,2±34.5 pg/ml in 49 patients with cancers (p [de

A Possible Role of Acrolein in Diabetic Retinopathy: Involvement of a VEGF/TGFβ Signaling Pathway of the Retinal Pigment Epithelium in Hyperglycemia

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Grigsby, Jeffery; Betts, Brandi; Vidro-Kotchan, Eileen; Culbert, Richard; Tsin, Andrew

2015-01-01

Purpose Acrolein has been implicated in retinal pigment epithelium (RPE) cell death, and has been associated with diabetic retinopathy. Our purpose was to investigate the potential effect of high glucose in influencing acrolein-mediated RPE cytokine production and cell death. We investigated the influence of the acrolein effect on ARPE-19 cells in high glucose conditions and quantified the release of transforming growth factor β (TGFβ1 and 2) and vascular endothelial growth factor (VEGF). We assessed the ability of N-benzylhydroxylamine(NBHA) as well as TGFβ pathway inhibitors SIS3 and SB431542 to prevent this effect of acrolein on ARPE-19 cells. Materials and methods Confluent ARPE-19 cells were treated with acrolein and/or NBHA in both 5.5 and 18.8 mM glucose conditions. Cells were also pretreated with SIS3, a specific inhibitor of the SMAD3 pathway, and SB431542, a specific inhibitor of TGFβ signaling pathway, before treating them with acrolein. Viable cells were counted and ELISAs were performed to measure the cytokines TGFβ1 and 2, and VEGF released into the conditioned media. Results In ARPE-19 cells exposed to acrolein and hyperglycemia there was reduced cell viability and an increase in the cell media of VEGF, TGFβ1, and TGFβ2, which was reversed by NBHA. Acrolein/hyperglycemia-induced cell viability reduction and cytokine overproduction was also reduced by TGFβ pathway blockade. Conclusions We conclude that the effect of acrolein on the reduction of viability and VEGF increase by ARPE-19 cells in hyperglycemic media is conducted through the TGFβ signaling pathway. Our results suggest that benefits of sequestering acrolein by NBHA and the blockage of the TGFβ pathway by SB431542 and SIS3 offer suggestions as to potential useful pharmacological drug candidates for the prevention of diabetes-induced complications in the eye. PMID:22906079

A possible role of acrolein in diabetic retinopathy: involvement of a VEGF/TGFβ signaling pathway of the retinal pigment epithelium in hyperglycemia.

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Grigsby, Jeffery; Betts, Brandi; Vidro-Kotchan, Eileen; Culbert, Richard; Tsin, Andrew

2012-11-01

Acrolein has been implicated in retinal pigment epithelium (RPE) cell death, and has been associated with diabetic retinopathy. Our purpose was to investigate the potential effect of high glucose in influencing acrolein-mediated RPE cytokine production and cell death. We investigated the influence of the acrolein effect on ARPE-19 cells in high glucose conditions and quantified the release of transforming growth factor β (TGFβ1 and 2) and vascular endothelial growth factor (VEGF). We assessed the ability of N-benzylhydroxylamine(NBHA) as well as TGFβ pathway inhibitors SIS3 and SB431542 to prevent this effect of acrolein on ARPE-19 cells. Confluent ARPE-19 cells were treated with acrolein and/or NBHA in both 5.5 and 18.8 mM glucose conditions. Cells were also pretreated with SIS3, a specific inhibitor of the SMAD3 pathway, and SB431542, a specific inhibitor of TGFβ signaling pathway, before treating them with acrolein. Viable cells were counted and ELISAs were performed to measure the cytokines TGFβ1 and 2, and VEGF released into the conditioned media. In ARPE-19 cells exposed to acrolein and hyperglycemia there was reduced cell viability and an increase in the cell media of VEGF, TGFβ1, and TGFβ2, which was reversed by NBHA. Acrolein/hyperglycemia-induced cell viability reduction and cytokine overproduction was also reduced by TGFβ pathway blockade. We conclude that the effect of acrolein on the reduction of viability and VEGF increase by ARPE-19 cells in hyperglycemic media is conducted through the TGFβ signaling pathway. Our results suggest that benefits of sequestering acrolein by NBHA and the blockage of the TGFβ pathway by SB431542 and SIS3 offer suggestions as to potential useful pharmacological drug candidates for the prevention of diabetes-induced complications in the eye.

Tumour cells expressing single VEGF isoforms display distinct growth, survival and migration characteristics.

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Chryso Kanthou

Full Text Available Vascular endothelial growth factor-A (VEGF is produced by most cancer cells as multiple isoforms, which display distinct biological activities. VEGF plays an undisputed role in tumour growth, vascularisation and metastasis; nevertheless the functions of individual isoforms in these processes remain poorly understood. We investigated the effects of three main murine isoforms (VEGF188, 164 and 120 on tumour cell behaviour, using a panel of fibrosarcoma cells we developed that express them individually under endogenous promoter control. Fibrosarcomas expressing only VEGF188 (fs188 or wild type controls (fswt were typically mesenchymal, formed ruffles and displayed strong matrix-binding activity. VEGF164- and VEGF120-producing cells (fs164 and fs120 respectively were less typically mesenchymal, lacked ruffles but formed abundant cell-cell contacts. On 3D collagen, fs188 cells remained mesenchymal while fs164 and fs120 cells adopted rounded/amoeboid and a mix of rounded and elongated morphologies respectively. Consistent with their mesenchymal characteristics, fs188 cells migrated significantly faster than fs164 or fs120 cells on 2D surfaces while contractility inhibitors accelerated fs164 and fs120 cell migration. VEGF164/VEGF120 expression correlated with faster proliferation rates and lower levels of spontaneous apoptosis than VEGF188 expression. Nevertheless, VEGF188 was associated with constitutively active/phosphorylated AKT, ERK1/2 and Stat3 proteins. Differences in proliferation rates and apoptosis could be explained by defective signalling downstream of pAKT to FOXO and GSK3 in fs188 and fswt cells, which also correlated with p27/p21 cyclin-dependent kinase inhibitor over-expression. All cells expressed tyrosine kinase VEGF receptors, but these were not active/activatable suggesting that inherent differences between the cell lines are governed by endogenous VEGF isoform expression through complex interactions that are independent of tyrosine

Increased expression of EMMPRIN and VEGF in the rat brain after gamma irradiation.

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Wei, Ming; Li, Hong; Huang, Huiling; Xu, Desheng; Zhi, Dashi; Liu, Dong; Zhang, Yipei

2012-03-01

The extracellular matrix metalloproteinase inducer (EMMPRIN) has been known to play a key regulatory role in pathological angiogenesis. A elevated activation of vascular endothelial growth factor (VEGF) following radiation injury has been shown to mediate blood-brain barrier (BBB) breakdown. However, the roles of EMMPRIN and VEGF in radiation-induced brain injury after gamma knife surgery (GKS) are not clearly understood. In this study, we investigated EMMPRIN changes in a rat model of radiation injury following GKS and examined potential associations between EMMPRIN and VEGF expression. Adult male rats were subjected to cerebral radiation injury by GKS under anesthesia. We found that EMMPRIN and VEGF expression were markedly upregulated in the target area at 8-12 weeks after GKS compared with the control group by western blot, immunohistochemistry, and RT-PCR analysis. Immunofluorescent double staining demonstrated that EMMPRIN signals colocalized with caspase-3 and VEGF-positive cells. Our data also demonstrated that increased EMMPRIN expression was correlated with increased VEGF levels in a temporal manner. This is the first study to show that EMMPRIN and VEGF may play a role in radiation injuries of the central nervous system after GKS.

AdVEGF-B186 and AdVEGF-DΔNΔC induce angiogenesis and increase perfusion in porcine myocardium.

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Nurro, Jussi; Halonen, Paavo J; Kuivanen, Antti; Tarkia, Miikka; Saraste, Antti; Honkonen, Krista; Lähteenvuo, Johanna; Rissanen, Tuomas T; Knuuti, Juhani; Ylä-Herttuala, Seppo

2016-11-01

Coronary heart disease remains a significant clinical problem, and new therapies are needed especially for patients with refractory angina for whom the current therapies do not provide sufficient relief. The aim of this study was to find out if angiogenic gene therapy using new members of the vascular endothelial growth factor (VEGF) family, VEGF-B 186 and VEGF-D ΔNΔC , increase myocardial perfusion as measured by the positron emission tomography (PET) 15 O-imaging, and whether there would be coronary steal effect to the contralateral side. Furthermore, safety of intramyocardial angiogenic adenoviral gene transfer was evaluated. Intramyocardial adenoviral (Ad) VEGF-B 186 or AdVEGF-D ΔNΔC gene transfers were given endovascularly into the porcine posterolateral wall of the left ventricle (n=34). Six days later, PET 15 O-imaging for myocardial perfusion and coronary angiography were performed. AdVEGF-B 186 and AdVEGF-D ΔNΔC induced angiogenesis and increased total microvascular area 1.8-fold (95% CI 0.2 to 3.5) and 2.8-fold (95% CI 1.4 to 4.3), respectively. At rest, perfusion was maintained at normal levels, but at stress, relative perfusion was increased 1.4-fold (95% CI 1.1 to 1.7) for AdVEGF-B 186 and 1.3-fold (95% CI 1.0 to 1.7) for AdVEGF-D ΔNΔC , without causing coronary steal effect in the control area. The therapy was well tolerated and did not lead to any significant changes in laboratory safety parameters. Both AdVEGF-B 186 and AdVEGF-D ΔNΔC gene transfers induced efficient angiogenesis in the myocardium resulting in an increased myocardial perfusion measured by PET. Importantly, local perfusion increase did not induce any coronary steal effect. As such, both treatments seem suitable new candidates for the induction of therapeutic angiogenesis for the treatment of refractory angina. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Efficiency and safety of subconjunctival injection of anti-VEGF agent - bevacizumab - in treating dry eye.

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Jiang, Xiaodan; Lv, Huibin; Qiu, Weiqiang; Liu, Ziyuan; Li, Xuemin; Wang, Wei

2015-01-01

Dry eye is a chronic inflammatory ocular surface disease with high prevalence. The current therapies for dry eye remain to be unspecific and notcomprehensive. This study aims to explore safety and efficacy of a novel treatment - subconjunctival injection of bevacizumab - in dry eye patients. Sixty-four eyes of 32 dry eye patients received subconjunctival injection of 100 μL 25 mg/mL bevacizumab. Dry eye symptoms, signs (corrected visual acuity, intraocular pressure, conjunctival vascularity, corneal staining, tear break-up time, Marx line score, and blood pressure), and conjunctival impression cytology were evaluated 3 days before and 1 week, 1 month, and 3 months after injection. Significant improvements were observed in dry eye symptoms, tear break-up time, and conjunctival vascularization area at all the visits after injection compared to the baseline (Pdry eye disease.

Prolonged presence of VEGF promotes vascularization in 3D bioprinted scaffolds with defined architecture

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Poldervaart, Michelle T; Gremmels, Hendrik; van Deventer, Kelly; Fledderus, Joost O; Oner, F Cumhur; Verhaar, Marianne C; Dhert, Wouter J A; Alblas, Jacqueline

2014-01-01

Timely vascularization is essential for optimal performance of bone regenerative constructs. Vascularization is efficiently stimulated by vascular endothelial growth factor (VEGF), a substance with a short half-life time. This study investigates the controlled release of VEGF from gelatin

Expression of the angiogenic mediator, angiopoietin-like 4, in the eyes of patients with proliferative sickle retinopathy.

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Kathleen Jee

Full Text Available The recent success of therapies directly targeting the angiogenic mediator, vascular endothelial growth factor (VEGF, for the treatment of proliferative diabetic retinopathy has encouraged clinicians to extend the use of anti-VEGF therapies for the treatment of another ischemic retinal vascular disease, proliferative sickle cell retinopathy (PSR, the most common cause of irreversible blindness in patients with sickle cell disease. However, results from case reports evaluating anti-VEGF therapies for PSR have been mixed. This highlights the need to identify alternative therapeutic targets for the treatment of retinal neovascularization in sickle cell patients. In this regard, angiopoietin-like 4 (ANGPTL4 is a novel angiogenic factor regulated by the transcription factor, hypoxia-inducible factor 1, the master regulator of angiogenic mediators (including VEGF in ischemic retinal disease. In an effort to identify alternative targets for the treatment of sickle cell retinopathy, we have explored the expression of ANGPTL4 in the eyes of patients with PSR. To this end, we examined expression and localization of ANGPTL4 by immunohistochemistry in autopsy eyes from patients with known PSR (n = 5 patients. Complementary studies were performed using enzyme-linked immunosorbent assays in aqueous (n = 8; 7 patients, 2 samples from one eye of same patient and vitreous (n = 3 patients samples from a second group of patients with active PSR. We detected expression of ANGPTL4 in neovascular tissue and in the ischemic inner retina in PSR, but not control, eyes. We further observed elevated expression of ANGPTL4 in the aqueous and vitreous of PSR patients compared to controls. These results suggest that ANGPTL4 could contribute to the development of retinal neovascularization in sickle cell patients and could therefore be a therapeutic target for the treatment of PSR.

Prognostic importance of VEGF-A haplotype combinations in a stage II colon cancer population

DEFF Research Database (Denmark)

Kjaer-Frifeldt, Sanne; Fredslund, Rikke; Lindebjerg, Jan

2012-01-01

To investigate the prognostic effect of three VEGF-A SNPs, -2578, -460 and 405, as well as the corresponding haplotype combinations, in a unique population of stage II colon cancer patients.......To investigate the prognostic effect of three VEGF-A SNPs, -2578, -460 and 405, as well as the corresponding haplotype combinations, in a unique population of stage II colon cancer patients....

Vascular endothelial growth factor ( VEGF ) receptor expression ...

African Journals Online (AJOL)

Avidin-biotin complex method was employed for immunohistochemical detection of VEGF. Results: VEGF immuno-expression was positive in 51.9% of CRC, while it was 18.2% in the normal colonic tissue (p<0.05). VEGF immunostaining was positively correlated with grade of colonic malignancy (p<0.05). Conclusion: ...

Removal of choroidal neovascular membrane in a case of macular hole after anti-VEGF therapy for age-related macular degeneration.

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Hirata, Akira; Hayashi, Ken; Murata, Kazuhisa; Nakamura, Kei-Ichiro

2018-03-01

The formation of macular hole after receiving anti-vascular endothelial growth factor (anti-VEGF) therapy is rare. We report a case of macular hole that occurred after intravitreal injection of an anti-VEGF agent for age-related macular degeneration (AMD) in a patient, who underwent vitrectomy combined with choroidal neovascularization (CNV) removal. A 64-year-old female with AMD affecting her right eye received an intravitreal injection of an anti-VEGF agent. After treatment, we identified a full thickness macular hole (MH) that was associated with the rapid resolution of the macular edema and contraction of the CNV. After performing vitrectomy combined with CNV removal, the MH closed and her visual acuity improved. Examination of the removed CNV revealed a network of microvessels devoid of pericytes. and Importance: The present findings suggest that rapid resolution of macular edema and contraction of the CNV and/or mild increase in the vitreous traction after anti-VEGF therapy could potentially cause MH. CNV removal via the MH may be an acceptable procedure, if the MH remains open, the CNV is of the classic type, and it spares a central portion of the fovea.

VEGF immunoexpression in penile carcinoma

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Antonio Carlos Pereira Martins

2002-01-01

Full Text Available OBJECTIVE: To investigate the vessel endothelial growth factor (VEGF as a risk factor in squamous cell carcinoma of the penis (SCCP. METHODS: Forty-seven patients with penile carcinoma were evaluated retrospectively. The mean age and standard deviation were 61.1±11.7 years. All of them were treated by penectomy and those with positive nodes underwent groin lymphadenectomy. Tumor grading was 35 G1 and 12 G2/3. Primary lesion stage was 24 pT1 and 23 pT2-4. Positive inguinal nodes were observed in 15 patients. Selected paraffin embedded sections were submitted to VEGF immunohistochemical analysis by the avidin-biotin-immunoperoxidase method with antigen retrieval. All slides were examined using an automatic analyzer system and the proportion of labeled cells in 10 high magnification power fields (400X were recorded in a blind analysis. RESULTS: Median (% labeling index was 2.3 in G1 versus 2.2 in G2/3 tumors (p=0.60, and 4.0 in pT1 versus 1.8 pT2-4 tumors (p=0.10. The respective data for pN0 patients was 2.8 and for pN+ was 2.1 (p=0.20. Survival curves showed no association with patients survival. CONCLUSION: In squamous cell carcinoma of the penis the VEGF immunoexpression has no association with tumor grade or stage, as well as with patient survival.

A Case-Control Study on the Oxidative Balance of 50% Autologous Serum Eye Drops

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Patrícia Ioschpe Gus

2016-01-01

Full Text Available Importance. Autologous serum (AS eye drops are recommended for severe dry eye in patients with ocular surface disease. No description of the antioxidant balance of AS eye drops has been reported in the literature. Objective. This study sought to evaluate the total reactive antioxidant potential (TRAP and concentration of reactive oxygen species (ROS in samples of 50% AS eye drops and their correlations with the demographic characteristics and lifestyle habits of patients with ocular surface disease and healthy controls. Design. This was a case-control study with a 3-month follow-up period. Participants. 16 patients with severe dry eye disease of different etiologies and 17 healthy controls matched by age, gender, and race were included. Results. TRAP and ROS were detected at all evaluated times. There were no differences in the mean ROS (p=0.429 or TRAP (p=0.475 levels between cases and controls. No statistically significant differences in the concentrations of ROS or TRAPs were found at 0, 15, or 30 days (p for ROS = 0.087 and p for TRAP = 0.93. Neither the demographic characteristics nor the lifestyle habits were correlated with the oxidative balance of the 50% AS eye drops. Conclusions and Relevance. Both fresh and frozen 50% AS eye drops present antioxidant capacities and ROS in an apparently stable balance. Moreover, patients with ocular surface disease and normal controls produce equivalent AS eye drops in terms of oxidative properties.

Identification of functional VEGF receptors on human platelets.

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Selheim, Frode; Holmsen, Holm; Vassbotn, Flemming S

2002-02-13

Platelets secrete platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) upon stimulation. We have demonstrated that platelets have functionally active PDGF alpha-receptors, a transmembrane tyrosine kinase involved in negative feedback regulation. Here we demonstrate the presence of the related VEGF receptors fms-like tyrosine kinase-1 and kinase-insert domain region on human platelets. VEGF itself did not cause platelet aggregation. However, addition of exogenous VEGF to SFRLLN or thrombin-stimulated platelets potentiated platelet aggregation. Moreover, thrombin-induced phosphoinositide 3-kinase and mitogen-activated protein kinase activity were enhanced in the presence of VEGF.

VEGF-A is increased in exogenous endophthalmitis.

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Seamone, Mark E; Lewis, Darrell R; Haidl, Ian D; Gupta, R Rishi; O' Brien, Daniel M; Dickinson, John; Samad, Arif; Marshall, Jean S; Cruess, Alan F

2017-06-01

Exogenous endophthalmitis is an ophthalmologic emergency defined by panocular inflammation. Vascular endothelial growth factor A (VEGF-A) contributes to inflammation by promoting chemotaxis of monocytes and granulocytes and by increasing vascular permeability. The purpose of this article is to determine if VEGF-A is elevated in the vitreous samples obtained from individuals with exogenous endophthalmitis. Vitreous samples from individuals with exogenous endophthalmitis (n = 18) were analyzed via Luminex assay and enzyme-linked immunosorbent assay for the cytokines VEGF-A, tumor necrosis factor (TNF), interleukin 6 (IL-6), IL-8 (chemokine [CXCL]-8), IL-1β, IL-10, IL-12p70, IL-33, interferon (IFN)-γ, IFN-α, IFN-β, chemokine ligand (CCL)-3, IL-2, IL-5, IL-15, CXCL-10, CCL-2, IL-1Ra, CCL-5, IL-17, and CCL-11. Vitreous samples obtained at the time of macular hole surgery served as controls (n = 8). Concentrations of VEGF-A were significantly elevated in vitreous samples from individuals with exogenous endophthalmitis compared with macular hole (p exogenous endophthalmitis after cataract surgery (p = 0.001), vitrectomy (p = 0.024), and intravitreal injection (p = 0.012). VEGF-A concentrations were similar in both culture-positive and culture-negative populations (p > 0.05). In a linear regression model, levels of VEGF-A correlated significantly with the chemokine CXCL-8 (p = 0.028). We demonstrate that VEGF-A is potently upregulated in exogenous endophthalmitis. This observation provides a foundation for future studies of targeted VEGF-A blockade in the management of endophthalmitis. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Vibration induced hearing loss in guinea pig cochlea: expression of TNF-alpha and VEGF.

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Zou, Jing; Pyykkö, Ilmari; Sutinen, Päivi; Toppila, Esko

2005-04-01

Transcranial vibration was applied for seven animals at a frequency of 250 Hz for 15 min, and five animals were used as normal controls to investigate cellular and molecular mechanism linked to vibration-induced hearing loss in animal model. Compound action potential (CAP) thresholds were measured by round window niche electrode. The expression of tumour necrosis factor alpha (TNF-alpha) and its receptors (TNF R1, TNF R2), vascular endothelium growth factor (VEGF) and its receptors (VEGF R1, VEGF R2) were analysed by immunohistochemistry. Transcranial vibration caused expression of TNF-alpha, TNF R1 and TNF R2 in the cochlea and the expression of TNF R2 was stronger than that of TNF R1. Vibration also induced VEGF and VEGF R2 expression in the cochlea. The average immediate hearing loss was 62 dB and after three days still 48 dB. It is concluded that transcranial vibration as during temporal bone drilling produces cochlear shear stress that is connected with up-regulation of TNF-alpha and its receptors. Also VEGF and VEGF R2 are up-regulated. These responses may be linked to both the damage and repair process of the cochlea.

A model for investigating developmental eye repair in Xenopus laevis.

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Kha, Cindy X; Son, Philip H; Lauper, Julia; Tseng, Kelly Ai-Sun

2018-04-01

Vertebrate eye development is complex and requires early interactions between neuroectoderm and surface ectoderm during embryogenesis. In the African clawed frog, Xenopus laevis, individual eye tissues such as the retina and lens can undergo regeneration. However, it has been reported that removal of either the specified eye field at the neurula stage or the eye during tadpole stage does not induce replacement. Here we describe a model for investigating Xenopus developmental eye repair. We found that tailbud embryos can readily regrow eyes after surgical removal of over 83% of the specified eye and lens tissues. The regrown eye reached a comparable size to the contralateral control by 5 days and overall animal development was normal. It contained the expected complement of eye cell types (including the pigmented epithelium, retina and lens), and is connected to the brain. Our data also demonstrate that apoptosis, an early mechanism that regulates appendage regeneration, is also required for eye regrowth. Treatment with apoptosis inhibitors (M50054 or NS3694) blocked eye regrowth by inhibiting caspase activation. Together, our findings indicate that frog embryos can undergo successful eye repair after considerable tissue loss and reveals a required role for apoptosis in this process. Furthermore, this Xenopus model allows for rapid comparisons of productive eye repair and developmental pathways. It can also facilitate the molecular dissection of signaling mechanisms necessary for initiating repair. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Statins in rhegmatogenous retinal detachment are associated with low intravitreal angiopoietin-2, VEGF and MMP-2 levels, and improved visual acuity gain in vitrectomized patients.

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Tuuminen, Raimo; Haukka, Jari; Loukovaara, Sirpa

2015-10-01

In rhegmatogenous retinal detachment (RRD), intravitreal growth factors and cytokines may compromise post-vitrectomy outcomes. Here, we analysed perioperative intravitreal protein levels of potent vasoactive, pro-inflammatory, and extracellular matrix-remodelling factors in RRD eyes of patients treated with statins and evaluated post-vitrectomy outcome in the same study eyes. Institutional, retrospective, observational study of 14 patients operated on for RRD while on statins compared to patients without statin medication (n = 82). Vitreous samples were subjected to protein measurements of angiopoietin (ANGPT)-1 and -2, transforming growth factor-β1, and vascular endothelial growth factor (VEGF) by ELISA, and of matrix metalloproteinase (MMP)-2 and -9 by gelatin zymography. A 1-month best-corrected visual acuity (BCVA) gain was modelled by Student's T-test and multivariate linear regression with concomitant perioperative medication. Cumulative 12-month revitrectomy frequency was modelled by Kaplan-Meier log-rank test. Intravitreal levels of ANGPT-2 (49.2 ± 33.1 vs. 112.8 ± 134.1 pg/ml, mean ± SD, p < 0.001), VEGF (2.3 ± 2.4 vs. 17.7 ± 57.8 pg/ml, p = 0.021), and MMP-2 (1107.1 ± 884.6 vs 1976.4 ± 970.1 AU/ml, p = 0.005) in RRD eyes of patients treated with statins were lower than in non-statin-treated controls. Patients on statins had better 1-month BCVA improvement than did those not on statins (p = 0.022), with no difference in 1-year re-vitrectomy rates. Intravitreal levels of ANGPT-2, VEGF, factors involved in vascular permeability and inflammation, and activity of MMP-2, the factor connected with breakdown of basement membrane and fibroproliferation, were lower in RRD eyes of patients with statin treatment. At 1-month, postoperative BCVA gain was improved in statin-treated RRD eyes, suggesting that statin administration may be effective in preventing inflammation-related PVR formation.

RELATIONSHIP BETWEEN THE PROANGIOGENIC ROLE OF EG-VEGF, CLINICOPATHOLOGICAL CHARACTERISTICS AND SURVIVAL IN TUMORAL OVARY.

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Lozneanu, Ludmila; Avădănei, Roxana; Cîmpean, Anca Maria; Giuşcă, Simona Eliza; Amălinei, Cornelia; Căruntu, Irina-Draga

2015-01-01

To prove the presence of EG-VEGF in tumor ovary and to analyze its involvement in the ovarian carcinogenesis, as promoter of angiogenesis, in relationship with the clinicopathological prognostic factors and survival. The study group comprises tumor tissue specimens from 50 cases of surgically treated ovarian cancer that were immunohistochemically investigated. A scoring system based on the percentage of positive cells and the intensity of staining was applied for the semiquantitative assessment of EG-VEGF, as negative or positive. Statistics involved χ2 test, and Kaplan-Meier and log-rank test. EG-VEGF was positive in 35 cases (70%) and negative in 15 cases (30%). Our data confirmed the predominance of EG-VEGF positivity in the serous subiype as compared to endometrioid and clear cell subtypes, and its absence in mucinous subtype. Moreover, we demonstrated that EG-VEGF is overexpressed mainly in high-grade ovarian carcinomas (type II) than in low-grade ones. Significant differences were registered between the EG-VEGF positive or negative expression and tumor stage and histological subtypes, respectively. Survival analysis showed no differences in patient's survival and EG-VEGF positive and negative cases. The analysis of EG-VEGF expression in ovarian tumors points out the relationship between the enhanced potential for tumor angiogenesis and the tumor aggressivity.

Intraocular Vascular Endothelial Growth Factor Levels in Pachychoroid Neovasculopathy and Neovascular Age-Related Macular Degeneration.

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Hata, Masayuki; Yamashiro, Kenji; Ooto, Sotaro; Oishi, Akio; Tamura, Hiroshi; Miyata, Manabu; Ueda-Arakawa, Naoko; Takahashi, Ayako; Tsujikawa, Akitaka; Yoshimura, Nagahisa

2017-01-01

To investigate the difference in intraocular vascular endothelial growth factor (VEGF) concentration between pachychoroid neovasculopathy and neovascular age-related macular degeneration (nAMD) and its associations with responses to three monthly anti-VEGF injections as an initial treatment for the two conditions. This study included nine eyes with treatment-naïve pachychoroid neovasculopathy and 21 eyes with treatment-naïve nAMD. Before the initial intravitreal anti-VEGF injection, aqueous humor samples were collected and the concentration of VEGF was measured using enzyme-linked immunosorbent assay. The concentration was compared between the two conditions, and its associations with responses to anti-VEGF therapy were investigated. The mean VEGF concentration in pachychoroid neovasculopathy was significantly lower than that in nAMD (63.4 ± 17.8 pg/ml and 89.8 ± 45.0 pg/ml, respectively; P = 0.035). The VEGF concentration was associated with the presence or absence of drusen (β = 0.503, P = 0.004). After anti-VEGF therapy, 6 (66.7%) of 9 eyes with pachychoroid neovasculopathy and 17 (81.0%) of 21 eyes with nAMD achieved dry macula (P = 0.640). Dry macula at 3 months and 12 months was significantly associated with a low VEGF concentration in pachychoroid neovasculopathy (P = 0.013 and P = 0.042, respectively), but not in nAMD (P = 0.108 and P = 0.219). The mean VEGF concentration in pachychoroid neovasculopathy was lower than that in nAMD, suggesting that the way in which VEGF is involved in angiogenesis may differ between pachychoroid neovasculopathy and nAMD.

VEGF-mediated angiogenesis stimulates neural stem cell proliferation and differentiation in the premature brain

International Nuclear Information System (INIS)

Sun, Jinqiao; Sha, Bin; Zhou, Wenhao; Yang, Yi

2010-01-01

This study investigated the effects of angiogenesis on the proliferation and differentiation of neural stem cells in the premature brain. We observed the changes in neurogenesis that followed the stimulation and inhibition of angiogenesis by altering vascular endothelial growth factor (VEGF) expression in a 3-day-old rat model. VEGF expression was overexpressed by adenovirus transfection and down-regulated by siRNA interference. Using immunofluorescence assays, Western blot analysis, and real-time PCR methods, we observed angiogenesis and the proliferation and differentiation of neural stem cells. Immunofluorescence assays showed that the number of vWF-positive areas peaked at day 7, and they were highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at every time point. The number of neural stem cells, neurons, astrocytes, and oligodendrocytes in the subventricular zone gradually increased over time in the VEGF up-regulation group. Among the three groups, the number of these cells was highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at the same time point. Western blot analysis and real-time PCR confirmed these results. These data suggest that angiogenesis may stimulate the proliferation of neural stem cells and differentiation into neurons, astrocytes, and oligodendrocytes in the premature brain.

Expression and significance of HIF-1α and VEGF in rats with diabetic retinopathy

Institute of Scientific and Technical Information of China (English)

Hong-Tao Yan; Guan-Fang Su

2014-01-01

Objective:To investigate the expression of hypoxia inducible factor-1α(HIF-1α) and vascular endothelial growth factor(VEGF) in diabetic retinopathy(DR) rats and its effect on theDR occurrence and development.Methods:A total of120SD rats were randomly divided into trial group and control group with60 in each.STZi.p. was used in the trial group to establish theDM model, citrate buffer salt of same amount was usedi.p. to the control group.1,3 and6 months after injection, respective20 rats were sacrificed in each group to observe expression ofHIF-1α andVEGF in the rat retina tissue at different time points.Results:Expression ofHIF-1α andVEGF were negative in the control group; expression ofHIF-1α andVEGF protein in retinal tissue were weak after1 month ofDR mold formation.It showed progressive enhancement along with the progression in different organizations, differences between groups were significant (P<0.05).Conclusions:Expressions ofHIF-1α andVEGF were correlated with disease progression in early diabetic retinopathy.Retinal oxygen can induce over-expression ofHIF-1α andVEGF.It shows thatHIF-1α andVEGF play an important role in the pathogenesis ofDR.

Lymphatics and Lymphangiogenesis in the Eye

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Shintaro Nakao

2012-01-01

Full Text Available Lymphatic is a prerequisite for the maintenance of tissue fluid balance and immunity in the body. A body of evidence also shows that lymphangiogenesis plays important roles in the pathogenesis of diseases such as tumor metastasis and inflammation. The eye was thought to lack lymphatic vessels except for the conjunctiva; however, advances in the field, including the identification of lymphatic endothelial markers (e.g., LYVE-1 or podoplanin and lymphangiogenic factors (e.g., VEGF-C, have revealed the exsitence and possible roles of lymphatics and lymphangiogenesis in the eye. Recent studies have shown that corneal limbus, ciliary body, lacrimal gland, orbital meninges, and extraocular muscles contain lymphatic vessels and that the choroid might have a lymphatic-like system. There is no known lymphatic outflow from the eye. However, several lymphatic channels including uveolymphatic pathway might serve the ocular fluid homeostasis. Furthermore, lymphangiogenesis plays important roles in pathological conditions in the eye including corneal transplant rejection and ocular tumor progression. Yet, the role of lymphangiogenesis in most eye diseases, especially inflammatory disease or edema, remains unknown. A better understanding of lymphatic and lymphangiogenesis in the eye will open new therapeutic opportunities to prevent vision loss in ocular diseases.

Differential regulation of ANG2 and VEGF-A in human granulosa lutein cells by choriogonadotropin.

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Pietrowski, D; Keck, C

2004-04-01

The growth and development of the corpus luteum after rupture of the follicle is a highly regulated process characterised by a rapid vascularization of the follicle surrounding granulosa cells. Vascularization is regulated by a large number of growth factors and cytokines whereas members of the angiopoietin family and VEGF-A are reported to play a principal role. The gonadotropic hormones luteinizing hormone and choriogonadotropin are reported to be essential for corpus luteum formation. In this study we investigated by RT PCR if the growth factors PGF, PDGF-A, PDGF-B, VEGF-A, VEGF-B, VEGF-C, VEGF-D, ANG1, ANG2, ANG3 and ANG4 are expressed in granulosa cells. We show the expression of VEGF-A, VEGF-B, PDGF-A, ANG1 and ANG2 in granulosa cells. Using RT-PCR and Real-Time PCR we demonstrate that angiopoietin 2 is downregulated in human granulosa cells in vitro after choriogonadotropin treatment whereas the expression of angiopoietin 1 is not significantly altered. The expression of VEGF on the RNA- and on the protein level was determined. It was shown that in granulosa cells VEGF is upregulated after choriogonadotropin treatment on the RNA level and that increasing concentrations of choriogonadotropin from 0 to 10 U/ml leads to an increasing amount of VEGF in the cell culture supernatants. The amount of VEGF in the supernatants reaches a plateau at 0.5 U/ml and is increased only slightly and not significantly after treatment of the cells with 10 U/ml choriogonadotropin compared to 0.5 U/ml. In total these findings suggests that in granulosa cells the mRNA of various growth factors is detectable by RT-PCR and that VEGF-A and ANG2 is regulated by the gonadotropic hormone choriogonadotropin. These findings may add impact on the hypothesis of choriogonadotropin as a novel angiogenic factor.

Angiogenesis in cancer of unknown primary: clinicopathological study of CD34, VEGF and TSP-1

International Nuclear Information System (INIS)

Karavasilis, Vasilis; Malamou-Mitsi, Vasiliki; Briasoulis, Evangelos; Tsanou, Elena; Kitsou, Evangelia; Kalofonos, Haralambos; Fountzilas, George; Fotsis, Theodore; Pavlidis, Nicholas

2005-01-01

Cancer of unknown primary remains a mallignancy of elusive biology and grim prognosis that lacks effective therapeutic options. We investigated angiogenesis in cancer of unknown primary to expand our knowledge on the biology of these tumors and identify potential therapeutic targets. Paraffin embedded archival material from 81 patients diagnosed with CUP was used. Tumor histology was adenocarcinoma (77%), undifferentiated carcinoma (18%) and squamous cell carcinoma (5%). The tissue expression of CD34, VEGF and TSP-1 was assessed immunohistochemically by use of specific monoclonal antibodies and was analyzed against clinicopathological data. VEGF expression was detected in all cases and was strong in 83%. Stromal expression of TSP-1 was seen in 80% of cases and was strong in 20%. The expression of both proteins was not associated with any clinical or pathological parameters. Tumor MVD was higher in tumors classified as unfavorable compared to more favorable and was positively associated with VEGF and negatively with TSP-1. Angiogenesis is very active and expression of VEGF is almost universal in cancers of unknown primary. These findings support the clinical investigation of VEGF targeted therapy in this clinical setting

The effects of biomimetically conjugated VEGF on osteogenesis and angiogenesis of MSCs (human and rat) and HUVECs co-culture models.

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Lü, Lanxin; Deegan, Anthony; Musa, Faiza; Xu, Tie; Yang, Ying

2018-07-01

The purpose of this work was to investigate if the biomimetically conjugated VEGF and HUVECs co-culture could modulate the osteogenic and angiogenic differentiation of MSCs derived from rat and human bone marrow (rMSCs and hMSCs). After treated by ammonia plasma, Poly(lactic-co-glycolic acid) (PLGA) electrospun nanofibers were immobilized with VEGF through heparin to fulfil the sustained release. The proliferation capacity of rMSCs and hMSCs on neat PLGA nanofibers (NF) and VEGF immobilized NF (NF-VEGF) surfaces were assessed by CCK-8 and compared when MSCs were mono-cultured and co-cultured with HUVECs. The effect of VEGF and HUVECs co-culturing on osteogenic and angiogenic differentiation of rMSCs and hMSCs were investigated by calcium deposits and CD31 expression on NF and NF-VEGF surfaces. The results indicated that VEGF has been biomimetically immobilized onto PLGA nanofibers surface and kept sustained release successfully. The CD31 staining results showed that both VEGF and HUVECs co-culture could enhance the angiogenesis of rMSCs and hMSCs. However, the proliferation and osteogenic differentiation of MSCs when cultured with VEGF and HUVECs showed a species dependent response. Taken together, VEGF immobilization and co-culture with HUVECs promoted angiogenesis of MSCs, indicating a good strategy for vascularization in bone tissue engineering. Copyright © 2018. Published by Elsevier B.V.

Antagonism of EG-VEGF Receptors as Targeted Therapy for Choriocarcinoma Progression In Vitro and In Vivo.

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Traboulsi, Wael; Sergent, Frédéric; Boufettal, Houssine; Brouillet, Sophie; Slim, Rima; Hoffmann, Pascale; Benlahfid, Mohammed; Zhou, Qun Y; Balboni, Gianfranco; Onnis, Valentina; Bolze, Pierre A; Salomon, Aude; Sauthier, Philippe; Mallet, François; Aboussaouira, Touria; Feige, Jean J; Benharouga, Mohamed; Alfaidy, Nadia

2017-11-15

Purpose: Choriocarcinoma (CC) is the most malignant gestational trophoblastic disease that often develops from complete hydatidiform moles (CHM). Neither the mechanism of CC development nor its progression is yet characterized. We recently identified endocrine gland-derived vascular endothelial growth factor (EG-VEGF) as a novel key placental growth factor that controls trophoblast proliferation and invasion. EG-VEGF acts via two receptors, PROKR1 and PROKR2. Here, we demonstrate that EG-VEGF receptors can be targeted for CC therapy. Experimental Design: Three approaches were used: (i) a clinical investigation comparing circulating EG-VEGF in control ( n = 20) and in distinctive CHM ( n = 38) and CC ( n = 9) cohorts, (ii) an in vitro study investigating EG-VEGF effects on the CC cell line JEG3, and (iii) an in vivo study including the development of a novel CC mouse model, through a direct injection of JEG3-luciferase into the placenta of gravid SCID-mice. Results: Both placental and circulating EG-VEGF levels were increased in CHM and CC (×5) patients. EG-VEGF increased JEG3 proliferation, migration, and invasion in two-dimensional (2D) and three-dimensional (3D) culture systems. JEG3 injection in the placenta caused CC development with large metastases compared with their injection into the uterine horn. Treatment of the animal model with EG-VEGF receptor's antagonists significantly reduced tumor development and progression and preserved pregnancy. Antibody-array and immunohistological analyses further deciphered the mechanism of the antagonist's actions. Conclusions: Our work describes a novel preclinical animal model of CC and presents evidence that EG-VEGF receptors can be targeted for CC therapy. This may provide safe and less toxic therapeutic options compared with the currently used multi-agent chemotherapies. Clin Cancer Res; 23(22); 7130-40. ©2017 AACR . ©2017 American Association for Cancer Research.

Revisiting the role of hCG: new regulation of the angiogenic factor EG-VEGF and its receptors.

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Brouillet, S; Hoffmann, P; Chauvet, S; Salomon, A; Chamboredon, S; Sergent, F; Benharouga, M; Feige, J J; Alfaidy, N

2012-05-01

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor reported to be specific for endocrine tissues, including the placenta. Its biological activity is mediated via two G protein-coupled receptors, prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). We have recently shown that (i) EG-VEGF expression peaks between the 8th and 11th weeks of gestation, (ii) its mRNA and protein levels are up-regulated by hypoxia, (iii) EG-VEGF is a negative regulator of trophoblast invasion and (iv) its circulating levels are increased in preeclampsia (PE), the most threatening pathology of pregnancy. Here, we investigated the regulation of the expression of EG-VEGF and its receptors by hCG, a key pregnancy hormone that is also deregulated in PE. During the first trimester of pregnancy, hCG and EG-VEGF exhibit the same pattern of expression, suggesting that EG-VEGF is potentially regulated by hCG. Both placental explants (PEX) and primary cultures of trophoblasts from the first trimester of pregnancy were used to investigate this hypothesis. Our results show that (i) LHCGR, the hCG receptor, is expressed both in cyto- and syncytiotrophoblasts, (ii) hCG increases EG-VEGF, PROKR1 and PROKR2 mRNA and protein expression in a dose- and time-dependent manner, (iii) hCG increases the release of EG-VEGF from PEX conditioned media, (iv) hCG effects are transcriptional and post-transcriptional and (v) the hCG effects are mediated by cAMP via cAMP response elements present in the EG-VEGF promoter region. Altogether, these results demonstrate a new role for hCG in the regulation of EG-VEGF and its receptors, an emerging regulatory system in placental development.

VEGF concentration in aqueous humor and its significance to radiation retinopathy%放射性视网膜病变患者房水中VEGF的浓度及其临床意义

Institute of Scientific and Technical Information of China (English)

刘清云; 李加青; 袁玲; 李涛; 李建桥; 胡旭颋; 唐仕波

2010-01-01

目的 研究放射性视网膜病变(Radiation Retinopathy)患者房水中血管内皮生长因子(Vascular Endothelial Growth Factor.VEGF)的浓度,明确其对发病的意义.方法 选择2007年3月至2009年3月就诊的放射性视网膜病变患者4例8只眼,增殖性糖尿病性视网膜病变(Proliferative Diabetic Retinopathv,PDR)9名患者10只眼,在行玻璃体腔注入Bevcizumab(1.5mg)治疗前分别抽取100μl前房水;年龄相关性白内障患者10例10只眼,在超声乳化白内障吸除术前,分别抽取lOOμl前房水,所有房水样本均用酶联免疫吸附试验(Enzyme-Linked Immunosorbent Assay,ELISA)检测VEGF浓度.用Kruskal-Wallis H检验对三组患者术前房水中VEGF浓度进行分析,用Mann-Whitney U分别比较三组之间的差异,以P<0.05为差异有统计学意义.结果 放射性视网膜病变与PDR患者房水中VEGF浓度无显著性差异,二者均显著高于白内障患者房水中VEGF水平.结论 放射性视网膜病变患者房水中VEGF浓度显著升高,VEGF可能是引起放射性视网膜病变的重要因素.%Objective To investigate VEGF concentration in aqueous humor and its significance to radiation retinopathy. Methods Patients with radiation retinopathy totally 8 eyes of 4 patients and proliferative diabetic retinopathy (PDR) totally 10 eyes of 9 patients from March 2007 to March 2009 came to our hospital were included. Aqueous humor from all these patients was collected before intravitreally injection of Bevacizumab (1.5mg). Ten eyes of 10 age-related cataracts were as controls. Aqueous humor was collected before phacomulcification in cataract patients. VEGF concentrations were detected by enzyme-linked immunosorbent assay (ELISA). VEGF concentrations were compared with Kruskal-Wallis H test among three groups. Mann-Whitney U test was used to compare the differences between two of them. For all statistical tests, P<0.05 was considered significant. Results There was no significant difference between

Bee products prevent VEGF-induced angiogenesis in human umbilical vein endothelial cells

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Mishima Satoshi

2009-11-01

Full Text Available Abstract Background Vascular endothelial growth factor (VEGF is a key regulator of pathogenic angiogenesis in diseases such as cancer and diabetic retinopathy. Bee products [royal jelly (RJ, bee pollen, and Chinese red propolis] from the honeybee, Apis mellifera, have been used as traditional health foods for centuries. The aim of this study was to investigate the anti-angiogenic effects of bee products using human umbilical vein endothelial cells (HUVECs. Methods In an in vitro tube formation assay, HUVECs and fibroblast cells were incubated for 14 days with VEGF and various concentrations of bee products [RJ, ethanol extract of bee pollen, ethanol extract of Chinese red propolis and its constituent, caffeic acid phenethyl ester (CAPE]. To clarify the mechanism of in vitro angiogenesis, HUVEC proliferation and migration were induced by VEGF with or without various concentrations of RJ, bee pollen, Chinese red propolis, and CAPE. Results RJ, bee pollen, Chinese red propolis, and CAPE significantly suppressed VEGF-induced in vitro tube formation in the descending order: CAPE > Chinese red propolis >> bee pollen > RJ. RJ and Chinese red propolis suppressed both VEGF-induced HUVEC proliferation and migration. In contrast, bee pollen and CAPE suppressed only the proliferation. Conclusion Among the bee products, Chinese red propolis and CAPE in particular showed strong suppressive effects against VEGF-induced angiogenesis. These findings indicate that Chinese red propolis and CAPE may have potential as preventive and therapeutic agents against angiogenesis-related human diseases.

VEGF signaling inside vascular endothelial cells and beyond.

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Eichmann, Anne; Simons, Michael

2012-04-01

Vascular endothelial growth factor-A (VEGF-A) has long been recognized as the key regulator of vascular development and function in health and disease. VEGF is a secreted polypeptide that binds to transmembrane tyrosine kinase VEGF receptors on the plasma membrane, inducing their dimerization, activation and assembly of a membrane-proximal signaling complex. Recent studies have revealed that many key events of VEGFR signaling occur inside the endothelial cell and are regulated by endosomal receptor trafficking. Plasma membrane VEGFR interacting molecules, including vascular guidance receptors Neuropilins and Ephrins also regulate VEGFR endocytosis and trafficking. VEGF signaling is increasingly recognized for its roles outside of the vascular system, notably during neural development, and blood vessels regulate epithelial branching morphogenesis. We review here recent advances in our understanding of VEGF signaling and its biological roles. Copyright © 2012 Elsevier Ltd. All rights reserved.

Investigation of two-frequency Paul traps for antihydrogen production

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Leefer, Nathan; Krimmel, Kai, E-mail: kkrimmel@students.uni-mainz.de [Helmholtz-Institut Mainz (Germany); Bertsche, William [University of Manchester (United Kingdom); Budker, Dmitry [Helmholtz-Institut Mainz (Germany); Fajans, Joel [University of California at Berkeley, Department of Physics (United States); Folman, Ron [Ben-Gurion University of the Negev, Department of Physics (Israel); Häffner, Hartmut [University of California at Berkeley, Department of Physics (United States); Schmidt-Kaler, Ferdinand [Helmholtz-Institut Mainz (Germany)

2017-11-15

Radio-frequency (rf) Paul traps operated with multifrequency rf trapping potentials provide the ability to independently confine charged particle species with widely different charge-to-mass ratios. In particular, these traps may find use in the field of antihydrogen recombination, allowing antiproton and positron clouds to be trapped and confined in the same volume without the use of large superconducting magnets. We explore the stability regions of two-frequency Paul traps and perform numerical simulations of small samples of multispecies charged-particle mixtures of up to twelve particles that indicate the promise of these traps for antihydrogen recombination.

Crosstalk between VEGF-A/VEGFR2 and GDNF/RET signaling pathways

International Nuclear Information System (INIS)

Tufro, Alda; Teichman, Jason; Banu, Nazifa; Villegas, Guillermo

2007-01-01

Vascular endothelial growth factor (VEGF-A) plays multiple roles in kidney development: stimulates cell proliferation, survival, tubulogenesis, and branching morphogenesis. However, the mechanism that mediates VEGF-A induced ureteric bud branching is unclear. Glial-derived neurotrophic factor (GDNF) signaling through tyrosine kinase c-RET is the major regulator of ureteric bud branching. Here we examined whether VEGF-A regulates RET signaling. We determined that ureteric bud-derived cells express the main VEGF-A signaling receptor, VEGFR2 and RET, by RT-PCR, immunoblotting, and immunocytochemistry. We show that the VEGF-A isoform VEGF 165 induces RET-tyr 1062 phosphorylation in addition to VEGFR2 autophosphorylation, that VEGF 165 and GDNF have additive effects on RET-tyr 1062 phosphorylation, and that VEGFR2 and RET co-immunoprecipitate. Functionally, VEGF 165 induces ureteric bud cell proliferation and branching morphogenesis. Similarly, in embryonic kidney explants VEGF 165 induces RET-tyr 1062 phosphorylation and upregulates GDNF. These findings provide evidence for a novel cooperative interaction between VEGFR2 and RET that mediates VEGF-A functions in ureteric bud cells

Improvement in autologous human fat transplant survival with SVF plus VEGF-PLA nano-sustained release microspheres.

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Li, Liqun; Pan, Shengsheng; Ni, Binting; Lin, Yuanshao

2014-08-01

Early neovascularization is important for autologous fat transplant survival. SVF cells are ideal seed cells. Both vascular endothelial growth factor (VEGF) and SVF cells can promote neovascularization. However, the half-life (about 50 min) of VEGF is too short to sustain an adequate local concentration. We have investigated whether VEGF-polylactic acid (PLA) nano-sustained release microspheres plus SVF cells can improve neovascularization and survival of transplanted fat tissues. SVF cells were harvested and constructed VEGF-PLA nano-sustained release microspheres in vitro. Human fat tissues was mixed with SVF cells plus VEGF-PLA, SVF cells alone or Dulbecco's modified Eagle's medium as the control. These three mixtures were injected into random sites in 18 nude mice. Two months later, the transplants were weighed and examined histologically; and capillaries were counted to quantify neovascularization. Hematoxylin-eosin (HE) and anti-VEGF stains were applied to reveal cell infiltration. The mean wet weight of fat in the SVF plus VEGF-PLA, SVF alone, and control transplants were 0.18 ± 0.013 g, 0.16 ± 0.015 g, and 0.071 ± 0.12 g, respectively; the differences between groups were statistically significant. More vessels were present in the SVF plus VEGF-PLA transplants than in the other two types. Transplants mixed with SVF cells also had an acceptable density of capillaries. Histological analysis revealed that both the SVF plus VEGF-PLA and SVF alone transplants, but not the control transplants, were composed of adipose tissue, and had less fat necrosis and less fibrosis than control specimens. SVF plus VEGF-PLA transplants had significantly greater capillary density and VEGF expression than the other two transplant groups. Thus transplanted fat tissue survival and quality can be enhanced by the addition of VEGF-PLA nano-sustained release microspheres plus SVF cells. © 2014 International Federation for Cell Biology.

VEGF promotes tumorigenesis and angiogenesis of human glioblastoma stem cells

International Nuclear Information System (INIS)

Oka, Naoki; Soeda, Akio; Inagaki, Akihito; Onodera, Masafumi; Maruyama, Hidekazu; Hara, Akira; Kunisada, Takahiro; Mori, Hideki; Iwama, Toru

2007-01-01

There is increasing evidence for the presence of cancer stem cells (CSCs) in malignant brain tumors, and these CSCs may play a pivotal role in tumor initiation, growth, and recurrence. Vascular endothelial growth factor (VEGF) promotes the proliferation of vascular endothelial cells (VECs) and the neurogenesis of neural stem cells. Using CSCs derived from human glioblastomas and a retrovirus expressing VEGF, we examined the effects of VEGF on the properties of CSCs in vitro and in vivo. Although VEGF did not affect the property of CSCs in vitro, the injection of mouse brains with VEGF-expressing CSCs led to the massive expansion of vascular-rich GBM, tumor-associated hemorrhage, and high morbidity, suggesting that VEGF promoted tumorigenesis via angiogenesis. These results revealed that VEGF induced the proliferation of VEC in the vascular-rich tumor environment, the so-called stem cell niche

Exposure of chick embryos to cadmium changes the extra-embryonic vascular branching pattern and alters expression of VEGF-A and VEGF-R2

Energy Technology Data Exchange (ETDEWEB)

Gheorghescu, Anna Kaskova [School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4 (Ireland); Tywoniuk, Bartlomiej [School of Physics, University College Dublin, Belfield, Dublin 4 (Ireland); Complex and Adaptive Systems Laboratory, University College Dublin, Belfield, Dublin 4 (Ireland); Duess, Johannes [School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4 (Ireland); National Children' s Research Centre, Our Lady' s Children' s Hospital, Crumlin, Dublin 12 (Ireland); Buchete, Nicolae-Viorel, E-mail: buchete@ucd.ie [School of Physics, University College Dublin, Belfield, Dublin 4 (Ireland); Complex and Adaptive Systems Laboratory, University College Dublin, Belfield, Dublin 4 (Ireland); Thompson, Jennifer, E-mail: jennifer.thompson@ucd.ie [School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4 (Ireland)

2015-11-15

Cadmium (Cd) has several industrial applications, and is found in tobacco products, a notable source of human exposure. Vascular endothelial cells are key targets of Cd toxicity. Here, we aim to quantify the alteration to vascular branching pattern following Cd exposure in the chick extra-embryonic membrane (EEM) using fractal analysis, and explore molecular cues to angiogenesis such as VEGF-A and VEGF-R2 expression following Cd treatment. Chicken embryos were incubated for 60 h to Hamburger–Hamilton developmental stage 16–17, then explanted and treated with 50 μL of 50 μmol cadmium acetate (CdAc) or an equivalent volume of equimolar sodium acetate (NaAc). Images of embryos and their area vasculosa (AV) were captured and analyzed at 4 different time points (4, 8, 24 and 48 h) following treatment. Vascular branching in the AV was quantified using its fractal dimension (D{sub f}), estimated using a box counting method. Gallinaceous VEGF ELISA was used to measure the VEGF-A concentration in the EEM following treatment, with determination of the relative expression of VEGF-A and VEGF-R2 using quantitative real-time RT-PCR. Vascular branching increased monotonically in the control group at all time points. The anti-angiogenic effect of Cd exposure on the AV was reflected by a significant reduction in D{sub f} when compared with controls. D{sub f} was more markedly reduced in cultures with abnormal embryos. The expression of VEGF-A protein, and VEGF-A and VEGF-R2 mRNA were reduced in Cd-exposed EEMs. Both molecules contribute to growth, vessel sprouting and branching processes, which supports our findings using fractal analysis. - Highlights: • The chick area vasculosa was undersized in embryos exposed to 50 μM cadmium acetate. • Fractal dimension was reduced in the AV after Cd exposure, indicating decreased branching. • VEGF-A protein was decreased in Cd-treated extraembryonic membranes. • VEGF-A and VEGF-R2 mRNA was decreased in Cd-treated extraembryonic

Radiation up-regulated the expression of VEGF in a canine oral melanoma cell line

International Nuclear Information System (INIS)

Flickinger, I.; Rütgen, B.C.; Gerner, W.; Tichy, A.; Saalmüller, A.; Kleiter, M.; Calice, I.

2013-01-01

To evaluate radiosensitivity and the effects of radiation on the expression of vascular endothelial growth factor (VEGF) and VEGF receptors in the canine oral melanoma cell line, TLM 1, cells were irradiated with doses of 0, 2, 4, 6, 8 and 10 Gray (Gy). Survival rates were then determined by a MTT assay, while vascular endothelial growth factor receptor (VEGFR)-1 and -2 expression was measured by flow cytometry and apoptotic cell death rates were investigated using an Annexin assay. Additionally, a commercially available canine VEGF ELISA kit was used to measure VEGF. Radiosensitivity was detected in TLM 1 cells, and mitotic and apoptotic cell death was found to occur in a radiation dose dependent manner. VEGF was secreted constitutively and significant up-regulation was observed in the 8 and 10 Gy irradiated cells. In addition, a minor portion of TLM 1 cells expressed vascular endothelial growth factor receptor (VEGFR)-1 intracellularly. VEGFR-2 was detected in the cytoplasm and was down-regulated following radiation with increasing dosages. In TLM 1 cells, apoptosis plays an important role in radiation induced cell death. It has also been suggested that the significantly higher VEGF production in the 8 and 10 Gy group could lead to tumour resistance. (author)

Neovascular events in eyes with central retinal vein occlusion undergoing serial bevacizumab or ranibizumab intravitreal injections: A retrospective review

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Francis Char DeCroos

2014-01-01

Conclusion: Neovascular events occur in eyes with CRVO undergoing serial anti-VEGF therapy, and these events may be delayed compared to the natural history of CRVO-associated neovascularization. Iris neovascularization occurred most frequently.

Vascular endothelial growth factor (VEGF and prostate pathology

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Francisco Botelho

2010-08-01

Full Text Available PURPOSE: Previous studies suggest that vascular endothelial growth factor (VEGF circulating levels might improve identification of patients with prostate cancer but results are conflicting. Our aim was to compare serum VEGF levels across different prostate pathologies (including benign prostatic hyperplasia, prostatitis, high grade prostate intraepithelial neoplasia and prostate cancer in patients at high risk of prostate cancer. MATERIALS AND METHODS: We consecutively enrolled 186 subjects with abnormal digital rectal examination and/or total PSA (tPSA = 2.5 ng/mL. Blood was collected before diagnostic ultrasound guided trans-rectal prostate biopsy, or any prostate oncology treatment, to measure PSA isoforms and VEGF. Unconditional logistic regression was used to compute age-, tPSA- and free/total PSA-adjusted odds ratios (OR and respective 95% confidence intervals (95% CI for the association between serum VEGF and different prostatic pathologies. RESULTS: Prostate biopsy main diagnoses were normal or benign prostatic hyperplasia (27.3%, prostatitis (16.6%, and prostatic cancer (55.0%. The median VEGF levels (ng/mL in these groups were 178.2, 261.3 and 266.4 (p = 0.029, respectively, but no significant differences were observed for benign vs. malignant pathologies (215.2 vs. 266.4, p = 0.551. No independent association was observed between VEGF (3rd vs. 1st third and prostate cancer, when compared to benign conditions (adjusted OR = 1.44; CI 95%: 0.64-3.26. CONCLUSIONS: In patients at high risk of prostate cancer, circulating VEGF levels have no clinical role in deciding which patients should be submitted to prostate biopsy. Prostatitis patients, often with higher PSA levels, also present high serum levels of VEGF, and their inclusion in control groups might explain the heterogeneous results in previous studies.

Polymorphisms of VEGF and VEGF receptors are associated with the occurrence of ovarian hyperstimulation syndrome (OHSS)-a retrospective case-control study.

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Nouri, Kazem; Haslinger, Peter; Szabo, Ladislaus; Sator, Michael; Schreiber, Martin; Schneeberger, Christian; Pietrowski, Detlef

2014-01-01

Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of IVF/ICSI therapy. The pathophysiology and etiology of the disease is still not fully clarified. To assess whether polymorphisms of the VEGF/VEGF-receptor system contribute to the occurrence of ovarian hyperstimulation syndrome (OHSS), we performed a retrospective analysis of 116 OHSS patients, and 124 female controls. The following SNPs were genotyped: Rs2071559 (VEGFR2-604); rs2305948 (VEGFR2-1192); rs1870377 (VEGFR2-1719); rs2010963 (VEGF-405); and rs111458691 (VEGFR1-519). Odds ratios (ORs) were estimated with a 95% confidence interval (CI). Linkage disequilibrium (LD) analysis was performed in the three loci of the VEGFR2 gene. We found an overrepresentation of the T allele of the VEGFR1-519 polymorphism in OHSS patients (P = 0.02, OR: 3.62, CI: 1.16 - 11.27). By genotype modeling, we found that polymorphism of VEGFR1-519 and VEGF-405 showed significant differences in patients and controls (p = 0.02, OR: 3.79 CI: 1.98 - 11.97 and p = 0.000005, OR: 0.29, CI: 0.17 - 0.50). LD analysis revealed significant linkage disequilibrium in VEGFR2. Polymorphisms in the VEGFR2 gene and in the VEGF gene are associated with the occurrence of OHSS. This strengthens the evidence for an important role of the VEGF/VEGF- receptor system in the occurrence of OHSS.

Thrombospondin-1 and VEGF in inflammatory bowel disease

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Canan Alkim

2012-01-01

Full Text Available Angiogenesis is an important process in the pathogenesis of chronic inflammation. We aimed to study the angiogeneic balance in inflammatory bowel disease (IBD by evaluating the expression of vascular endothelial growth factor (VEGF and thrombospondin-1 (TSP-1 on colonic epithelial cells, together with the expression of inducible nitric oxide synthase (iNOS.Twenty-one ulcerative colitis (UC, 14 Crohn's disease (CD, 11 colorectal cancer patients, and 11 healthy controls colonic biopsy samples were evaluated immunohistochemically.The expressions of TSP-1, VEGF, and iNOS in UC and CD groups were higher than expression in healthy control group, all with statistical significance. However, in colorectal cancer group, VEGF and iNOS expressions were increased importantly, but TSP-1 expression was not statistically different from healthy control group's expression. Both TSP-1 and VEGF expressions were correlated with iNOS expression distinctly but did not correlate with each other.Both pro-angiogeneic VEGF and antiangiogeneic TSP-1 expressions were found increased in our IBD groups, but in colorectal cancer group, only VEGF expression was increased. TSP-1 increases in IBD patients as a response to inflammatory condition, but this increase was not enough to suppress pathologic angiogenesis and inflammation in IBD.

A two-compartment model of VEGF distribution in the mouse.

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Phillip Yen

Full Text Available Vascular endothelial growth factor (VEGF is a key regulator of angiogenesis--the growth of new microvessels from existing microvasculature. Angiogenesis is a complex process involving numerous molecular species, and to better understand it, a systems biology approach is necessary. In vivo preclinical experiments in the area of angiogenesis are typically performed in mouse models; this includes drug development targeting VEGF. Thus, to quantitatively interpret such experimental results, a computational model of VEGF distribution in the mouse can be beneficial. In this paper, we present an in silico model of VEGF distribution in mice, determine model parameters from existing experimental data, conduct sensitivity analysis, and test the validity of the model. The multiscale model is comprised of two compartments: blood and tissue. The model accounts for interactions between two major VEGF isoforms (VEGF(120 and VEGF(164 and their endothelial cell receptors VEGFR-1, VEGFR-2, and co-receptor neuropilin-1. Neuropilin-1 is also expressed on the surface of parenchymal cells. The model includes transcapillary macromolecular permeability, lymphatic transport, and macromolecular plasma clearance. Simulations predict that the concentration of unbound VEGF in the tissue is approximately 50-fold greater than in the blood. These concentrations are highly dependent on the VEGF secretion rate. Parameter estimation was performed to fit the simulation results to available experimental data, and permitted the estimation of VEGF secretion rate in healthy tissue, which is difficult to measure experimentally. The model can provide quantitative interpretation of preclinical animal data and may be used in conjunction with experimental studies in the development of pro- and anti-angiogenic agents. The model approximates the normal tissue as skeletal muscle and includes endothelial cells to represent the vasculature. As the VEGF system becomes better characterized in

Reading strategies in mild to moderate strabismic amblyopia: an eye movement investigation.

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Kanonidou, Evgenia; Proudlock, Frank A; Gottlob, Irene

2010-07-01

PURPOSE. To investigate oculomotor strategies in strabismic amblyopia and evaluate abnormalities during monocular and binocular reading. METHODS. Eye movements were recorded with a head-mounted infrared video eye-tracker (250 Hz, amblyopia, reading is impaired, not only during monocular viewing with the amblyopic eye, but also with the nonamblyopic eye and binocularly, even though normal visual acuity pertains to the latter two conditions. The impaired reading performance is associated with differences in both the saccadic and fixational patterns, most likely as adaptation strategies to abnormal sensory experiences such as crowding and suppression.

Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2.

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Peach, Chloe J; Mignone, Viviane W; Arruda, Maria Augusta; Alcobia, Diana C; Hill, Stephen J; Kilpatrick, Laura E; Woolard, Jeanette

2018-04-23

Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, survival, migration and vascular permeability. Distinct VEGF-A isoforms result from alternative splicing of the Vegfa gene at exon 8, resulting in VEGF xxx a or VEGF xxx b isoforms. Alternative splicing events at exons 5⁻7, in addition to recently identified posttranslational read-through events, produce VEGF-A isoforms that differ in their bioavailability and interaction with the co-receptor Neuropilin-1. This review explores the molecular pharmacology of VEGF-A isoforms at VEGFR2 in respect to ligand binding and downstream signalling. To understand how VEGF-A isoforms have distinct signalling despite similar affinities for VEGFR2, this review re-evaluates the typical classification of these isoforms relative to the prototypical, “pro-angiogenic” VEGF 165 a. We also examine the molecular mechanisms underpinning the regulation of VEGF-A isoform signalling and the importance of interactions with other membrane and extracellular matrix proteins. As approved therapeutics targeting the VEGF-A/VEGFR signalling axis largely lack long-term efficacy, understanding these isoform-specific mechanisms could aid future drug discovery efforts targeting VEGF receptor pharmacology.

Clinical significance of determination of changes of serum TSGF and plasma VEGF levels after treatment in patients with endometriosis

International Nuclear Information System (INIS)

Shi Shaohong; Tian Xiaoping

2006-01-01

Objective: To investigate the changes of serum TSGF and plasma VEGF levels after treatment in patients with endometriosis. Methods: Serum TSGF levels were determined with ELISA mad plasma VEGF levels with biochemistry in 31 patients with endometriosis both before and after treatment as well as in 30 controls. Results: Before treatment the serum TSGF and plasma VEGF levels in patients were significantly higher than those in the controls (P 0.05). Conclusion: Development of endometriosis were closely related to the plasma levels of VEGF and serum TSGF levels. (authors)

VEGF induces proliferation of human hair follicle dermal papilla cells through VEGFR-2-mediated activation of ERK

International Nuclear Information System (INIS)

Li, Wei; Man, Xiao-Yong; Li, Chun-Ming; Chen, Jia-Qi; Zhou, Jiong; Cai, Sui-Qing; Lu, Zhong-Fa; Zheng, Min

2012-01-01

Vascular endothelial growth factor (VEGF) is one of the strongest regulators of physiological and pathological angiogenesis. VEGF receptor 2 (VEGFR-2), the primary receptor for VEGF, is thought to mediate major functional effects of VEGF. Previously, we have localized both VEGF and VEGFR-2 in human hair follicles. In this study, we further defined the expression and roles of VEGFR-2 on human hair follicle dermal papilla (DP) cells. The expression of VEGFR-2 on DP cells was examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis separately, and localization of VEGFR-2 was defined by immunofluorescence. The effect of VEGF on DP cells was analyzed by MTT assays and specific inhibitors. Finally, the role of VEGF involved in the signaling pathways was investigated by Western blot. RT-PCR and Western blot analysis demonstrated the expression of VEGFR-2 on DP cells. Immunostaining for VEGFR-2 showed strong signal on cultured human DP cells in vitro. Exogenous VEGF 165 stimulated proliferation of DP cells in a dose-dependent manner. Furthermore, this stimulation was blocked by a VEGFR-2 neutralizing antibody (MAB3571) and an ERK inhibitor (PD98059). VEGF 165 -induced phosphorylation of ERK1/2 was abolished by MAB3571 and PD98059, while the phosphorylation of p38, JNK and AKT were not changed by VEGF 165 . Taken together, VEGFR-2 is expressed on primary human hair follicle DP cells and VEGF induces proliferation of DP cells through VEGFR-2/ERK pathway, but not p38, JNK or AKT signaling. -- Highlights: ► We examine the expression of VEGFR-2 on cultured human dermal papilla (DP) cells. ► VEGF 165 stimulated proliferation of human DP cells in a dose-dependent manner. ► This stimulation was through VEGFR-2-mediated activation of ERK.

VEGF expression in hepatectomized tumor-bearing mice.

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Andrini, L; Blanco, A Fernandez; Inda, A; García, M; Garcia, A; Errecalde, A

2011-01-01

The experiments were designed in order to study the VEGF expression in intact (group I), hepatectomized (group II), and hepatectomized-tumor bearing mice (group III) throughout one complete circadian time span. Adult male mice were used for the VEGF expression study. The statistical analysis was performed using analysis of variance (ANOVA). The results showed statistical differences in the VEGF expression between groups I and II, but the most significant differences were found between groups I and III. In conclusion, these expressions have a circadian rhythm in all groups; moreover, in group III, this expression was higher and appeared before than in the others.

Clinical procedure for colon carcinoma tissue sampling directly affects the cancer marker-capacity of VEGF family members

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Pringels, Sarah; Van Damme, Nancy; De Craene, Bram; Pattyn, Piet; Ceelen, Wim; Peeters, Marc; Grooten, Johan

2012-01-01

mRNA levels of members of the Vascular Endothelial Growth Factor family (VEGF-A, -B, -C, -D, Placental Growth Factor/PlGF) have been investigated as tissue-based markers of colon cancer. These studies, which used specimens obtained by surgical resection or colonoscopic biopsy, yielded contradictory results. We studied the effect of the sampling method on the marker accuracy of VEGF family members. Comparative RT-qPCR analysis was performed on healthy colon and colon carcinoma samples obtained by biopsy (n = 38) or resection (n = 39) to measure mRNA expression levels of individual VEGF family members. mRNA levels of genes encoding the eicosanoid enzymes cyclooxygenase 2 (COX2) and 5-lipoxygenase (5-LOX) and of genes encoding the hypoxia markers glucose transporter 1 (GLUT-1) and carbonic anhydrase IX (CAIX) were included as markers for cellular stress and hypoxia. Expression levels of COX2, 5-LOX, GLUT-1 and CAIX revealed the occurrence in healthy colon resection samples of hypoxic cellular stress and a concurrent increment of basal expression levels of VEGF family members. This increment abolished differential expression of VEGF-B and VEGF-C in matched carcinoma resection samples and created a surgery-induced underexpression of VEGF-D. VEGF-A and PlGF showed strong overexpression in carcinoma samples regardless of the sampling method. Sampling-induced hypoxia in resection samples but not in biopsy samples affects the marker-reliability of VEGF family members. Therefore, biopsy samples provide a more accurate report on VEGF family mRNA levels. Furthermore, this limited expression analysis proposes VEGF-A and PlGF as reliable, sampling procedure insensitive mRNA-markers for molecular diagnosis of colon cancer

Effect of eye NGF administration on two animal models of retinal ganglion cells degeneration

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Valeria Colafrancesco

2011-01-01

Full Text Available The aim of this study was to investigate the effect of nerve growth factor (NGF administration on retinal ganglion cells (RGCs in experimentally induced glaucoma (GL and diabetic retinopathy (DR. GL was induced in adult rats by injection of hypertonic saline into the episcleral vein of the eye and diabetes (DT was induced by administration of streptozoticin. Control and experimental rats were treated daily with either ocular application of NGF or vehicle solution. We found that both animal models present a progressive degeneration of RGCs and changing NGF and VEGF levels in the retina and optic nerve. We then proved that NGF eye drop administration exerts a protective effect on these models of retinal degeneration. In brief, our findings indicate that NGF can play a protective role against RGC degeneration occurring in GL and DR and suggest that ocular NGF administration might be an effective pharmacological approach.

Genetic variation in VEGF does not contribute significantly to the risk of congenital cardiovascular malformation.

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Helen R Griffin

Full Text Available Several previous studies have investigated the role of common promoter variants in the vascular endothelial growth factor (VEGF gene in causing congenital cardiovascular malformation (CVM. However, results have been discrepant between studies and no study to date has comprehensively characterised variation throughout the gene. We genotyped 771 CVM cases, of whom 595 had the outflow tract malformation Tetralogy of Fallot (TOF, and carried out TDT and case-control analyses using haplotype-tagging SNPs in VEGF. We carried out a meta-analysis of previous case-control or family-based studies that had typed VEGF promoter SNPs, which included an additional 570 CVM cases. To identify rare variants potentially causative of CVM, we carried out mutation screening in all VEGF exons and splice sites in 93 TOF cases. There was no significant effect of any VEGF haplotype-tagging SNP on the risk of CVM in our analyses of 771 probands. When the results of this and all previous studies were combined, there was no significant effect of the VEGF promoter SNPs rs699947 (OR 1.05 [95% CI 0.95-1.17]; rs1570360 (OR 1.17 [95% CI 0.99-1.26]; and rs2010963 (OR 1.04 [95% CI 0.93-1.16] on the risk of CVM in 1341 cases. Mutation screening of 93 TOF cases revealed no VEGF coding sequence variants and no changes at splice consensus sequences. Genetic variation in VEGF appears to play a small role, if any, in outflow tract CVM susceptibility.

Roxithromycin inhibits VEGF-induced human airway smooth muscle cell proliferation: Opportunities for the treatment of asthma

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Pei, Qing-Mei; Jiang, Ping; Yang, Min; Qian, Xue-Jiao; Liu, Jiang-Bo; Kim, Sung-Ho

2016-01-01

Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodelling, which is associated with increased airway smooth muscle (ASM) mass. Roxithromycin (RXM) has been widely used in asthma treatment; however, its mechanism of action is poorly understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodelling in patients with asthma, and shown to promote ASM cell proliferation. Here, we investigated the effect of RXM on VEGF-induced ASM cell proliferation and attempted to elucidate the underlying mechanisms of action. We tested the effect of RXM on proliferation and cell cycle progression, as well as on the expression of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), phospho-Akt, and caveolin-1 in VEGF-stimulated ASM cells. RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed by inhibiting the activity of ERK1/2, but not that of Akt. Furthermore, RXM treatment inhibits VEGF-induced activation of VEGFR2 and ERK and downregulation of caveolin-1 in a dose-dependent manner. RXM also inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. Collectively, our findings suggest that RXM inhibits VEGF-induced ASM cell proliferation by suppression of VEGFR2 and ERK1/2 activation and caveolin-1 down-regulation, which may be involved in airway remodelling. Further elucidation of the mechanisms underlying these observations should enable the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma. - Highlights: • RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. • VEGF-induced cell proliferation was suppressed by inhibiting the activity of ERK1/2. • RXM inhibits activation of VEGFR2 and ERK and downregulation

Inhibition of VEGF: a novel mechanism to control angiogenesis by Withania somnifera's key metabolite Withaferin A.

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Saha, Sanjib; Islam, Md Khirul; Shilpi, Jamil A; Hasan, Shihab

2013-01-01

Angiogenesis, or new blood vessel formation from existing one, plays both beneficial and detrimental roles in living organisms in different aspects. Vascular endothelial growth factor (VEGF), a signal protein, well established as key regulator of vasculogenesis and angiogenesis. VEGF ensures oxygen supply to the tissues when blood supply is not adequate, or tissue environment is in hypoxic condition. Limited expression of VEGF is necessary, but if it is over expressed, then it can lead to serious disease like cancer. Cancers that have ability to express VEGF are more efficient to grow and metastasize because solid cancers cannot grow larger than a limited size without adequate blood and oxygen supply. Anti-VEGF drugs are already available in the market to control angiogenesis, but they are often associated with severe side-effects like fetal bleeding and proteinuria in the large number of patients. To avoid such side-effects, new insight is required to find potential compounds as anti-VEGF from natural sources. In the present investigation, molecular docking studies were carried out to find the potentiality of Withaferin A, a key metabolite of Withania somnifera, as an inhibitor of VEGF. Molecular Docking studies were performed in DockingServer and SwissDock. Bevacizumab, a commercial anti-VEGF drug, was used as reference to compare the activity of Withaferin A. X-ray crystallographic structure of VEGF, was retrieved from Protein Data Bank (PDB), and used as drug target protein. Structure of Withaferin A and Bevacizumab was obtained from PubChem and ZINC databases. Molecular visualization was performed using UCSF Chimera. Withaferin A showed favorable binding with VEGF with low binding energy in comparison to Bevacizumab. Molecular Docking studies also revealed potential protein-ligand interactions for both Withaferin A and Bevacizumab. Conclusively our results strongly suggest that Withaferin A is a potent anti-VEGF agent as ascertained by its potential

Roxithromycin inhibits VEGF-induced human airway smooth muscle cell proliferation: Opportunities for the treatment of asthma

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Pei, Qing-Mei, E-mail: 34713316@qq.com [Department of Radiology, Tianjin Hospital of Integrated Traditional Chinese and Western Medicine, Tianjin (China); Jiang, Ping, E-mail: jiangping@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Yang, Min, E-mail: YangMin@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Qian, Xue-Jiao, E-mail: qianxuejiao@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Liu, Jiang-Bo, E-mail: LJB1984@163.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China); Kim, Sung-Ho, E-mail: chenghao0726@hotmail.com [Department of Respiration, Tianjin First Central Hospital, Tianjin (China)

2016-10-01

Asthma is a chronic respiratory disease characterized by reversible airway obstruction with persistent airway inflammation and airway remodelling, which is associated with increased airway smooth muscle (ASM) mass. Roxithromycin (RXM) has been widely used in asthma treatment; however, its mechanism of action is poorly understood. Vascular endothelial growth factor (VEGF) has been implicated in inflammatory and airway blood vessel remodelling in patients with asthma, and shown to promote ASM cell proliferation. Here, we investigated the effect of RXM on VEGF-induced ASM cell proliferation and attempted to elucidate the underlying mechanisms of action. We tested the effect of RXM on proliferation and cell cycle progression, as well as on the expression of phospho-VEGF receptor 2 (VEGFR2), phospho-extracellular signal-regulated kinase 1/2 (ERK1/2), phospho-Akt, and caveolin-1 in VEGF-stimulated ASM cells. RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. Additionally, VEGF-induced ASM cell proliferation was suppressed by inhibiting the activity of ERK1/2, but not that of Akt. Furthermore, RXM treatment inhibits VEGF-induced activation of VEGFR2 and ERK and downregulation of caveolin-1 in a dose-dependent manner. RXM also inhibited TGF-β-induced VEGF secretion by ASM cells and BEAS-2B cells. Collectively, our findings suggest that RXM inhibits VEGF-induced ASM cell proliferation by suppression of VEGFR2 and ERK1/2 activation and caveolin-1 down-regulation, which may be involved in airway remodelling. Further elucidation of the mechanisms underlying these observations should enable the development of treatments for smooth muscle hyperplasia-associated diseases of the airway such as asthma. - Highlights: • RXM inhibited VEGF-induced ASM cell proliferation and induced cell cycle arrest. • VEGF-induced cell proliferation was suppressed by inhibiting the activity of ERK1/2. • RXM inhibits activation of VEGFR2 and ERK and downregulation

Neutralizing VEGF bioactivity with a soluble chimeric VEGF receptor protein flt (1-3) IGG inhibits testosterone stimulated prostate growth in castrated mice

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Hammarsten, P.; Lissbrant, E.; Lissbrant, I.-F.; Haeggstroem-Rudolfsson, S.; Bergh, A.; Ferrara, N.

2003-01-01

Recent studies show that testosterone stimulated growth of the glandular tissue in the ventral prostate in adult castrated rats is preceded by increased epithelial VEGF synthesis, endothelial cell proliferation, vascular growth, and increased blood flow. These observations suggest that testosterone stimulated prostate growth could be angiogenesis dependent, and that VEGF could play a central role in this. To test this hypothesis adult male mice were castrated and after one week treated with testosterone and vehicle, or with testosterone and a soluble chimeric VEGF-receptor flt(1-3)IgG protein. Treatment with testosterone markedly increased endothelial cell proliferation, vascular volume and organ weight in the ventral prostate lobe in the vehicle groups, but these responses were inhibited but not fully prevented by anti-VEGF treatment. The testosterone stimulated increase in epithelial cell proliferation was unaffected by flt(1-3)IgG, but endothelial and epithelial cell apoptosis were increased in the anti-VEGF compared to the vehicle treated group. This study, together with our previous observations, suggest that testosterone stimulates vascular growth in the ventral prostate lobe indirectly by increasing epithelial VEGF synthesis and that this is a necessary component in testosterone stimulated prostate growth

Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia.

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Hulse, R P; Beazley-Long, N; Hua, J; Kennedy, H; Prager, J; Bevan, H; Qiu, Y; Fernandes, E S; Gammons, M V; Ballmer-Hofer, K; Gittenberger de Groot, A C; Churchill, A J; Harper, S J; Brain, S D; Bates, D O; Donaldson, L F

2014-11-01

Vascular endothelial growth factor-A (VEGF-A) is best known as a key regulator of the formation of new blood vessels. Neutralization of VEGF-A with anti-VEGF therapy e.g. bevacizumab, can be painful, and this is hypothesized to result from a loss of VEGF-A-mediated neuroprotection. The multiple vegf-a gene products consist of two alternatively spliced families, typified by VEGF-A165a and VEGF-A165b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165a is upregulated and predominates over the VEGF-A165b isoform. We show here that in rats and mice VEGF-A165a and VEGF-A165b have opposing effects on pain, and that blocking the proximal splicing event - leading to the preferential expression of VEGF-A165b over VEGF165a - prevents pain in vivo. VEGF-A165a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165b blocks the effect of VEGF-A165a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxxa compared to VEGF-Axxxb, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxxa expression and reversed associated neuropathic pain. Exogenous VEGF-A165b also ameliorated neuropathic pain. We conclude that the relative levels of alternatively spliced VEGF-A isoforms are critical for pain modulation under both normal conditions and in sensory neuropathy. Altering VEGF-Axxxa/VEGF-Axxxb balance by targeting alternative RNA splicing may be a new analgesic strategy. Copyright © 2014. Published by Elsevier Inc.

Differential expression of VEGF ligands and receptors in prostate cancer.

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Woollard, David J; Opeskin, Kenneth; Coso, Sanja; Wu, Di; Baldwin, Megan E; Williams, Elizabeth D

2013-05-01

Prostate cancer disseminates to regional lymph nodes, however the molecular mechanisms responsible for lymph node metastasis are poorly understood. The vascular endothelial growth factor (VEGF) ligand and receptor family have been implicated in the growth and spread of prostate cancer via activation of the blood vasculature and lymphatic systems. The purpose of this study was to comprehensively examine the expression pattern of VEGF ligands and receptors in the glandular epithelium, stroma, lymphatic vasculature and blood vessels in prostate cancer. The localization of VEGF-A, VEGF-C, VEGF-D, VEGF receptor (VEGFR)-1, VEGFR-2, and VEGFR-3 was examined in cancerous and adjacent benign prostate tissue from 52 subjects representing various grades of prostate cancer. Except for VEGFR-2, extensive staining was observed for all ligands and receptors in the prostate specimens. In epithelial cells, VEGF-A and VEGFR-1 expression was higher in tumor tissue compared to benign tissue. VEGF-D and VEGFR-3 expression was significantly higher in benign tissue compared to tumor in the stroma and the endothelium of lymphatic and blood vessels. In addition, the frequency of lymphatic vessels, but not blood vessels, was lower in tumor tissue compared with benign tissue. These results suggest that activation of VEGFR-1 by VEGF-A within the carcinoma, and activation of lymphatic endothelial cell VEGFR-3 by VEGF-D within the adjacent benign stroma may be important signaling mechanisms involved in the progression and subsequent metastatic spread of prostate cancer. Thus inhibition of these pathways may contribute to therapeutic strategies for the management of prostate cancer. Copyright © 2012 Wiley Periodicals, Inc.

A boundary element model for investigating the effects of eye tumor on the temperature distribution inside the human eye.

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Ooi, E H; Ang, W T; Ng, E Y K

2009-08-01

A three-dimensional boundary element model of the human eye is developed to investigate the thermal effects of eye tumor on the ocular temperature distribution. The human eye is modeled as comprising several regions which have different thermal properties. The tumor is one of these regions. The thermal effects of the tumor are simulated by taking it to have a very high metabolic heat generation and blood perfusion rate. Inside the tumor, the steady state temperature is governed by the Pennes bioheat equation. Elsewhere, in normal tissues of the eye, the temperature satisfies the Laplace's equation. To compute the temperature on the corneal surface, the surface boundary of each region is divided into triangular elements.

Renal Involvement in Preeclampsia: Similarities to VEGF Ablation Therapy

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Janina Müller-Deile

2011-01-01

Full Text Available Glomerular VEGF expression is critical for the maintenance and function of an intact filtration barrier. Alterations in glomerular VEGF bioavailability result in endothelial as well as in podocyte damage. Renal involvement in preeclampsia includes proteinuria, podocyturia, elevated blood pressure, edema, glomerular capillary endotheliosis, and thrombotic microangiopathy. At least the renal signs, symptoms, and other evidence can sufficiently be explained by reduced VEGF levels. The aim of this paper was to summarize our pathophysiological understanding of the renal involvement of preeclampsia and point out similarities to the renal side effects of VEGF-ablation therapy.

Changing paradigms of anti-VEGF in the Indian scenario

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P Mahesh Shanmugam

2014-01-01

Full Text Available Anti-vascular endothelial growth factors (VEGF agents have revolutionized the treatment of retinal diseases. Use of anti-VEGF agents in the Indian Scenario present some unique challenges considering the absence of compounding pharmacies, poor penetrance of health insurance and limited affordability of the citizens of a developing economy. To study the changing paradigms of anti-VEGF use in the Indian scenario, all articles published by Indian authors, data from web-based surveys amongst Indian vitreo-retinal specialists were reviewed. In the paucity of compounding pharmacies in India, fractionation and injection techniques differ from those of developed countries. Frequent anti-VEGF monotherapy offers the best anatomical and visual results, but economics of scale do not allow the same in the Indian scenario, resulting in PRN dosing and combination of anti-VEGF with laser photocoagulation, being the commonly employed treatment protocols.

Radiation-induced VEGF-C expression and endothelial cell proliferation in lung cancer

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Chen, Yu-Hsuan [National Taiwan University Hospital, Department of Oncology, Taipei (China); National Taiwan University, Pharmacological Institute, College of Medicine, Taipei (China); Pan, Shiow-Lin; Wang, Jing-Chi; Teng, Che-Ming [National Taiwan University, Pharmacological Institute, College of Medicine, Taipei (China); Kuo, Sung-Hsin [National Taiwan University Hospital, Department of Oncology, Taipei (China); National Taiwan University College of Medicine, Department of Internal Medicine, Taipei (China); Cheng, Jason Chia-Hsien [National Taiwan University Hospital, Department of Oncology, Taipei (China); National Taiwan University College of Medicine, Graduate Institute of Clinical Medicine, Taipei (China)

2014-12-15

The present study was undertaken to investigate whether radiation induces the expression of vascular endothelial growth factor C (VEGF-C) through activation of the PI3K/Akt/mTOR pathway,subsequently affecting endothelial cells. Radiotherapy-induced tumor micro-lymphatic vessel density (MLVD) was determined in a lung cancer xenograft model established in SCID mice. The protein expression and phosphorylation of members of the PI3K/Akt/mTOR pathway and VEGF-C secretion and mRNA expression in irradiated lung cancer cells were assessed by Western blot analysis, enzyme-linked immunosorbent assays (ELISAs), and reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, specific chemical inhibitors were used to evaluate the role of the PI3K/Akt/mTOR signaling pathway. Conditioned medium (CM) from irradiated control-siRNA or VEGF-C-siRNA-expressing A549 cells was used to evaluate the proliferation of endothelial cells by the MTT assay. Radiation increased VEGF-C expression in a dose-dependent manner over time at the protein but not at the mRNA level. Radiation also up-regulated the phosphorylation of Akt, mTOR, 4EBP, and eIF4E, but not of p70S6K. Radiation-induced VEGF-C expression was down-regulated by LY294002 and rapamycin (both p < 0.05). Furthermore, CM from irradiated A549 cells enhanced human umbilical vein endothelial cell (HUVEC) and lymphatic endothelial cell (LEC) proliferation, which was not observed with CM from irradiated VEGF-C-siRNA-expressing A549 cells. Radiation-induced activation of the PI3K/Akt/mTOR signaling pathway increases VEGF-C expression in lung cancer cells, thereby promoting endothelial cell proliferation. (orig.) [German] Die vorliegende Studie untersucht, ob die Strahlung die Expression von VEGF-C (vascular endothelial growth factor C) mittels Aktivierung des PI3K/Akt/mTOR-Signalwegs induziert und anschliessend die endothelialen Zellen beeinflusst. Die durch Strahlentherapie induzierte Mikrolymphgefaessdichte (MLVD) im Tumor wurde in

Primary Cilium-Regulated EG-VEGF Signaling Facilitates Trophoblast Invasion.

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Wang, Chia-Yih; Tsai, Hui-Ling; Syu, Jhih-Siang; Chen, Ting-Yu; Su, Mei-Tsz

2017-06-01

Trophoblast invasion is an important event in embryo implantation and placental development. During these processes, endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is the key regulator mediating the crosstalk at the feto-maternal interface. The primary cilium is a cellular antenna receiving environmental signals and is crucial for proper development. However, little is known regarding the role of the primary cilium in early human pregnancy. Here, we demonstrate that EG-VEGF regulates trophoblast cell invasion via primary cilia. We found that EG-VEGF activated ERK1/2 signaling and subsequent upregulation of MMP2 and MMP9, thereby facilitating cell invasion in human trophoblast HTR-8/SVneo cells. Inhibition of ERK1/2 alleviated the expression of MMPs and trophoblast cell invasion after EG-VEGF treatment. In addition, primary cilia were observed in all the trophoblast cell lines tested and, more importantly, in human first-trimester placental tissue. The receptor of EG-VEGF, PROKR1, was detected in primary cilia. Depletion of IFT88, the intraflagellar transporter required for ciliogenesis, inhibited primary cilium growth, thereby ameliorating ERK1/2 activation, MMP upregulation, and trophoblast cell invasion promoted by EG-VEGF. These findings demonstrate a novel function of primary cilia in controlling EG-VEGF-regulated trophoblast invasion and reveal the underlying molecular mechanism. J. Cell. Physiol. 232: 1467-1477, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Vascular endothelial growth factor (VEGF-634G/C) polymorphism and retinopathy of prematurity: a meta-analysis

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Malik, Manzoor Ahmad; Shukla, Swati; Azad, Shorya Vardhan; Kaur, Jasbir

2014-01-01

Purpose Vascular endothelial growth factor polymorphism (VEGF-634G/C, rs 2010963) has been considered a risk factor for the development of retinopathy of prematurity (ROP). However, the results remain controversial. Therefore, the aim of the present meta-analysis was to determine the association between VEGF-634G/C polymorphism and ROP risk. Methods Published literature from PubMed and other databases were retrieved. All studies evaluating the association between VEGF-634G/C polymorphism and ROP risk were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random or fixed effects model. A total of six case-control studies including 355 cases and 471 controls were included. Results By pooling all the studies, we found that VEGF-634G/C polymorphism was not associated with ROP risk at co-dominant and allele levels and no association was also found in dominant and recessive models. While stratifying on ethnicity level no association was observed in Caucasian and Asian population. Discussion This meta-analysis suggests that VEGF-634G/C polymorphism may not be associated with ROP risk, the association between single VEGF-634G/C polymorphism and ROP risk awaits further investigation. PMID:25473347

CCL5 promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-507 in human chondrosarcoma cells.

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Wang, Li-Hong; Lin, Chih-Yang; Liu, Shih-Chia; Liu, Guan-Ting; Chen, Yen-Ling; Chen, Jih-Jung; Chan, Chia-Han; Lin, Ting-Yi; Chen, Chi-Kuan; Xu, Guo-Hong; Chen, Shiou-Sheng; Tang, Chih-Hsin; Wang, Shih-Wei

2016-06-14

Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the major lymphangiogenic factor, and makes crucial contributions to tumor lymphangiogenesis and lymphatic metastasis. Chemokine CCL5 has been reported to facilitate angiogenesis and metastasis in chondrosarcoma. However, the effect of chemokine CCL5 on VEGF-C regulation and lymphangiogenesis in chondrosarcoma has largely remained a mystery. In this study, we showed a clinical correlation between CCL5 and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that CCL5 promoted VEGF-C expression and secretion in human chondrosarcoma cells. The conditioned medium (CM) from CCL5-overexpressed cells significantly induced tube formation of human lymphatic endothelial cells (LECs). Mechanistic investigations showed that CCL5 activated VEGF-C-dependent lymphangiogenesis by down-regulating miR-507. Moreover, inhibiting CCL5 dramatically reduced VEGF-C and lymphangiogenesis in the chondrosarcoma xenograft animal model. Collectively, we document for the first time that CCL5 induces tumor lymphangiogenesis by the induction of VEGF-C in human cancer cells. Our present study reveals miR-507/VEGF-C signaling as a novel mechanism in CCL5-mediated tumor lymphangiogenesis. Targeting both CCL5 and VEGF-C pathways might serve as the potential therapeutic strategy to block cancer progression and metastasis in chondrosarcoma.

VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis

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Gareth W. Fearnley

2016-05-01

Full Text Available Vascular endothelial growth factor A (VEGF-A binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A–VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor–ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145 promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes.

VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis.

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Fearnley, Gareth W; Smith, Gina A; Abdul-Zani, Izma; Yuldasheva, Nadira; Mughal, Nadeem A; Homer-Vanniasinkam, Shervanthi; Kearney, Mark T; Zachary, Ian C; Tomlinson, Darren C; Harrison, Michael A; Wheatcroft, Stephen B; Ponnambalam, Sreenivasan

2016-05-15

Vascular endothelial growth factor A (VEGF-A) binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A-VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor-ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145) promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes. © 2016. Published by The Company of Biologists Ltd.

Expression and significance of VEGF, CD34, Ki-67 and p21 in pterygium

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Li-Bo Wang

2014-07-01

Full Text Available AIM: To investigate the expression of VEGF, CD34, Ki-67 and p21 in pterygium as well as the correlation between their expression and clinical pathological characteristics; explore its pathogenesis. METHODS: Immunohistochemical S-P staining method was adopted in detecting the expression of VEGF, CD34, Ki-67 and p21 in 62 cases of pterygia and 20 cases of normal conjunctival tissues. Relationship between these markers and clinical pathological characteristics was analyzed. RESULTS:(1The positive expression of VEGF, CD34, Ki-67 and p21 in 62 cases of pterygia was 74.2%(46/62, 77.4%(48/62, 66.1%(41/62and 40.3%(25/62respectively. The differences were statistically significant compared with normal conjunctival tissues(PPP>0.05; the expression of Ki-67 was correlated with clinical stages(PP>0.05; the expression of p21 was correlated with clinical stages and pterygium characters(PP>0.05.(3Spearman correlation showed that there was a positive correlation between VEGF and Ki-67(r=0.279, Pr=0.299, Pr=-0.267, PP>0.05.CONCLUSION:(1Overexpression of VEGF, Ki-67, CD34 and low expression of p21 suggest that these markers are concerned with the development and progression of pterygium.(2Expression of VEGF and CD34 increases along with the increase of clinical types and stages, expression of Ki-67 increases along with the increase of clinical stages, and expression of p21 decreases along with the improvement of clinical types or stages; they suggest that these markers may play important roles in the development and recurrence of pterygium.(3There is positive correlation between VEGF and Ki-67, VEGF and CD34 as well as negative correlation between VEGF and p21. They suggest that there may be synergistic action between two factors during the development and progression of pterygium.

Outcomes in Eyes with Retinal Angiomatous Proliferation in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).

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Daniel, Ebenezer; Shaffer, James; Ying, Gui-shuang; Grunwald, Juan E; Martin, Daniel F; Jaffe, Glenn J; Maguire, Maureen G

2016-03-01

To compare baseline characteristics, visual acuity (VA), and morphologic outcomes between eyes with retinal angiomatous proliferation (RAP) and all other eyes among patients with neovascular age-related macular degeneration (NVAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs. Prospective cohort study within the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). Patients with NVAMD. Reading center staff evaluated digital color fundus photographs, fluorescein angiography (FA) images, and optical coherence tomography (OCT) scans of eyes with NVAMD treated with either ranibizumab or bevacizumab over a 2-year period. Retinal angiomatous proliferation was identified by the intense intra-retinal leakage of fluorescein in combination with other associated features. Visual acuity; fluorescein leakage; scar; geographic atrophy (GA) on FA; retinal thickness, fluid, and subretinal hyperreflective material (SHRM) on OCT; and the number of intravitreal anti-VEGF injections at 1 and 2 years. Retinal angiomatous proliferation was present in 126 of 1183 (10.7%) study eyes at baseline. Mean VA improvement from baseline was greater (10.6 vs. 6.9 letters; P = 0.01) at 1 year, but similar at 2 years (7.8 vs. 6.2 letters; P = 0.34). At 1 year, eyes with RAP were more likely to have no fluid (46% vs. 26%; P treatment in CATT, eyes with RAP were less likely to have fluid, FA leakage, scar, and SHRM and more likely to have GA than eyes without RAP. Mean improvement in VA was similar at 2 years. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Aflibercept: a review of its use in the treatment of choroidal neovascularization due to age-related macular degeneration

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Balaratnasingam C

2015-12-01

Full Text Available Chandrakumar Balaratnasingam,1–3 Elona Dhrami-Gavazi,1,2,4 Jesse T McCann,1,2,4,5 Quraish Ghadiali,1,2 K Bailey Freund1,2,4,5 1Vitreous-Retina-Macula Consultants of New York, NY, USA; 2LuEsther T Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, NY, USA; 3Centre for Ophthalmology and Visual Sciences, Lions Eye Institute, University of Western Australia, Perth, WA, Australia; 4Department of Ophthalmology, Edward S Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, NY, USA; 5Department of Ophthalmology, New York University School of Medicine, New York, NY, USA Abstract: Choroidal neovascularization (CNV due to age-related macular degeneration (AMD is an important cause of visual morbidity globally. Modern treatment strategies for neovascular AMD achieve regression of CNV by suppressing the activity of key growth factors that mediate angiogenesis. Vascular endothelial growth factor (VEGF has been the major target of neovascular AMD therapy for almost two decades, and there have been several intravitreally-administered agents that have enabled anatomical restitution and improvement in visual function with continual dosing. Aflibercept (EYLEA®, initially named VEGF Trap-eye, is the most recent anti-VEGF agent to be granted US Food and Drug Administration approval for the treatment of neovascular AMD. Biologic advantages of aflibercept include its greater binding affinity for VEGF, a longer intravitreal half-life relative to other anti-VEGF agents, and the capacity to antagonize growth factors other than VEGF. This paper provides an up-to-date summary of the molecular mechanisms mediating CNV. The structural, pharmacodynamic, and pharmacokinetic advantages of aflibercept are also reviewed to rationalize the utility of this agent for treating CNV. Results of landmark clinical investigations, including VIEW 1 and 2 trials, and other important studies are then summarized and used to

Differential expression of OPN, VEGF-A, and HIF-1α and its clinical significance in hepatocellular carcinoma

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ZHENG Yan

2013-01-01

Full Text Available ObjectiveTo investigate the expression patterns of osteopontin (OPN, vascular endothelial growth factor-A (VEGF-A, and hypoxia-inducible factor-1α(HIF-1α in primary hepatocellular carcinoma (HCC and determine the clinical significance of this differential expression profile. MethodsImmunohistochemical staining of OPN, VEGF-A, and HIF-1α was carried out on primary HCC tissues from 90 patients, HCC-adjacent cirrhosis tissues from 20 of those patients, and normal liver tissues from 15 healthy controls. Correlations between expression levels and HCC clinicopathological characteristics were assessed by Spearman's correlation coefficient. ResultsThe majority of HCC tissues showed positive immunostaining for OPN (69/90, 76.67%, VEGF-A (64/90, 71.11%, and HIF-1α (66/90, 73.33%. OPN- and VEGF-A-positivity were significantly higher than the results from the cirrhosis tissues and normal tissues. HIF-1α-positivity was similar between the HCC and cirrhosis tissues, but both were significantly different from the normal tissues. The differential expressions of OPN, VEGF-A, and HIF-1α were significantly correlated with tumor thrombus, capsular integrity, tumor differentiation and stage, and metastasis (P＜0.05. ConclusionHCC tissues overexpress OPN, VEGF-A, and HIF-1α and this differential profile may be related to HCC progression. Future investigations of this triad of factors may provide novel insights into the biological characteristics of HCC and reveal important targets of molecular therapy.

VEGF regulates TRPC6 channels in podocytes

DEFF Research Database (Denmark)

Thilo, Florian; Liu, Ying; Loddenkemper, Christoph

2012-01-01

increased TRPC6 mRNA expression and TRPC6 protein levels. The effects of VEGF165 were dose dependent and could be blocked by phosphoinositide-3-kinase inhibitors. In the presence of cycloheximide, an inhibitor of protein biosynthesis, we did not observe an effect of VEGF on TRPC6 protein levels, indicating...

Irresponsiveness of two retinoblastoma cases to conservative therapy correlates with up- regulation of hERG1 channels and of the VEGF-A pathway

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La Torre Agostino

2010-09-01

Full Text Available Abstract Background Treatment strategies for Retinoblastoma (RB, the most common primary intraocular tumor in children, have evolved over the past few decades and chemoreduction is currently the most popular treatment strategy. Despite success, systemic chemotherapeutic treatment has relevant toxicity, especially in the pediatric population. Antiangiogenic therapy has thus been proposed as a valuable alternative for pediatric malignancies, in particolar RB. Indeed, it has been shown that vessel density correlates with both local invasive growth and presence of metastases in RB, suggesting that angiogenesis could play a pivotal role for both local and systemic invasive growth in RB. We present here two cases of sporadic, bilateral RB that did not benefit from the conservative treatment and we provide evidence that the VEGF-A pathway is significantly up-regulated in both RB cases along with an over expression of hERG1 K+ channels. Case presentation Two patients showed a sporadic, bilateral RB, classified at Stage II of the Reese-Elsworth Classification. Neither of them got benefits from conservative treatment, and the two eyes were enucleated. In samples from both RB cases we studied the VEGF-A pathway: VEGF-A showed high levels in the vitreous, the vegf-a, flt-1, kdr, and hif1-α transcripts were over-expressed. Moreover, both the transcripts and proteins of the hERG1 K+ channels turned out to be up-regulated in the two RB cases compared to the non cancerous retinal tissue. Conclusions We provide evidence that the VEGF-A pathway is up-regulated in two particular aggressive cases of bilateral RB, which did not experience any benefit from conservative treatment, showing the overexpression of the vegf-a, flt-1, kdr and hif1-α transcripts and the high secretion of VEGF-A. Moreover we also show for the first time that the herg1 gene transcripts and protein are over expressed in RB, as occurs in several aggressive tumors. These results further stress

Excess HB-EGF, which promotes VEGF signaling, leads to hydrocephalus

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Shim, Joon W.; Sandlund, Johanna; Hameed, Mustafa Q.; Blazer-Yost, Bonnie; Zhou, Feng C.; Klagsbrun, Michael; Madsen, Joseph R.

2016-01-01

Heparin binding epidermal growth factor-like growth factor (HB-EGF) is an angiogenic factor mediating radial migration of the developing forebrain, while vascular endothelial growth factor (VEGF) is known to influence rostral migratory stream in rodents. Cell migratory defects have been identified in animal models of hydrocephalus; however, the relationship between HB-EGF and hydrocephalus is unclear. We show that mice overexpressing human HB-EGF with β-galactosidase reporter exhibit an elevated VEGF, localization of β-galactosidase outside the subventricular zone (SVZ), subarachnoid hemorrhage, and ventriculomegaly. In Wistar polycystic kidney rats with hydrocephalus, alteration of migratory trajectory is detected. Furthermore, VEGF infusions into the rats result in ventriculomegaly with an increase of SVZ neuroblast in rostral migratory stream, whereas VEGF ligand inhibition prevents it. Our results support the idea that excess HB-EGF leads to a significant elevation of VEGF and ventricular dilatation. These data suggest a potential pathophysiological mechanism that elevated HB-EGF can elicit VEGF induction and hydrocephalus. PMID:27243144

Modulation of VEGF-induced migration and network formation by lymphatic endothelial cells: Roles of platelets and podoplanin.

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Langan, Stacey A; Navarro-Núñez, Leyre; Watson, Steve P; Nash, Gerard B

2017-07-20

Lymphatic endothelial cells (LEC) express the transmembrane receptor podoplanin whose only known endogenous ligand CLEC-2 is found on platelets. Both podoplanin and CLEC-2 are required for normal lymphangiogenesis as mice lacking either protein develop a blood-lymphatic mixing phenotype. We investigated the roles of podoplanin and its interaction with platelets in migration and tube formation by LEC. Addition of platelets or antibody-mediated crosslinking of podoplanin inhibited LEC migration induced by vascular endothelial growth factors (VEGF-A or VEGF-C), but did not modify basal migration or the response to basic fibroblast growth factor or epidermal growth factor. In addition, platelets and podoplanin crosslinking disrupted networks of LEC formed in co-culture with fibroblasts. Depletion of podoplanin in LEC using siRNA negated the pro-migratory effect of VEGF-A and VEGF-C. Inhibition of RhoA or Rho-kinase reduced LEC migration induced by VEGF-C, but had no further effect after crosslinking of podoplanin, suggesting that podoplanin is required for signaling downstream of VEGF-receptors but upstream of RhoA. Together, these data reveal for the first time that podoplanin is an intrinsic specific regulator of VEGF-mediated migration and network formation in LEC and identify crosslinking of podoplanin by platelets or antibodies as mechanisms to modulate this pathway.

Phase I trial of aflibercept (VEGF trap) with radiation therapy and concomitant and adjuvant temozolomide in patients with high-grade gliomas.

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Nayak, Lakshmi; de Groot, John; Wefel, Jeffrey S; Cloughesy, Timothy F; Lieberman, Frank; Chang, Susan M; Omuro, Antonio; Drappatz, Jan; Batchelor, Tracy T; DeAngelis, Lisa M; Gilbert, Mark R; Aldape, Kenneth D; Yung, Alfred W K; Fisher, Joy; Ye, Xiaobu; Chen, Alice; Grossman, Stuart; Prados, Michael; Wen, Patrick Y

2017-03-01

Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGF-A, VEGF-B and placental growth factor, depleting circulating levels of these growth factors. The Adult Brain Tumor Consortium conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed HGG with 2 dose levels and a 3+3 design. Three arms using aflibercept were examined; with radiation and concomitant temozolomide; with adjuvant temozolomide using the 5/28 regimen; and with adjuvant temozolomide using the 21/28 day regimen. Fifty-nine patients were enrolled, 21 in arm 1, 20 in arm 2 and 18 in arm 3. Median age was 56 years (24-69); median KPS 90 (60-100). The maximum tolerated dose (MTD) of aflibercept for all 3 arms was 4 mg/kg every 2 weeks. Dose limiting toxicities at the MTD were: Arm 1: 0/21 patients; Arm 2: 2/20 patients (G3 deep vein thrombosis, G4 neutropenia; Arm 3: 3/18 patients) (G4 biopsy-confirmed thrombotic microangiopathy, G3 rash, G4 thrombocytopenia). The median number of cycles of aflibercept was 5 (range, 1-16). All patients stopped treatment; 28 (47%) for disease progression, 21 (36%) for toxicities, 8 (14%) for other reasons, and 2 (3%) patients completed the full treatment course. This study met its primary endpoint and the MTD of aflibercept with radiation and concomitant and adjuvant temozolomide is 4 mg/kg every 2 weeks.

PPARγ controls pregnancy outcome through activation of EG-VEGF: new insights into the mechanism of placental development.

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Garnier, Vanessa; Traboulsi, Wael; Salomon, Aude; Brouillet, Sophie; Fournier, Thierry; Winkler, Carine; Desvergne, Beatrice; Hoffmann, Pascale; Zhou, Qun-Yong; Congiu, Cenzo; Onnis, Valentina; Benharouga, Mohamed; Feige, Jean-Jacques; Alfaidy, Nadia

2015-08-15

PPARγ-deficient mice die at E9.5 due to placental abnormalities. The mechanism by which this occurs is unknown. We demonstrated that the new endocrine factor EG-VEGF controls the same processes as those described for PPARγ, suggesting potential regulation of EG-VEGF by PPARγ. EG-VEGF exerts its functions via prokineticin receptor 1 (PROKR1) and 2 (PROKR2). This study sought to investigate whether EG-VEGF mediates part of PPARγ effects on placental development. Three approaches were used: 1) in vitro, using human primary isolated cytotrophoblasts and the extravillous trophoblast cell line (HTR-8/SVneo); 2) ex vivo, using human placental explants (n = 46 placentas); and 3) in vivo, using gravid wild-type PPARγ(+/-) and PPARγ(-/-) mice. Major processes of placental development that are known to be controlled by PPARγ, such as trophoblast proliferation, migration, and invasion, were assessed in the absence or presence of PROKR1 and PROKR2 antagonists. In both human trophoblast cell and placental explants, we demonstrated that rosiglitazone, a PPARγ agonist, 1) increased EG-VEGF secretion, 2) increased EG-VEGF and its receptors mRNA and protein expression, 3) increased placental vascularization via PROKR1 and PROKR2, and 4) inhibited trophoblast migration and invasion via PROKR2. In the PPARγ(-/-) mouse placentas, EG-VEGF levels were significantly decreased, supporting an in vivo control of EG-VEGF/PROKRs system during pregnancy. The present data reveal EG-VEGF as a new mediator of PPARγ effects during pregnancy and bring new insights into the fine mechanism of trophoblast invasion. Copyright © 2015 the American Physiological Society.

K20E, an oxidative-coupling compound of methyl caffeate, exhibits anti-angiogenic activities through down-regulations of VEGF and VEGF receptor-2

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Pan, Chun-Hsu [Department of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan (China); Lin, Wen-Hsin; Chien, Yi-Chung; Liu, Fon-Chang; Sheu, Ming-Jyh [School of Pharmacy, China Medical University, Taichung 40402, Taiwan (China); Kuo, Yueh-Hsiung, E-mail: kuoyh@mail.cmu.edu.tw [Tsuzuki Institute for Traditional Medicine, China Medical University, Taichung 40402, Taiwan (China); Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 40402, Taiwan (China); Department of Biotechnology, Asia University, Taichung 41354, Taiwan (China); Wu, Chieh-Hsi, E-mail: chhswu@tmu.edu.tw [Department of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan (China); School of Pharmacy, China Medical University, Taichung 40402, Taiwan (China); Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan (China)

2015-01-15

Anti-angiogenesis is one of the most popular clinical interventions for cancer chemotherapy. A series of synthesized derivative of methyl caffeate were used to evaluate the anti-angiogenic activity and to investigate possible pharmacological mechanisms in the present study. The most potent anti-angiogenic compound was evaluated in the experiments of murine allograft tumor model and Matrigel plug assay as well as cell models in the human umbilical vascular endothelial cells (HUVECs) and the LLC1 lung cancer cells. Our results suggested that K20E suppressed the tumor growth in the allograft tumor model and exhibited anti-angiogenic activity in Matrigel plug assay. Besides, HUVEC viability was found to be significantly reduced by arresting cell cycle at G{sub 2}/M phase and apoptosis. Cell migration, invasion, and tube formation of the HUVECs were also markedly suppressed by K20E treatment. K20E largely down-regulated the intracellular and secreted vascular endothelial growth factor (VEGF) in the LLC1 cancer cells. Besides, VEGF receptor-2 (VEGFR-2) and its downstream signaling cascades (AKT-mTOR and MEK1/2-ERK1/2) as well as gelatinases were all evidently reduced in the HUVECs treated with K20E. Inversely, K20E can up-regulate the expression levels of p53 and p21 proteins in the HUVECs. Based on these results, our study suggested that K20E possessed inhibiting angiogenesis through regulation of VEGF/VEGFR-2 and its downstream signaling cascades in the vascular endothelial cells (VECs). - Highlights: • K20E is an oxidative-coupling compound of methyl caffeate. • K20E exhibits anti-tumor and anti-angiogenesis effects. • K20E suppresses the expressions of VEGF and VEGF receptor-2 (VEGFR-2) proteins. • K20E deactivates VEGFR-2-mediated downstream signaling pathways to inhibit angiogenesis. • K20E up-regulates p53-p21 pathway to induce apoptosis and cell arrest at G2/M phase.

SREBP inhibits VEGF expression in human smooth muscle cells

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Motoyama, Koka [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Fukumoto, Shinya [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Koyama, Hidenori [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Emoto, Masanori [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan); Shimano, Hitoshi [Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki (Japan); Maemura, Koji [Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo (Japan); Nishizawa, Yoshiki [Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka (Japan)

2006-03-31

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate expression of genes encoding enzymes for lipid biosynthesis. SREBPs are activated by HMG-CoA reductase inhibitors (statins). Statins have been also reported to suppress vascular endothelial growth factor (VEGF) expression in vascular smooth muscle cells (VSMCs). Therefore, we hypothesized that SREBPs are involved in statin-mediated regulation of VEGF production in VSMCs. SREBP1 was robustly expressed, and was activated by atorvastatin in VSMCs, as demonstrated by increased levels of the mature nuclear form of SREBP1, and increased promoter activities of a reporter containing sterol regulatory elements by atorvastatin. Moreover, overexpression of SREBP1a dose-dependently suppressed VEGF promoter activity. Site-specific mutation or deletion of the proximal Sp1 sites reduced the inhibitory effects of SREBP1a on VEGF promoter activity. These data demonstrated that SREBP1, activated by atorvastatin, suppressed VEGF expression through the indirect interaction with the proximal tandem Sp1 sites in VSMCs.

SREBP inhibits VEGF expression in human smooth muscle cells

International Nuclear Information System (INIS)

Motoyama, Koka; Fukumoto, Shinya; Koyama, Hidenori; Emoto, Masanori; Shimano, Hitoshi; Maemura, Koji; Nishizawa, Yoshiki

2006-01-01

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate expression of genes encoding enzymes for lipid biosynthesis. SREBPs are activated by HMG-CoA reductase inhibitors (statins). Statins have been also reported to suppress vascular endothelial growth factor (VEGF) expression in vascular smooth muscle cells (VSMCs). Therefore, we hypothesized that SREBPs are involved in statin-mediated regulation of VEGF production in VSMCs. SREBP1 was robustly expressed, and was activated by atorvastatin in VSMCs, as demonstrated by increased levels of the mature nuclear form of SREBP1, and increased promoter activities of a reporter containing sterol regulatory elements by atorvastatin. Moreover, overexpression of SREBP1a dose-dependently suppressed VEGF promoter activity. Site-specific mutation or deletion of the proximal Sp1 sites reduced the inhibitory effects of SREBP1a on VEGF promoter activity. These data demonstrated that SREBP1, activated by atorvastatin, suppressed VEGF expression through the indirect interaction with the proximal tandem Sp1 sites in VSMCs

Role of EG-VEGF in human placentation: Physiological and pathological implications.

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Hoffmann, Pascale; Saoudi, Yasmina; Benharouga, Mohamed; Graham, Charles H; Schaal, Jean-Patrick; Mazouni, Chafika; Feige, Jean-Jacques; Alfaidy, Nadia

2009-08-01

Pre-eclampsia (PE), the major cause of maternal morbidity and mortality, is thought to be caused by shallow invasion of the maternal decidua by extravillous trophoblasts (EVT). Data suggest that a fine balance between the expressions of pro- and anti-invasive factors might regulate EVT invasiveness. Recently, we showed that the expression of the new growth factor endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is high in early pregnancy but falls after 11 weeks, suggesting an essential role for this factor in early pregnancy. Using human villous explants and HTR-8/SVneo, a first trimester extravillous trophoblast cell line, we showed differential expression of EG-VEGF receptors, PKR1 and PKR2, in the placenta and demonstrated that EG-VEGF inhibits EVT migration, invasion and tube-like organisation. EG-VEGF inhibitory effect on invasion was supported by a decrease in matrix metalloproteinase (MMP)-2 and MMP-9 production. Interference with PKR2 expression, using specific siRNAs, reversed the EG-VEGF-induced inhibitory effects. Furthermore, we determined EG-VEGF circulating levels in normal and PE patients. Our results showed that EG-VEGF levels were highest during the first trimester of pregnancy and decreased thereafter to non-pregnant levels. More important, EG-VEGF levels were significantly elevated in PE patients compared with age-matched controls. These findings identify EG-VEGF as a novel paracrine regulator of trophoblast invasion. We speculate that a failure to correctly down-regulate placental expression of EG-VEGF at the end of the first trimester of pregnancy might lead to PE.

Radioiodinated VEGF to image tumor angiogenesis in a LS180 tumor xenograft model

International Nuclear Information System (INIS)

Yoshimoto, Mitsuyoshi; Kinuya, Seigo; Kawashima, Atsuhiro; Nishii, Ryuichi; Yokoyama, Kunihiko; Kawai, Keiichi

2006-01-01

Introduction: Angiogenesis is essential for tumor growth or metastasis. A method involving noninvasive detection of angiogenic activity in vivo would provide diagnostic information regarding antiangiogenic therapy targeting vascular endothelial cells as well as important insight into the role of vascular endothelial growth factor (VEGF) and its receptor (flt-1 and KDR) system in tumor biology. We evaluated radioiodinated VEGF 121 , which displays high binding affinity for KDR, and VEGF 165 , which possesses high binding affinity for flt-1 and low affinity for KDR, as angiogenesis imaging agents using the LS180 tumor xenograft model. Methods: VEGF 121 and VEGF 165 were labeled with 125 I by the chloramine-T method. Biodistribution was observed in an LS180 human colon cancer xenograft model. Additionally, autoradiographic imaging and immunohistochemical staining of tumors were performed with 125 I-VEGF 121 . Results: 125 I-VEGF 121 and 125 I-VEGF 165 exhibited strong, continuous uptake by tumors and the uterus, an organ characterized by angiogenesis. 125 I-VEGF 121 uptake in tumors was twofold higher than that of 125 I-VEGF 165 (9.12±98 and 4.79±1.08 %ID/g at 2 h, respectively). 125 I-VEGF 121 displayed higher tumor to nontumor (T/N) ratios in most normal organs in comparison with 125 I-VEGF 165 . 125 I-VEGF 121 accumulation in tumors decreased with increasing tumor volume. Autoradiographic and immunohistochemical analyses confirmed that the difference in 125 I-VEGF 121 tumor accumulation correlated with degree of tumor vascularity. Conclusion: Radioiodinated VEGF 121 is a promising tracer for noninvasive delineation of angiogenesis in vivo

Potent neutralization of VEGF biological activities with a fully human antibody Fab fragment directed against VEGF receptor 2

International Nuclear Information System (INIS)

Miao, H.-Q.; Hu, Kun; Jimenez, Xenia; Navarro, Elizabeth; Zhang, Haifan; Lu Dan; Ludwig, Dale L.; Balderes, Paul; Zhu Zhenping

2006-01-01

Compelling evidence suggest that vascular endothelial growth factor (VEGF) and its receptors, especially receptor 2 (VEGFR2, or kinase insert domain-containing receptor, KDR), play a critical role in angiogenesis under both physiological and pathological conditions, including cancer and angiogenic retinopathies such as age-related macular degeneration (AMD). To this end, inhibition of angiogenesis with antagonists to either VEGF or KDR has yielded significant therapeutic efficacy both in preclinical studies in animal models and in clinical trials in patients with cancer and AMD. We previously reported the identification of a high affinity, fully human anti-KDR antibody fragment, 1121B Fab, through a highly stringent affinity maturation process with a Fab originally isolated from a naive human antibody phage display library. In this study, we demonstrate that 1121B Fab is able to strongly block KDR/VEGF interaction, resulting in potent inhibition of an array of biological activities of VEGF, including activation of the receptor and its signaling pathway, intracellular calcium mobilization, and migration and proliferation of endothelial cells. Taken together, our data lend strong support to the further development of 1121B Fab fragment as an anti-angiogenesis agent in both cancer and angiogenic retinopathies

EG-VEGF: a key endocrine factor in placental development.

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Brouillet, Sophie; Hoffmann, Pascale; Feige, Jean-Jacques; Alfaidy, Nadia

2012-10-01

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF), also named prokineticin 1, is the canonical member of the prokineticin family. Numerous reports suggest a direct involvement of this peptide in normal and pathological reproductive processes. Recent advances propose EG-VEGF as a key endocrine factor that controls many aspects of placental development and suggest its involvement in the development of preeclampsia (PE), the most threatening pathology of human pregnancy. This review describes the finely tuned action and regulation of EG-VEGF throughout human pregnancy, argues for its clinical relevance as a potential diagnostic marker of the onset of PE, and discusses future research directions for therapeutic targeting of EG-VEGF. Copyright © 2012 Elsevier Ltd. All rights reserved.

Determination of serum leptin and vascular endothelial growth factor (VEGF) contents in patients with breast cancer

International Nuclear Information System (INIS)

Huang Xudong; Jin Wentao; Pan Meizhen

2006-01-01

Objective: To investigate the serum expression of leptin and vascular endothelial growth factor (VEGF) in patients with breast cancer and assess its diagnostic significance. Methods: Thirty-six patients with breast cancer and thirty-one patients with benign breast disorders entered this study. Serum concentration of leptin (with RIA) and VEGF ( with ELISA) were determined in these patients before operation as well as in 56 controls. All the tested subjects were post-menopausal women. Results: The difference between the leptin levels in the controls and patients with benign breast disorders was significantly; 80 was the difference between the leptin levels in controls and patients with breast cancer. Significant difference also existed between the VEGF levels in controls and patients with cancer as well as between the levels in patients with benign breast disease and patients with cancer. Also, the serum leptin and VEGF levels in the cancerous patients with axillary metastasis were significantly higher than those in patients without metastasis. Conclusion: Serum leptin and VEGF might be taken as diagnostic tumor markers for malignanay and metastasis in patients with breast cancer. (authors)

Analysis on concentration of VEGF in aqueous humor in patients with wAMD after Ranibizumab treating at high altitude

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Rui-Juan Guan

2017-05-01

Full Text Available AIM: To study the concentration of vascular endothelial growth factor(VEGFin aqueous humor in patients with wet age-related macular degeneration(wAMDbefore and after Ranibizumab treating at high altitude and the correlation of VEGF concentration with central fovea macula thickness. METHODS: The patients with wAMD in our hospital from Jun. 2014. to Oct. 2015 were retrospectively analyzed, diagnosed after best corrected visual acuity, intraocular pressure, fundus examination, fundus color photography, fluorescence fundus angiography(FFAand optical coherence tomography(OCTinspection. Seventy- six patients with cataract without choroidal neovascularization(CNVwere selected as control group. In the 76 patients(76 eyes, 46 were male, 30 were female, aged 40-80(55±11.18. The course was 0.3-6mo. The corrected visual acuity was 0.01-0.6. The intraocular press was 15.24±3.12mmHg. The CNV in all cases was within the range of the 500μm in diameter. Under surface anesthesia, Ranibizumab(0.5mgwas injected into vitreous cavity. Before and after injection, aqueous humor was obtained and used to detect the concentration of VEGF through ELISA. Best corrected visual acuity, slit lamp microscope, intraocular pressure, OCT and FFA were observed after treatment. RESULTS:The clinical curative effect is the best at 1mo after treatment with statistical significance(PPPCONCLUSION: For wAMD patients, Ranibizumab injection is effective for it reduces the concentration of VEGF in aqueous humor and the central fovea macula thickness. The VEGF concentration in aqueous humor and foveal retinal thickness has a positive correlation.

Regulation of VEGF signaling by membrane traffic.

Science.gov (United States)

Horowitz, Arie; Seerapu, Himabindu Reddy

2012-09-01

Recent findings have drawn attention to the role of membrane traffic in the signaling of vascular endothelial growth factor (VEGF). The significance of this development stems from the pivotal function of VEGF in vasculogenesis and angiogenesis. The outline of the regulation of VEGF receptor (VEGFR) signaling by membrane traffic is similar to that of the epidermal growth factor receptor (EGFR), a prototype of the intertwining between membrane traffic and signaling. There are, however, unique features in VEGFR signaling that are conferred in part by the involvement of the co-receptor neuropilin (Nrp). Nrp1 and VEGFR2 are integrated into membrane traffic through the adaptor protein synectin, which recruits myosin VI, a molecular motor that drives inward trafficking [17,21,64]. The recent detection of only mild vascular defects in a knockin mouse model that expresses Nrp1 lacking a cytoplasmic domain [104], questions the co-receptor's role in VEGF signaling and membrane traffic. The regulation of endocytosis by ephrin-B2 is another feature unique to VEGR2/3 [18,19], but it awaits a mechanistic explanation. Current models do not fully explain how membrane traffic bridges between VEGFR and the downstream effectors that produce its functional outcome, such as cell migration. VEGF-A appears to accomplish this task in part by recruiting endocytic vesicles carrying RhoA to internalized active VEGFR2 [58]. Copyright © 2012 Elsevier Inc. All rights reserved.

Investigation of retinal damage during refractive eye surgery

Science.gov (United States)

Schumacher, S.; Sander, M.; Dopke, C.; Grone, A.; Ertmer, W.; Lubatschowski, H.

2005-04-01

Ultrashort laser pulses are increasingly used in refractive eye surgery to cut inside transparent corneal tissue. This is exploited by the fs-LASIK procedure which affords the opportunity to correct ametropia without any mechanical effects. The cutting process is caused by the optical breakdown occurring in the laser focus. During this process only a certain amount of the pulse energy is deposited into the tissue. The remaining pulse energy propagates further through the eye and interacts with the retina and the strong absorbing tissue layers behind. Therefore this investigation shall clarify if the intensity of the remaining laser pulse and the resulting temperature field can damage the retina and the surrounding tissue. Threshold values of the retinal tissue and theoretical calculations of the temperature field will be presented.

The electron trap parameter extraction-based investigation of the relationship between charge trapping and activation energy in IGZO TFTs under positive bias temperature stress

Science.gov (United States)

Rhee, Jihyun; Choi, Sungju; Kang, Hara; Kim, Jae-Young; Ko, Daehyun; Ahn, Geumho; Jung, Haesun; Choi, Sung-Jin; Myong Kim, Dong; Kim, Dae Hwan

2018-02-01

Experimental extraction of the electron trap parameters which are associated with charge trapping into gate insulators under the positive bias temperature stress (PBTS) is proposed and demonstrated for the first time in amorphous indium-gallium-zinc-oxide thin-film transistors. This was done by combining the PBTS/recovery time-evolution of the experimentally decomposed threshold voltage shift (ΔVT) and the technology computer-aided design (TCAD)-based charge trapping simulation. The extracted parameters were the trap density (NOT) = 2.6 × 1018 cm-3, the trap energy level (ΔET) = 0.6 eV, and the capture cross section (σ0) = 3 × 10-19 cm2. Furthermore, based on the established TCAD framework, the relationship between the electron trap parameters and the activation energy (Ea) is comprehensively investigated. It is found that Ea increases with an increase in σ0, whereas Ea is independent of NOT. In addition, as ΔET increases, Ea decreases in the electron trapping-dominant regime (low ΔET) and increases again in the Poole-Frenkel (PF) emission/hopping-dominant regime (high ΔET). Moreover, our results suggest that the cross-over ΔET point originates from the complicated temperature-dependent competition between the capture rate and the emission rate. The PBTS bias dependence of the relationship between Ea and ΔET suggests that the electric field dependence of the PF emission-based electron hopping is stronger than that of the thermionic field emission-based electron trapping.

The growth and aggressive behavior of human osteosarcoma is regulated by a CaMKII-controlled autocrine VEGF signaling mechanism.

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Daft, Paul G; Yang, Yang; Napierala, Dobrawa; Zayzafoon, Majd

2015-01-01

Osteosarcoma (OS) is a hyperproliferative malignant tumor that requires a high vascular density to maintain its large volume. Vascular Endothelial Growth Factor (VEGF) plays a crucial role in angiogenesis and acts as a paracrine and autocrine agent affecting both endothelial and tumor cells. The alpha-Ca2+/Calmodulin kinase two (α-CaMKII) protein is an important regulator of OS growth. Here, we investigate the role of α-CaMKII-induced VEGF in the growth and tumorigenicity of OS. We show that the pharmacologic and genetic inhibition of α-CaMKII results in decreases in VEGF gene expression (50%) and protein secretion (55%), while α- CaMKII overexpression increases VEGF gene expression (250%) and protein secretion (1,200%). We show that aggressive OS cells (143B) express high levels of VEGF receptor 2 (VEGFR-2) and respond to exogenous VEGF (100nm) by increasing intracellular calcium (30%). This response is ameliorated by the VEGFR inhibitor CBO-P11, suggesting that secreted VEGF results in autocrine stimulated α-CaMKII activation. Furthermore, we show that VEGF and α-CaMKII inhibition decreases the transactivation of the HIF-1α and AP-1 reporter constructs. Additionally, chromatin immunoprecipitation assay shows significantly decreased binding of HIF-1α and AP-1 to their responsive elements in the VEGF promoter. These data suggest that α-CaMKII regulates VEGF transcription by controlling HIF-1α and AP-1 transcriptional activities. Finally, CBO-P11, KN-93 (CaMKII inhibitor) and combination therapy significantly reduced tumor burden in vivo. Our results suggest that VEGF-induced OS tumor growth is controlled by CaMKII and dual therapy by CaMKII and VEGF inhibitors could be a promising therapy against this devastating adolescent disease.

The growth and aggressive behavior of human osteosarcoma is regulated by a CaMKII-controlled autocrine VEGF signaling mechanism.

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Paul G Daft

Full Text Available Osteosarcoma (OS is a hyperproliferative malignant tumor that requires a high vascular density to maintain its large volume. Vascular Endothelial Growth Factor (VEGF plays a crucial role in angiogenesis and acts as a paracrine and autocrine agent affecting both endothelial and tumor cells. The alpha-Ca2+/Calmodulin kinase two (α-CaMKII protein is an important regulator of OS growth. Here, we investigate the role of α-CaMKII-induced VEGF in the growth and tumorigenicity of OS. We show that the pharmacologic and genetic inhibition of α-CaMKII results in decreases in VEGF gene expression (50% and protein secretion (55%, while α- CaMKII overexpression increases VEGF gene expression (250% and protein secretion (1,200%. We show that aggressive OS cells (143B express high levels of VEGF receptor 2 (VEGFR-2 and respond to exogenous VEGF (100nm by increasing intracellular calcium (30%. This response is ameliorated by the VEGFR inhibitor CBO-P11, suggesting that secreted VEGF results in autocrine stimulated α-CaMKII activation. Furthermore, we show that VEGF and α-CaMKII inhibition decreases the transactivation of the HIF-1α and AP-1 reporter constructs. Additionally, chromatin immunoprecipitation assay shows significantly decreased binding of HIF-1α and AP-1 to their responsive elements in the VEGF promoter. These data suggest that α-CaMKII regulates VEGF transcription by controlling HIF-1α and AP-1 transcriptional activities. Finally, CBO-P11, KN-93 (CaMKII inhibitor and combination therapy significantly reduced tumor burden in vivo. Our results suggest that VEGF-induced OS tumor growth is controlled by CaMKII and dual therapy by CaMKII and VEGF inhibitors could be a promising therapy against this devastating adolescent disease.

Investigation on de-trapping mechanisms related to non-monotonic kink pattern in GaN HEMT devices

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Chandan Sharma

2017-08-01

Full Text Available This article reports an experimental approach to analyze the kink effect phenomenon which is usually observed during the GaN high electron mobility transistor (HEMT operation. De-trapping of charge carriers is one of the prominent reasons behind the kink effect. The commonly observed non-monotonic behavior of kink pattern is analyzed under two different device operating conditions and it is found that two different de-trapping mechanisms are responsible for a particular kink behavior. These different de-trapping mechanisms are investigated through a time delay analysis which shows the presence of traps with different time constants. Further voltage sweep and temperature analysis corroborates the finding that different de-trapping mechanisms play a role in kink behavior under different device operating conditions.

Investigation on de-trapping mechanisms related to non-monotonic kink pattern in GaN HEMT devices

Science.gov (United States)

Sharma, Chandan; Laishram, Robert; Amit, Rawal, Dipendra Singh; Vinayak, Seema; Singh, Rajendra

2017-08-01

This article reports an experimental approach to analyze the kink effect phenomenon which is usually observed during the GaN high electron mobility transistor (HEMT) operation. De-trapping of charge carriers is one of the prominent reasons behind the kink effect. The commonly observed non-monotonic behavior of kink pattern is analyzed under two different device operating conditions and it is found that two different de-trapping mechanisms are responsible for a particular kink behavior. These different de-trapping mechanisms are investigated through a time delay analysis which shows the presence of traps with different time constants. Further voltage sweep and temperature analysis corroborates the finding that different de-trapping mechanisms play a role in kink behavior under different device operating conditions.

[Systemic safety following intravitreal injections of anti-VEGF].

Science.gov (United States)

Baillif, S; Levy, B; Girmens, J-F; Dumas, S; Tadayoni, R

2018-03-01

The goal of this manuscript is to assess data suggesting that intravitreal injection of anti-vascular endothelial growth factors (anti-VEGFs) could result in systemic adverse events (AEs). The class-specific systemic AEs should be similar to those encountered in cancer trials. The most frequent AE observed in oncology, hypertension and proteinuria, should thus be the most common expected in ophthalmology, but their severity should be lower because of the much lower doses of anti-VEGFs administered intravitreally. Such AEs have not been frequently reported in ophthalmology trials. In addition, pharmacokinetic and pharmacodynamic data describing systemic diffusion of anti-VEGFs should be interpreted with caution because of significant inconsistencies reported. Thus, safety data reported in ophthalmology trials and pharmacokinetic/pharmacodynamic data provide robust evidence that systemic events after intravitreal injection are very unlikely. Additional studies are needed to explore this issue further, as much remains to be understood about local and systemic side effects of anti-VEGFs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

c-myc Amplification Is Frequent in Esophageal Adenocarcinoma and Correlated with the Upregulation of VEGF-A Expression

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Burkhard H.A. von Rahden

2006-09-01

Full Text Available BACKGROUND: Deregulation of c-myc plays a major role in the carcinogenesis of human malignancies. We investigated the amplification of the c-myc gene in a surgical series of Barrett cancers. METHODS: Primary resected esophageal (Barrett adenocarcinomas (n = 84 were investigated for c-myc amplification using chromogene in situ hybridization. Tumor samples were assembled in a tissue microarray. c-myc gene dosage was correlated with clinicopathologic parameters, including the survival and gene expression of cyclooxygenases (COX-1 and COX-2 and proangiogenic growth factors (VEGF-A and VEGF-C. RESULTS: The majority (70 of 84; 83.3% exhibited amplification of the c-myc gene. There were low-level amplifications in 63 (75.0% cases and high-level amplifications in 7 (8.3% cases. No amplification was found in 14 (16.7% cases. Tumors without c-myc amplification had lower VEGF-A, VEGF-C, and COX-2 expression levels than tumors with low-level and high-level c-myc amplification (statistically significant for VEGF-A; P = .0348. c-myc amplification was not correlated with clinicopathological parameters or survival. Only diffuse and mixed-type tumors, according to Lauren classification, exhibited c-myc amplifications more frequently (P = .0466. CONCLUSIONS: Amplifications of the c-myc gene are frequent in Barrett cancer. c-myc may be involved in the regulation of angiogenesis.

The role of VEGF and KDR polymorphisms in moyamoya disease and collateral revascularization.

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Young Seok Park

Full Text Available We conducted a case-control study to investigate whether vascular endothelial growth factor (VEGF -2578, -1154, -634, and 936 and kinase insert domain containing receptor (KDR -604, 1192, and 1719 polymorphisms are associated with moyamoya disease. Korean patients with moyamoya disease (n = 107, mean age, 20.9±15.9 years; 66.4% female and 243 healthy control subjects (mean age, 23.0±16.1 years; 56.8% female were included. The subjects were divided into pediatric and adult groups. Among the 64 surgical patients, we evaluated collateral vessel formation after 2 years and divided patients into good (collateral grade A or poor (collateral grade B and C groups. The frequencies and distributions of four VEGF (-2578, -1154, -634, and 936 and KDR (-604, 1192, and 1719 polymorphisms were assessed from patients with moyamoya disease and compared to the control group. No differences were observed in VEGF -2578, -1154, -634, and 936 or KDR -604, 1192, and 1719 polymorphisms between the control group and moyamoya disease group. However, we found the -634CC genotype occurred less frequently in the pediatric moyamoya group (p = 0.040 whereas the KDR -604C/1192A/1719T haplotype increased the risk of pediatric moyamoya (p = 0.024. Patients with the CC genotype of VEGF -634 had better collateral vessel formation after surgery. Our results suggest that the VEGF -634G allele is associated with pediatric moyamoya disease and poor collateral vessel formation.

Expression of Ang-2 and VEGF in the endometriosis

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Xiao-Li Chen

2016-01-01

Full Text Available Objective: To detect the expression of Ang-2 and VEGF in the endometriosis (EMT, and to explore the correlation of Ang-2 and VEGF with the pathogenesis of EMT. Methods: A total of 60 patients with EMT who were confirmed by laparoscopy and admitted in our hospital from August, 2014 to August, 2015 were included in the study and served as the observation group; moreover, 60 women who came for laparoscopy at the same stage were served as the control group. A volume of 5mL morning fasting elbow venous blood in the two groups was extracted, standing in the room temperature for 1h, centrifuged at 3 500 r/min for 20 min. The supernatant was extracted and stored at -70 ℃ for inspection. During the laparoscopy, a volume of 5 mL peritoneal fluid was collected, standing in the room temperature for 1 h, centrifuged at 3 500 r/min for 20 min. The supernatant was extracted and stored at -70 ℃ for inspection. ELISA was used to detect the levels of Ang-2 and VEGF. Results: The levels of Ang-2 and VEGF in the serum and peritoneal fluid in the observation group were significantly higher than those in the control group (P<0.05. The serum Ang-2 level in the severe patients was significantly higher than that in the mild patients, while the comparison of VEGF was not statistically significant. The levels of Ang-2 and VEGF in the peritoneal fluid in the severe patients were significantly higher than those in the mild patients. Conclusions: Ang-2 and VEGF can promote the angiogenesis in EMT patients, and their high expressions in the serum and peritoneal fluid are correlated with the occurrence and development of EMT; therefore, detection of the levels of Ang-2 and VEGF is of great significance in estimating the progression of EMT in the clinic.

MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia.

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Zhong Hua

Full Text Available MicroRNAs (miRNAs are a class of 20-24 nt non-coding RNAs that regulate gene expression primarily through post-transcriptional repression or mRNA degradation in a sequence-specific manner. The roles of miRNAs are just beginning to be understood, but the study of miRNA function has been limited by poor understanding of the general principles of gene regulation by miRNAs. Here we used CNE cells from a human nasopharyngeal carcinoma cell line as a cellular system to investigate miRNA-directed regulation of VEGF and other angiogenic factors under hypoxia, and to explore the principles of gene regulation by miRNAs. Through computational analysis, 96 miRNAs were predicted as putative regulators of VEGF. But when we analyzed the miRNA expression profile of CNE and four other VEGF-expressing cell lines, we found that only some of these miRNAs could be involved in VEGF regulation, and that VEGF may be regulated by different miRNAs that were differentially chosen from 96 putative regulatory miRNAs of VEGF in different cells. Some of these miRNAs also co-regulate other angiogenic factors (differential regulation and co-regulation principle. We also found that VEGF was regulated by multiple miRNAs using different combinations, including both coordinate and competitive interactions. The coordinate principle states that miRNAs with independent binding sites in a gene can produce coordinate action to increase the repressive effect of miRNAs on this gene. By contrast, the competitive principle states when multiple miRNAs compete with each other for a common binding site, or when a functional miRNA competes with a false positive miRNA for the same binding site, the repressive effects of miRNAs may be decreased. Through the competitive principle, false positive miRNAs, which cannot directly repress gene expression, can sometimes play a role in miRNA-mediated gene regulation. The competitive principle, differential regulation, multi-miRNA binding sites, and false

VEGF improves survival of mesenchymal stem cells in infarcted hearts

International Nuclear Information System (INIS)

Pons, Jennifer; Huang Yu; Arakawa-Hoyt, Janice; Washko, Daniel; Takagawa, Junya; Ye, Jianqin; Grossman, William; Su Hua

2008-01-01

Bone marrow-derived mesenchymal stem cells (MSC) are a promising source for cell-based treatment of myocardial infarction (MI), but existing strategies are restricted by low cell survival and engraftment. We examined whether vascular endothelial growth factor (VEGF) improve MSC viability in infracted hearts. We found long-term culture increased MSC-cellular stress: expressing more cell cycle inhibitors, p16 INK , p21 and p19 ARF . VEGF treatment reduced cellular stress, increased pro-survival factors, phosphorylated-Akt and Bcl-xL expression and cell proliferation. Co-injection of MSCs with VEGF to MI hearts increased cell engraftment and resulted in better improvement of cardiac function than that injected with MSCs or VEGF alone. In conclusion, VEGF protects MSCs from culture-induce cellular stress and improves their viability in ischemic myocardium, which results in improvements of their therapeutic effect for the treatment of MI

Shrew trap efficiency

DEFF Research Database (Denmark)

Gambalemoke, Mbalitini; Mukinzi, Itoka; Amundala, Drazo

2008-01-01

We investigated the efficiency of four trap types (pitfall, Sherman LFA, Victor snap and Museum Special snap traps) to capture shrews. This experiment was conducted in five inter-riverine forest blocks in the region of Kisangani. The total trapping effort was 6,300, 9,240, 5,280 and 5,460 trap......, our results indicate that pitfall traps are the most efficient for capturing shrews: not only do they have a higher efficiency (yield), but the taxonomic diversity of shrews is also higher when pitfall traps are used....

Clinical significance of determination of changes of plasma vascular endothelial growth factor (VEGF) contents after treatment in patients with acute leukemia

International Nuclear Information System (INIS)

Guo Min

2006-01-01

Objective: To investigate the changes of plasma VEGF after treatment in patients with acute leukemia. Methods: Plasma VEGF levels were determined with (ELISA) in 34 patients with acute leukemia both before and after treatment as well as in 35 controls. Results: Before treatment the plasma levels of VEGF levels in patients were significantly higher than those in the controls (P<0.01). After three months of treatment the levels dropped markedly but still remained significantly higher than those in controls (P<0.05). Conclusion: Development of acute leukemia was closely related to the plasma levels of VEGF. (authors)

NLRC5 promotes cell proliferation via regulating the AKT/VEGF-A signaling pathway in hepatocellular carcinoma

International Nuclear Information System (INIS)

He, Ying-hua; Li, Ming-fang; Zhang, Xing-yan; Meng, Xiao-ming; Huang, Cheng; Li, Jun

2016-01-01

NLRC5, a newly found member of the NLR family and the largest member of nucleotide-binding, has been reported to regulate immune responses and is associated with hepatocellular carcinoma (HCC). We investigated the mechanisms and signaling pathways of NLRC5 in HCC progression. Increased expression of NLRC5, vascular endothelial growth factor-A (VEGF-A) were found in human HCC tissue. There was a positive correlation between NLRC5 and VEGF-A expression and cell proliferation were enhanced in NLRC5-overexpressing HepG2 cells, but inhibited in cells with NLRC5 silencing treatment. Interestingly, we found that up-regulation of NLRC5 also coordinated the activation of PI3K/AKT signaling pathway. An AKT inhibitor LY294002 blocked VEGF-A expression and AKT phosphorylation in HepG2 cells and NLRC5-overexpressing HepG2 cells. These results demonstrate that NLRC5 promotes HCC progression via the AKT/VEGF-A signaling pathway.

Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis

International Nuclear Information System (INIS)

Shibuya, Masabumi; Claesson-Welsh, Lena

2006-01-01

The VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) ligands and receptors are crucial regulators of vasculogenesis, angiogenesis, lymphangiogenesis and vascular permeability in vertebrates. VEGF-A, the prototype VEGF ligand, binds and activates two tyrosine kinase receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). VEGFR1, which occurs in transmembrane and soluble forms, negatively regulates vasculogenesis and angiogenesis during early embryogenesis, but it also acts as a positive regulator of angiogenesis and inflammatory responses, playing a role in several human diseases such as rheumatoid arthritis and cancer. The soluble VEGFR1 is overexpressed in placenta in preeclampsia patients. VEGFR2 has critical functions in physiological and pathological angiogenesis through distinct signal transduction pathways regulating proliferation and migration of endothelial cells. VEGFR3, a receptor for the lymphatic growth factors VEGF-C and VEGF-D, but not for VEGF-A, regulates vascular and lymphatic endothelial cell function during embryogenesis. Loss-of-function variants of VEGFR3 have been identified in lymphedema. Formation of tumor lymphatics may be stimulated by tumor-produced VEGF-C, allowing increased spread of tumor metastases through the lymphatics. Mapping the signaling system of these important receptors may provide the knowledge necessary to suppress specific signaling pathways in major human diseases

Intravitreally Injected Anti-VEGF Antibody Reduces Brown Fat in Neonatal Mice.

Science.gov (United States)

Jo, Dong Hyun; Park, Sung Wook; Cho, Chang Sik; Powner, Michael B; Kim, Jin Hyoung; Fruttiger, Marcus; Kim, Jeong Hun

2015-01-01

Anti-vascular endothelial growth factor (VEGF) agents are the mainstay treatment for various angiogenesis-related retinal diseases. Currently, bevacizumab, a recombinant humanized anti-VEGF antibody, is trailed in retinopathy of prematurity, a vasoproliferative retinal disorder in premature infants. However, the risks of systemic complications after intravitreal injection of anti-VEGF antibody in infants are not well understood. In this study, we show that intravitreally injected anti-VEGF antibody is transported into the systemic circulation into the periphery where it reduces brown fat in neonatal C57BL/6 mice. A considerable amount of anti-VEGF antibody was detected in serum after intravitreal injection. Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat. With increasing age and body weight, brown fat restored its morphology and vascularity. Our results show that there is a transient, but significant impact of intravitreally administered anti-VEGF antibody on brown adipose tissue in neonatal mice. We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

Intravitreally Injected Anti-VEGF Antibody Reduces Brown Fat in Neonatal Mice.

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Dong Hyun Jo

Full Text Available Anti-vascular endothelial growth factor (VEGF agents are the mainstay treatment for various angiogenesis-related retinal diseases. Currently, bevacizumab, a recombinant humanized anti-VEGF antibody, is trailed in retinopathy of prematurity, a vasoproliferative retinal disorder in premature infants. However, the risks of systemic complications after intravitreal injection of anti-VEGF antibody in infants are not well understood. In this study, we show that intravitreally injected anti-VEGF antibody is transported into the systemic circulation into the periphery where it reduces brown fat in neonatal C57BL/6 mice. A considerable amount of anti-VEGF antibody was detected in serum after intravitreal injection. Furthermore, in interscapular brown adipose tissue, we found lipid droplet accumulation, decreased VEGF levels, loss of vascular network, and decreased expression of mitochondria-related genes, Ppargc1a and Ucp1, all of which are characteristics of "whitening" of brown fat. With increasing age and body weight, brown fat restored its morphology and vascularity. Our results show that there is a transient, but significant impact of intravitreally administered anti-VEGF antibody on brown adipose tissue in neonatal mice. We suggest that more attention should be focused on the metabolic and developmental significance of brown adipose tissue in bevacizumab treated retinopathy of prematurity infants.

The VEGF system and tie-2 are spatio-temporal expressed during tayassu placentation

DEFF Research Database (Denmark)

Miglino, M.A.; Santos, T.C.; Papa, P.C.

Objectives: The vascular endothelial growth factor (VEGF) is one of the most important vascular mitogens, while the angiotensin receptor Tie-2 binds to the angiopoietin and stabilizes newly formed vessels. We therefore wanted to localize VEGF and its receptors VEGF-R1, VEGF-R2 and the Tie-2 recep...

VEGF111b, a new member of VEGFxxxb isoforms and induced by mitomycin C, inhibits angiogenesis

Energy Technology Data Exchange (ETDEWEB)

Gu, Fang; Li, Xiuli [Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing (China); Kong, Jian [Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing (China); Pan, Bing [The Institute of Cardiovascular Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing (China); Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing (China); Sun, Min [Department of Obstetrics and Gynecology, Tangdu Hospital, Fourth Military Medical University, Xian (China); Zheng, Lemin, E-mail: zhengl@bjmu.edu.cn [The Institute of Cardiovascular Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing (China); Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences of Education Ministry, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Health Ministry, Beijing (China); Yao, Yuanqing, E-mail: yqyao@126.com [Department of Obstetrics and Gynecology, Chinese PLA General Hospital, Beijing (China)

2013-11-08

Highlights: •We discovered a new member of VEGFxxxb family-VEGF111b. •We found VEGF111b mRNA and protein can be induced by mitomycin C. •We confirmed VEGF111b over-expression inhibits angiogenesis. •VEGF111b inhibits angiogenesis through inhibiting VEGF-R2/PI3K/Akt and VEGF-R2/ERK1/2 phosphorylation. -- Abstract: Vascular endothelial growth factor (VEGF-A) stimulating angiogenesis is required for tumor growth and progression. The conventional VEGF-A isoforms have been considered as pro-angiogenic factors. Another family of VEGF-A isoforms generated by alternative splicing, termed VEGFxxxb isoforms, has anti-angiogenic property, exemplified by VEGF165b. Here, we identify a new number of VEGFxxx family-VEGF111b induced by mitomycin C, although not detected in mitomycin C-unexposed ovarian cancer cells. SKOV3 cells were transfected with pcDNA{sub 3.1} empty vector, pcDNA{sub 3.1}-VEGF111b or pcDNA{sub 3.1}-VEGF165b to collect conditioned mediums respectively. VEGF111b overexpression inhibits proliferation, migration and tube formation of endothelial cell by inhibiting VEGF-R2 phosphorylation and its downstream signaling, similar to VEGF165b but slightly lower than VEGF165b. The anti-angiogenic property depends on the six amino acids of exon 8b of the VEGFxxxb isoforms. Our results show that VEGF111b is a novel potent anti-angiogenic agent that can target the VEGF-R2 and its signaling pathway to inhibit ovarian tumor growth.

VEGF111b, a new member of VEGFxxxb isoforms and induced by mitomycin C, inhibits angiogenesis

International Nuclear Information System (INIS)

Gu, Fang; Li, Xiuli; Kong, Jian; Pan, Bing; Sun, Min; Zheng, Lemin; Yao, Yuanqing

2013-01-01

Highlights: •We discovered a new member of VEGFxxxb family-VEGF111b. •We found VEGF111b mRNA and protein can be induced by mitomycin C. •We confirmed VEGF111b over-expression inhibits angiogenesis. •VEGF111b inhibits angiogenesis through inhibiting VEGF-R2/PI3K/Akt and VEGF-R2/ERK1/2 phosphorylation. -- Abstract: Vascular endothelial growth factor (VEGF-A) stimulating angiogenesis is required for tumor growth and progression. The conventional VEGF-A isoforms have been considered as pro-angiogenic factors. Another family of VEGF-A isoforms generated by alternative splicing, termed VEGFxxxb isoforms, has anti-angiogenic property, exemplified by VEGF165b. Here, we identify a new number of VEGFxxx family-VEGF111b induced by mitomycin C, although not detected in mitomycin C-unexposed ovarian cancer cells. SKOV3 cells were transfected with pcDNA 3.1 empty vector, pcDNA 3.1 -VEGF111b or pcDNA 3.1 -VEGF165b to collect conditioned mediums respectively. VEGF111b overexpression inhibits proliferation, migration and tube formation of endothelial cell by inhibiting VEGF-R2 phosphorylation and its downstream signaling, similar to VEGF165b but slightly lower than VEGF165b. The anti-angiogenic property depends on the six amino acids of exon 8b of the VEGFxxxb isoforms. Our results show that VEGF111b is a novel potent anti-angiogenic agent that can target the VEGF-R2 and its signaling pathway to inhibit ovarian tumor growth

The association between MCP-1, VEGF polymorphisms and their serum levels in patients with diabetic foot ulcer.

Science.gov (United States)

Li, Xiaolei

2018-06-01

The purpose of the present study was to investigate distribution of monocyte chemoattractant protein-1 (MCP-1) -2518A/G and vascular endothelial growth factor (VEGF) -634G/C polymorphisms in type 2 diabetes melitus patients (T2DM) presenting diabetic foot ulcer (DFU). Additionally, we evaluated the effects of these 2 polymorphisms on serum levels of MCP-1 and VEGF in the study population.Patients diagnosed with T2DM without or with DFU were recruited in the study. The distribution of MCP-1 -2518A/G and VEGF -634G/C polymorphisms was investigated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Enzyme-linked immunosorbent assay (ELISA) was applied to detect the protein levels of MCP-1 and VEGF. The comparisons of protein levels in DFU patients were performed by student t test according to their genotypes.The frequencies of GG genotype and G allele of MCP-1 -2518A/G was increased in DFU patients, compared with T2DM patients (odds ratio [OR] = 2.60, 95% confidence interval [CI] = 1.23-5.50, P = .011 and OR = 1.72, 95% CI = 1.18-2.50, P = .005, respectively). Moreover, the increased frequency of GG was significantly associated with up-regulated MCP-1 level in DFU patients (P < .001). Analysis for VEGF -634G/C polymorphisms indicated that the prevalence of CC genotype and C allele of the polymorphisms was decreased in DFU patients, compared with T2DM patients (OR = 0.36, 95% CI = 0.17-0.77, P = .008 and OR = 0.63, 95% CI = 0.43-0.91, P = .015, respectively). DFU patients carrying CC genotype had a higher level of VEGF than those with other genotypes (P = .007).MCP-1 -2518A/G and VEGF -634G/C polymorphisms may involve in occurrence and progress of DFU through regulating transcription activity of the genes.

Heat Shock Protein 70 Negatively Regulates TGF-β-Stimulated VEGF Synthesis via p38 MAP Kinase in Osteoblasts

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Go Sakai

2017-11-01

Full Text Available Background/Aims: We previously demonstrated that transforming growth factor-β (TGF-β stimulates the synthesis of vascular endothelial growth factor (VEGF through the activation of p38 mitogen-activated protein (MAP kinase in osteoblast-like MC3T3-E1 cells. Heat shock protein70 (HSP70 is a ubiquitously expressed molecular chaperone. In the present study, we investigated the involvement of HSP70 in the TGF-β-stimulated VEGF synthesis and the underlying mechanism in these cells. Methods: Culture MC3T3-E1 cells were stimulated by TGF-β. Released VEGF was measured using an ELISA assay. VEGF mRNA level was quantified by RT-PCR. Phosphorylation of each protein kinase was analyzed by Western blotting. Results: VER-155008 and YM-08, both of HSP70 inhibitors, significantly amplified the TGF-β-stimulated VEGF release. In addition, the expression level of VEGF mRNA induced by TGF-β was enhanced by VER-155008. These inhibitors markedly strengthened the TGF-β-induced phosphorylation of p38 MAP kinase. The TGF-β-induced phosphorylation of p38 MAP kinase was amplified in HSP70-knockdown cells. SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by these inhibitors of the TGF-β-induced VEGF release. Conclusion: These results strongly suggest that HSP70 acts as a negative regulator in the TGF-β-stimulated VEGF synthesis in osteoblasts, and that the inhibitory effect of HSP70 is exerted at a point upstream of p38 MAP kinase.

Experimental investigation of the stability diagram for Paul traps in the case of praseodymium ions

International Nuclear Information System (INIS)

Koczorowski, W.; Szawiola, G.; Walaszyk, A.; Buczek, A.; Stefanska, D.; Stachowska, E.

2006-01-01

The present paper describes an investigation of non-linear resonances of praseodymium ion clouds stored in a Paul trap as a function of the storage parameters. These have been observed in traps with different ring electrode diameters. In these different traps the resonances occur for different values of the operating parameters. Discrepancies with the approximation model for one ion have been found. The intensity of the fluorescence signal and the Doppler half width have been recorded as a function of one of the storage parameters: q. We use our results to optimize the fluorescence signal of the stored ions, which is especially useful in the case of the double-resonance method.

Eye tracking to evaluate evidence recognition in crime scene investigations.

Science.gov (United States)

Watalingam, Renuka Devi; Richetelli, Nicole; Pelz, Jeff B; Speir, Jacqueline A

2017-11-01

Crime scene analysts are the core of criminal investigations; decisions made at the scene greatly affect the speed of analysis and the quality of conclusions, thereby directly impacting the successful resolution of a case. If an examiner fails to recognize the pertinence of an item on scene, the analyst's theory regarding the crime will be limited. Conversely, unselective evidence collection will most likely include irrelevant material, thus increasing a forensic laboratory's backlog and potentially sending the investigation into an unproductive and costly direction. Therefore, it is critical that analysts recognize and properly evaluate forensic evidence that can assess the relative support of differing hypotheses related to event reconstruction. With this in mind, the aim of this study was to determine if quantitative eye tracking data and qualitative reconstruction accuracy could be used to distinguish investigator expertise. In order to assess this, 32 participants were successfully recruited and categorized as experts or trained novices based on their practical experiences and educational backgrounds. Each volunteer then processed a mock crime scene while wearing a mobile eye tracker, wherein visual fixations, durations, search patterns, and reconstruction accuracy were evaluated. The eye tracking data (dwell time and task percentage on areas of interest or AOIs) were compared using Earth Mover's Distance (EMD) and the Needleman-Wunsch (N-W) algorithm, revealing significant group differences for both search duration (EMD), as well as search sequence (N-W). More specifically, experts exhibited greater dissimilarity in search duration, but greater similarity in search sequences than their novice counterparts. In addition to the quantitative visual assessment of examiner variability, each participant's reconstruction skill was assessed using a 22-point binary scoring system, in which significant group differences were detected as a function of total

Exercise induced capillary growth in human skeletal muscle and the dynamics of VEGF

DEFF Research Database (Denmark)

Høier, Birgitte; Hellsten, Ylva

2014-01-01

, such as shear stress and passive stretch, lead to cellular signalling, enhanced expression of angiogenic factors and initiation of capillary growth. The most central angiogenic factor in skeletal muscle capillary growth is vascular endothelial growth factor (VEGF). During muscle contraction, VEGF increases...... in the muscle interstitium, acts on VEGF receptors on the capillary endothelium and thereby stimulates angiogenic processes. A primary source of muscle interstitial VEGF during exercise is the skeletal muscle fibers which contain large stores of VEGF within vesicles. We propose that, during muscle activity...

VEGF induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity.

Science.gov (United States)

Malykhina, Anna P; Lei, Qi; Erickson, Chris S; Epstein, Miles L; Saban, Marcia R; Davis, Carole A; Saban, Ricardo

2012-12-19

This work tests the hypothesis that bladder instillation with vascular endothelial growth factor (VEGF) modulates sensory and motor nerve plasticity, and, consequently, bladder function and visceral sensitivity.In addition to C57BL/6J, ChAT-cre mice were used for visualization of bladder cholinergic nerves. The direct effect of VEGF on the density of sensory nerves expressing the transient receptor potential vanilloid subfamily 1 (TRPV1) and cholinergic nerves (ChAT) was studied one week after one or two intravesical instillations of the growth factor.To study the effects of VEGF on bladder function, mice were intravesically instilled with VEGF and urodynamic evaluation was assessed. VEGF-induced alteration in bladder dorsal root ganglion (DRG) neurons was performed on retrogradly labeled urinary bladder afferents by patch-clamp recording of voltage gated Na+ currents. Determination of VEGF-induced changes in sensitivity to abdominal mechanostimulation was performed by application of von Frey filaments. In addition to an overwhelming increase in TRPV1 immunoreactivity, VEGF instillation resulted in an increase in ChAT-directed expression of a fluorescent protein in several layers of the urinary bladder. Intravesical VEGF caused a profound change in the function of the urinary bladder: acute VEGF (1 week post VEGF treatment) reduced micturition pressure and longer treatment (2 weeks post-VEGF instillation) caused a substantial reduction in inter-micturition interval. In addition, intravesical VEGF resulted in an up-regulation of voltage gated Na(+) channels (VGSC) in bladder DRG neurons and enhanced abdominal sensitivity to mechanical stimulation. For the first time, evidence is presented indicating that VEGF instillation into the mouse bladder promotes a significant increase in peripheral nerve density together with alterations in bladder function and visceral sensitivity. The VEGF pathway is being proposed as a key modulator of neural plasticity in the pelvis and

VEGF induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity

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Malykhina Anna P

2012-12-01

Full Text Available Abstract Background This work tests the hypothesis that bladder instillation with vascular endothelial growth factor (VEGF modulates sensory and motor nerve plasticity, and, consequently, bladder function and visceral sensitivity. In addition to C57BL/6J, ChAT-cre mice were used for visualization of bladder cholinergic nerves. The direct effect of VEGF on the density of sensory nerves expressing the transient receptor potential vanilloid subfamily 1 (TRPV1 and cholinergic nerves (ChAT was studied one week after one or two intravesical instillations of the growth factor. To study the effects of VEGF on bladder function, mice were intravesically instilled with VEGF and urodynamic evaluation was assessed. VEGF-induced alteration in bladder dorsal root ganglion (DRG neurons was performed on retrogradly labeled urinary bladder afferents by patch-clamp recording of voltage gated Na+ currents. Determination of VEGF-induced changes in sensitivity to abdominal mechanostimulation was performed by application of von Frey filaments. Results In addition to an overwhelming increase in TRPV1 immunoreactivity, VEGF instillation resulted in an increase in ChAT-directed expression of a fluorescent protein in several layers of the urinary bladder. Intravesical VEGF caused a profound change in the function of the urinary bladder: acute VEGF (1 week post VEGF treatment reduced micturition pressure and longer treatment (2 weeks post-VEGF instillation caused a substantial reduction in inter-micturition interval. In addition, intravesical VEGF resulted in an up-regulation of voltage gated Na+ channels (VGSC in bladder DRG neurons and enhanced abdominal sensitivity to mechanical stimulation. Conclusions For the first time, evidence is presented indicating that VEGF instillation into the mouse bladder promotes a significant increase in peripheral nerve density together with alterations in bladder function and visceral sensitivity. The VEGF pathway is being proposed as a

Hypoxia induced VEGF synthesis in visceral adipose depots of obese diabetic patients.

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Fusaru, Ana Marina; Pisoschi, Cătălina Gabriela; Bold, Adriana; Taisescu, C; Stănescu, R; Hîncu, Mihaela; Crăiţoiu, Stefania; Baniţă, Ileana Monica

2012-01-01

VEGF is one the pro-inflammatory adipokines synthesized by the "adipose secretoma" of obese subjects as a response to hypoxic conditions; but the main function of VEGF is angiogenesis, being recognized as the most important factor increasing blood capillaries in the adipose tissue by stimulating endothelial cell growth. In this paper, we propose a comparative study of the vascular response to VEGF synthesis in the subcutaneous and central-peritoneal adipose depots in lean, obese and obese diabetic patients. We used CD31 to label the endothelial cells in order to evaluate the response of the vascular network to VEGF synthesis. Our results showed an increase of VEGF protein synthesis in obese and obese-diabetic patients compared to lean subjects where the protein was absent. The positivity for VEGF in obese diabetic samples was observed in numerous structures from the adipose depots, both in the stromal vascular fraction--blood vessels and stromal cells--as well as in the cytoplasm of adipocytes. Positivity in the vascular wall was observed more frequently in areas of perivascular and intralobular fibrosis. Obese and diabetic patients showed similar incidence of CD31 immunoreactivity with lean subjects in both subcutaneous and peritoneal depots. In conclusion, human adipose depots show a different incidence of VEGF positive cells in relation with their disposal and the metabolic status. VEGF synthesis in visceral adipose tissue is inefficient being not followed by angiogenesis to counterbalance tissue hypoxia. We suggest that may be a pathogenic link between the degrees of intralobular fibrosis in adipose depots and VEGF expression.

VEGF-independent angiogenic pathways induced by PDGF-C

Science.gov (United States)

Kumar, Anil; Zhang, Fan; Lee, Chunsik; Li, Yang; Tang, Zhongshu; Arjunan, Pachiappan

2010-01-01

VEGF is believed to be a master regulator in both developmental and pathological angiogenesis. The role of PDGF-C in angiogenesis, however, is only at the beginning of being revealed. We and others have shown that PDGF-C is a critical player in pathological angiogenesis because of its pleiotropic effects on multiple cellular targets. The angiogenic pathways induced by PDGF-C are, to a large extent, VEGF-independent. These pathways may include, but not limited to, the direct effect of PDGF-C on vascular cells, the effect of PDGF-C on tissue stroma fibroblasts, and its effect on macrophages. Taken together, the pleiotropic, versatile and VEGF-independent angiogenic nature of PDGF-C has placed it among the most important target genes for antiangiogenic therapy. PMID:20871734

The inhibitory effect of different concentrations of KH902 eye drops on corneal neovascularization induced by alkali burn

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Yan Wu

2017-01-01

Full Text Available Purpose: The aim of this study was to evaluate the inhibitory effect of different concentrations of KH902 eye drops on rabbit corneal neovascularization (CNV induced by alkali burn. Methods: Forty-eight adult rabbits were randomized into four groups after alkali burning: Group A (2.5 mg/ml, Group B (5 mg/ml, and Group C (10 mg/ml by different concentrations of KH902 eye drops and Group D by saline solution as control with three times a day for 2 weeks. At days 7, 14, and 28, the anterior segment photographs, confocal microscopy, and histopathology were performed to evaluate corneal opacity, neovascularization, inflammatory cell density, vessel size, and edema. Immunohistochemistry was applied to analyze the vascular endothelial growth factor (VEGF level. Results: (1 The CNV in the medicine-treated groups showed a reduction without obvious corneal side effects histologically. (2 Compared to the control group, the three medicine-treated groups showed a reduction in the VEGF levels and CNV areas on days 7, 14, and 28 and in the inflammatory cell density on days 14 and 28 (P 0.05. Conclusion: KH902 eye drops in lower concentration showed an obvious reduction of the CNV growing for rabbit corneal alkali burn without side effects.

Integrating reaction and analysis: investigation of higher-order reactions by cryogenic trapping

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Skrollan Stockinger

2013-09-01

Full Text Available A new approach for the investigation of a higher-order reaction by on-column reaction gas chromatography is presented. The reaction and the analytical separation are combined in a single experiment to investigate the Diels–Alder reaction of benzenediazonium-2-carboxylate as a benzyne precursor with various anthracene derivatives, i.e. anthracene, 9-bromoanthracene, 9-anthracenecarboxaldehyde and 9-anthracenemethanol. To overcome limitations of short reaction contact times at elevated temperatures a novel experimental setup was developed involving a cooling trap to achieve focusing and mixing of the reactants at a defined spot in a fused-silica capillary. This trap functions as a reactor within the separation column in the oven of a gas chromatograph. The reactants are sequentially injected to avoid undefined mixing in the injection port. An experimental protocol was developed with optimized injection intervals and cooling times to achieve sufficient conversions at short reaction times. Reaction products were rapidly identified by mass spectrometric detection. This new approach represents a practical procedure to investigate higher-order reactions at an analytical level and it simultaneously provides valuable information for the optimization of the reaction conditions.

Bone mesenchymal stem cells co-expressing VEGF and BMP-6 genes to combat avascular necrosis of the femoral head.

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Liao, Hongxing; Zhong, Zhixiong; Liu, Zhanliang; Li, Liangping; Ling, Zemin; Zou, Xuenong

2018-01-01

The aim of the present study was to investigate the potential of bone mesenchymal stem cells (BMSCs) treated with a combination of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-6 (BMP-6) genes for the treatment of avascular necrosis of the femoral head (ANFH). Rat BMSCs were isolated and purified using a density gradient centrifugation method. The purity and characteristics of the BMSCs were detected by cell surface antigens identification using flow cytometry. The experimental groups were administered with one of the following adeno-associated virus (AAV) vector constructs: AAV-green fluorescent protein (AAV-GFP), AAV-BMP-6, AAV-VEGF or AAV-VEGF-BMP-6. The expression of VEGF and BMP-6 was detected by reverse transcription-quantitative polymerase chain reaction, western blotting and ELISA assays. The effects of VEGF and BMP-6 on BMSCs were evaluated by angiogenic and osteogenic assays. The transfected BMSCs were combined with a biomimetic synthetic scaffold poly lactide-co-glycolide (PLAGA) and they were then subcutaneously implanted into nude mice. After four weeks, the implants were analyzed with histology and subsequent immunostaining to evaluate the effects of BMSCs on blood vessel and bone formation in vivo . In the AAV-VEGF-BMP-6 group, the expression levels of VEGF and BMP-6 were significantly increased and human umbilical vein endothelial cells tube formation was significantly enhanced compared with other groups. Capillaries and bone formation in the AAV-VEGF-BMP-6 group was significantly higher compared with the other groups. The results of the present study suggest that BMSCs expressing both VEGF and BMP-6 induce an increase in blood vessels and bone formation, which provides theoretical support for ANFH gene therapy.

Correlation between serum VEGF level and CT perfusion imaging in patients with primary liver cancer pre-and post TACE

International Nuclear Information System (INIS)

Jia Zhongzhi; Huang Yuanquan; Feng Yaoliang; Shi Haibin

2010-01-01

Objective: To investigate the correlation between serum vascular endothelial growth factor(VEGF) level and CT perfusion parameters in patients with primary liver cancer (PLC) pre-and post-transcatheter arterial chemoembolization (TACE) treatment. Methods: Serum VEGF level was measured and CT perfusion imaging was performed 1 day before and 6 ∼ 8, 32 ∼ 40 days after TACE in 18 patients with PLC. Before and after TACE, the serum VEGF level, the tumor's artery liver perfusion (ALP), the portal vein perfusion (PVP) and the hepatic artery perfusion index (HPI) were measured pre-and post-TACE. The pre-TACE and post-TACE results were compared and statistically analyzed. Results: Based on the therapeutic results, the patients were divided into complete response (CR) group and partial response or stable disease(PR+SD) group. Although no significant difference in serum VEGF level, tumor's ALP, PVP and HPI existed between two groups pre-TACE, there was significant difference in ALP, HPI 6-8 days after TACE (P<0.05). Significant difference in serum VEGF level also existed in CR group (P<0.05), but not in (PR+SD) group, at (32-40) days post-TACE (P=0.221). The serum VEGF level carried a positive correlation with the tumor's ALP and HPI. Conclusion: The serum VEGF level can indirectly reflect the neovascularization of the tumor, while the CTPI can directly and quantitatively reflect the hemodynamic changes of the tumor post-TACE. Moreover, a positive correlation exists between serum VEGF level and ALP, HPI. Therefore, the determination of serum VEGF level together with CTPI is very useful in both evaluating TACE efficacy and making therapeutic schedule. (authors)

Investigation of the morbidity of dry eye among special crowd in Shunde district

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Zhi-Hui Li

2013-08-01

Full Text Available AIM: To investigate the morbidity of dry eye in policeman of Shunde district, and to analyze the related factors and proposed methods of preventing and treating dry eye.METHODS:Totally 650 policemen who came for physical examination in Shunde district recived questionnaire survey. The patients with dye eye disease were finally diagnosed through slit lamp examination, Schirmer test, tear film break-up time(BUTmeasurement and keratoconjunctival fluorescent staining. The morbidity among different policemen was further analyzed and stasticed.RESULTS:The results showed that 152 in 650 policemen suffered from dry eye disease, the ratio was 23.4%. Comparied with security police and crimanl police, the ratio in traffic police, patrolman,and back office police was significantly higher. The prevalence was higher when the ages were greater than 40.CONCLUSION: Unsuitable working environment, air contamination are high risk factors of dry eye disease.

Evaluation of anticancer peptide VEGF111b secretion in HEK293 human cells

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Morteza Sadeghi

2017-04-01

Full Text Available Background: VEGF111b is a new isoform of vascular endothelial growth factor (VEGF recently considered as a new anticancer drug. The aim of this study was to evaluate the VEGF111b secretion from HEK293 cell wall in order to commercial production of this recombinant factor. Materials and Methods: After the design of VEGF111b sequence using OLIGO software and NCBI gene bank data, it was cloned into the pBUD.cE4.1 vector. The pBUD.VEGF111b recombinant vector was transfected into HEK293 cells using lipofectamine kit. Forty-eight hours after the transfection the production of VEGF111b was estimated by Western blotting and Human anti VEGF antibody. The VEGF111b secretion into cell culture and cell lysate extract was measured using ELISA. Results: The correct cloning of VEGF111b into pBUD.cE4.1vector was confirmed using enzymatic digestion and gel electrophoresis. The observed production of recombinant peptide in HEK293 was confirmed with 12KDa band in cell lysate extract of Western blotting. The ELISA results at 450 nanometer absorbance for cell culture media and cell lysate extract were 19.20±2.81 pg/ml and 32.87±7.42 pg/ml, respectively. However, no VEGF111b expression was observed in negative controls. Conclusion: The findings of this study indicate the powerful ability of transformation and secretion of VEGF111b from HEK293 cell wall to cell culture media with no breaking and proteolytic digestion. It seems that the commercial production and purification of this therapeutic peptide from HEK293 cell culture would be possible with high efficiency.

A pharmacogenetics study to predict outcome in patients receiving anti-VEGF therapy in age related macular degeneration

Science.gov (United States)

Kitchens, John W; Kassem, Nawal; Wood, William; Stone, Thomas W; Isernhagen, Rick; Wood, Edward; Hancock, Brad A; Radovich, Milan; Waymire, Josh; Li, Lang; Schneider, Bryan P

2013-01-01

Purpose To ascertain whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth factor (VEGFA), Complement Factor H (CFH), and LOC387715 genes could predict outcome to anti-VEGF therapy for patients with age related macular degeneration (AMD). Methods Patients with “wet” AMD were identified by chart review. Baseline optical coherence tomography (OCT) and visual acuity (VA) data, and at least 6 months of clinical follow up after 3 initial monthly injections of bevacizumab or ranibizumab were required for inclusion. Based on OCT and VA, patients were categorized into two possible clinical outcomes: (a) responders and (b) non-responders. DNA was extracted from saliva and genotyped for candidate SNPs in the VEGFA, LOC387715, and CFH genes. Clinical outcomes were statistically compared to patient genotypes. Results 101 patients were recruited, and one eye from each patient was included in the analysis. 97% of samples were successfully genotyped for all SNPs. We found a statistically significant association between the LOC387715 A69S TT genotype and outcome based on OCT. Conclusion Genetic variation may be associated with outcome in patients receiving anti-VEGF therapy. PMID:24143065

[VEGF165 transfected endothelial progenitor cells mediated by lentivirus alleviated ALI in rats].

Science.gov (United States)

He, Zhaohui; He, Huiwei; Lu, Yuanhua; Chen, Zhi; Xu, Fanghua; Wang, Rongsheng; Yang, Chunli

2017-11-01

To investigate the protective effects of vascular endothelial growth factor-165 (VEGF165) transfected the endothelial progenitor cells (EPCs) mediated by lentivirus on acute lung injury (ALI) in rats. The mononuclear cells from the male Sprague-Dawley (SD) rats were isolated and cultured to get the EPCs for study. The lentivirus vector carrying the human VEGF165 gene was constructed. According to the random number table method, 90 male SD rats were divided into ALI model group, phosphate buffer solution (PBS) group, EPCs treatment group, none transfected EPCs treatment group and VEGF165 transfected EPCs treatment group, and the rats in each group were subdivided into 4, 12 and 48 hours subgroups, with 6 rats in each subgroup. The rat model of ALI was reproduced by intravenous injection of oleic acid (0.15 μL/g). Then each treatment group was given PBS, EPCs, none transfected EPCs and VEGF165 transfected EPCs respectively with the same volume of 0.2 mL. For the groups with cells, about 1×10 6 cells were contained. Abdominal aortic blood and lung tissue were harvested at 4, 12 and 48 hours. Arterial blood gas analysis was performed. The lung wet/dry weight ratio (W/D) was calculated. The expressions of induced nitric oxide synthase (iNOS), endothelin-1 (ET-1) and VEGF165 were determined by enzyme-linked immunosorbent assay (ELISA). After dyed with hematoxylin-eosin (HE), the lung tissue pathology was observed and the lung injury score was performed. Compared with the ALI model group, the arterial partial pressure of oxygen (PaO 2 ) in EPCs, none transfected EPCs and VEGF165 transfected EPCs treatment groups was significantly increased from 4 hours, and lung W/D, expressions of iNOS and ET-1 were significantly decreased, and VEGF165 expression was significantly increased. Compared with the EPCs treatment group, the increase in PaO 2 , the decrease in lung W/D and expressions of iNOS and ET-1, and the increase in VEGF165 expression in VEGF165 transfected EPCs

VEGF-A promotes lymphoma tumour growth by activation of STAT proteins and inhibition of p27(KIP1) via paracrine mechanisms

NARCIS (Netherlands)

Roorda, Berber D.; ter Elst, Arja; Scherpen, Frank J. G.; Meemusen-de Boer, Tiny G. J.; Kamps, Willem A.; de Bont, Eveline S. J. M.

Increased levels of circulating VEGF-A have been demonstrated in patients with non-Hodgkin lymphoma (NHL) and are associated with progressive disease and poor clinical outcome. We investigated the role of VEGF-A in lymphoma tumour growth on a molecular level in order to identify the mechanism of

Changes in neurophysiologic markers of visual processing following beneficial anti-VEGF treatment in macular degeneration

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Vottonen P

2013-02-01

Full Text Available Pasi Vottonen,1 Kai Kaarniranta,1,2 Ari Pääkkönen,3 Ina M Tarkka41Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland; 2Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; 3Department of Clinical Neurophysiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland; 4Department of Health Sciences, University of Jyväskylä, Jyväskylä, FinlandPurpose: Antivascular endothelial growth factor (VEGF agents have been shown to improve visual acuity and prevent vision loss in exudative age-related macular degeneration. As the vision improves relatively quickly in response to intravitreal injections, we wanted to know whether this improvement is reflected in electrophysiological markers of visual cortical processing.Patients and methods: Our interventional case series included six elderly patients who underwent injection treatment to the affected eye. Their visual acuity, tomographic images of retinal thickness, and visual evoked potentials (VEP were assessed before treatment and six weeks after the last injection.Results: All patients showed improved visual acuity and reduced retinal fluid after the treatment. All but one patient showed increased VEP P100 component amplitudes and/or shortened latencies in the treated eye. These VEP changes were consistent with improved vision while the untreated eyes showed no changes.Conclusions: Our results indicate that antivascular endothelial growth factor injections improved visual function of the treated eyes both in the level of the retina and in the level of visual cortical processing.Keywords: age-related eye diseases, exudative age-related macular degeneration, visual evoked potentials, scalp-recorded EEG, visual acuity

Characteristics of trapped electrons and electron traps in single crystals

International Nuclear Information System (INIS)

Budzinski, E.E.; Potter, W.R.; Potienko, G.; Box, H.C.

1979-01-01

Two additional carbohydrates are reported whose crystal structures trap electrons intermolecularly in single crystals x irradiated at low temperature, namely sucrose and rhamnose. Five carbohydrate and polyhydroxy compounds are now known which exhibit this phenomenon. The following characteristics of the phenomenon were investigated: (1) the hyperfine couplings of the electron with protons of the polarized hydroxy groups forming the trap; (2) the distances between these protons and the trapped electron; (3) the spin density of the electron at the protons and (4) the relative stabilities of the electron trapped in various crystal structures

Increased Levels of VEGF-A and HIF-1α in Turkish Children with Crimean-Congo Hemorrhagic Fever

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Murat Sefikogullari

2017-04-01

Full Text Available Background: Crimean-Congo Hemorrhagic Fever (CCHF is a disease characterized by serious course, including acute viral fever, ecchymosis, thrombocytopenia, liver dysfunction and high rate of mortality. Hypoxia Inducible Factor-1α (HIF-1α and Vascular Endothelial Growth Factor-A (VEGF-A play an important role both in the inflamma­tory process and plasma leakage. The aim of this study was to define HIF-1α and VEGF-A serum levels obtained from CCHF patients and control group and to investigate whether these factors were correlated with the pathogenesis of this disease.Methods: Thirty cases younger than 17 yr confirmed by RT-PCR and/or ELISA for CCHF were included in this study. Thirty age and sex matched healthy peoples were enrolled as controls. Blood samples collected from the pa­tient and control groups. Serum levels of HIF-1α and VEGF-A were measured with ELISA.Results: Levels of HIF-1α and VEGF-A were statistically significantly increased in CCHF patients compared to the control group (P< 0.05.  A significant positive correlation was found between the levels of HIF-1α and VEGF-A in the patient group (P< 0.01. The levels of ALT, AST, CK, aPTT, WBC and Thrombocyte count were significantly higher in the patients than in the control group (P< 0.001. A positive correlation was found among the levels of AST and CK from biochemical parame­ters and VEGF and HIF-1α in the patient group (P< 0.05Conclusion: HIF-1α and VEGF-A might play an important role in CCHF pathogenesis.

Current and emerging therapies for the treatment of age-related macular degeneration

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M Vaughn Emerson

2008-06-01

Full Text Available M Vaughn Emerson, Andreas K LauerCasey Eye Institute, Oregon Health and Science University, Portland, OR, USAAbstract: Age-related macular degeneration (AMD is the leading cause of vision loss in the industrialized world. In the last few decades, the mainstay of treatment for choroidal neovascularization (CNV due to AMD has been thermal laser photocoagulation. In the last decade, photodynamic therapy with verteporfin extended treatment for more patients. While both of these treatments have prevented further vision loss in a subset of patients, improvement in visual acuity is rare. Anti-vascular endothelial growth factor A (VEGF therapy has revolutionized the treatment of AMD-related CNV. Pegaptanib, an anti-VEGF aptamer prevents vision loss in CNV, although the performance is similar to that of photodynamic therapy. Ranibizumab, an antibody fragment and bevacizumab, a full-length humanized monoclonal antibody against VEGF have both shown promising results with improvements in visual acuity with either agent. VEGF trap, a modified soluble VEGF receptor analogue, binds VEGF more tightly than all other anti-VEGF agents and has also shown promising results in early trials. Other treatment strategies to decrease the effect of VEGF have used small interfering ribonucleic acid (RNA to inhibit VEGF production and VEGF receptor production. Steroids, including anecortave acetate in the treatment and prevention of CNV, have shown promise in controlled trials. Receptor tyrosine kinase inhibitors, such as vatalanib, inhibit downstream effects of VEGF, and have been effective in the treatment of CNV in early studies. Squalamine lactate inhibits plasma membrane ion channels with downstream effects on VEGF, and has shown promising results with systemic administration. Other growth factors, including pigment epithelium-derived growth factor that has been administered via an adenoviral vector has shown promising initial results. In some patients ciliary

In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft

NARCIS (Netherlands)

Nagengast, Wouter B.; Hospers, Geke A.; Mulder, Nanno H.; de Jong, Johan R.; Hollema, Harry; Brouwers, Adrienne H.; van Dongen, Guns A.; Perk, Lars R.; Lub-de Hooge, Marjolijn N.

Vascular endothelial growth factor (VEGF), released by tumor cells, is an important growth factor in tumor angiogenesis. The humanized monoclonal antibody bevacizumab blocks VEGF-induced tumor angiogenesis by binding, thereby neutralizing VEGF. Our aim was to develop radiolabeled bevacizumab for

Serial measurements of serum PDGF-AA, PDGF-BB, FGF2, and VEGF in multiresistant ovarian cancer patients treated with bevacizumab

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Madsen Christine

2012-09-01

Full Text Available Abstract Introduction Anti-VEGF treatment has proven effective in recurrent ovarian cancer. However, the identification of the patients most likely to respond is still pending. It is well known that the angiogenesis is regulated by several other pro-angiogenic proteins, e.g. the platelet - derived growth factor (PDGF system and the fibroblast growth factor (FGF system. These other signaling pathways may remain active or become upregulated during anti-VEGF treatment. The aim of the present study was to investigate if potential changes of PDGF-BB, PDGF-AA, and FGF2 before and during bevacizumab treatment had predictive value for early progression or survival. Furthermore, we wanted to investigate the importance of serum VEGF in the same cohort. Methods This study included 106 patients with chemotherapy-resistant epithelial ovarian cancer who were treated with single agent bevacizumab as part of a biomarker protocol. Patients were evaluated for response by the Response Evaluation Criteria In Solid Tumors (RECIST and/ or Gynecologic Cancer Intergroup (GCIG CA125 criteria. Serum samples were collected at baseline and prior to each treatment. FGF2, PDGF-BB, PDGF-AA were quantified simultaneously using the Luminex system, and VEGF-A was measured by ELISA. Eighty-eight baseline samples were avaliable for FGF2, PDGF-BB, PDGF-AA analysis, and 93 baseline samples for VEGF. Results High baseline serum VEGF was related to poor overall survival. Furthermore, high serum PDGF-BB and FGF2 was of prognostic significance. None of the markers showed predictive value, neither at baseline level nor during the treatment.

Systemic administration of thrombin peptide TP508 enhances VEGF-stimulated angiogenesis and attenuates effects of chronic hypoxia

Science.gov (United States)

Olszewska-Pazdrak, Barbara; Carney, Darrell H.

2015-01-01

Revascularization of chronic wounds and ischemic tissue is attenuated by endothelial dysfunction and the inability of angiogenic factors to stimulate angiogenesis. We recently showed that TP508, a nonproteolytic thrombin peptide, increases perfusion and NO-dependent vasodilation in hearts with chronic ischemia and stimulates NO production by endothelial cells. In this study, we investigated systemic in vivo effects of TP508 on VEGF-stimulated angiogenesis in vitro using aortic explants in normoxic and hypoxic conditions. Mice were injected with saline or TP508 and 24h later aortas were removed and cultured to quantify endothelial sprouting. TP508 injection increased endothelial sprouting and potentiated the in vitro response to VEGF. Exposure of control explants to hypoxia inhibited basal and VEGF-stimulated endothelial cell sprouting. This effect of hypoxia was significantly prevented by TP508 injection. Thus, TP508 systemic administration increases responsiveness of aortic endothelial cells to VEGF and diminishes the effect of chronic hypoxia on endothelial cell sprouting. Studies using human endothelial cells in culture suggest that protective effects of TP508 during hypoxia may involve stimulation of endothelial cell NO production. These data suggest potential clinical benefit of using a combination of systemic TP508 and local VEGF as a therapy for revascularization of ischemic tissue. PMID:23594718

Kaempferol inhibited VEGF and PGF expression and in vitro angiogenesis of HRECs under diabetic-like environment.

Science.gov (United States)

Xu, X H; Zhao, C; Peng, Q; Xie, P; Liu, Q H

2017-03-02

Diabetic retinopathy (DR) is one of the common and specific microvascular complications of diabetes. This study aimed to investigate the anti-angiogenic effect of kaempferol and explore its underlying molecular mechanisms. The mRNA expression level of vascular endothelial growth factor (VEGF) and placenta growth factor (PGF) and the concentrations of secreted VEGF and PGF were measured by qTR-PCR and ELISA assay, respectively. Human retinal endothelial cells (HRECs) proliferation, migration, and sprouting were measured by CCK-8 and transwell, scratching wound, and tube formation assays, respectively. Protein levels were determined by western blot. High glucose (25 mM) increased the mRNA expression levels of VEGF and PGF as well as the concentrations of secreted VEGF and PGF in HRECs, which can be antagonized by kaempferol (25 µM). Kaempferol (5-25 µM) significantly suppressed cell proliferation, migration, migration distance and sprouting of HRECs under high glucose condition. The anti-angiogenic effect of kaempferol was mediated via downregulating the expression of PI3K and inhibiting the activation of Erk1/2, Src, and Akt1. This study indicates that kaempferol suppressed angiogenesis of HRECs via targeting VEGF and PGF to inhibit the activation of Src-Akt1-Erk1/2 signaling pathway. The results suggest that kaempferol may be a potential drug for better management of DR.

The power of VEGF (vascular endothelial growth factor) family molecules.

Science.gov (United States)

Thomas, Jean-Leon; Eichmann, Anne

2013-05-01

Vascular endothelial growth factors (VEGFs) and their high-affinity tyrosine kinase VEGF receptors (VEGFRs) are key regulators of both angiogenesis and neurogenesis. The current issue of CMLS discusses recent literature and work implementing these signals in nervous system development, maintenance and disease pathology.

Investigation on the Use of trapping in the Management of the ...

African Journals Online (AJOL)

In this 11-month study, the potential of two trap types (pseudostem and pheromone traps) to lure weevils in banana fields was determined at three different ecological sites (Clemencia, Nouvelle France and Rivière du Poste). The effect of treatment of pseudostem trap with insecticides (Imidachloprid, Cyfluthrin and ...

VEGF and bFGF Gene Polymorphisms in Patients with Non-Hodgkin's Lymphoma

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Tomasz Wróbel

2013-01-01

Full Text Available Angiogenesis and lymphangiogenesis are important in the proliferation and survival of the malignant hematopoietic neoplasms, including non-Hodgkin’s lymphomas (NHLs. Vascular endothelial growth factor (VEGF and basic fibroblast growth factor (bFGF play an important role in the initiation of angiogenesis. Both VEGF and bFGF have been reported to have prognostic significance in NHL. The present study aimed to determine an association between the VEGF and bFGF gene polymorphisms and disease susceptibility and progression. VEGF (rs3025039; 936 C>T and bFGF (rs308395, −921 G>C variants were determined in 78 NHL patients and 122 healthy individuals by PCR-RFLP technique. The presence of the VEGF 936T allele was found to significantly associate with worse prognosis of the disease (expressed by the highest International Prognostic Index (IPI (0.41 versus 0.20, for IPI 4 among patients having and lacking the T allele. The VEGF 936T variant was also more frequent among patients with IPI 4 than in controls (OR = 3.37, . The bFGF −921G variant was more frequently detected among patients with aggressive as compared to those with indolent histological subtype (0.37 versus 0.18, and healthy individuals (0.37 versus 0.19, OR = 2.51, . These results imply that VEGF and bFGF gene polymorphisms have prognostic significance in patients with NHL.

VEGF-121 plasma level as biomarker for response to anti-angiogenetic therapy in recurrent glioblastoma.

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Martini, Maurizio; de Pascalis, Ivana; D'Alessandris, Quintino Giorgio; Fiorentino, Vincenzo; Pierconti, Francesco; Marei, Hany El-Sayed; Ricci-Vitiani, Lucia; Pallini, Roberto; Larocca, Luigi Maria

2018-05-10

Vascular endothelial growth factor (VEGF) isoforms, particularly the diffusible VEGF-121, could play a major role in the response of recurrent glioblastoma (GB) to anti-angiogenetic treatment with bevacizumab. We hypothesized that circulating VEGF-121 may reduce the amount of bevacizumab available to target the heavier isoforms of VEGF, which are the most clinically relevant. We assessed the plasma level of VEGF-121 in a brain xenograft model, in human healthy controls, and in patients suffering from recurrent GB before and after bevacizumab treatment. Data were matched with patients' clinical outcome. In athymic rats with U87MG brain xenografts, the level of plasma VEGF-121 relates with tumor volume and it significantly decreases after iv infusion of bevacizumab. Patients with recurrent GB show higher plasma VEGF-121 than healthy controls (p = 0.0002) and treatment with bevacizumab remarkably reduced the expression of VEGF-121 in plasma of these patients (p = 0.0002). Higher plasma level of VEGF-121 was significantly associated to worse PFS and OS (p = 0.0295 and p = 0.0246, respectively). Quantitative analysis of VEGF-121 isoform in the plasma of patients with recurrent GB could be a promising predictor of response to anti-angiogenetic treatment.

Prospective Preliminary In Vitro Investigation of a Magnetic Iron Oxide Nanoparticle Conjugated with Ligand CD80 and VEGF Antibody As a Targeted Drug Delivery System for the Induction of Cell Death in Rodent Osteosarcoma Cells

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Anne Marie Kay Kovach

2016-10-01

Full Text Available Target drug deliveries using nanotechnology are a novel consideration in the treatment of cancer. We present herein an in vitro mouse model for the preliminary investigation of the efficacy of an iron oxide nanoparticle complex conjugated to vascular endothelial growth factor (VEGF antibody and ligand cluster of differentiation 80 (CD80 for the purpose of eventual translational applications in the treatment of human osteosarcoma (OSA. The 35 nm diameter iron oxide magnetic nanoparticles are functionalized with an n-hydroxysuccinimide biocompatible coating and are conjugated on the surface to proteins VEGF antibody and ligand CD80. Combined, these proteins have the ability to target OSA cells and induce apoptosis. The proposed system was tested on a cancerous rodent osteoblast cell line (ATCCTMNPO CRL-2836 at four different concentrations (0.1, 1.0, 10.0, and 100.0 μg/mL of ligand CD80 alone, VEGF antibody alone, and a combination thereof (CD80+VEGF. Systems were implemented every 24 h over different sequential treatment timelines: 24, 48, and 72 h, to find the optimal protein concentration required for a reduction in cell proliferation. Results demonstrated that a combination of ligand CD80 and VEGF antibody was consistently most effective at reducing aberrant osteoblastic proliferation for both the 24- and 72-h timelines. At 48 h, however, an increase in cell proliferation was documented for the 0.1 and 1 μg/mL groups. For the 24- and 72-h tests, concentrations of 1.0 μg/mL of CD80+VEGF and 0.1 μg/mL of VEGF antibody were most effective. Concentrations of 10.0 and 100.0 μg/mL of CD80+VEGF reduced cell proliferation, but not as remarkably as the 1.0 μg/mL concentration. In addition, cell proliferation data showed that multiple treatments (72-h test induced cell death in the osteoblasts better than a single treatment. Future targeted drug delivery system research includes trials in OSA cell lines from greater phylum

The ARMOUR Study: Anti-VEGF in Neovascular AMD--Our Understanding in a Real-World Indian Setting.

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Jain, Nimesh; Yadav, Naresh Kumar; Jayadev, Chaitra; Srinivasan, Priya; Mohan, Ashwin; Shetty, Bhujang K

2017-01-01

The aim of our study was to share our experience with anti-vascular endothelial growth factor (anti-VEGF) injections in the treatment of neovascular age-related macular degeneration (nAMD) in a real-world setting. A retrospective, observational study. Patients of Indian origin with nAMD receiving anti-VEGF with a minimum follow-up of 12 months were enrolled in this study. In group 1, patients were treated on a pro re nata (PRN) basis; in group 2, patients received a loading dose (3 injecti Results: Overall, we observed that 77.31% (92/119 eyes) of patients either maintained or had improved visual acuity at 12 months' follow-up. Similar visual outcome was observed in both groups. The average number of injections given in group 1 was 4.98 and in group 2 was 3.7. CDVA at 12 months was significantly correlated with type of drug molecule, CSFT at 3 and 12 months, baseline visual acuity, and CDVA at 3 months. PRN treatment with significantly fewer injections achieved similar anatomical and functional outcomes when compared with the loading dose group. The results of this study need to be validated with a larger study group and a longer follow-up. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

Investigation on H-containing shallow trap of hydrogenated TiO2 with in situ Fourier transform infrared diffuse reflection spectroscopy.

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Han, Bing; Hang Hu, Yun

2017-07-28

A novel technique, high temperature high pressure in situ Fourier transform infrared diffuse reflection spectroscopy, was successfully used to investigate the formation and stability of shallow trap states in P25 TiO 2 nanoparticles. Two types of shallow traps (with and without H atoms) were identified. The H-containing shallow trap can be easily generated by heating in H 2 atmosphere. However, the trap is unstable in vacuum at 600 °C. In contrast, the H-free shallow trap, which can be formed by heating in vacuum, is stable even at 600 °C. The energy gaps between shallow trap states and the conduction band are 0.09 eV for H-containing shallow trap and 0.13 eV for H-free shallow trap, indicating that the H-containing shallow trap state is closer to the conduction band than that without H.

VEGF Correlates with Inflammation and Fibrosis in Tuberculous Pleural Effusion

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Bien, Mauo-Ying; Wu, Ming-Ping; Chen, Wei-Lin; Chung, Chi-Li

2015-01-01

Objective. To investigate the relationship among angiogenic cytokines, inflammatory markers, and fibrinolytic activity in tuberculous pleural effusion (TBPE) and their clinical importance. Methods. Forty-two patients diagnosed with TBPE were studied. Based on chest ultrasonography, there were 26 loculated and 16 nonloculated TBPE patients. The effusion size radiological scores and effusion vascular endothelial growth factor (VEGF), interleukin- (IL-) 8, plasminogen activator inhibitor type-1 ...

Long-term Results of Intravitreal Anti-VEGF Injections in Wet AMD: A Meta-Analysis.

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Gerding, H

2016-04-01

Although intravitreal anti-VEGF medications are widely used in age-related macular degeneration, no systematic data analysis is available on the long-term prognosis of this relatively new therapeutic approach. A meta-analysis was performed on available Medline literature. 13 relevant clinical studies (14 case series) could be identified, covering 10 247 treated eyes. The majority of available reports originate from single centre retrospective real-life environments. The mean improvement in average visual gain was 0.9 ± 0.5 (mean ± 1 standard deviation, median; 0.8 lines) at year 1, 1.2 ± 1.1 (median: 1.1) letters at year 2, 0.7 ± 1.0 (median: 0.7) letters at year 3, and 0.2 ± 0.8 (median: 0.5), 0.4 ± 0.4 (median: 0.5) at years 4 and 5. The drop-out rates in these studies was relatively high. At the end of year 3, the average percentage of observed eyes was 44.3 ± 18.4 % (mean ± 1 standard deviation), at the end of year 4 23.5 ± 23.9 % and after years 6 and 7 below 10 % (8.2 and 7.9 %). The mean treatment frequency of injections in all available studies was highest in year 1 (6.4 ± 1.2, 6.1 - mean ± SD; median), followed by relatively consistent mean values of 4.1 and 5.1 (year (Y)2: 4.4, Y3: 4.3, Y4: 4.7, Y5: 4.1, Y6: 5.1, Y7: 4.7) injections per year. The results of this meta-analysis clearly indicate that intravitreal anti-VEGF injection therapy is capable of maintaining visual acuity on a long-term basis of at least 4-5 years. Georg Thieme Verlag KG Stuttgart · New York.

Angular trap for macroparticles

International Nuclear Information System (INIS)

Aksyonov, D.S.

2013-01-01

Properties of angular macroparticle traps were investigated in this work. These properties are required to design vacuum arc plasma filters. The correlation between trap geometry parameters and its ability to absorb macroparticles were found. Calculations allow one to predict the behaviour of filtering abilities of separators which contain such traps in their design. Recommendations regarding the use of angular traps in filters of different builds are given.

Cytotoxicity of VEGF121/rGel on vascular endothelial cells resulting in inhibition of angiogenesis is mediated via VEGFR-2

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Hittelman Walter N

2011-08-01

Full Text Available Abstract Background The fusion protein VEGF121/rGel composed of the growth factor VEGF121 and the plant toxin gelonin targets the tumor neovasculature and exerts impressive anti-vascular effects. We have previously shown that VEGF121/rGel is cytotoxic to endothelial cells overexpressing VEGFR-2 but not to endothelial cells overexpressing VEGFR-1. In this study, we examined the basis for the specific toxicity of this construct and assessed its intracellular effects in vitro and in vivo. Methods We investigated the binding, cytotoxicity and internalization profile of VEGF121/rGel on endothelial cells expressing VEGFR-1 or VEGFR-2, identified its effects on angiogenesis models in vitro and ex vivo, and explored its intracellular effects on a number of molecular pathways using microarray analysis. Results Incubation of PAE/VEGFR-2 and PAE/VEGFR-1 cells with 125I-VEGF121/rGel demonstrated binding specificity that was competed with unlabeled VEGF121/rGel but not with unlabeled gelonin. Assessment of the effect of VEGF121/rGel on blocking tube formation in vitro revealed a 100-fold difference in IC50 levels between PAE/VEGFR-2 (1 nM and PAE/VEGFR-1 (100 nM cells. VEGF121/rGel entered PAE/VEGFR-2 cells within one hour of treatment but was not detected in PAE/VEGFR-1 cells up to 24 hours after treatment. In vascularization studies using chicken chorioallantoic membranes, 1 nM VEGF121/rGel completely inhibited bFGF-stimulated neovascular growth. The cytotoxic effects of VEGF121/rGel were not apoptotic since treated cells were TUNEL-negative with no evidence of PARP cleavage or alteration in the protein levels of select apoptotic markers. Microarray analysis of VEGF121/rGel-treated HUVECs revealed the upregulation of a unique "fingerprint" profile of 22 genes that control cell adhesion, apoptosis, transcription regulation, chemotaxis, and inflammatory response. Conclusions Taken together, these data confirm the selectivity of VEGF121/rGel for VEGFR-2

The tetrapeptide Arg-Leu-Tyr-Glu inhibits VEGF-induced angiogenesis

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Baek, Yi-Yong; Lee, Dong-Keon; So, Ju-Hoon; Kim, Cheol-Hee; Jeoung, Dooil; Lee, Hansoo; Choe, Jongseon; Won, Moo-Ho; Ha, Kwon-Soo; Kwon, Young-Guen; Kim, Young-Myeong

2015-01-01

Kringle 5, derived from plasminogen, is highly capable of inhibiting angiogenesis. Here, we have designed and synthesized 10 tetrapeptides, based on the amino acid properties of the core tetrapeptide Lys-Leu-Tyr-Asp (KLYD) originating from anti-angiogenic kringle 5 of human plasminogen. Of these, Arg-Leu-Tyr-Glu (RLYE) effectively inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration and tube formation, with an IC 50 of 0.06–0.08 nM, which was about ten-fold lower than that of the control peptide KLYD (0.79 nM), as well as suppressed developmental angiogenesis in a zebrafish model. Furthermore, this peptide effectively inhibited the cellular events that precede angiogenesis, such as ERK and eNOS phosphorylation and nitric oxide production, in endothelial cells stimulated with VEGF. Collectively, these data demonstrate that RLYE is a potent anti-angiogenic peptide that targets the VEGF signaling pathway. - Highlights: • The tetrapeptide RLYE inhibited VEGF-induced angiogenesis in vitro. • RLYE also suppressed neovascularization in a zebrafish model. • Its effect was correlated with inhibition of VEGF-induced ERK and eNOS activation. • RLYE may be used as a therapeutic drug for angiogenesis-related diseases

The tetrapeptide Arg-Leu-Tyr-Glu inhibits VEGF-induced angiogenesis

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Baek, Yi-Yong; Lee, Dong-Keon [Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); So, Ju-Hoon; Kim, Cheol-Hee [Department of Biology, Chungnam National University, Daejeon, 305-764 (Korea, Republic of); Jeoung, Dooil [Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); Lee, Hansoo [Department of Life Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); Choe, Jongseon [Department of Immunology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); Won, Moo-Ho [Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); Ha, Kwon-Soo [Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); Kwon, Young-Guen [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-752 (Korea, Republic of); Kim, Young-Myeong, E-mail: ymkim@kangwon.ac.kr [Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of)

2015-08-07

Kringle 5, derived from plasminogen, is highly capable of inhibiting angiogenesis. Here, we have designed and synthesized 10 tetrapeptides, based on the amino acid properties of the core tetrapeptide Lys-Leu-Tyr-Asp (KLYD) originating from anti-angiogenic kringle 5 of human plasminogen. Of these, Arg-Leu-Tyr-Glu (RLYE) effectively inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration and tube formation, with an IC{sub 50} of 0.06–0.08 nM, which was about ten-fold lower than that of the control peptide KLYD (0.79 nM), as well as suppressed developmental angiogenesis in a zebrafish model. Furthermore, this peptide effectively inhibited the cellular events that precede angiogenesis, such as ERK and eNOS phosphorylation and nitric oxide production, in endothelial cells stimulated with VEGF. Collectively, these data demonstrate that RLYE is a potent anti-angiogenic peptide that targets the VEGF signaling pathway. - Highlights: • The tetrapeptide RLYE inhibited VEGF-induced angiogenesis in vitro. • RLYE also suppressed neovascularization in a zebrafish model. • Its effect was correlated with inhibition of VEGF-induced ERK and eNOS activation. • RLYE may be used as a therapeutic drug for angiogenesis-related diseases.

Autocrine VEGF and IL-8 Promote Migration via Src/Vav2/Rac1/PAK1 Signaling in Human Umbilical Vein Endothelial Cells.

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Ju, Li; Zhou, Zhiwen; Jiang, Bo; Lou, Yue; Guo, Xirong

2017-01-01

Pro-angiogenic factors VEGF and IL-8 play a major role in modulating the migratory potential of endothelial cells. The goal of this study was to investigate the effect of autocrine VEGF and IL-8 in the form of self-conditioned medium (CM) on human umbilical vein endothelial cells (HUVECs). Enzyme-linked immunosorbent assay (ELISA) examined the automatic secretion of VEGF and IL-8 protein by HUVECs. Western blot, small interfering RNA (siRNA), pulldown and Transwell assays were used to explore the role and the mechanism of autocrine VEGF and IL-8 in migration of HUVECs. Neutralizing VEGF and IL-8 in CM significantly abrogated CM-induced migration of HUVECs. Autocrine VEGF and IL-8 increased Src phosphorylation, Rac1 activity and PAK1 phosphorylation in a time dependent manner. Additionally, blocking Rac1 activity with Rac1 siRNA largely abolished autocrine VEGF and IL-8-induced cell migration. Vav2 siRNA suppressed autocrine VEGF and IL-8-induced Rac1 activation and cell migration. Furthermore, blocking Src signaling with PP2, a specific inhibitor for Src, markedly prevented autocrine VEGF and IL-8-induced Vav2 and Rac1 activation as well as consequently cell migration. PAK1 siRNA also significantly abolished autocrine VEGF and IL-8-induced cell migration. We demonstrated for the first time that autocrine VEGF and IL-8 promoted endothelial cell migration via the Src/Vav2/Rac1/PAK1 signaling pathway. This finding reveals the molecular mechanism in the increase of endothelial cell migration induced by autocrine growth factors and cytokines, which is expected to provide a novel therapeutic target in vascular diseases. © 2017 The Author(s)Published by S. Karger AG, Basel.

Role of Endocrine Gland-Derived Vascular Endothelial Growth Factor (EG-VEGF) and Its Receptors in Adrenocortical Tumors.

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Heck, Dorothee; Wortmann, Sebastian; Kraus, Luitgard; Ronchi, Cristina L; Sinnott, Richard O; Fassnacht, Martin; Sbiera, Silviu

2015-12-01

Angiogenesis is essential for tumor growth and metastasis. Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor predominantly expressed in steroidogenic organs like the adrenal gland, ovary, testes, and placenta. EG-VEGF has antiapoptotic, mitogenic, and chemoattractive properties mediated via the two G protein-coupled receptors prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2). We investigated the expression of EG-VEGF and its receptors in a large number of normal adrenal glands (NAG), adrenocortical adenomas (ACA), and carcinomas (ACC) using real-time PCR (NAG, n = 12; ACA, n = 24; and ACC, n = 30) and immunohistochemistry (NAG, n = 9; ACA, n = 23; and ACC, n = 163) and evaluated its impact on patients' survival. EG-VEGF, PKR1, and PKR2 mRNA and protein are expressed in NAG and the vast majority of ACA and ACC samples. The mean EG-VEGF mRNA expression was significantly lower in ACC (606.5 ± 77.1 copies) compared to NAG (4,043 ± 1,111) and cortisol-producing adenomas (CPA) (4,433 ± 2,378) (p < 0.01 and p < 0.05, respectively). However, cytoplasmic and nuclear EG-VEGF protein expression was either significantly higher or similar in ACC (H score 2.4 ± 0.05, p < 0.05 and 1.7 ± 0.08, n.s., respectively) compared to NAG (1.8 ± 0.14 and 1.7 ± 0.2). Nuclear protein expression of either EG-VEGF or PKR1 or both is predictive for a higher mortality compared to patients without nuclear expression (hazard ratio (HR) = 5.15; 95% confidence interval (CI) = 1.24-21.36, n = 100, p = 0.02 independent of age, sex, and tumor stage). These findings suggest that EG-VEGF and its receptor PKR1 might play a role in the pathogenesis of adrenocortical tumors and could serve as prognostic markers for this rare malignant disease.

Immunohistochemical Expression of VEGF and Podoplanin in Uterine Cervical Squamous Intraepithelial Lesions

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Patrícia Napoli Belfort-Mattos

2016-01-01

Full Text Available VEGF and podoplanin (PDPN have been identified as angiogenesis and/or lymphangiogenesis regulators and might be essential to restrict tumor growth, progression, and metastasis. In the present study, we evaluate the association between the expression of these markers and CIN grade. Immunohistochemistry was performed in 234 uterine cervical samples using conventional histologic sections or TMA with the monoclonal antibodies to VEGF (C-1 clone and podoplanin (D2-40 clone. Positive-staining rates of VEGF in 191 CIN specimens were significantly associated with histological grade (P<0.001. Negative and/or focal immunostaining for PDPN were more frequent in CIN 3 (P=0.016. We found that patients with CIN 3 more frequently had strong and more diffuse staining for VEGF and diminished staining for PDPN (P=0.018. Strong and more diffuse VEGF immunoexpressions in CIN 2 and CIN 3 were detected when compared to CIN 1. Negative and/or focal PDPN immunoexpression appear to be more frequent in CIN 3. Moderate to strong VEGF expression may be a tendency among patients with high-grade lesions and diminished PDPN expression.

Cryogenic surface ion traps

International Nuclear Information System (INIS)

Niedermayr, M.

2015-01-01

Microfabricated surface traps are a promising architecture to realize a scalable quantum computer based on trapped ions. In principle, hundreds or thousands of surface traps can be located on a single substrate in order to provide large arrays of interacting ions. To this end, trap designs and fabrication methods are required that provide scalable, stable and reproducible ion traps. This work presents a novel surface-trap design developed for cryogenic applications. Intrinsic silicon is used as the substrate material of the traps. The well-developed microfabrication and structuring methods of silicon are utilized to create simple and reproducible traps. The traps were tested and characterized in a cryogenic setup. Ions could be trapped and their life time and motional heating were investigated. Long ion lifetimes of several hours were observed and the measured heating rates were reproducibly low at around 1 phonon per second at a trap frequency of 1 MHz. (author) [de

1-o-acetylbritannilactone (ABL) inhibits angiogenesis and lung cancer cell growth through regulating VEGF-Src-FAK signaling

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Zhengfu, He; Hu, Zhang; Huiwen, Miao; Zhijun, Li [Department of Thoracic Surgery, Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou (China); Jiaojie, Zhou [Zhejiang University School of Medicine, Hangzhou (China); Xiaoyi, Yan, E-mail: xiaoyiyan163@163.com [Zhejiang University School of Medicine, Hangzhou (China); Xiujun, Cai, E-mail: xiujuncaomaj@163.com [Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Hangzhou (China)

2015-08-21

The search for safe, effective and affordable therapeutics against non-small cell lung cancer (NSCLC) and other lung cancers is important. Here we explored the potential effect of 1-o-acetylbritannilactone (ABL), a novel extract from Inula britannica-F, on angiogenesis and lung cancer cell growth. We demonstrated that ABL dose-dependently inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration, and capillary structure formation of cultured human umbilical vascular endothelial cells (HUVECs). In vivo, ABL administration suppressed VEGF-induced new vasculature formation in Matrigel plugs. For the mechanism investigations, we found that ABL largely inhibited VEGF-mediated activation of Src kinase and focal adhesion kinase (FAK) in HUVECs. Furthermore, treatment of A549 NSCLC cells with ABL resulted in cell growth inhibition and Src-FAK in-activation. Significantly, administration of a single dose of ABL (12 mg/kg/day) remarkably suppressed growth of A549 xenografts in nude mice. In vivo microvessels formation and Src activation were also significantly inhibited in ABL-treated xenograft tumors. Taken together, our findings suggest that ABL suppresses angiogenesis and lung cancer cell growth possibly via regulating the VEGFR-Src-FAK signaling. - Highlights: • 1-o-acetylbritannilactone (ABL) inhibits VEGF-induced angiogenesis in vivo. • ABL inhibits VEGF-induced HUVEC migration, proliferation, capillary tube formation. • ABL inhibits VEGF-mediated activation of Src and FAK in HUVECs. • ABL inhibits growth and Src-FAK activation in A549 cells. • ABL administration inhibits A549 tumor angiogenesis and growth in nude mice.

VEGF and GLUT1 are highly heritable, inversely correlated and affected by dietary fat intake: Consequences for cognitive function in humans

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Rita Schüler

2018-05-01

Full Text Available Objective: Reduction of brain glucose transporter GLUT1 results in severe neurological dysfunction. VEGF is required to restore and maintain brain glucose uptake across the blood brain barrier via GLUT1, which was shown to be acutely diminished in response to a high fat diet (HFD in mice. The genetic and HFD-related regulation and association of VEGF and GLUT1 (SLC2A1 in humans was investigated in the NUtriGenomic Analysis in Twins (NUGAT study. Methods: 92 healthy and non-obese twins were standardized to a high-carbohydrate low-fat diet for 6 weeks before switched to a 6-week HFD under isocaloric conditions. Three clinical investigation days were conducted: after 6 weeks of low-fat diet and after 1 and 6 weeks of HFD. Serum VEGF and other cytokine levels were measured using ELISA. Gene expression in subcutaneous adipose tissue was assessed by quantitative Real-Time PCR. Genotyping was performed using microarray. The Auditory Verbal Learning Task was conducted to measure cognitive performance. Results: In this human study, we showed that the environmental regulation of SLC2A1 expression and serum VEGF by HFD was inversely correlated and both factors showed strong heritability (>90%. In response to the HFD containing 45% fat, serum VEGF levels increased (P = 0.002 while SLC2A1 mRNA expression in adipose tissue decreased (P = 0.001. Higher BMI was additionally associated with lower SLC2A1 expression. AA-genotypes of the rs9472159 polymorphism, which explained ∼39% of the variation in circulating VEGF concentrations, showed significantly reduced serum VEGF levels (P = 6.4 × 10−11 but higher SLC2A1 expression (P = 0.009 in adipose tissue compared to CC/CA-genotypes after 6 weeks of HFD. Memory performance in AA-genotypes declined in response to the HFD compared to CC- and CA-genotypes. Conclusions: The results provide evidence to suggest the translatability of the dietary regulation of VEGF and GLUT1 from mouse models to humans. Our

Anti-VEGF agents in metastatic colorectal cancer (mCRC: are they all alike?

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Saif MW

2013-06-01

Full Text Available Muhammad Wasif Saif GI Oncology Program, Tufts University School of Medicine, Boston, MA, USA Abstract: Bevacizumab is a monoclonal antibody that binds and neutralizes vascular endothelial growth factor (VEGF-A, a key player in the angiogenesis pathway. Despite benefits of bevacizumab in cancer therapy, it is clear that the VEGF pathway is complex, involving multiple isoforms, receptors, and alternative ligands such as VEGF-B, and placental growth factor, which could enable escape from VEGF-A-targeted angiogenesis inhibition. Recently developed therapies have targeted other ligands in the VEGF pathway (eg, aflibercept, known as ziv-aflibercept in the United States, VEGF receptors (eg, ramucirumab, and their tyrosine kinase signaling (ie, tyrosine kinase inhibitors. The goal of the current review was to identify comparative preclinical data for the currently available VEGF-targeted therapies. Sources were compiled using PubMed searches (2007 to 2012, using search terms including, but not limited to: “bevacizumab,” “aflibercept,” “ramucirumab,” and “IMC-18F1.” Two preclinical studies were identified that compared bevacizumab and the newer agent, aflibercept. These studies identified some important differences in binding and pharmacodynamic activity, although the potential clinical relevance of these findings is not known. Newer antiangiogenesis therapies should help further expand treatment options for colorectal and other cancers. Comparative preclinical data on these agents is currently lacking. Keywords: aflibercept, antiangiogenesis, metastatic colorectal cancer (mCRC, tyrosine kinase inhibitor (TKI, vascular endothelial growth factor (VEGF

Clinical significance of determination of changes of serum TNF-α and plasma VEGF contents after treatment in pediatric patients with acute nephritis

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Ding Guomin

2008-01-01

Objective: To investigate the serum TNF-α and plasma VEGF levels after treatment in pediatric patients with acute nephritis. Methods: Serum TNF-α levels (with RIA) and plasma VEGF levels (with ELISA) were determined in 32 pediatric patients with acute nephritis both before and after treatment as well as in 35 controls. Results: Before treatment the serum TNF-α and plasma VEGF levels in the patients were significantly higher than those in the controls (P<0.01). After one month of treatment with combined traditional Chinese and western medicine, the levels though dropped markedly, still remained significantly higher than those in controls (P<0.05). Conclusion: Development of acute nephritis in pediatric patients was closely related to the serum TNF-α and plasma VEGF levels. (authors)

An Experimental and Clinical Justification for Prolongation of Action of Anti-VEGF Drug in the “Wet” Form Age-related Macular Degeneration by the Introduction in the Back Subtenon Space on the Basis of Viscous Media

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R. V. Gaybaryan

2017-01-01

Full Text Available Purpose. Experimental-clinical substantiation of the effectiveness of subtenon injection of anti-VEGF drug on the viscous media with the purpose of strengthening and prolong of therapeutic effect in the treatment of wet form of age-related macular degeneration (AMD.Material and methods. The experimental part of the work was carried out on 10 rabbits (20 eyes. The main group of rabbits (10 eyes were injected into the back subtenon space 0,5 ml of a 10% solution of fluorescein on the viscous mediа, which was used as a 2% solution of hydroxypropylmethylcellulose; a control (10 eyes — without the viscous medium. After enucleation and isolation of ocular tissues in the posterior pole was performed water extraction of the dye determined the intensity of fluorescence after 3, 7, 10, 14 and 16 days after injection. In the clinical part of the work included 32 patients (34 eyes with the wet form of AMD, to be administered anti-VEGF drug at a dose of 12,5 mg (0,5 ml into the back subtenon space аt the same viscous media. The efficacy and safety were evaluated for 6 months.Results. As a result of the experimental study found that the length of stay in the back subtenon space of fluorescein solution of rabbit’s eye, introduced in the viscous medium to 2 times longer than without it. In a clinical study of stabilization was observed in 52,9 % of cases, improved visual function in 35,3 % of cases. Deterioration in visual functions noted in 11,8 % of cases. It was also noted improvement in photo-stress test. According OCT showed a decrease in central retinal thickness 2 times by reducing the size and volume of lesions by 30%, a significant decrease transsudativ processes in the retina in all patients, indicating that suppression of choroidal neovascularization.Conclusion: Subtenon injections of anti-VEGF drug is safe and has a positive effect in wet AMD, and its application to a viscous media has a prolonged action or property interest in any material or

VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

International Nuclear Information System (INIS)

Garcia-Roman, Jonathan; Ibarra-Sanchez, Alfredo; Lamas, Monica; Gonzalez Espinosa, Claudia

2010-01-01

Research highlights: → Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. → CoCl 2 -induced VEGF secretion in mast cells occurs by a Ca 2+ -insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. → Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits FcεRI-dependent anaphylactic degranulation in mast cells. → Src family kinase Fyn activation after free radical production is necessary for hypoxia-induced VEGF secretion in mast cells. -- Abstract: Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl 2 ) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl 2 promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl 2 -induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle-associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl 2 -induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl 2 in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N-acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals-dependent Fyn kinase activation.

VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells

Energy Technology Data Exchange (ETDEWEB)

Garcia-Roman, Jonathan; Ibarra-Sanchez, Alfredo; Lamas, Monica [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del IPN (Cinvestav, IPN) (Mexico); Gonzalez Espinosa, Claudia, E-mail: cgonzal@cinvestav.mx [Departamento de Farmacobiologia, Centro de Investigacion y de Estudios Avanzados del IPN (Cinvestav, IPN) (Mexico)

2010-10-15

Research highlights: {yields} Bone marrow-derived mast cells (BMMCs) secrete functional VEGF but do not degranulate after Cobalt chloride-induced hypoxia. {yields} CoCl{sub 2}-induced VEGF secretion in mast cells occurs by a Ca{sup 2+}-insensitive but brefeldin A and Tetanus toxin-sensitive mechanism. {yields} Trolox and N-acetylcysteine inhibit hypoxia-induced VEGF secretion but only Trolox inhibits Fc{epsilon}RI-dependent anaphylactic degranulation in mast cells. {yields} Src family kinase Fyn activation after free radical production is necessary for hypoxia-induced VEGF secretion in mast cells. -- Abstract: Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl{sub 2}) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl{sub 2} promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl{sub 2}-induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle-associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl{sub 2}-induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl{sub 2} in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N-acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals

PGC-1alpha mediates exercise-induced skeletal muscle VEGF expression in mice

DEFF Research Database (Denmark)

Leick, Lotte; Hellsten, Ylva; Fentz, Joachim

2009-01-01

The aim of the present study was to test the hypothesis that PGC-1alpha is required for exercise-induced VEGF expression in both young and old mice and that AMPK activation leads to increased VEGF expression through a PGC-1alpha-dependent mechanism. Whole body PGC-1alpha knockout (KO......) and littermate wild-type (WT) mice were submitted to either 1) 5 wk of exercise training, 2) lifelong (from 2 to 13 mo of age) exercise training in activity wheel, 3) a single exercise bout, or 4) 4 wk of daily subcutaneous AICAR or saline injections. In skeletal muscle of PGC-1alpha KO mice, VEGF protein...... expression was approximately 60-80% lower and the capillary-to-fiber ratio approximately 20% lower than in WT. Basal VEGF mRNA expression was similar in WT and PGC-1alpha KO mice, but acute exercise and AICAR treatment increased the VEGF mRNA content in WT mice only. Exercise training of young mice increased...

VEGF Gene Polymorphisms are Associated with Risk of Tetralogy of Fallot

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Li, Xiang; Liu, Chao-Liang; Li, Xiao-Xia; Li, Qing-Chen; Ma, Li-Ming; Liu, Gao-Li

2015-01-01

Background The aim of this study was to investigate associations of 3 common polymorphisms in the VEGF gene, −2578C>A, −634C>G, and 936C>T, with risk of tetralogy of Fallot (TOF) in Chinese Han children. Material/Methods From January 2010 to June 2013, a total of 400 pediatric subjects were recruited, including 160 cases with TOF (TOF group) and 240 healthy controls (control group). The genotypes of 3 common VEGF polymorphisms, −2578C>A, −634C>G, and 936C>T, were analyzed by polymerase chain reaction restriction fragment length polymorphism. All data were analyzed with SPSS 18.0 software. Results No significant differences were observed in body mass index or sex between TOF patients and controls (both P>0.05), but significant differences in age and family history of TOF were observed between the 2 groups (both PA of VEGF was correlated with a significantly increased risk of TOF, and TOF risk in A allele carrier was 1.54-fold higher than that of C allele carrier (OR=1.54, 95%CI=1.14–2.09, P=0.005); the statistical significance was still present after Bonferroni correction (Pc=0.045). GG genotype in −634C>G of VEGF gene was also associated with an increased risk of TOF, and TOF risk in patients with G allele was 1.62-fold higher compared to patients with C allele (OR=1.62, 95%CI=1.19–2.21, P=0.002); the statistical significance was still present after Bonferroni correction (Pc=0.018). Interestingly, T allele in VEGF 936C>T polymorphism is associated with a decreased TOF risk (OR=0.65, 95%CI=0.49–0.87, P=0.003, the statistical significance was still present after Bonferroni correction (Pc=0.027). The result of logistic regression analysis revealed that −2578C>A, −634C>G, and 936C>T genotypes are independently related to the prevalence of TOF (all PA and −634C>G, may be associated with an increased TOF risk, while 936C>T polymorphism may be associated with decreased TOF risk. PMID:26558525

VEGF receptor blockade markedly reduces retinal microglia/macrophage infiltration into laser-induced CNV.

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Hu Huang

Full Text Available Although blocking VEGF has a positive effect in wet age-related macular degeneration (AMD, the effect of blocking its receptors remains unclear. This was an investigation of the effect of VEGF receptor (VEGFR 1 and/or 2 blockade on retinal microglia/macrophage infiltration in laser-induced choroidal neovascularization (CNV, a model of wet AMD. CNV lesions were isolated by laser capture microdissection at 3, 7, and 14 days after laser and analyzed by RT-PCR and immunofluorescence staining for mRNA and protein expression, respectively. Neutralizing antibodies for VEGFR1 or R2 and the microglia inhibitor minocycline were injected intraperitoneally (IP. Anti-CD11b, CD45 and Iba1 antibodies were used to confirm the cell identity of retinal microglia/macrophage, in the RPE/choroidal flat mounts or retinal cross sections. CD11b(+, CD45(+ or Iba1(+ cells were counted. mRNA of VEGFR1 and its three ligands, PlGF, VEGF-A (VEGF and VEGF-B, were expressed at all stages, but VEGFR2 were detected only in the late stage. PlGF and VEGF proteins were expressed at 3 and 7 days after laser. Anti-VEGFR1 (MF1 delivered IP 3 days after laser inhibited infiltration of leukocyte populations, largely retinal microglia/macrophage to CNV, while anti-VEGFR2 (DC101 had no effect. At 14 days after laser, both MF1 and DC101 antibodies markedly inhibited retinal microglia/macrophage infiltration into CNV. Therefore, VEGFR1 and R2 play differential roles in the pathogenesis of CNV: VEGFR1 plays a dominant role at 3 days after laser; but both receptors play pivotal roles at 14 days after laser. In vivo imaging demonstrated accumulation of GFP-expressing microglia into CNV in both CX3CR1(gfp/gfp and CX3CR1(gfp/+ mice. Minocycline treatment caused a significant increase in lectin(+ cells in the sub-retinal space anterior to CNV and a decrease in dextran-perfused neovessels compared to controls. Targeting the chemoattractant molecules that regulate trafficking of retinal microglia

COX-2, VEGF and tumour angiogenesis.

LENUS (Irish Health Repository)

Toomey, D P

2009-06-01

Epidemiological evidence suggests a protective effective of regular NSAID use against developing cancer. Cyclooxygenase-2, a target of NSAIDs, is upregulated in many cancers and has been associated with increased VEGF production and angiogenesis. Angiogenesis is the formation of new vessels from existing vasculature and as an essential process for tumour development represents an important therapeutic target. Following an extensive review of the literature this article details the current knowledge on the role of COX-2 in tumorigenesis focusing on its relationship to angiogenesis and VEGF production by tumour cells. While COX-2 is clearly detrimental to prognosis and NSAIDs have a beneficial effect, the possibility of COX-2 independent effects being partly or wholly responsible for this benefit cannot be excluded.

Radiolabeling of VEGF165 with 99mTc to evaluate VEGFR expression in tumor angiogenesis.

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Galli, Filippo; Artico, Marco; Taurone, Samanta; Manni, Isabella; Bianchi, Enrica; Piaggio, Giulia; Weintraub, Bruce D; Szkudlinski, Mariusz W; Agostinelli, Enzo; Dierckx, Rudi A J O; Signore, Alberto

2017-06-01

Angiogenesis is the main process responsible for tumor growth and metastatization. The principal effector of such mechanism is the vascular endothelial growth factor (VEGF) secreted by cancer cells and other components of tumor microenvironment. Radiolabeled VEGF analogues may provide a useful tool to noninvasively image tumor lesions and evaluate the efficacy of anti-angiogenic drugs that block the VEGFR pathway. Aim of the present study was to radiolabel the human VEGF165 analogue with 99mTechnetium (99mTc) and to evaluate the expression of VEGFR in both cancer and endothelial cells in the tumor microenvironment. 99mTc-VEGF showed in vitro binding to HUVEC cells and in vivo to xenograft tumors in mice (ARO, K1 and HT29). By comparing in vivo data with immunohistochemical analysis of excised tumors we found an inverse correlation between 99mTc-VEGF165 uptake and VEGF histologically detected, but a positive correlation with VEGF receptor expression (VEGFR1). Results of our studies indicate that endogenous VEGF production by cancer cells and other cells of tumor microenvironment should be taken in consideration when performing scintigraphy with radiolabeled VEGF, because of possible false negative results due to saturation of VEGFRs.

VEGF-A isoform-specific regulation of calcium ion flux, transcriptional activation and endothelial cell migration.

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Fearnley, Gareth W; Bruns, Alexander F; Wheatcroft, Stephen B; Ponnambalam, Sreenivasan

2015-04-24

Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology such as cell migration, proliferation, tubulogenesis and cell-cell interactions. Numerous isoforms of VEGF-A exist but their physiological significance is unclear. Here we evaluated two different VEGF-A isoforms and discovered differential regulation of cytosolic calcium ion flux, transcription factor localisation and endothelial cell response. Analysis of VEGF-A isoform-specific stimulation of VEGFR2-dependent signal transduction revealed differential capabilities for isoform activation of multiple signal transduction pathways. VEGF-A165 treatment promoted increased phospholipase Cγ1 phosphorylation, which was proportional to the subsequent rise in cytosolic calcium ions, in comparison to cells treated with VEGF-A121. A major consequence of this VEGF-A isoform-specific calcium ion flux in endothelial cells is differential dephosphorylation and subsequent nuclear translocation of the transcription factor NFATc2. Using reverse genetics, we discovered that NFATc2 is functionally required for VEGF-A-stimulated endothelial cell migration but not tubulogenesis. This work presents a new mechanism for understanding how VEGF-A isoforms program complex cellular outputs by converting signal transduction pathways into transcription factor redistribution to the nucleus, as well as defining a novel role for NFATc2 in regulating the endothelial cell response. © 2015. Published by The Company of Biologists Ltd.

VEGF-A isoform-specific regulation of calcium ion flux, transcriptional activation and endothelial cell migration

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Gareth W. Fearnley

2015-07-01

Full Text Available Vascular endothelial growth factor A (VEGF-A regulates many aspects of vascular physiology such as cell migration, proliferation, tubulogenesis and cell-cell interactions. Numerous isoforms of VEGF-A exist but their physiological significance is unclear. Here we evaluated two different VEGF-A isoforms and discovered differential regulation of cytosolic calcium ion flux, transcription factor localisation and endothelial cell response. Analysis of VEGF-A isoform-specific stimulation of VEGFR2-dependent signal transduction revealed differential capabilities for isoform activation of multiple signal transduction pathways. VEGF-A165 treatment promoted increased phospholipase Cγ1 phosphorylation, which was proportional to the subsequent rise in cytosolic calcium ions, in comparison to cells treated with VEGF-A121. A major consequence of this VEGF-A isoform-specific calcium ion flux in endothelial cells is differential dephosphorylation and subsequent nuclear translocation of the transcription factor NFATc2. Using reverse genetics, we discovered that NFATc2 is functionally required for VEGF-A-stimulated endothelial cell migration but not tubulogenesis. This work presents a new mechanism for understanding how VEGF-A isoforms program complex cellular outputs by converting signal transduction pathways into transcription factor redistribution to the nucleus, as well as defining a novel role for NFATc2 in regulating the endothelial cell response.

Clinical significance of determination of serum VEGF and CEA levels in patients with colorectal cancer

International Nuclear Information System (INIS)

Du Xiaohui; Song Shaobai; Zheng Wei

2007-01-01

Objective: To study the applicability of combined determination of serum VEGF and CEA levels in the diagnosis of colorectal cancer as well as the relationship between VEGF level and stage of the disease. Methods: Serum VEGF (with ELISA) and CEA (with RIA) levels serum were detected in 28 patients with colorectal cancer of various stages and 29 controls. Results: The diagnostic positive rate was 53.6% (15/28), 39.3% (11/28), 71.4% (20/28) with CEA, VEGF and combined test for colorectal cancer, respectively. The serum VEGF levels in patients with advance colorectal cancer were significantly higher than those in patients with earlier stages diseases and controls, VEGF levels were positively correlated with CEA levels (P<0.05). Conclusion: Combined detection of the levels of serum VEGF and CEA could improve significantly the diagnostic positive rate in patients with colorectal cancer. (authors)

Thymosin beta 10 Prompted the VEGF-C Expression in Lung Cancer Cell

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Zixuan LI

2014-05-01

Full Text Available Background and objective Our previous study found that thymosin β10 overexpressed in lung cancer and positively correlated with differentiation, lymph node metastasis and stage of lung cancer. In this reasearch we aim to study the effects and mechanism of exogenous human recombinant Tβ10 on the expression of VEGF-C on non-small cell lung cancer. Methods After SPC, A549 and LK2 cells were treated with 100 ng/mL recombinant human Tβ10, the mRNA level of VEGF-C were detected by RT-PCR. The mean while the protein expression of VEGF-C, P-AKT and AKT were determined by Western blot assay. Results Exogenous recombinant human Tβ10 were significantly promote the expression levels of VEGF-C mRNA and protein while promoting the phosphorylation of AKT. Exogenous Tβ10 can promote the expression of VEGF-C mRNA and protein in lung cancer cell lines A549 and LK2 (P<0.05, and this effect can be inhibited by use AKT inhibitor LY294002 (P<0.05. Conclusion Tβ10 human recombinant proteins can promote the expression of VEGF-C by activating AKT phosphorylation in lung cancer cell lines.

Maternal uterine artery VEGF gene therapy for treatment of intrauterine growth restriction.

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David, Anna L

2017-11-01

Intrauterine growth restriction (IUGR) is a serious pregnancy complication affecting approximately 8% of all pregnancies. The aetiology is believed to be insufficient maternal uteroplacental perfusion which prevents adequate nutrient and oxygen availability for the fetus. There is no treatment that can improve uteroplacental perfusion and thereby increase fetal growth in the uterus. Maternal uterine artery gene therapy presents a promising treatment strategy for IUGR, with the use of adenoviral vectors encoding for proteins such as Vascular Endothelial Growth Factor (VEGF) demonstrating improvements in fetal growth and neonatal outcome in preclinical studies. Mechanistically, maternal VEGF gene therapy delivered to the uterine arteries increases uterine blood flow and enhances vascular relaxation short term, while reducing vascular contractility long term. It also leads to vascular remodeling with increased endothelial cell proliferation in the perivascular adventitia of uterine arteries. Safety assessments suggest no vector spread to the fetus and no adverse risk to the mother or fetus; a clinical trial is in development. This article assesses research into VEGF maternal uterine artery directed gene therapy for IUGR, investigating the use of transgenes and vectors, their route of administration in obstetrics, and the steps that will be needed to take this treatment modality into the clinic. Copyright © 2017 Elsevier Ltd. All rights reserved.

In vivo tumor angiogenesis imaging with site-specific labeled 99mTc-HYNIC-VEGF

International Nuclear Information System (INIS)

Blankenberg, Francis G.; Backer, Marina V.; Patel, Vimalkumar; Backer, Joseph M.; Levashova, Zoia

2006-01-01

We recently developed a cysteine-containing peptide tag (C-tag) that allows for site-specific modification of C-tag-containing fusion proteins with a bifunctional chelator, HYNIC (hydrazine nicotinamide)-maleimide. We then constructed and expressed C-tagged vascular endothelial growth factor (VEGF) and labeled it with HYNIC. We wished to test 99m Tc-HYNIC-C-tagged VEGF ( 99m Tc-HYNIC-VEGF) for the imaging of tumor vasculature before and after antiangiogenic (low continuous dosing, metronomic) and tumoricidal (high-dose) cyclophosphamide treatment. HYNIC-maleimide was reacted with the two thiol groups of C-tagged VEGF without any effect on biologic activity in vitro. 99m Tc-HYNIC-VEGF was prepared using tin/tricine as an exchange reagent, and injected via the tail vein (200-300 μCi, 1-2 μg protein) followed by microSPECT imaging 1 h later. Sequencing analysis of HYNIC-containing peptides obtained after digestion confirmed the site-specific labeling of the two accessible thiol groups of C-tagged VEGF. Tumor vascularity was easily visualized with 99m Tc/VEGF in Balb/c mice with 4T1 murine mammary carcinoma 10 days after implantation into the left axillary fat pad in controls (12.3±5.0 tumor/bkg, n=27) along with its decrease following treatment with high (150 mg/kg q.o.d. x 4; 1.14±0.48 tumor/bkg, n=9) or low (25 mg/kg q.d. x 7; 1.03±0.18 tumor/bkg, n=9) dose cyclophosphamide. Binding specificity was confirmed by observing a 75% decrease in tumor uptake of 99m Tc/biotin-inactivated VEGF, as compared with 99m Tc-HYNIC-VEGF. 99m Tc can be loaded onto C-tagged VEGF in a site-specific fashion without reducing its bioactivity. 99m Tc-HYNIC-VEGF can be rapidly prepared for the imaging of tumor vasculature and its response to different types of chemotherapy. (orig.)

Gene Therapy with Endogenous Inhibitors of Angiogenesis for Neovascular Age-Related Macular Degeneration: Beyond Anti-VEGF Therapy

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Selwyn M. Prea

2015-01-01

Full Text Available Age-related macular degeneration (AMD is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or “wet” form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF. However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly, potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins.

The effect of formoterol on peritoneal VEGF levels in rats with endometriosis.

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Yilmaz, Nafiye; Ozaksit, Gulnur; Keskin, Raziye; Tapisiz, Omer; Mollamahmutoglu, Leyla; Uysal, Sema; Astarci, Muzeyyen; Ustun, Huseyin; Mulazımoglu, Baris

2012-04-01

The aim of this study is to investigate the effect of formoterol (β2 adrenergic receptor agonist) on peritoneal VEGF levels in rats with endometriosis. Experimental endometriosis was constituted with implantation of endometrial tissue. The implants were examined by second laparatomy and rats were divided randomly into four groups. One cc saline was applied ip to the control (C) group (n=8) daily, 22.5μg/kg/day ip formoterol was applied to the second (F) group (n=10) daily, 22.5μg/kg/day ip formoterol and 10mg/kg/day ip propranolol were applied to the third (FP) group (n=10) daily, 45μg/kg/day ip formoterol was applied to the fourth (FF) group (n=9). Before treatment and after 30 days treatment period, peritoneal VEGF levels, the volumes and histopathological properties of the implants were evaluated. There were significant differences in between the peritoneal VEGF levels before and after treatment in group 2(F) and group 4(FF) (p(a): 0.01, 0.01 respectively). But there were no significant changes in between the volumes of implants before and after treatment among the groups (p>0.05). There were no significant differences among the groups in histopathological parameters (p>0.05). Formoterol treatment was seen to have no effect on the volumes and histopathological structure of endometriotic implants in our study. On the other hand, based on the group 2(F) and 4's (FF) VEGF levels after the treatment, low dose or high dose formoterol may be effective with long term therapy. Formoterol may reduce the development of endometriosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

Skeletal myofiber VEGF regulates contraction-induced perfusion and exercise capacity but not muscle capillarity in adult mice.

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Knapp, Amy E; Goldberg, Daniel; Delavar, Hamid; Trisko, Breanna M; Tang, Kechun; Hogan, Michael C; Wagner, Peter D; Breen, Ellen C

2016-07-01

A single bout of exhaustive exercise signals expression of vascular endothelial growth factor (VEGF) in the exercising muscle. Previous studies have reported that mice with life-long deletion of skeletal myofiber VEGF have fewer capillaries and a severe reduction in endurance exercise. However, in adult mice, VEGF gene deletion conditionally targeted to skeletal myofibers limits exercise capacity without evidence of capillary regression. To explain this, we hypothesized that adult skeletal myofiber VEGF acutely regulates skeletal muscle perfusion during muscle contraction. A tamoxifen-inducible skeletal myofiber-specific VEGF gene deletion mouse (skmVEGF-/-) was used to reduce skeletal muscle VEGF protein by 90% in adult mice. Three weeks after inducing deletion of the skeletal myofiber VEGF gene, skmVEGF-/- mice exhibited diminished maximum running speed (-10%, P Contraction-induced perfusion measured by optical imaging during a period of electrically stimulated muscle contraction was 85% lower in skmVEGF-/- than control mice. No evidence of capillary rarefication was detected in the soleus, gastrocnemius, and extensor digitorum longus (EDL) up to 8 wk after tamoxifen-induced VEGF ablation, and contractility and fatigue resistance of the soleus measured ex vivo were also unchanged. The force-frequency of the EDL showed a small right shift, but fatigue resistance did not differ between EDL from control and skmVEGF-/- mice. These data suggest myofiber VEGF is required for regulating perfusion during periods of contraction and may in this manner affect endurance capacity. Copyright © 2016 the American Physiological Society.

Acute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alphaVbeta3 Integrin Signaling in the Glomerulus

Science.gov (United States)

Veron, Delma; Villegas, Guillermo; Aggarwal, Pardeep Kumar; Bertuccio, Claudia; Jimenez, Juan; Velazquez, Heino; Reidy, Kimberly; Abrahamson, Dale R.; Moeckel, Gilbert; Kashgarian, Michael; Tufro, Alda

2012-01-01

Podocyte or endothelial cell VEGF-A knockout causes thrombotic microangiopathy in adult mice. To study the mechanism involved in acute and local injury caused by low podocyte VEGF-A we developed an inducible, podocyte-specific VEGF-A knockdown mouse, and we generated an immortalized podocyte cell line (VEGFKD) that downregulates VEGF-A upon doxycycline exposure. Tet-O-siVEGF:podocin-rtTA mice express VEGF shRNA in podocytes in a doxycycline-regulated manner, decreasing VEGF-A mRNA and VEGF-A protein levels in isolated glomeruli to ∼20% of non-induced controls and urine VEGF-A to ∼30% of control values a week after doxycycline induction. Induced tet-O-siVEGF:podocin-rtTA mice developed acute renal failure and proteinuria, associated with mesangiolysis and microaneurisms. Glomerular ultrastructure revealed endothelial cell swelling, GBM lamination and podocyte effacement. VEGF knockdown decreased podocyte fibronectin and glomerular endothelial alphaVbeta3 integrin in vivo. VEGF receptor-2 (VEGFR2) interacts with beta3 integrin and neuropilin-1 in the kidney in vivo and in VEGFKD podocytes. Podocyte VEGF knockdown disrupts alphaVbeta3 integrin activation in glomeruli, detected by WOW1-Fab. VEGF silencing in cultured VEGFKD podocytes downregulates fibronectin and disrupts alphaVbeta3 integrin activation cell-autonomously. Collectively, these studies indicate that podocyte VEGF-A regulates alphaVbeta3 integrin signaling in the glomerulus, and that podocyte VEGF knockdown disrupts alphaVbeta3 integrin activity via decreased VEGFR2 signaling, thereby damaging the three layers of the glomerular filtration barrier, causing proteinuria and acute renal failure. PMID:22808199

The significance of VEGF expression in stage II carcinoma of uterine cervix treated with definitive radiotherapy

International Nuclear Information System (INIS)

Park, Won; Choi, Yoon La; Huh, Seung Jae; Yoon, Sang Min; Park, Young Je; Nam, Hee Rim; Ahn, Yong Chan; Lim, Do Hoon; Park, Hee Chul

2006-01-01

We wanted to determine the clinical characteristics and prognosis according to the VEGF expression in stage II cervical carcinoma patients treated with definitive radiotherapy. We enrolled 31 patients who were diagnosed with cervical cancer from 1995 to 2003 at Samsumg Medical Center and their paraffin block tissue samples were available for study. The median age of the patients was 65 years. The mean tumor size was 4.1 cm (range: 1.2 ∼8.2 cm). Seven patients (22.6%) were suspected of having pelvic lymph node metastasis. An external beam irradiation dose of 45-56.4 Gy was administered to the whole pelvis with a 15 MV linear accelerator, and an additional 24 Gy was given to point A by HDR intracavitary brachytherapy. VEGF staining was defined as positive when more than 10% of the tumor cells were stained. The median follow-up duration was 58 months. A positive VEGF expression was observed in 21 patients (67.7%). There was no significant correlation between the VEGF expression and pelvic lymph node metastasis, tumor size and the response of radiotherapy. During follow-up, 7 patients had recurrence. The complete response rate was not significant between the VEGF (-) and VEGF(+) tumors. However, the VEGF(+) tumors showed a significantly higher recurrence rate in comparison with the VEGF(-) tumors (ρ = 0.040). The three year disease-free survival rates were 100% and 66.7%, respectively, for patients with VEGF(-) or VEGF(+) tumor (ρ = 0.047). The VEGF expression was a significant factor for recurrence and disease-free survival. However, the significance of the VEGF expression is still controversial because of the various definitions of VEGF expression and the mismatches of the clinical data in the previous studies

Connecting eye to eye

DEFF Research Database (Denmark)

Dau, Susanne; Rask, Anders Bindslev

2017-01-01

Computer Supported Collaborative Learning (CSCL) is used a frame for supporting online and blended learning in educations. The online communication and collaboration are afforded by the social collaboration. However, the social collaboration is based on the establishment of direct eye contact...... (Khalid, Deska & Hugenberg, 2016), but direct eye contact is challenged by the position of the digital devices and thus CSCL. Lack of eye contact is the chief contributor to the negative effects of online disinhibition (Lapidot-Lefler & Barak, 2012) and the problem is the location of the web camera...... at the computer. Eye contact is challenged by the displacement between the senders´ and receivers´ focus on the screen picture and the camera's location at the top or bottom of screens on all digital devices. The aim of this paper is accordingly to investigate the influence of the displacement in eye contact...

VEGF and VEGFR-2 (KDR) internalization is required for endothelial recovery during wound healing

International Nuclear Information System (INIS)

Constantino Rosa Santos, Susana; Miguel, Claudia; Domingues, Ines; Calado, Angelo; Zhu Zhenping; Wu Yan; Dias, Sergio

2007-01-01

Vascular endothelial growth factor (VEGF) receptor activation regulates endothelial cell (EC) survival, migration and proliferation. Recently, it was suggested the cross-talk between the VEGF receptors-1 (FLT-1) and -2 (KDR) modulated several of these functions, but the detailed molecular basis for such interactions remained unexplained. Here we demonstrate for the first time that VEGF stimulation of EC monolayers induced a rapid FLT-1-mediated internalization of KDR to the nucleus, via microtubules and the endocytic pathway, internalization which required the activation of PI 3-kinase/AKT. KDR deletion mutants were generated in several tyrosine residues; in these, VEGF-induced KDR internalization was impaired, demonstrating this process required activation (phosphorylation) of the receptor. Furthermore, we demonstrate that in vitro wounding of EC monolayers leads to a rapid and transient internalization of VEGF + KDR to the nucleus, which is essential for monolayer recovery. Notably, FLT-1 blockade impedes VEGF and KDR activation and internalization, blocking endothelial monolayer recovery. Our data reveal a previously unrecognized mechanism induced by VEGF on EC, which regulates EC recovery following wounding, and as such indicate novel targets for therapeutic intervention

Long-Term Visual Outcomes for a Treat and Extend Anti-Vascular Endothelial Growth Factor Regimen in Eyes with Neovascular Age-Related Macular Degeneration

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Sarah Mrejen

2015-07-01

Full Text Available With the advent of anti-vascular endothelial growth factor (VEGF therapy, clinicians are now focused on various treatment strategies to better control neovascular age-related macular degeneration (NVAMD, a leading cause of irreversible blindness. Herein, we retrospectively reviewed consecutive patients with treatment-naïve NVAMD initially classified based on fluorescein angiography (FA alone or with an anatomic classification utilizing both FA and optical coherence tomography (OCT and correlated long-term visual outcomes of these patients treated with an anti-VEGF Treat-and-Extend Regimen (TER with baseline characteristics including neovascular phenotype. Overall, 185 patients (210 eyes were followed over an average of 3.5 years (range 1–6.6 with a retention rate of 62.9%, and visual acuity significantly improved with a TER that required a mean number of 8.3 (±1.6 (± standard deviation intravitreal anti-VEGF injections/year (range 4–13. The number of injections and the anatomic classification were independent predictors of visual acuity at 6 months, 1, 2, 3 and 4 years. Patients with Type 1 neovascularization had better visual outcomes and received more injections than the other neovascular subtypes. There were no serious adverse events. A TER provided sustained long-term visual gains. Eyes with Type 1 neovascularization had better visual outcomes than those with other neovascular subtypes.

Mathematical Modeling of Cellular Cross-Talk Between Endothelial and Tumor Cells Highlights Counterintuitive Effects of VEGF-Targeted Therapies.

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Jain, Harsh; Jackson, Trachette

2018-05-01

Tumor growth and progression are critically dependent on the establishment of a vascular support system. This is often accomplished via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. VEGF ligands are overexpressed in a wide variety of solid tumors and therefore have inspired optimism that inhibition of the different axes of the VEGF pathway-alone or in combination-would represent powerful anti-angiogenic therapies for most cancer types. When considering treatments that target VEGF and its receptors, it is difficult to tease out the differential anti-angiogenic and anti-tumor effects of all combinations experimentally because tumor cells and vascular endothelial cells are engaged in a dynamic cross-talk that impacts key aspects of tumorigenesis, independent of angiogenesis. Here we develop a mathematical model that connects intracellular signaling responsible for both endothelial and tumor cell proliferation and death to population-level cancer growth and angiogenesis. We use this model to investigate the effect of bidirectional communication between endothelial cells and tumor cells on treatments targeting VEGF and its receptors both in vitro and in vivo. Our results underscore the fact that in vitro therapeutic outcomes do not always translate to the in vivo situation. For example, our model predicts that certain therapeutic combinations result in antagonism in vivo that is not observed in vitro. Mathematical modeling in this direction can shed light on the mechanisms behind experimental observations that manipulating VEGF and its receptors is successful in some cases but disappointing in others.

EVALUATION OF FISHING LOBSTERS PALINURUS ELEPHAS (FABRICIUS, 1787 BY LOBSTER TRAPS IN THE MIDDLE ADRIATIC SEA

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Perica Cetinić

1997-04-01

Full Text Available The work contains the results of fishing lobsters Palinurus elephas by lobsters traps from Komiža, island Vis with one eye side size of 60 mm as well as the evaluation of its effect to their population. The correct size of her eye was evaluated by the analysis of representation of immature lobsters in the catchs of the lobsters traps. 171 examples of lobsters were analyzed (116 males and 55 females with their lengths ranging from 22 to 45 cm. Total of 53 units (31% were less than 28 mm and at that length lobsters are barred from catch and transport. Such a length has been regulated by the valid Regulation on protection of fish and other sea organisms. Therefore, the lobster trap from Komiža, island Vis was evaluated as having the negative impact on the lobsters population.

Identification and in vitro characterization of phage-displayed VHHs targeting VEGF

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Farajpour, Zahra; Rahbarizadeh, Fatemeh; Kazemi, Bahram

2014-01-01

Vascular endothelial growth factor (VEGF) is a potential target for cancer treatment because of its role in angiogenesis and its overexpression in most human cancers. Currently, anti-VEGF antibodies have been shown to be promising tools for therapeutic applications. However, large size, poor tumo...

Experimental Investigation of Trapped Sine-Gordon Solitons

DEFF Research Database (Denmark)

Davidson, A.; Dueholm, B.; Kryger, B.

1985-01-01

We have observed for the first time a single sine-Gordon soliton trapped in an annular Josephson junction. This system offers a unique possibility to study undisturbed soliton motion. In the context of perturbation theory, the soliton may be viewed as a relativistic particle moving under a uniform...

A novel low cost pulse excitation source to study trap spectroscopy of persistent luminescent materials

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Chandrasekhar, Ngangbam; Singh, Nungleppam Monorajan; Gartia, R. K.

2018-04-01

Luminescent techniques require one or the other source of excitations which may vary from high cost X-rays, γ-rays, β-rays etc. to low cost LED. Persistent luminescent materials or Glow-in-the-Dark phosphors are the optical harvesters which store the optical energy from day light illuminating a whole night. They are so sensitive that they can be excited even with the low light of firefly. Therefore, instead of using a high cost excitation source authors have developed a low cost functioning of excitation source controlling short pulses of LED to excite persistent phosphors with the aid of ExpEYES Junior (Hardware/software framework developed by IUAC, New Delhi). Using this, the authors have excited the sample under investigation upto 10 ms. Trap spectroscopy of the pre-excited sample with LED is studied using Thermoluminescence (TL) technique. In this communication, development of the excitation source is discussed and demonstrate the its usefulness in the study of trap spectroscopy of commercially available CaS:Eu2+, Sm3+. Trapping parameters are also evaluated using Computerized Glow Curve Deconvolution (CGCD) technique.

Expression of p53, Bcl-2, VEGF, Ki67 and PCNA and prognostic significance in hepatocellular carcinoma.

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Stroescu, Cezar; Dragnea, Adrian; Ivanov, Bogdan; Pechianu, Catalin; Herlea, Vlad; Sgarbura, Olivia; Popescu, Andra; Popescu, Irinel

2008-12-01

Hepatocellular carcinoma is one of the most common malignant tumors that carry a poor prognosis. To improve the long-term outlook for HCC, an accurate prognosis is important. To study the immunohistochemical expressions of p53, Ki67, Bcl-2, VEGF and PCNA and their potential role as prognostic factors in patients with radical resection of hepatocellular carcinoma. Forty-seven formalin-fixed paraffin-embedded tumor samples from patients with HCC receiving liver resection were investigated immunohistochemically for the expression of cellular proliferation markers PCNA, Ki67, p53, Bcl-2 and VEGF and their correlation with tumor characteristics and survival time after resection. p53 was expressed in a higher percentage (85.7 vs. 42.1%) in undifferentiated histological tumor grades (Edmondson Steiner G3/G4 vs. G1/G2). Patients with p53 accumulating tumors showed a worse survival than patients with p53 non-accumulating tumors (median 9.5 vs. 16.5 months). Over-expression of VEGF was found in 38.3% of all HCCs. VEGF expression was significantly correlated with p53 expression and recurrence rates. The results showed that the labeling index of PCNA and expression of p53 are correlated. The high labeling index of PCNA or over-expression of p53 resulted in high risk of tumor recurrence, more aggressive growth and poor survival. High labeling index of PCNA, p53 nuclear accumulation and VEGF high expression are associated with poor survival in patients with HCC.

DSGOST inhibits tumor growth by blocking VEGF/VEGFR2-activated angiogenesis.

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Choi, Hyeong Sim; Lee, Kangwook; Kim, Min Kyoung; Lee, Kang Min; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong-Gyu

2016-04-19

Tumor growth requires a process called angiogenesis, a new blood vessel formation from pre-existing vessels, as newly formed vessels provide tumor cells with oxygen and nutrition. Danggui-Sayuk-Ga-Osuyu-Saenggang-Tang (DSGOST), one of traditional Chinese medicines, has been widely used in treatment of vessel diseases including Raynaud's syndrome in Northeast Asian countries including China, Japan and Korea. Therefore, we hypothesized that DSGOST might inhibit tumor growth by targeting newly formed vessels on the basis of its historical prescription. Here, we demonstrate that DSGOST inhibits tumor growth by inhibiting VEGF-induced angiogenesis. DSGOST inhibited VEGF-induced angiogenic abilities of endothelial cells in vitro and in vivo, which resulted from its inhibition of VEGF/VEGFR2 interaction. Furthermore, DSGOST attenuated pancreatic tumor growth in vivo by reducing angiogenic vessel numbers, while not affecting pancreatic tumor cell viability. Thus, our data conclude that DSGOST inhibits VEGF-induced tumor angiogenesis, suggesting a new indication for DSGOST in treatment of cancer.

Celecoxib alleviates tamoxifen-instigated angiogenic effects by ROS-dependent VEGF/VEGFR2 autocrine signaling

International Nuclear Information System (INIS)

Kumar, B N Prashanth; Rajput, Shashi; Dey, Kaushik Kumar; Parekh, Aditya; Das, Subhasis; Mazumdar, Abhijit; Mandal, Mahitosh

2013-01-01

Tamoxifen (TAM) is widely used in the chemotherapy of breast cancer and as a preventive agent against recurrence after surgery. However, extended TAM administration for breast cancer induces increased VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy. Celecoxib (CXB), a selective COX-2 inhibitor, suppresses VEGF gene expression by targeting the VEGF promoter responsible for its inhibitory effect. For this study, we had selected CXB as non-steroidal anti-inflammatory drug in combination with TAM for suppressing VEGF expression and simultaneously reducing doses of both the drugs. The effects of CXB combined with TAM were examined in two human breast cancer cell lines in culture, MCF7 and MDA-MB-231. Assays of proliferation, apoptosis, angiogenesis, metastasis, cell cycle distribution, and receptor signaling were performed. Here, we elucidated how the combination of TAM and CXB at nontoxic doses exerts anti-angiogenic effects by specifically targeting VEGF/VEGFR2 autocrine signaling through ROS generation. At the molecular level, TAM-CXB suppresses VHL-mediated HIF-1α activation, responsible for expression of COX-2, MMP-2 and VEGF. Besides low VEGF levels, TAM-CXB also suppresses VEGFR2 expression, confirmed through quantifying secreted VEGF levels, luciferase and RT-PCR studies. Interestingly, we observed that TAM-CXB was effective in blocking VEGFR2 promoter induced expression and further 2 fold decrease in VEGF levels was observed in combination than TAM alone in both cell lines. Secondly, TAM-CXB regulated VEGFR2 inhibits Src expression, responsible for tumor progression and metastasis. FACS and in vivo enzymatic studies showed significant increase in the reactive oxygen species upon TAM-CXB treatment. Taken together, our experimental results indicate that this additive combination shows promising outcome in anti-metastatic and apoptotic studies. In a line, our preclinical studies evidenced that this additive

Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease.

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Falkevall, Annelie; Mehlem, Annika; Palombo, Isolde; Heller Sahlgren, Benjamin; Ebarasi, Lwaki; He, Liqun; Ytterberg, A Jimmy; Olauson, Hannes; Axelsson, Jonas; Sundelin, Birgitta; Patrakka, Jaakko; Scotney, Pierre; Nash, Andrew; Eriksson, Ulf

2017-03-07

Diabetic kidney disease (DKD) is the most common cause of severe renal disease, and few treatment options are available today that prevent the progressive loss of renal function. DKD is characterized by altered glomerular filtration and proteinuria. A common observation in DKD is the presence of renal steatosis, but the mechanism(s) underlying this observation and to what extent they contribute to disease progression are unknown. Vascular endothelial growth factor B (VEGF-B) controls muscle lipid accumulation through regulation of endothelial fatty acid transport. Here, we demonstrate in experimental mouse models of DKD that renal VEGF-B expression correlates with the severity of disease. Inhibiting VEGF-B signaling in DKD mouse models reduces renal lipotoxicity, re-sensitizes podocytes to insulin signaling, inhibits the development of DKD-associated pathologies, and prevents renal dysfunction. Further, we show that elevated VEGF-B levels are found in patients with DKD, suggesting that VEGF-B antagonism represents a novel approach to treat DKD. Copyright © 2017 Elsevier Inc. All rights reserved.

Transcription regulation of the vegf gene by the BMP/Smad pathway in the angioblast of zebrafish embryos

International Nuclear Information System (INIS)

He Chen; Chen Xiaozhuo

2005-01-01

Vascular endothelial growth factor (VEGF) is a mitogen that is critically involved in vasculogenesis, angiogenesis, and hematopoiesis. However, what and how transcription factors participate in the regulation of vegf gene expression are not fully understood. Here we report the cloning and sequencing of the zebrafish vegf promoter which revealed that the promoter contains a number of bone morphogenetic protein (BMP)-activated Smad binding elements (SBE), implicating Smad1 and Smad5 in the regulation of BMP-induced expression of vegf. Electrophoretic mobility shift assays of adding recombinant Smad proteins to the SBE-containing DNA oligonucleotides that represent portions of zebrafish vegf promoter resulted in mobility shift of the oligonucleotides. These changes demonstrate potential interactions between Smad1/5 and the vegf promoter. Reporter activity assays using the wild-type or SBE-deleted vegf promoters to drive the luciferase reporter gene expression revealed that Smad1 stimulated while Smad5 repressed the vegf promoter activity in zebrafish embryos. These data indicate that the BMP/Smad signaling pathway is involved in the regulation of zebrafish vegf transcription. In addition, we demonstrate that transgenic expression of human BMP4 in zebrafish embryos induced an expansion of the posterior intermediate cell mass (ICM, also commonly called blood island), a population of cells containing endothelial and hematopoietic precursors. In the expanded ICM, vegf and VEGF receptor 2 (flk-1) were ectopically co-expressed, suggesting that an autocrine/paracrine regulation of vegf expression may exist and contribute to the BMP-induced hemangiogenic cell proliferation

Theoretical and Experimental Investigation of Particle Trapping via Acoustic Bubbles

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Chen, Yun; Fang, Zecong; Merritt, Brett; Saadat-Moghaddam, Darius; Strack, Dillon; Xu, Jie; Lee, Sungyon

2014-11-01

One important application of lab-on-a-chip devices is the trapping and sorting of micro-objects, with acoustic bubbles emerging as an effective, non-contact method. Acoustically actuated bubbles are known to exert a secondary radiation force on micro-particles and trap them, when this radiation force exceeds the drag force that acts to keep the particles in motion. In this study, we theoretically evaluate the magnitudes of these two forces for varying actuation frequencies and voltages. In particular, the secondary radiation force is calculated directly from bubble oscillation shapes that have been experimentally measured for varying acoustic parameters. Finally, based on the force estimates, we predict the threshold voltage and frequency for trapping and compare them to the experimental results.

Monitoring PAI-1 and VEGF Levels in 6 Human Squamous Cell Carcinoma Xenografts During Fractionated Irradiation

International Nuclear Information System (INIS)

Bayer, Christine; Kielow, Achim; Schilling, Daniela; Maftei, Constantin-Alin; Zips, Daniel; Yaromina, Ala; Baumann, Michael; Molls, Michael; Multhoff, Gabriele

2012-01-01

Purpose: Previous studies have shown that the plasminogen activator inhibitor type-1 (PAI-1) and vascular endothelial growth factor (VEGF) are regulated by hypoxia and irradiation and are involved in neoangiogenesis. The aim of this study was to determine in vivo whether changes in PAI-1 and VEGF during fractionated irradiation could predict for radiation resistance. Methods and Materials: Six xenografted tumor lines from human squamous cell carcinomas (HSCC) of the head and neck were irradiated with 0, 3, 5, 10, and 15 daily fractions of 2 Gy. The PAI-1 and VEGF antigen levels in tumor lysates were determined by enzyme-linked immunosorbent assay kits. The amounts of PAI-1 and VEGF were compared with the dose to cure 50% of tumors (TCD 50 ). Colocalization of PAI-1, pimonidazole (hypoxia), CD31 (endothelium), and Hoechst 33342 (perfusion) was examined by immunofluorescence. Results: Human PAI-1 and VEGF (hVEGF) expression levels were induced by fractionated irradiation in UT-SCC-15, UT-SCC-14, and UT-SCC-5 tumors, and mouse VEGF (msVEGF) was induced only in UT-SCC-5 tumors. High hVEGF levels were significantly associated with radiation sensitivity after 5 fractions (P=.021), and high msVEGF levels were significantly associated with radiation resistance after 10 fractions (P=.007). PAI-1 staining was observed in the extracellular matrix, the cytoplasm of fibroblast-like stroma cells, and individual tumor cells at all doses of irradiation. Colocalization studies showed PAI-1 staining close to microvessels. Conclusions: These results indicate that the concentration of tumor-specific and host-specific VEGF during fractionated irradiation could provide considerably divergent information for the outcome of radiation therapy.

Sulodexide prevents activation of the PLA2/COX-2/VEGF inflammatory pathway in human retinal endothelial cells by blocking the effect of AGE/RAGE.

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Giurdanella, Giovanni; Lazzara, Francesca; Caporarello, Nunzia; Lupo, Gabriella; Anfuso, Carmelina Daniela; Eandi, Chiara M; Leggio, Gian Marco; Drago, Filippo; Bucolo, Claudio; Salomone, Salvatore

2017-10-15

Diabetic retinopathy is characterized by the breakdown of endothelial blood-retinal barrier. We tested the hypothesis that sulodexide (SDX), a highly purified glycosaminoglycan composed of 80% iduronylglycosaminoglycan sulfate and 20% dermatan sulfate, protects human retinal endothelial cells (HREC) from high glucose (HG)-induced damage, through the suppression of inflammatory ERK/cPLA2/COX-2/PGE 2 pathway, by blocking the effect of advanced glycation end-products (AGEs). HREC were treated with HG (25mM) or AGEs (glycated-BSA, 2mg/ml) for 48h, with or without SDX (60μg/ml) or aflibercept (AFL, 40μg/ml), a VEGF-trap. SDX protected HREC from HG-induced damage (MTT and LDH release) and preserved their blood-retinal barrier-like properties (Trans Endothelial Electrical Resistance and junction proteins, claudin-5, VE-cadherin and occludin, immunofluorescence and immunoblot) as well as their angiogenic potential (Tube Formation Assay). Both HG and AGEs increased phosphoERK and phospho-cPLA 2 , an effect counteracted by SDX and, less efficiently, by AFL. Both HG and exogenous VEGF (80ng/ml) increased PGE 2 release, an effect partially reverted by SDX for HG and by AFL for VEGF. Analysis of NFκB activity revealed that HG increased the abundance of p65 in the nuclear fraction (nuclear translocation), an effect entirely reverted by SDX, but only partially by AFL. SDX, AFL and SDX+AFL protected HREC even when added 24h after HG. These data show that SDX protects HREC from HG damage and suggest that it counteracts the activation of ERK/cPLA2/COX-2/PGE 2 pathway by reducing AGE-related signaling and downstream NFκB activity. This mechanism, partially distinct from VEGF blockade, may contribute to the therapeutic effect of SDX. Copyright © 2017 Elsevier Inc. All rights reserved.

Alteration of protein expression pattern of vascular endothelial growth factor (VEGF) from soluble to cell-associated isoform during tumourigenesis

International Nuclear Information System (INIS)

Cressey, Ratchada; Wattananupong, Onusa; Lertprasertsuke, Nirush; Vinitketkumnuen, Usanee

2005-01-01

Vascular endothelial growth factor (VEGF) is a potent mitogen for endothelial cells, and its expression has been correlated with increased tumour angiogenesis. Although numerous publications dealing with the measurement of circulating VEGF for diagnostic and therapeutic monitoring have been published, the relationship between the production of tissue VEGF and its concentration in blood is still unclear. The aims of this study were to determine: 1) The expression pattern of VEGF isoforms at the protein level in colorectal and lung adenocarcinoma in comparison to the pattern in corresponding adjacent normal tissues 2) The relationship between the expression pattern of VEGF and total level of circulating VEGF in the blood to clarify whether the results of measuring circulating VEGF can be used to predict VEGF expression in tumour tissues. Ninety-four tissue samples were obtained from patients, 76 colorectal tumour tissues and 18 lung tumour tissues. VEGF protein expression pattern and total circulating VEGF were examined using western blot and capture ELISA, respectively. Three major protein bands were predominately detected in tumour samples with an apparent molecular mass under reducing conditions of 18, 23 and 26 kDa. The 18 kDa VEGF protein was expressed equally in both normal and colorectal tumour tissues and predominately expressed in normal tissues of lung, whereas the 23 and 26 kDa protein was only detected at higher levels in tumour tissues. The 18, 23 and 26 kDa proteins are believed to represent the VEGF 121 , the VEGF 165 and the VEGF 189 , respectively. There was a significant correlation of the expression of VEGF 165 with a smaller tumour size maximum diameter <5 cm (p < 0.05), and there was a significant correlation of VEGF 189 with advanced clinical stage of colorectal tumours. The measurement of total circulating VEGF in serum revealed that cancer patients significantly (p < 0.001) possessed a higher level of circulating VEGF (1081 ± 652 pg/ml in

Gene-gene interactions and gene polymorphisms of VEGFA and EG-VEGF gene systems in recurrent pregnancy loss.

Science.gov (United States)

Su, Mei-Tsz; Lin, Sheng-Hsiang; Chen, Yi-Chi; Kuo, Pao-Lin

2014-06-01

Both vascular endothelial growth factor A (VEGFA) and endocrine gland-derived vascular endothelial growth factor (EG-VEGF) systems play major roles in angiogenesis. A body of evidence suggests VEGFs regulate critical processes during pregnancy and have been associated with recurrent pregnancy loss (RPL). However, little information is available regarding the interaction of these two major major angiogenesis-related systems in early human pregnancy. This study was conducted to investigate the association of gene polymorphisms and gene-gene interaction among genes in VEGFA and EG-VEGF systems and idiopathic RPL. A total of 98 women with history of idiopathic RPL and 142 controls were included, and 5 functional SNPs selected from VEGFA, KDR, EG-VEGF (PROK1), PROKR1 and PROKR2 were genotyped. We used multifactor dimensionality reduction (MDR) analysis to choose a best model and evaluate gene-gene interactions. Ingenuity pathways analysis (IPA) was introduced to explore possible complex interactions. Two receptor gene polymorphisms [KDR (Q472H) and PROKR2 (V331M)] were significantly associated with idiopathic RPL (P<0.01). The MDR test revealed that the KDR (Q472H) polymorphism was the best loci to be associated with RPL (P=0.02). IPA revealed EG-VEGF and VEGFA systems shared several canonical signaling pathways that may contribute to gene-gene interactions, including the Akt, IL-8, EGFR, MAPK, SRC, VHL, HIF-1A and STAT3 signaling pathways. Two receptor gene polymorphisms [KDR (Q472H) and PROKR2 (V331M)] were significantly associated with idiopathic RPL. EG-VEGF and VEGFA systems shared several canonical signaling pathways that may contribute to gene-gene interactions, including the Akt, IL-8, EGFR, MAPK, SRC, VHL, HIF-1A and STAT3.

SU-F-T-51: Investigating the Effect of Eye Size and Eccentricity On Normal Tissue Doses From Eye Plaque Brachytherapy

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Polsdofer, E; Crilly, R [Oregon Health & Science University Portland, OR (United States)

2016-06-15

Purpose: This study investigates the effect of eye size and eccentricity on doses to critical tissues by simulating doses in the Plaque Simulator (v. 6.3.1) software. Present OHSU plaque brachytherapy treatment focuses on delivering radiation to the tumor measured with ocular ultrasound plus a small margin and assumes the orbit has the dimensions of a “standard eye.” Accurately modeling the dimensions of the orbit requires a high resolution ocular CT. This study quantifies how standard differences in equatorial diameters and eccentricity affect calculated doses to critical structures in order to query the justification of the additional CT scan to the treatment planning process. Methods: Tumors of 10 mm × 10 mm × 5 mm were modeled at the 12:00:00 hour with a latitude of 45 degrees. Right eyes were modeled at a number of equatorial diameters from 17.5 to 28 mm for each of the standard non-notched COMS plaques with silastic inserts. The COMS plaques were fully loaded with uniform activity, centered on the tumor, and prescribed to a common tumor dose (85 Gy/100 hours). Variations in the calculated doses to normal structures were examined to see if the changes were significant. Results: The calculated dose to normal structures show a marked dependence on eye geometry. This is exemplified by fovea dose which more than doubled in the smaller eyes and nearly halved in the larger model. Additional significant dependence was found in plaque size on the calculated dose in spite of all plaques giving the same dose to the prescription point. Conclusion: The variation in dose with eye dimension fully justifies the addition of a high resolution ocular CT to the planning technique. Additional attention must be made to plaque size beyond simply covering the tumor when considering normal tissue dose.

Vascular endothelial growth factor (VEGF), produced by feline infectious peritonitis (FIP) virus-infected monocytes and macrophages, induces vascular permeability and effusion in cats with FIP.

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Takano, Tomomi; Ohyama, Taku; Kokumoto, Aiko; Satoh, Ryoichi; Hohdatsu, Tsutomu

2011-06-01

Feline infectious peritonitis virus (FIPV) causes a fatal disease called FIP in Felidae. The effusion in body cavity is commonly associated with FIP. However, the exact mechanism of accumulation of effusion remains unclear. We investigated vascular endothelial growth factor (VEGF) to examine the relationship between VEGF levels and the amounts of effusion in cats with FIP. Furthermore, we examined VEGF production in FIPV-infected monocytes/macrophages, and we used feline vascular endothelial cells to examine vascular permeability induced by the culture supernatant of FIPV-infected macrophages. In cats with FIP, the production of effusion was related with increasing plasma VEGF levels. In FIPV-infected monocytes/macrophages, the production of VEGF was associated with proliferation of virus. Furthermore, the culture supernatant of FIPV-infected macrophages induced hyperpermeability of feline vascular endothelial cells. It was suggested that vascular permeability factors, including VEGF, produced by FIPV-infected monocytes/macrophages might increase the vascular permeability and the amounts of effusion in cats with FIP. Copyright © 2011 Elsevier B.V. All rights reserved.

Therapeutic action of the mitochondria-targeted antioxidant SkQ1 on retinopathy in OXYS rats linked with improvement of VEGF and PEDF gene expression.

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Anton M Markovets

Full Text Available UNLABELLED: The incidence of age-related macular degeneration (AMD, the main cause of blindness in older patients in the developed countries, is increasing with the ageing population. At present there is no effective treatment for the prevailing geographic atrophy, dry AMD, whereas antiangiogenic therapies successful used in managing the wet form of AMD. Recently we showed that mitochondria-targeted antioxidant plastoquinonyl-decyl-triphenylphosphonium (SkQ1 is able to prevent the development and moreover caused regression of pre-existing signs of the retinopathy in OXYS rats, an animal model of AMD. Here we examine the effects of SkQ1 on expression of key regulators of angiogenesis vascular endothelial growth factor A (VEGF and its antagonist pigment epithelium-derived factor (PEDF genes in the retina of OXYS rats as evidenced by real-time PCR and an ELISA test for VEGF using Wistar rats as control. Ophthalmoscopic examinations confirmed that SkQ1 supplementation (from 1.5 to 3 months of age, 250 nmol/kg prevented development while eye drops SkQ1 (250 nM, from 9 to 12 months caused some reduction of retinopathy signs in OXYS rats and did not reveal any negative effects on the control Wistar rat's retina. Prevention of premature retinopathy by SkQ1 was connected with an increase of VEGF mRNA and protein in OXYS rat's retina up to the levels corresponding to the Wistar rats, and did not involve changes in PEDF expression. In contrast the treatment with SkQ1 drops caused a decrease of VEGF mRNA and protein levels and an increase in the PEDF mRNA level in the middle-aged OXYS rats, but in Wistar rats the changes of gene expression were the opposite. CONCLUSIONS: The beneficial effects of SkQ1 on retinopathy connected with normalization of expression of VEGF and PEDF in the retina of OXYS rats and depended on age of the animals and the stage of retinopathy.

Ligand-receptor assay for evaluation of functional activity of human recombinant VEGF and VEGFR-1 extracellular fragment.

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Leopol'd, A V; Baklaushev, V P; Korchagina, A A; Shein, S A; Grinenko, N F; Pavlov, K A; Ryabukhin, I A; Chekhonin, V P

2012-04-01

cDNA encoding VEGF and Ig-like extracellular domains 2-4 of VEGFR-1 (sFlt-1(2-4)) were cloned into prokaryotic expression vectors pET32a and pQE60. Recombinant proteins were purified (metal affinity chromatography) and renatured. Chemiluminescent study for the interaction of recombinant VEGF and sFlt-1(2-4) showed that biotinylated VEGF specifically binds to the polystyrene-immobilized receptor extracellular fragment. Biotinylated recombinant sFlt-1 interacts with immobilized VEGF. Analysis of the interaction of immobilized recombinant VEGFR-1 and VEGF with C6 glioma cells labeled with CFDA-SE (vital fluorescent dye) showed that recombinant VEGFR-1 also binds to native membrane-associated VEGF. Recombinant VEGF was shown to bind to specific receptors expressed on the surface of C6 glioma cells. Functional activity of these proteins was confirmed by ligand-receptor assay for VEGF and VEGFR-1 (sFlt-1) and quantitative chemiluminescent detection.

Serum TNF-α, IL-8, VEGF Levels in Helicobacter pylori Infection and Their Association with Degree of Gastritis

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Gontar A Siregar

2015-04-01

Full Text Available Aim: to investigate the serum levels of TNF-α, IL-8, VEGF in Helicobacter pylori infection, and their association with the degrees of gastritis histopathology. Methods: a cross-sectional study was done on 80 consecutive gastritis patients admitted to endoscopy units at Adam Malik General Hospital and Permata Bunda Hospital, Medan, Indonesia from July-December 2014. The Rapid Urease test was used for the diagnosis of H. pylori infection. The severity of chronic inflammation, neutrophil infiltration, atrophy, and intestinal metaplasia were assessed. Serum samples were obtained to determine circulating TNF-α, IL-8, and VEGF. Univariate and bivariate analysis (chi square, fisher’s exact, and mann-whitney test were done using SPSS version-22. Results: there were 41.25% of 80 patients infected with Helicobacter pylori. Serum TNF-α and VEGF levels in the infected group were significantly higher compared to H. pylori negative, but there were no significant differences between serum levels of IL-8 in H. pylori positive and negative. There were significant associations between serum level of TNF-α and IL-8 with degree of chronic inflammation, and also between serum level of IL-8 and degree of neutrophil infiltration. There were significant associations between serum level of VEGF and degree of atrophy, and also between serum level of VEGF and degree of intestinal metaplasia. Conclusion: High levels of TNF-α were associated with severe degree of chronic inflammation, high levels of IL-8 associated with severe degree of chronic inflammation and neutrophil infiltration, and high levels of VEGF associated with severe degree of premalignant gastric lesion. Key words: cytokine, neoangiogenesis, Helicobacter pylori, atrophic gastritis, intestinal metaplasia.

[Suppression of VEGF protein expression by arctigenin in oral squamous cell carcinoma].

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Pu, Guang-rui; Liu, Fa-yu; Wang, Bo

2015-08-01

To observe arctigenin's inhibitory effect on oral squamous cell carcinoma, and explore the possible mechanism. The expression of VEGF in 32 cases of oral squamous cell cancer and 20 adjacent tissue specimen were detected with immunohistochemistry. Human nude mouse transplantation tumor model of oral squamous cell cancer was prepared with HSC-3 cells line. Transplanted tumor growth and VEGF expression in transplanted tumor tissues were assayed after treatment with arctigenin. One-way ANOVA was used for comparison between groups with SPSS 16.0 software package. Compared with the adjacent tissue, immunohistochemical staining score of VEGF was significantly higher (Parctigenin, the growth of oral squamous cell transplanted tumors in nude mouse was inhibited (Parctigenin group (PArctigenin can dose-dependently inhibit the growth of oral squamous cell carcinomas, and this effect may be related to down regulation of VEGF expression.

Molecular characterization of EG-VEGF-mediated angiogenesis: differential effects on microvascular and macrovascular endothelial cells.

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Brouillet, Sophie; Hoffmann, Pascale; Benharouga, Mohamed; Salomon, Aude; Schaal, Jean-Patrick; Feige, Jean-Jacques; Alfaidy, Nadia

2010-08-15

Endocrine gland derived vascular endothelial growth factor (EG-VEGF) also called prokineticin (PK1), has been identified and linked to several biological processes including angiogenesis. EG-VEGF is abundantly expressed in the highest vascularized organ, the human placenta. Here we characterized its angiogenic effect using different experimental procedures. Immunohistochemistry was used to localize EG-VEGF receptors (PROKR1 and PROKR2) in placental and umbilical cord tissue. Primary microvascular placental endothelial cell (HPEC) and umbilical vein-derived macrovascular EC (HUVEC) were used to assess its effects on proliferation, migration, cell survival, pseudovascular organization, spheroid sprouting, permeability and paracellular transport. siRNA and neutralizing antibody strategies were used to differentiate PROKR1- from PROKR2-mediated effects. Our results show that 1) HPEC and HUVEC express both types of receptors 2) EG-VEGF stimulates HPEC's proliferation, migration and survival, but increases only survival in HUVECs. and 3) EG-VEGF was more potent than VEGF in stimulating HPEC sprout formation, pseudovascular organization, and it significantly increases HPEC permeability and paracellular transport. More importantly, we demonstrated that PROKR1 mediates EG-VEGF angiogenic effects, whereas PROKR2 mediates cellular permeability. Altogether, these data characterized angiogenic processes mediated by EG-VEGF, depicted a new angiogenic factor in the placenta, and suggest a novel view of the regulation of angiogenesis in placental pathologies.

Effects of antibodies to EG-VEGF on angiogenesis in the chick embryo chorioallantoic membrane.

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Feflea, Stefana; Cimpean, Anca Maria; Ceausu, Raluca Amalia; Gaje, Pusa; Raica, Marius

2012-01-01

Endocrine gland-related vascular endothelial growth factor (EG-VEGF), is an angiogenic factor specifically targeting endothelial cells derived from endocrine tissues. The inhibition of the EG-VEGF/prokineticin receptor pathway could represent a selective antiangiogenic and anticancer strategy. to evaluate the impact of an antibody to EG-VEGF on the rapidly growing capillary plexus of the chick embryo chorioallantoic membrane (CAM). The in ovo CAM assay was performed for the humanized EG-VEGF antibody. Hemorrhagic damage was induced in the capillaries, which led to early death of the embryos. Upon morphological staining, there was evidence of vascular disruption and extravasation of red blood cells in the chorion. Signs of vacuolization of the covering epithelium were also observed. Blocking endogenous EG-VEGF might represent a valuable approach of impairing or inhibiting angiogenesis in steroidogenic-derived embryonic tissues.

Effect of intensive insulin therapy on macular biometrics, plasma VEGF and its soluble receptor in newly diagnosed diabetic patients.

Science.gov (United States)

Hernández, Cristina; Zapata, Miguel A; Losada, Eladio; Villarroel, Marta; García-Ramírez, Marta; García-Arumí, José; Simó, Rafael

2010-07-01

To evaluate whether intensive insulin therapy leads to changes in macular biometrics (volume and thickness) in newly diagnosed diabetic patients with acute hyperglycaemia and its relationship with serum levels of vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1). Twenty-six newly diagnosed diabetic patients admitted to our hospital to initiate intensive insulin treatment were prospectively recruited. Examinations were performed on admission (day 1) and during follow-up (days 3, 10 and 21) and included a questionnaire regarding the presence of blurred vision, standardized refraction measurements and optical coherence tomography. Plasma VEGF and sFlt-1 were assessed by ELISA at baseline and during follow-up. At study entry seven patients (26.9%) complained of blurred vision and five (19.2%) developed burred vision during follow-up. Macular volume and thickness increased significantly (p = 0.008 and p = 0.04, respectively) in the group with blurred vision at day 3 and returned to the baseline value at 10 days. This pattern was present in 18 out of the 24 eyes from patients with blurred vision. By contrast, macular biometrics remained unchanged in the group without blurred vision. We did not detect any significant changes in VEGF levels during follow-up. By contrast, a significant reduction of sFlt-1 was observed in those patients with blurred vision at day 3 (p = 0.03) with normalization by day 10. Diabetic patients with blurred vision after starting insulin therapy present a significant transient increase in macular biometrics which is associated with a decrease in circulating sFlt-1. Copyright (c) 2010 John Wiley & Sons, Ltd.

Neovascular age-related macular degeneration without drusen in the fellow eye: clinical spectrum and therapeutic outcome

Directory of Open Access Journals (Sweden)

Chung WH

2016-12-01

Full Text Available Wing H Chung,1 Elon H C van Dijk,1 Danial Mohabati,1 Greet Dijkman,1 Suzanne Yzer,2 Eiko K de Jong,3 Sascha Fauser,4 Reinier O Schlingemann,5–7 Carel B Hoyng,3 Camiel J F Boon1,5 1Department of Ophthalmology, Leiden University Medical Center, Leiden, 2Rotterdam Eye Hospital, Rotterdam, 3Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; 4Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany; 5Department of Ophthalmology, 6Ocular Angiogenesis Group, Departments of Ophthalmology and Cell Biology and Histology, Academic Medical Center, 7Netherlands Institute for Neuroscience, Amsterdam, the Netherlands Purpose: To investigate the clinical characteristics and therapeutic outcome of patients with neovascular age-related macular degeneration (nAMD in 1 eye, without drusen in the fellow eye. Patients and methods: Medical records of 381 patients were analyzed to identify the cases. The main outcomes included Early Treatment Diabetic Retinopathy Study (ETDRS best-corrected visual acuity (BCVA and change in central retinal thickness (CRT. These parameters were reviewed at baseline, first follow-up visit, and after 6, 12, and 24 months. Results: Out of 381 patients, 29 cases (8% were included (of whom 3 had polypoidal choroidal vasculopathy [PCV] who were treated with anti-vascular endothelial growth factor (anti-VEGF therapy which was supplemented by photodynamic therapy (PDT in the PCV patients. Overall, no statistically significant change in mean BCVA was observed during follow-up. BCVA improved or remained stable (defined as a gain in BCVA, a stable BCVA, or a loss of <5 ETDRS letters in 22 patients (76%, and 7 patients (23% had lost ≥5 ETDRS letters at final follow-up. A gain of ≥15 ETDRS letters at final follow-up was seen in 5 patients (17%. Mean CRT had decreased significantly with 99 µm (P<0.001 at 24 months after the

Lentivirus-mediated RNA interference of vascular endothelial growth factor in monkey eyes with iris neovascularization.

Science.gov (United States)

Yuan, Meng-Ke; Tao, Yong; Yu, Wen-Zhen; Kai, Wang; Jiang, Yan-Rong

2010-08-25

To explore the in vivo anti-angiogenesis effects resulting from lentivirus-mediated RNAi of vascular endothelial growth factor (VEGF) in monkeys with iris neovascularization (INV). Five specific recombinant lentiviral vectors for RNA interference, targeting Macaca mulatta VEGFA, were designed and the one with best knock down efficacy (LV-GFP-VEGFi1) in H1299 cells and RF/6A cells was selected by real-time PCR for in vivo use. A laser-induced retinal vein occlusion model was established in one eye of seven cynomolgus monkeys. In monkeys number 1, 3, and 5 (Group 1), the virus (1x10(8) particles) was intravitreally injected into the preretinal space of the animal's eye immediately after laser coagulation; and in monkeys number 2, 4, and 6 (Group 2), the virus (1x10(8) particles) was injected at 10 days after laser coagulation. In monkey number 7, a blank control injection was performed. In monkeys number 1 and 2, virus without RNAi sequence was used; in monkeys number 3 and 4, virus with nonspecific RNAi sequence was used; and in monkeys 5 and 6, LV-GFP-VEGFi1 was used. In monkey number 5, at 23 days after laser treatment, no obvious INV was observed, while fluorescein angiography of the iris revealed high fluorescence at the margin of pupil and point posterior synechiae. At 50 days after laser treatment, only a slight ectropion uvea was found. However, in the other eyes, obvious INV or hyphema was observed. The densities of new iridic vessels all significantly varied: between monkey number 5 and number 3 (36.01+/-4.49/mm(2) versus 48.68+/-9.30/mm(2), p=0.025), between monkey number 3 and monkey number 7 (48.68+/-9.30/mm(2) versus 74.38+/-9.23/mm(2), p=0.002), and between monkey number 5 and number 7 (36.01+/-4.49/mm(2) versus 74.38+/-9.23/mm(2), p<0.001). Lentivirus-mediated RNAi of VEGF may be a new strategy to treat iris neovascularization, while further studies are needed to investigate the long-term effect.

Two-baffle trap for macroparticles

International Nuclear Information System (INIS)

Aksyonov, D.S.

2014-01-01

In this work, properties of two-baffle macroparticle traps were investigated. These properties are needed for designing and optimization of vacuum arc plasma filters. The dependencies between trap geometry parameters and its ability to absorb macroparticles were found. Calculations made allow one to predict the behaviour of filtering abilities of separators containing such traps in their design. Recommendations regarding the use of two-baffle traps in filters of different builds are given

Investigation of extended blinks and interblink intervals in subjects with and without dry eye

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Rodriguez JD

2013-02-01

Full Text Available John D Rodriguez,1 George W Ousler III,1 Patrick R Johnston,1 Keith Lane,1 Mark B Abelson1,21Ora, Inc, Andover, MA, 2Schepens Eye Research Institute and Harvard Medical School, Boston, MA, USABackground: The purpose of this study was to investigate the occurrence and duration of extended blinks ≥ 70 msec and their associated interblink intervals in normal subjects and in subjects with mild to moderate dry eye.Methods: This single-center, prospective, double-blind study included 11 subjects with dry eye and eight subjects with normal eyes. Extended blinks were defined as lid closure in at least two successive video frames (≥ 70 msec. Digital video imaging of each subject's eyes was recorded while the subject viewed a 10-minute documentary. The subjects did not know that blink was the outcome being measured. Following capture, the videos were manually analyzed in a masked fashion for the occurrence of extended blinks. The length of the interblink interval (ie, time between blinks before and after these extended blinks (the interblink interval ratio was calculated, as well as differences in lid contact times.Results: The dry eye group had a median extended blink duration which was 2.53 times longer than that of the normal group. For subjects with dry eye, interblink intervals post-extended blink were significantly longer than interblink intervals pre-extended blink (P < 0.001. Interblink intervals did not lengthen significantly in normal subjects. In both groups, the duration of the extended blink was significantly (P = 0.001 and positively correlated with interblink interval ratio (post-extended to pre-extended blink interblink interval, such that for each doubling of extended blink duration, the interblink interval ratio increased by 10%. Blinks longer than one second in duration occurred almost exclusively in subjects with dry eye.Conclusion: This study reports three central findings: blink duration tended to be longer in subjects with dry

Dosimetric Comparison of Simulated Human Eye And Water Phantom in Investigation of Iodine Source Effects on Tumour And Healthy Tissues

International Nuclear Information System (INIS)

Sadi, A.S.; Masoudi, F.S. K.N.Toosi University of Technology

2011-01-01

For better clinical analysis in ophthalmic brachytherapy dosimetry, there is a need for the dose determination in different parts of the eye, so simulating the eye and defining the material of any parts of that, is helpful for better investigating dosimetry in human eye. However in brachytherapy dosimetry, it is common to consider the water phantom as human eye globe. In this work, a full human eye is simulated with MCNP-4C code by considering all parts of the eye like; lens, cornea, retina, choroid, sclera, anterior chamber, optic nerve, bulk of the eye comprising vitreous body and tumour. The average dose in different parts of this full model of human eye is determined and the results are compared with the dose calculated in water phantom. The central axes depth dose and the dose in whole of the tumour for these two simulated eye model are calculated too, and the results are compared. At long last, as the aim of this work is comparing the result of investigating dosimetry between two water phantom as human eye and simulated eye globe, the ratios of the absorbed dose by the healthy tissues to the absorbed dose by the tumour are calculated in these simulations and the comparison between results is done eventually.

Demineralised human dentine matrix stimulates the expression of VEGF and accelerates the bone repair in tooth sockets of rats.

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Reis-Filho, Cláudio R; Silva, Elisângela R; Martins, Adalberto B; Pessoa, Fernanda F; Gomes, Paula V N; de Araújo, Mariana S C; Miziara, Melissa N; Alves, José B

2012-05-01

In this study we investigated the possible use of human demineralised dentine matrix (DHDM), obtained from the extracted teeth, as bone graft material and evaluated the expression of vascular endothelial growth factor (VEGF) induced by this material in the healing process of tooth sockets of rats. To evaluate bone regeneration and expression of VEGF induced by DHDM, thirty-two male Wistar rats weighing approximately 200 g were used. After maxillary second molar extraction, the left sockets were filled with DHDM and the right sockets were naturally filled by blood clot (control). The animals were sacrificed at 3, 7, 14 and 21 days after surgery and upper maxillaries were processed for histological, morphometric and immunohistochemical analyses. DHDM was used to evaluate the mechanical effect of bone graft material into sockets. Expression of VEGF was determined by immunohistochemistry in all groups. Our results demonstrated a significant increase in the newly formed bone tissue in sockets of 7, 14 and 21 days and a significant increase in VEGF expression at days 7 and 14 on treated sockets. Our results showed that DHDM increases the expression of VEGF and accelerates the healing process in rats tooth sockets, by stimulating bone deposition and also vessels formation. These results suggest that DHDM has osteoinductive/osteoconductive potential and may represent an efficient grafting material on guided bone regeneration. Copyright © 2011 Elsevier Ltd. All rights reserved.

Investigation of SAGD steam trap control in two and three dimensions

Energy Technology Data Exchange (ETDEWEB)

Edmunds, N. R. [Clearwater Engineering, AB (Canada)

1998-12-31

Steam trap production control has been traditionally recommended for steam-assisted gravity drainage (SAGD) operations. This study examines the relationship between producing steam trap subcool settings and related parameters of interest such as fluid level, pressure, production rate, and profitability for a prototype Athabasca reservoir. Study results indicate that the steam trap dynamics are far more complex than hitherto imagined, that 3-D simulations predict significantly lower production rates than 2-D simulations, and that these variations have implications for all aspects of SAGD engineering, including process optimization, production operations and performance analysis. 10 refs., 2 tabs., 15 figs.

Estimation of Immunohistochemical Expression of VEGF in Ductal Carcinomas of the Breast

DEFF Research Database (Denmark)

Maae, Else; Nielsen, Martin; Dahl Steffensen, Karina

2012-01-01

Introduction: Vascular endothelial growth factor A (VEGF-A) is a very important growth factor in angiogenesis and holds the potential as both a predictive marker for anti-angiogenic cancer treatment and as a prognostic variable. Consequently, reliable estimation of VEGF expression is crucial...

Perlecan Domain V induces VEGf secretion in brain endothelial cells through integrin α5β1 and ERK-dependent signaling pathways.

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Douglas N Clarke

Full Text Available Perlecan Domain V (DV promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs following stroke. In this study, we define the specific mechanism of DV interaction with the α(5β(1 integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV's angio-modulatory activity outside of the brain, binds poorly to α(5β(1 and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV's DGR sequence as an important element for the interaction of DV with α(5β(1. Furthermore, we investigated the importance of AKT and ERK signaling in DV-induced VEGF expression and secretion. We show that DV increases the phosphorylation of ERK, which leads to subsequent activation and stabilization of eIF4E and HIF-1α. Inhibition of ERK activity by U0126 suppressed DV-induced expression and secretion of VEGR in BECs. While DV was capable of phosphorylating AKT we show that AKT phosphorylation does not play a role in DV's induction of VEGF expression or secretion using two separate inhibitors, LY294002 and Akt IV. Lastly, we demonstrate that VEGF activity is critical for DV increases in BEC proliferation, as well as angiogenesis in a BEC-neuronal co-culture system. Collectively, our findings expand our understanding of DV's mechanism of action on BECs, and further support its potential as a novel stroke therapy.

Perlecan Domain V Induces VEGf Secretion in Brain Endothelial Cells through Integrin α5β1 and ERK-Dependent Signaling Pathways

Science.gov (United States)

Clarke, Douglas N.; Al Ahmad, Abraham; Lee, Boyeon; Parham, Christi; Auckland, Lisa; Fertala, Andrezj; Kahle, Michael; Shaw, Courtney S.; Roberts, Jill; Bix, Gregory J.

2012-01-01

Perlecan Domain V (DV) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs) following stroke. In this study, we define the specific mechanism of DV interaction with the α5β1 integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV’s angio-modulatory activity outside of the brain, binds poorly to α5β1 and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV’s DGR sequence as an important element for the interaction of DV with α5β1. Furthermore, we investigated the importance of AKT and ERK signaling in DV-induced VEGF expression and secretion. We show that DV increases the phosphorylation of ERK, which leads to subsequent activation and stabilization of eIF4E and HIF-1α. Inhibition of ERK activity by U0126 suppressed DV-induced expression and secretion of VEGR in BECs. While DV was capable of phosphorylating AKT we show that AKT phosphorylation does not play a role in DV’s induction of VEGF expression or secretion using two separate inhibitors, LY294002 and Akt IV. Lastly, we demonstrate that VEGF activity is critical for DV increases in BEC proliferation, as well as angiogenesis in a BEC-neuronal co-culture system. Collectively, our findings expand our understanding of DV’s mechanism of action on BECs, and further support its potential as a novel stroke therapy. PMID:23028886

Prokaryotic Soluble Overexpression and Purification of Human VEGF165 by Fusion to a Maltose Binding Protein Tag.

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Minh Tan Nguyen

Full Text Available Human vascular endothelial growth factor (VEGF is a key regulator of angiogenesis and plays a central role in the process of tumor growth and metastatic dissemination. Escherichia coli is one of the most common expression systems used for the production of recombinant proteins; however, expression of human VEGF in E. coli has proven difficult because the E. coli-expressed VEGF tends to be misfolded and forms inclusion bodies, resulting in poor solubility. In this study, we successfully produced semi-preparative amounts of soluble bioactive human VEGF165 (hVEGF. We created seven N-terminal fusion tag constructs with hexahistidine (His6, thioredoxin (Trx, glutathione S-transferase (GST, maltose-binding protein (MBP, N-utilization substance protein A (NusA, human protein disulfide isomerase (PDI, and the b'a' domain of PDI (PDIb'a', and tested each construct for soluble overexpression in E. coli. We found that at 18°C, 92.8% of the MBP-tagged hVEGF to be soluble and that this tag significantly increased the protein's solubility. We successfully purified 0.8 mg of pure hVEGF per 500 mL cell culture. The purified hVEGF is stable after tag cleavage, contains very low levels of endotoxin, and is 97.6% pure. Using an Flk1+ mesodermal precursor cell (MPC differentiation assay, we show that the purified hVEGF is not only bioactive but has similar bioactivity to hVEGF produced in mammalian cells. Previous reports on producing hVEGF in E. coli have all been based on refolding of the protein from inclusion bodies. To our knowledge, this is the first report on successfully expressing and purifying soluble hVEGF in E. coli.

Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity.

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Jais, Alexander; Solas, Maite; Backes, Heiko; Chaurasia, Bhagirath; Kleinridders, André; Theurich, Sebastian; Mauer, Jan; Steculorum, Sophie M; Hampel, Brigitte; Goldau, Julia; Alber, Jens; Förster, Carola Y; Eming, Sabine A; Schwaninger, Markus; Ferrara, Napoleone; Karsenty, Gerard; Brüning, Jens C

2016-05-05

High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGF(Δmyel) mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not in lean mice. Moreover, obese VEGF(Δmyel) mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer's disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associated macrophage activation a homeostatic role to restore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity. Copyright © 2016 Elsevier Inc. All rights reserved.

Cellular and molecular aspects of diabetic nephropathy; the role of VEGF-A.

Science.gov (United States)

Carranza, Katherine; Veron, Dolores; Cercado, Alicia; Bautista, Noemi; Pozo, Wilson; Tufro, Alda; Veron, Delma

2015-01-01

The prevalence of diabetes mellitus increased during the last century and it is estimated that 45% of the patients are not diagnosed. In South America the prevalence of diabetes and chronic kidney disease (CKD) increased, with a great disparity among the countries with respect to access to dialysis. In Ecuador it is one of the main causes of mortality, principally in the provinces located on the coast of the Pacific Ocean. The greatest single cause of beginning dialysis is diabetic nephropathy (DN). Even using the best therapeutic options for DN, the residual risk of proteinuria and of terminal CKD remains high. In this review we indicate the importance of the problem globally and in our region. We analyse relevant cellular and molecular studies that illustrate the crucial significance of glomerular events in DN development and evolution and in insulin resistance. We include basic anatomical, pathophysiological and clinical concepts, with special attention to the role of angiogenic factors such as the vascular endothelial growth factor (VEGF-A) and their relationship to the insulin receptor, endothelial isoform of nitric oxide synthase (eNOS) and angiopoietins. We also propose various pathways that have therapeutic potential in our opinion. Greater in-depth study of VEGF-A and angiopoietins, the state of glomerular VEGF resistance, the relationship of VEGF receptor 2/nephrin, VEGF/insulin receptors/nephrin and the relationship of VEGF/eNOS-NO at glomerular level could provide solutions to the pressing world problem of DN and generate new treatment alternatives. Copyright © 2015. Published by Elsevier España, S.L.U.

Endocrine gland-derived endothelial growth factor (EG-VEGF) is a potential novel regulator of human parturition.

Science.gov (United States)

Dunand, C; Hoffmann, P; Sapin, V; Blanchon, L; Salomon, A; Sergent, F; Benharouga, M; Sabra, S; Guibourdenche, J; Lye, S J; Feige, J J; Alfaidy, N

2014-09-01

EG-VEGF is an angiogenic factor that we identified as a new placental growth factor during human pregnancy. EG-VEGF is also expressed in the mouse fetal membrane (FM) by the end of gestation, suggesting a local role for this protein in the mechanism of parturition. However, injection of EG-VEGF to gravid mice did not induce labor, suggesting a different role for EG-VEGF in parturition. Here, we searched for its role in the FM in relation to human parturition. Human pregnant sera and total FM, chorion, and amnion were collected during the second and third trimesters from preterm no labor, term no labor, and term labor patients. Primary human chorion trophoblast and FM explants cultures were also used. We demonstrate that circulating EG-VEGF increased toward term and significantly decreased at the time of labor. EG-VEGF production was higher in the FM compared to placentas matched for gestational age. Within the FM, the chorion was the main source of EG-VEGF. EG-VEGF receptors, PROKR1 and PROKR2, were differentially expressed within the FM with increased expression toward term and an abrupt decrease with the onset of labor. In chorion trophoblast and FM explants collected from nonlaboring patients, EG-VEGF decreased metalloproteinase-2 and -9 activities and increased PGDH (prostaglandin-metabolizing enzyme) expression. Altogether these data demonstrate that EG-VEGF is a new cytokine that acts locally to ensure FM protection in late pregnancy. Its fine contribution to the initiation of human labor is exhibited by the abrupt decrease in its levels as well as a reduction in its receptors. © 2014 by the Society for the Study of Reproduction, Inc.

Estimation of Immunohistochemical Expression of VEGF in Ductal Carcinomas of the Breast

DEFF Research Database (Denmark)

Maae, Else; Nielsen, Martin; Dahl Steffensen, Karina

2011-01-01

Vascular endothelial growth factor A (VEGF-A) is a very important growth factor in angiogenesis and holds the potential as both a predictive marker for anti-angiogenic cancer treatment and as a prognostic variable. Consequently, reliable estimation of VEGF expression is crucial. We immunostained ...

Estimation of Immunohistochemical Expression of VEGF in Ductal Carcinomas of the Breast

DEFF Research Database (Denmark)

Maae, Else; Nielsen, Martin; Dahl Steffensen, Karina

2011-01-01

Vascular endothelial growth factor A (VEGF-A) is a very important growth factor in angiogenesis and holds the potential as both a predictive marker for anti-angiogenic cancer treatment and as a prognostic variable. Consequently, reliable estimation of VEGF expression is crucial. We immunostained...

Synthesis of the human VEGF165 gene based on overlap PCR and ...

African Journals Online (AJOL)

Yomi

2012-01-16

Jan 16, 2012 ... recombinant human VEGF165 (rhVEGF165) protein in CHO cells. ... The PCR program consisted of a denaturation step at 95°C for 3 min, then 25 cycles at ... PCR product for template and two oligos introduced at one end for.

Mural cell associated VEGF is required for organotypic vessel formation.

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Lasse Evensen

Full Text Available BACKGROUND: Blood vessels comprise endothelial cells, mural cells (pericytes/vascular smooth muscle cells and basement membrane. During angiogenesis, mural cells are recruited to sprouting endothelial cells and define a stabilizing context, comprising cell-cell contacts, secreted growth factors and extracellular matrix components, that drives vessel maturation and resistance to anti-angiogenic therapeutics. METHODS AND FINDINGS: To better understand the basis for mural cell regulation of angiogenesis, we conducted high content imaging analysis on a microtiter plate format in vitro organotypic blood vessel system comprising primary human endothelial cells co-cultured with primary human mural cells. We show that endothelial cells co-cultured with mural cells undergo an extensive series of phenotypic changes reflective of several facets of blood vessel formation and maturation: Loss of cell proliferation, pathfinding-like cell migration, branching morphogenesis, basement membrane extracellular matrix protein deposition, lumen formation, anastamosis and development of a stabilized capillary-like network. This phenotypic sequence required endothelial-mural cell-cell contact, mural cell-derived VEGF and endothelial VEGFR2 signaling. Inhibiting formation of adherens junctions or basement membrane structures abrogated network formation. Notably, inhibition of mural cell VEGF expression could not be rescued by exogenous VEGF. CONCLUSIONS: These results suggest a unique role for mural cell-associated VEGF in driving vessel formation and maturation.

Coffee induces vascular endothelial growth factor (VEGF) expression in human neuroblastama SH-SY5Y cells.

Science.gov (United States)

Kakio, Shota; Funakoshi-Tago, Megumi; Kobata, Kenji; Tamura, Hiroomi

2017-07-01

Recent evidence indicates that hypoxia-inducible vascular endothelial growth factor (VEGF) has neurotrophic and neuroprotective effects on neuronal and glial cells. On the other hand, recent epidemiological studies showed that daily coffee consumption has been associated with a lower risk of several neuronal disorders. Therefore, we investigated the effect of coffee on VEGF expression in human neuroblastoma SH-SY5Y cells. We found that even low concentration of coffee (coffee was attributed to the coffee-dependent inhibition of prolyl hydroxylation of HIF1α, which is essential for proteolytic degradation of HIF-1α. However, no inhibition was observed at the catalytic activity in vitro. Coffee component(s) responsible for the activation of HIF-1α was not major constituents such as caffeine, caffeic acid, chlorogenic acid, and trigonelline, but was found to emerge during roasting process. The active component(s) was extractable with ethyl acetate. Our results suggest that daily consumption of coffee may induce VEGF expression in neuronal cells. This might be related to protective effect of coffee on neural disorders such as Alzheimer's disease and Parkinson's disease.

Early VEGF inhibition attenuates blood-brain barrier disruption in ischemic rat brains by regulating the expression of MMPs.

Science.gov (United States)

Zhang, Hai-Tao; Zhang, Ping; Gao, Yi; Li, Chen-Long; Wang, Hong-Jun; Chen, Ling-Chao; Feng, Yan; Li, Rui-Yan; Li, Yong-Li; Jiang, Chuan-Lu

2017-01-01

Vascular endothelial growth factor (VEGF) inhibition has been demonstrated to be an effective strategy in preserving the integrity of the blood-brain barrier (BBB) in patients with acute ischemic stroke. Loss of the BBB is the key event associated with morbidity and mortality in these patients. However, the underlying mechanisms remain poorly understood. In the present study, the effects of VEGF inhibition and the possible mechanism that underlies acute cerebral ischemia in rats was investigated. Following the induction of transient middle cerebral artery occlusion for a 90‑min period, either an anti‑VEGF neutralizing antibody (RB‑222; 5 or 10 µg), or IgG (control), was administered by intracerebroventricular injection at 1 h following reperfusion. Functional outcomes, BBB leakage, brain edema, microvessel numbers and the relative protein levels of VEGF, matrix metalloproteinase (MMP)-2, MMP-9, occludin and collagen-IV were then determined using neurological assessments, Evans Blue staining, brain water content, CD31 staining and western blotting. Treatment with RB‑222 at a dose of 5 and 10 µg significantly improved neurological functional outcomes and diminished infarct size, BBB leakage and brain edema compared with the MCAO and IgG groups at 24 h following reperfusion; 10 µg RB‑222 was more effective than a 5 µg dose of the antibody. In addition, RB‑222 reduced the number of immature microvessels, which subsequently attenuated BBB permeability. RB‑222 significantly repressed VEGF expression as well as decreased MMP‑2 and MMP‑9 expression. However, it enhanced occludin and collagen‑IV levels in the ischemic rat brain compared with the MCAO and IgG groups. Taken together, the results indicate that early inhibition of VEGF may have significant potential against cerebral ischemia, partly by regulating the expression of MMPs.

Development of biocompatible and VEGF-targeted paclitaxel nanodrugs on albumin and graphene oxide dual-carrier for photothermal-triggered drug delivery in vitro and in vivo.

Science.gov (United States)

Deng, Wentao; Qiu, Juhui; Wang, Shaoting; Yuan, Zhi; Jia, Yuefeng; Tan, Hailin; Lu, Jiru; Zheng, Ruqiang

2018-01-01

In this study, we performed the characterization and synthesis of biocompatible and targeted albumin and graphene oxide (GO) dual-carrier paclitaxel (PTX) nanoparticles for photothermal-triggered tumor therapy. PTX absorbed on GO nanosheets as cores were coated with human serum albumin (HSA), following surface conjugation with monoclonal antibodies (mAb) against vascular endothelial growth factor (VEGF; denoted as mAbVEGF) via polyethylene glycol linker to form targeted nanoparticles (PTX-GHP-VEGF). The spherical nanoparticles were 191±5 nm in size with good stability and biocompatibility. GO functioned as the first carrier and a near infrared absorber that can generate photothermal effects under 5-minute 808-nm laser irradiation to thermal trigger the release of PTX from the second carrier HSA nanoparticles. The mechanism of thermal-triggered drug release was also investigated preliminarily, in which the heat generated by GO induced swelling of PTX-GHP-VEGF nanoparticles which released the drugs. In vitro studies found that PTX-GHP-VEGF can efficiently target human SW-13 adrenocortical carcinoma cells as evaluated by confocal fluorescence microscopy as well as transmission electron microscopy, and showed an obvious thermal-triggered antitumor effect, mediated by apoptosis. Moreover, PTX-GHP-VEGF combined with near infrared irradiation showed specific tumor suppression effects with high survival rate after 100 days of treatment. PTX-GHP-VEGF also demonstrated high biosafety with no adverse effects on normal tissues and organs. These results highlight the remarkable potential of PTX-GHP-VEGF in photothermal controllable tumor treatment.

FIB-SEM investigation of trapped intermetallic particles in anodic oxide films on AA1050 aluminium

DEFF Research Database (Denmark)

Jariyaboon, Manthana; Møller, Per; Dunin-Borkowski, Rafal E.

2011-01-01

-containing intermetallic particles incorporated into the anodic oxide films on industrially pure aluminium (AA1050, 99.5 per cent) has been investigated. AA1050 aluminium was anodized in a 100?ml/l sulphuric acid bath with an applied voltage of 14?V at 20°C ±2°C for 10 or 120?min. The anodic film subsequently was analyzed......Purpose - The purpose of this investigation is to understand the structure of trapped intermetallics particles and localized composition changes in the anodized anodic oxide film on AA1050 aluminium substrates. Design/methodology/approach - The morphology and composition of Fe......-shaped particles were embedded in the anodic oxide film as a thin strip structure and located near the top surface of the film, whereas the round-shaped particles were trapped in the film with a spherical structure, but partially dissolved and were located throughout the thickness of the anodic film. The Fe...

Activation of Protease-Activated Receptor 2 Induces VEGF Independently of HIF-1

DEFF Research Database (Denmark)

Rasmussen, J.G.; Riis, Simone Elkjær; Frøbert, O.

2012-01-01

Human adipose stem cells (hASCs) can promote angiogenesis through secretion of proangiogenic factors such as vascular endothelial growth factor (VEGF). In other cell types, it has been shown that induction of VEGF is mediated by both protease activated receptor 2 (PAR2) and hypoxia inducible fact...

Particle trapping in stimulated scattering processes

International Nuclear Information System (INIS)

Karttunen, S.J.; Heikkinen, J.A.

1981-01-01

Particle trapping effects on stimulated Brillouin and Raman scattering are investigated. A time and space dependent model assumes a Maxwellian plasma which is taken to be homogeneous in the interaction region. Ion trapping has a rather weak effect on stimulated Brillouin scattering and large reflectivities are obtained even in strong trapping regime. Stimulated Raman scattering is considerably reduced by electron trapping. Typically 15-20 times larger laser intensities are required to obtain same reflectivity levels than without trapping. (author)

Design, synthesis and evaluation of VEGF-siRNA/CRS as a novel vector for gene delivery

Directory of Open Access Journals (Sweden)

Zhao W

2016-11-01

Full Text Available Wen Zhao, Yifan Zhang, Xueyun Jiang, Chunying Cui School of Chemical Biology and Pharmaceutical Sciences, Capital Medical University, Beijing, China Abstract: Small interfering RNA (siRNA delivery is a prospective method in gene therapy, but it has application limitations such as negative charge, water solubility and high molecular weight. In this study, a safe and efficient nano-vector, CRS, was designed and synthesized to facilitate siRNA delivery. Physical and chemical properties of VEGF-siRNA/CRS were characterized by methods including scanning electron microscopy (SEM, transmission electron microscopy, zeta potential (ζ measurement, drug-releasing rate measurement, gel electrophoresis and confocal microscopy. The biological activities were evaluated using cell viability assay, gene-silencing efficacy assay in vitro, real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA and antitumor tests in vivo. The mean nanoparticle size of VEGF-siRNA/CRS was 121.4±0.3 nm with positive ζ potential of 7.69±4.47 mV. The release rate of VEGF-siRNA from VEGF-siRNA/CRS was 82.50% sustained for 48 h in Tris-ethylenediaminetetraacetic acid buffer (pH 8.0. Real-time polymerase chain reaction was used to analyze the efficiency of the transfection, and the result showed that VEGF mRNA expression had been knocked down by 82.36%. The expression of VEGF protein was also recorded to be downregulated to 14.83% using ELISA. The results of cytotoxicity measured by Cell Counting Kit-8 assay showed that VEGF-siRNA/CRS had significant inhibitory effect on HeLa cells. The results of antitumor assays indicated that VEGF-siRNA/CRS exhibited tumor cell growth inhibition in vivo. The results demonstrated that VEGF-siRNA could be delivered and transported by the designed carrier, while siRNA could be released constantly and led to an increasing gene-silencing effect against VEGF gene. In conclusion, VEGF-siRNA/CRS is a promising carrier for si

Estimation of Immunohistochemical Expression of VEGF in Ductal Carcinomas of the Breast

DEFF Research Database (Denmark)

Maae, Else; Nielsen, Martin; Dahl Steffensen, Karina

2012-01-01

Introduction: Vascular endothelial growth factor A (VEGF-A) is a very important growth factor in angiogenesis and holds the potential as both a predictive marker for anti-angiogenic cancer treatment and as a prognostic variable. Consequently, reliable estimation of VEGF expression is crucial...... an automated method for analyzing VEGF expression (so-called AI score) using the same tumor sections. Analysis of 100% of the tumor area was performed and the results were compared to the reduced analysis of 25% of the tumor area. These analyses were performed at 5x and 10x magnification and each analysis...... was repeated in a second run with a new delineation of the tumor area. Results: We found that the AI scores were correlated to the manual scoring of VEGF intensity, but the reproducibility of manual IHC scores was rather poor. The AI scores were reproducible and the restricted analysis of 25% of the tumor area...

Plasma levels and diagnostic utility of VEGF, MMP-2 and TIMP-2 in the diagnostics of breast cancer patients.

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Ławicki, Sławomir; Zajkowska, Monika; Głażewska, Edyta Katarzyna; Będkowska, Grażyna Ewa; Szmitkowski, Maciej

2017-03-01

We investigated plasma levels and diagnostic utility of vascular endothelial growth factor VEGF, matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinase-2 (TIMP-2) in comparison to cancer antigen 15-3 (CA 15-3). Plasma levels of tested parameters were determined using enzyme-linked immunosorbent assay (ELISA) while CA 15-3 with chemiluminescent microparticle immunoassay (CMIA). The plasma levels of VEGF, TIMP-2 showed significantly higher than CA 15-3 values of the diagnostic sensitivity, the predictive values of positive and negative test results (PPV, NPV) and the area under the receiver-operating characteristics (ROC) curve (AUC) in early stages of breast cancer (BC). The combined use of the tested parameters with CA 15-3 resulted in the increase in sensitivity, NPV and AUC, especially in the combination with VEGF (83%; 72%; 0.888) and TIMP-2 (83%; 72%; 0.894). The highest values were obtained for combination of all three parameters (93%; 85%; 0.923). These findings suggest the usefulness of the tested parameters in the diagnosis of BC, especially VEGF and TIMP-2 with CA 15-3 in early stages of BC, which could be a new diagnostic panel.

VEGF attenuated increase of outward delayed-rectifier potassium currents in hippocampal neurons induced by focal ischemia via PI3-K pathway.

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Wu, K W; Yang, P; Li, S S; Liu, C W; Sun, F Y

2015-07-09

We recently indicated that the vascular endothelial growth factor (VEGF) protects neurons against hypoxic death via enhancement of tyrosine phosphorylation of Kv1.2, an isoform of the delayed-rectifier potassium channels through activation of the phosphatidylinositol 3-kinase (PI3-K) signaling pathway. The present study investigated whether VEGF could attenuate ischemia-induced increase of the potassium currents in the hippocampal pyramidal neurons of rats after ischemic injury. Adult male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) to induce brain ischemia. The whole-cell patch-clamp technique was used to record the potassium currents of hippocampal neurons in brain slices from the ischemically injured brains of the rats 24h after MCAO. We detected that transient MCAO caused a significant increase of voltage-gated potassium currents (Kv) and outward delayed-rectifier potassium currents (IK), but not outward transient potassium currents (IA), in the ipsilateral hippocampus compared with the sham. Moreover, we found that VEGF could acutely, reversibly and voltage-dependently inhibit the ischemia-induced IK increase. This inhibitory effect of VEGF could be completely abolished by wortmannin, an inhibitor of PI3-K. Our data indicate that VEGF attenuates the ischemia-induced increase of IK via activation of the PI3-K signaling pathway. Published by Elsevier Ltd.

Cavity sideband cooling of trapped molecules

NARCIS (Netherlands)

Kowalewski, Markus; Morigi, Giovanna; Pinkse, Pepijn Willemszoon Harry; de Vivie-Riedle, Regina

2011-01-01

The efficiency of cavity sideband cooling of trapped molecules is theoretically investigated for the case in which the infrared transition between two rovibrational states is used as a cycling transition. The molecules are assumed to be trapped either by a radiofrequency or optical trapping

A nanobody directed to a functional epitope on VEGF, as a novel strategy for cancer treatment

International Nuclear Information System (INIS)

Farajpour, Zahra; Rahbarizadeh, Fatemeh; Kazemi, Bahram; Ahmadvand, Davoud

2014-01-01

Highlights: • A novel nanobody directed to antigenic regions on VEGF was identified. • Our nanobody was successfully purified. • Our nanobody significantly inhibited VEGF-induced proliferation of HUVECs in a dose dependent manner. - Abstract: Compelling evidence suggests that vascular endothelial growth factor (VEGF), due to its essential role in angiogenesis, is a critical target for cancer treatment. Neutralizing monoclonal antibodies against VEGF are important class of drugs used in cancer therapy. However, the cost of production, large size, and immunogenicity are main drawbacks of conventional monoclonal therapy. Nanobodies are the smallest antigen-binding antibody fragments, which occur naturally in camelidae. Because of their remarkable features, we decided to use an immune library of nanobody to direct phage display to recognition of novel functional epitopes on VEGF. Four rounds of selection were performed and six phage-displayed nanobodies were obtained from an immune phage library. The most reactive clone in whole-cell ELISA experiments, was purified and assessed in proliferation inhibition assay. Purified ZFR-5 not only blocked interaction of VEGF with its receptor in cell ELISA experiments, but also was able to significantly inhibit proliferation response of human umbilical vein endothelial cells to VEGF in a dose-dependent manner. Taken together, our study demonstrates that by using whole-cell ELISA experiments, nanobodies against antigenic regions included in interaction of VEGF with its receptors can be directed. Because of unique and intrinsic properties of a nanobody and the ability of selected nanobody for blocking the epitope that is important for biological function of VEGF, it represents novel potential drug candidate

A nanobody directed to a functional epitope on VEGF, as a novel strategy for cancer treatment

Energy Technology Data Exchange (ETDEWEB)

Farajpour, Zahra [Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of); Rahbarizadeh, Fatemeh, E-mail: rahbarif@modares.ac.ir [Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran (Iran, Islamic Republic of); Kazemi, Bahram [Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran (Iran, Islamic Republic of); Ahmadvand, Davoud [School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran (Iran, Islamic Republic of)

2014-03-28

Highlights: • A novel nanobody directed to antigenic regions on VEGF was identified. • Our nanobody was successfully purified. • Our nanobody significantly inhibited VEGF-induced proliferation of HUVECs in a dose dependent manner. - Abstract: Compelling evidence suggests that vascular endothelial growth factor (VEGF), due to its essential role in angiogenesis, is a critical target for cancer treatment. Neutralizing monoclonal antibodies against VEGF are important class of drugs used in cancer therapy. However, the cost of production, large size, and immunogenicity are main drawbacks of conventional monoclonal therapy. Nanobodies are the smallest antigen-binding antibody fragments, which occur naturally in camelidae. Because of their remarkable features, we decided to use an immune library of nanobody to direct phage display to recognition of novel functional epitopes on VEGF. Four rounds of selection were performed and six phage-displayed nanobodies were obtained from an immune phage library. The most reactive clone in whole-cell ELISA experiments, was purified and assessed in proliferation inhibition assay. Purified ZFR-5 not only blocked interaction of VEGF with its receptor in cell ELISA experiments, but also was able to significantly inhibit proliferation response of human umbilical vein endothelial cells to VEGF in a dose-dependent manner. Taken together, our study demonstrates that by using whole-cell ELISA experiments, nanobodies against antigenic regions included in interaction of VEGF with its receptors can be directed. Because of unique and intrinsic properties of a nanobody and the ability of selected nanobody for blocking the epitope that is important for biological function of VEGF, it represents novel potential drug candidate.

Effect of serum cytokines and VEGF levels on diabetic retinopathy and macular thickness.

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Ozturk, Banu Turgut; Bozkurt, Banu; Kerimoglu, Hurkan; Okka, Mehmet; Kamis, Umit; Gunduz, Kemal

2009-09-19

To investigate the role of serum inflammatory cytokines and vascular endothelial growth factor (VEGF) in diabetic retinopathy (DR) and evaluate their relationship with macular thickness measurements obtained with optical coherence tomography (OCT). The study enrolled 28 healthy subjects (Group 1), 31 patients without DR (Group 2), 49 patients with nonproliferative DR (Group 3), and 46 patients with proliferative DR (Group 4). Macular profile was assessed with Stratus OCT-3 and the serum concentrations of VEGF and interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), macrophage inflammatory protein (MIP-1 alpha), monocyte chemoattractant protein (MCP-1), and epidermal growth factor (EGF) were measured using multiplex bead immunoassay. The median value of the visual acuity was 20/20 (Groups 1 and 2), and 20/100 (Group 3), and 20/125 (Group 4). The median value of central subfield macular thickness was estimated as 165.50 microm in Group 1, 202.5 microm in Group 2, 318 microm in Group 3, and 310 microm in Group 4. The median serum VEGF level, which was 98.20 pg/ml in Group 1, demonstrated a progressive rise to 125.37 pg/ml in Group 2, to 153.07 pg/ml in Group 3, and to 149.12 pg/ml in Group 4. Statistical significance was found between all groups (p0.05). The median serum levels of IL-8, IL-10, MIP-1 alpha, and EGF revealed a wide range within each group, however, no statistically significant relationship was found between the groups (p>0.05). The median values of the serum MCP-1 concentrations presented a statistically significant rise with the progression of DR (p=0.02). No correlation was found between macular thickness and serum cytokine and VEGF levels (p>0.05). Increased serum levels of VEGF and MCP-1 may act as a key regulator of DR and provide a potential tool for risk assessment in diabetic patients. Further studies that evaluate both vitreous and serum levels in various stages of DR are needed to provide a

Angiomodulin is a specific marker of vasculature and regulates VEGF-A dependent neo-angiogenesis

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Hooper, Andrea T.; Shmelkov, Sergey V.; Gupta, Sunny; Milde, Till; Bambino, Kathryn; Gillen, Kelly; Goetz, Mollie; Chavala, Sai; Baljevic, Muhamed; Murphy, Andrew J.; Valenzuela, David M.; Gale, Nicholas W.; Thurston, Gavin; Yancopoulos, George D.; Vahdat, Linda; Evans, Todd; Rafii, Shahin

2010-01-01

Blood vessel formation is controlled by the balance between pro- and anti-angiogenic pathways. Although much is known about the factors that drive sprouting of neovessels, the factors that stabilize and pattern neovessels are undefined. The expression of angiomodulin (AGM), a VEGF-A binding protein, was increased in the vasculature of several human tumors as compared to normal tissue, raising the hypothesis that AGM may modulate VEGF-A-dependent vascular patterning. To elucidate the expression pattern of AGM, we developed an AGM knockin reporter mouse (AGMlacZ/+) wherein we demonstrate that AGM is predominantly expressed in the vasculature of developing embryos and adult organs. During physiological and pathological angiogenesis, AGM is upregulated in the angiogenic vasculature. Using the zebrafish model, we found that AGM is restricted to developing vasculature by 17-22 hpf. Blockade of AGM activity with morpholino oligomers (MO) results in prominent angiogenesis defects in vascular sprouting and remodeling. Concurrent knockdown of both AGM and VEGF-A results in synergistic angiogenesis defects. When VEGF-A is overexpressed, the compensatory induction of the VEGF-A receptor, VEGFR-2/flk-1, is blocked by the simultaneous injection of AGM MO. These results demonstrate that the vascular-specific marker AGM modulates vascular remodeling in part by temporizing the pro-angiogenic effects of VEGF-A. PMID:19542015

EGF-R is Expressed and AP-1 and NF-κ:B Are Activated in Stromal Myofibroblasts Surrounding Colon Adenocarcinomas Paralleling Expression of COX-2 and VEGF

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Panagiotis A. Konstantinopoulos

2007-01-01

Full Text Available Background: COX-2 and VEGF are important triggers of colon cancer growth, metastasis and angiogenesis. Cox-2 promoter contains transcriptional regulatory elements for AP-1 and NF-κ:B transcription factors whilst vegf is a known AP-1 downstream target gene. We investigated whether stromal myofibroblasts surrounding colon adenocarcinomas express COX-2 and VEGF and whether activation of AP-1 and NF-κ:B, as well as expression of EGF-R parallel expression of COX-2 and VEGF in these cells. Methods: Immunohistochemical methodology was performed on archival sections from 40 patients with colon adenocarcinomas. We evaluated c-FOS, p-c-JUN (phosphorylated c-JUN, p-Iκ:B-α (phosphorylated Iκ:B-α, EGF-R, COX-2, NF-κ:B and VEGF expression in stromal myofibroblasts surrounding colon adenocarcinomas. Double immunostaining with a-smooth muscle actin and each antibody was done to verify the expression of these molecules in stromal myofibroblasts. Results: VEGF, p-Iκ:B-α, NF-κ:B, c-FOS, p-c-JUN, EGF-R and COX-2 were expressed in stromal myofibroblasts surrounding colon adenocarcinomas in the majority of cases. EGF-R, p-Iκ:B-α, NF-κ:B, c-FOS and p-c-JUN correlated positively with COX-2 and VEGF expression. Conclusion: Stromal myofibroblasts surrounding colon adenocarcinomas are an important source of VEGF and COX-2 production, while AP-1 and NF-κ:B transcription factors are activated and EGF-R is expressed in these cells and associated with COX-2 and VEGF production.

Expression of VEGF and collagen using a latex biomembrane as bladder replacement in rabbits

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André Luís Alonso Domingos

2012-08-01

Full Text Available OBJECTIVE: To investigate the VEGF expression and collagen deposition using a latex biomembrane as bladder replacement in rabbits. MATERIALS AND METHODS: After partial cystectomy, a patch of a non-vulcanized latex biomembrane (2 x 2 cm was sewn to the bladder of rabbits with 5/0 monofilament polydioxanone sulfate sutures in a watertight manner. Groups of 5 animals were killed at 15, 45 and 90 days after surgery and the bladder was removed. Sections of 5µm were cut and stained with picrosirius-red in order to estimate the amount of extracellular matrix in the graft. To confirm the presence of VEGF in tissues, protein expression was determined by immunohistochemistry. RESULTS: No death, urinary leakage or graft extrusion occurred in any group. All bladders showed a spherical shape. A progressive reduction in the amount of collagen occurred in the graft area and was negatively and linearly correlated with time (p < 0.001. VEGF expression was higher in grafted areas when compared to controls at 15 and 45 days after surgery and decreased with time (p < 0.001. CONCLUSION: The latex biomembrane as a matrix for partial bladder replacement in rabbits promotes temporary collagen deposition and stimulates the angiogenic process.

IL-6 Promotes FSH-Induced VEGF Expression Through JAK/STAT3 Signaling Pathway in Bovine Granulosa Cells

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Meng Yang

2017-11-01

Full Text Available Background/Aims: Vascular endothelial growth factor (VEGF has been demonstrated to play a pivotal role in the regulation of angiogenesis in ovarian follicular development, particularly during the preovulatory period. Although numerous studies have shown that interleukin-6 (IL-6 is one of the major inducing factors that regulate the expression of VEGF in non-ovarian cells, whether it involved in regulating the expression of VEGF in normal ovarian granulosa cells is still unknown. The aim of this study was to elucidate the mechanisms underlying the effect of IL-6 on FSH-induced VEGF expression in bovine granulosa cells derived from large follicles. Methods: VEGF mRNA expression in granulosa cells after IL-6 with/without inhibitors treatment was analyzed by RT-qPCR. Phosphorylation levels of ERK1/2 and STAT3 proteins induced by IL-6 were analyzed by western blotting. The protein levels produced by granulosa cells were detected by ELISA. Results: High concentration of IL-6 (10ng/ml can significantly up-regulate FSH-induced VEGF gene and protein expression levels in granulosa cells, and also promote the VEGF upstream regulators HIF-1α and COX2 mRNA expression. VEGF expression levels were significantly decreased after specifically blocking HIF-1α and COX2 by using inhibitors. The up-regulation effect of IL-6 on FSH-induced VEGF expression in granulosa cells mainly through activating the JAK/STAT3 signaling pathway, which can be impaired by JAK inhibitors. Conclusion: IL-6 can promote FSH-induced VEGF expression in granulosa cells, which is mainly achieved by increasing the expression of HIF-1α and COX2.This promoting effect is mediated by activating the JAK/STAT3 pathway. Moreover, there may be a synergistic relationship between FSH and IL-6 in the regulation of VEGF expression.

Development of PLGA-coated β-TCP scaffolds containing VEGF for bone tissue engineering.

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Khojasteh, Arash; Fahimipour, Farahnaz; Eslaminejad, Mohamadreza Baghaban; Jafarian, Mohammad; Jahangir, Shahrbanoo; Bastami, Farshid; Tahriri, Mohammadreza; Karkhaneh, Akbar; Tayebi, Lobat

2016-12-01

Bone tissue engineering is sought to apply strategies for bone defects healing without limitations and short-comings of using either bone autografts or allografts and xenografts. The aim of this study was to fabricate a thin layer poly(lactic-co-glycolic) acid (PLGA) coated beta-tricalcium phosphate (β-TCP) scaffold with sustained release of vascular endothelial growth factor (VEGF). PLGA coating increased compressive strength of the β-TCP scaffolds significantly. For in vitro evaluations, canine mesenchymal stem cells (cMSCs) and canine endothelial progenitor cells (cEPCs) were isolated and characterized. Cell proliferation and attachment were demonstrated and the rate of cells proliferation on the VEGF released scaffold was significantly more than compared to the scaffolds with no VEGF loading. A significant increase in expression of COL1 and RUNX2 was indicated in the scaffolds loaded with VEGF and MSCs compared to the other groups. Consequently, PLGA coated β-TCP scaffold with sustained and localized release of VEGF showed favourable results for bone regeneration in vitro, and this scaffold has the potential to use as a drug delivery device in the future. Copyright © 2016. Published by Elsevier B.V.

Resistin facilitates VEGF-C-associated lymphangiogenesis by inhibiting miR-186 in human chondrosarcoma cells.

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Su, Chen-Ming; Tang, Chih-Hsin; Chi, Meng-Ju; Lin, Chih-Yang; Fong, Yi-Chin; Liu, Yueh-Ching; Chen, Wei-Cheng; Wang, Shih-Wei

2018-05-03

Chondrosarcoma is a common primary malignant tumor of the bone that can metastasize through the vascular system to other organs. A key step in the metastatic process, lymphangiogenesis, involves vascular endothelial growth factor-C (VEGF-C). However, the effects of lymphangiogenesis in chondrosarcoma metastasis remain to be clarified. Accumulating evidence shows that resistin, a cytokine secreted from adipocytes and monocytes, also promotes tumor pathogenesis. Notably, chondrosarcoma can easily metastasize. In this study, we demonstrate that resistin enhances VEGF-C expression and lymphatic endothelial cells (LECs)-associated lymphangiogenesis in human chondrosarcoma cells. We also show that resistin triggers VEGF-C-dependent lymphangiogenesis via the c-Src signaling pathway and down-regulating micro RNA (miR)-186. Overexpression of resistin in chondrosarcoma cells significantly enhanced VEGF-C production and LECs-associated lymphangiogenesis in vitro and tumor-related lymphangiogenesis in vivo. Resistin levels were positively correlated with VEGF-C-dependent lymphangiogenesis via the down-regulation of miR-186 expression in clinical samples from chondrosarcoma tissue. This study is the first to evaluate the mechanism underlying resistin-induced promotion of LECs-associated lymphangiogenesis via the upregulation of VEGF-C expression in human chondrosarcomas. We suggest that resistin may represent a molecular target in VEGF-C-associated tumor lymphangiogenesis in chondrosarcoma metastasis. Copyright © 2018 Elsevier Inc. All rights reserved.

Paying attention through eye movements: a computational investigation of the premotor theory of spatial attention.

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Casarotti, Marco; Lisi, Matteo; Umiltà, Carlo; Zorzi, Marco

2012-07-01

Growing evidence indicates that planning eye movements and orienting visuospatial attention share overlapping brain mechanisms. A tight link between endogenous attention and eye movements is maintained by the premotor theory, in contrast to other accounts that postulate the existence of specific attention mechanisms that modulate the activity of information processing systems. The strong assumption of equivalence between attention and eye movements, however, is challenged by demonstrations that human observers are able to keep attention on a specific location while moving the eyes elsewhere. Here we investigate whether a recurrent model of saccadic planning can account for attentional effects without requiring additional or specific mechanisms separate from the circuits that perform sensorimotor transformations for eye movements. The model builds on the basis function approach and includes a circuit that performs spatial remapping using an "internal forward model" of how visual inputs are modified as a result of saccadic movements. Simulations show that the latter circuit is crucial to account for dissociations between attention and eye movements that may be invoked to disprove the premotor theory. The model provides new insights into how spatial remapping may be implemented in parietal cortex and offers a computational framework for recent proposals that link visual stability with remapping of attention pointers.

Degenerative effects in rat eyes after experimental ocular hypertension

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G. Scarsella

2012-10-01

Full Text Available This study was used to evaluate the degenerative effects on the retina and eye-cup sections after experimental induction of acute ocular hypertension on animal models. In particular, vascular events were directly focused in this research in order to assess the vascular remodeling after transient ocular hypertension on rat models. After local anaesthesia by administration of eye drops of 0.4% oxibuprocaine, 16 male adult Wistar rats were injected in the anterior chamber of the right eye with 15 µL of methylcellulose (MTC 2% in physiological solution. The morphology and the vessels of the retina and eye-cup sections were examined in animals sacrificed 72 h after induction of ocular hypertension. In retinal fluorescein angiographies (FAGs, by means of fluorescein isothiocyanate-coniugated dextran (FITC, the radial venules showed enlargements and increased branching, while the arterioles appeared focally thickened. The length and size of actually perfused vessels appeared increased in the whole superficial plexus. In eye-cup sections of MTC-injected animals, in deep plexus and connecting layer there was a bigger increase of vessels than in controls. Moreover, the immunolocalization of astrocytic marker glial fibrillary acidic protein (GFAP revealed its increased expression in internal limiting membrane and ganglion cell layer, as well as its presence in Müller cells. Finally, the pro-angiogenic factor vascular endothelial growth factor (VEGF was found to be especially expressed by neurones of ganglion cell layer, both in control and in MTC-injected eyes. The data obtained in this experimental model on the interactions among glia, vessels and neurons should be useful to evaluate if also in glaucomatous patients the activation of vessel-adjacent glial cells might play key roles in following neuronal dysfunction.

Degenerative effects in rat eyes after experimental ocular hypertension.

Science.gov (United States)

Scarsella, G; Nebbioso, M; Stefanini, S; Pescosolido, N

2012-10-08

This study was used to evaluate the degenerative effects on the retina and eye-cup sections after experimental induction of acute ocular hypertension on animal models. In particular, vascular events were directly focused in this research in order to assess the vascular remodeling after transient ocular hypertension on rat models. After local anaesthesia by administration of eye drops of 0.4% oxibuprocaine, 16 male adult Wistar rats were injected in the anterior chamber of the right eye with 15 µL of methylcellulose (MTC) 2% in physiological solution. The morphology and the vessels of the retina and eye-cup sections were examined in animals sacrificed 72 h after induction of ocular hypertension. In retinal fluorescein angiographies (FAGs), by means of fluorescein isothiocyanate-coniugated dextran (FITC), the radial venules showed enlargements and increased branching, while the arterioles appeared focally thickened. The length and size of actually perfused vessels appeared increased in the whole superficial plexus. In eye-cup sections of MTC-injected animals, in deep plexus and connecting layer there was a bigger increase of vessels than in controls. Moreover, the immunolocalization of astrocytic marker glial fibrillary acidic protein (GFAP) revealed its increased expression in internal limiting membrane and ganglion cell layer, as well as its presence in Müller cells. Finally, the pro-angiogenic factor vascular endothelial growth factor (VEGF) was found to be especially expressed by neurones of ganglion cell layer, both in control and in MTC-injected eyes. The data obtained in this experimental model on the interactions among glia, vessels and neurons should be useful to evaluate if also in glaucomatous patients the activation of vessel-adjacent glial cells might play key roles in following neuronal dysfunction.

[Trapping techniques for Solenopsis invicta].

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Liang, Xiao-song; Zhang, Qiang; Zhuang, Yiong-lin; Li, Gui-wen; Ji, Lin-peng; Wang, Jian-guo; Dai, Hua-guo

2007-06-01

A field study was made to investigate the trapping effects of different attractants, traps, and wind directions on Solenopsis invicta. The results showed that among the test attractants, TB1 (50 g fishmeal, 40 g peptone, 10 ml 10% sucrose water solution and 20 ml soybean oil) had the best effect, followed by TB2 (ham), TB6 (100 g cornmeal and 20 ml soybean oil) and TB4 (10 ml 10% sucrose water solution, 100 g sugarcane powder and 20 ml soybean oil), with a mean capture efficiency being 77.6, 58.7, 29 and 7.7 individuals per trap, respectively. No S. invicta was trapped with TB3 (10 ml 10% sucrose water solution, 100 g cornmeal and 20 ml soybean oil) and TB5 (honey). Tube trap was superior to dish trap, with a trapping efficiency of 75.2 and 35 individuals per trap, respectively. The attractants had better effects in leeward than in windward.

Cytokine profiles of tumor supernatants in invasive ductal cancer and fibroadenoma of the breast and its relationship with VEGF-A expression in the tumors.

Science.gov (United States)

Autenshlyus, Alexander I; Arkhipov, Sergey A; Kunts, Tatiana A; Marinkin, Igor O; Mikhailova, Elena S; Karpukhina, Xenia V; Varaksin, Nikolay A

2017-03-01

Interrelations between cytokines, produced by invasive ductal carcinoma (IDC) and fibroadenoma (FA) of the breast, and angiogenic growth factor VEGF-A, expressed in IDC and FA, were investigated. The analysis of the cytokine profiles of IDC and FA was performed by cultivation of tumor biopsy specimens in vitro. Testing of the cytokine-producing reserve of the tumors for production of VEGF-A was conducted by culturing samples of IDC and FA in a medium containing polyclonal activator (a complex of phytohemagglutinin, concanavalin A, and lipopolysaccharide). Levels of cytokines and growth factors (IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1β, IL-1Ra, TNF-α, IFN-γ, G-CSF, GM-CSF, VEGF-A) and MCP-1 (monocyte chemoattractant protein-1) in tumor supernatants were determined by an ELISA. Expression of VEGF-A was analyzed in tumor biopsy specimens by immunohistochemical analysis. In the IDC supernatants, the concentrations of IL-17, IL-18, and IFN-γ were higher and the concentrations of IL-10 and MCP-1 were lower in comparison with the FA supernatants. We observed negative correlations between the macrophage infiltration and VEGF-A concentration in the IDC supernatants (r = -0.508; P = 0.011) and between VEGF-A expression and the IDC vascularization degree (r = -0.423, P = 0.039). Spontaneous expression of VEGF-A in samples of IDC significantly exceeded the VEGF-A expression in FA. There was no difference between IDC and FA in VEGF-A expression after treatment with the polyclonal activators. Our results indicate that greater malignancy may have a paradoxical effect that is controlled by cytokines and characterized by weakening of tumor angiogenesis during overproduction of VEGF-A. These findings point to complex mechanisms of positive and negative regulation of tumor angiogenesis by cytokines that are produced by the tumor and by cells in its microenvironment, whose cytokine profiles may change at different stages of tumor progression.

Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis

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Weidemann AK

2013-09-01

Full Text Available Anja K Weidemann,1 Ania A Crawshaw,2 Emily Byrne,3 Helen S Young1 1The Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester, UK; 2Royal Sussex County Hospital, Brighton, UK; 3University Hospital of South Manchester, Manchester, UK Abstract: Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased

Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism

DEFF Research Database (Denmark)

Yang, Yunlong; Zhang, Yin; Iwamoto, Hideki

2016-01-01

The impact of discontinuation of anti-VEGF cancer therapy in promoting cancer metastasis is unknown. Here we show discontinuation of anti-VEGF treatment creates a time-window of profound structural changes of liver sinusoidal vasculatures, exhibiting hyper-permeability and enlarged open-pore size...

Effects of oxaliplatin, leucovorin and fluorouracil on serum tumor markers, VEGF, CRP and matrix metalloproteinases in patients with advanced esophageal cancer

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Lei Lei

2017-08-01

Full Text Available Objective: To investigate the effects of oxaliplatin, leucovorin and fluorouracil on serum tumor markers, VEGF, CRP and matrix metalloproteinases in patients with advanced esophageal cancer. Methods: From March 2012 to March 2017 a total of 248 patients with advanced esophageal cancer were selected as the study subjects. According to random data table, they were divided into control group (n=123 and observation group (n=125 according to random data table. The control group was treated with cisplatin combined with fluorouracil, leucovorin chemotherapy, and patients in the observation group received oxaliplatin, leucovorin and fluorouracil chemotherapy, all patients were treated for 2 cycles. The changes of serum tumor markers, VEGF, CRP and matrix metalloproteinase levels in the two groups before and after treatment was compared. Results: Before treatment, there was no significant difference of the levels of serum CA125, CA19-9, CEA, VEGF, CRP, MMP-2 and MMP-9 between the control group and the observation group. Compared with the group before treatment, the levels of CA125, CA19-9, CEA, VEGF, CRP, MMP-2 and MMP-9 in the two groups were significantly lower. After treatment, the level of CA125, CA19-9, CEA, VEGF, CRP, MMP-2 and MMP-9 in the observation group was significantly lower than those of the control group. Conclusion: Oxaliplatin, leucovorin and fluorouracil chemotherapy can effectively reduce the levels of serum tumor markers, VEGF, CRP and matrix metalloproteinase in patients with advanced esophageal cancer, it has important clinical value.

M-CSF signals through the MAPK/ERK pathway via Sp1 to induce VEGF production and induces angiogenesis in vivo.

Directory of Open Access Journals (Sweden)

Jennifer M Curry

Full Text Available BACKGROUND: M-CSF recruits mononuclear phagocytes which regulate processes such as angiogenesis and metastases in tumors. VEGF is a potent activator of angiogenesis as it promotes endothelial cell proliferation and new blood vessel formation. Previously, we reported that in vitro M-CSF induces the expression of biologically-active VEGF from human monocytes. METHODOLOGY AND RESULTS: In this study, we demonstrate the molecular mechanism of M-CSF-induced VEGF production. Using a construct containing the VEGF promoter linked to a luciferase reporter, we found that a mutation reducing HIF binding to the VEGF promoter had no significant effect on luciferase production induced by M-CSF stimulation. Further analysis revealed that M-CSF induced VEGF through the MAPK/ERK signaling pathway via the transcription factor, Sp1. Thus, inhibition of either ERK or Sp1 suppressed M-CSF-induced VEGF at the mRNA and protein level. M-CSF also induced the nuclear localization of Sp1, which was blocked by ERK inhibition. Finally, mutating the Sp1 binding sites within the VEGF promoter or inhibiting ERK decreased VEGF promoter activity in M-CSF-treated human monocytes. To evaluate the biological significance of M-CSF induced VEGF production, we used an in vivo angiogenesis model to illustrate the ability of M-CSF to recruit mononuclear phagocytes, increase VEGF levels, and enhance angiogenesis. Importantly, the addition of a neutralizing VEGF antibody abolished M-CSF-induced blood vessel formation. CONCLUSION: These data delineate an ERK- and Sp1-dependent mechanism of M-CSF induced VEGF production and demonstrate for the first time the ability of M-CSF to induce angiogenesis via VEGF in vivo.

Eye Absence Does Not Regulate Planarian Stem Cells during Eye Regeneration.

Science.gov (United States)

LoCascio, Samuel A; Lapan, Sylvain W; Reddien, Peter W

2017-02-27

Dividing cells called neoblasts contain pluripotent stem cells and drive planarian flatworm regeneration from diverse injuries. A long-standing question is whether neoblasts directly sense and respond to the identity of missing tissues during regeneration. We used the eye to investigate this question. Surprisingly, eye removal was neither sufficient nor necessary for neoblasts to increase eye progenitor production. Neoblasts normally increase eye progenitor production following decapitation, facilitating regeneration. Eye removal alone, however, did not induce this response. Eye regeneration following eye-specific resection resulted from homeostatic rates of eye progenitor production and less cell death in the regenerating eye. Conversely, large head injuries that left eyes intact increased eye progenitor production. Large injuries also non-specifically increased progenitor production for multiple uninjured tissues. We propose a model for eye regeneration in which eye tissue production by planarian stem cells is not directly regulated by the absence of the eye itself. Copyright © 2017 Elsevier Inc. All rights reserved.

Universality in eye movements and reading: A trilingual investigation.

Science.gov (United States)

Liversedge, Simon P; Drieghe, Denis; Li, Xin; Yan, Guoli; Bai, Xuejun; Hyönä, Jukka

2016-02-01

Universality in language has been a core issue in the fields of linguistics and psycholinguistics for many years (e.g., Chomsky, 1965). Recently, Frost (2012) has argued that establishing universals of process is critical to the development of meaningful, theoretically motivated, cross-linguistic models of reading. In contrast, other researchers argue that there is no such thing as universals of reading (e.g., Coltheart & Crain, 2012). Reading is a complex, visually mediated psychological process, and eye movements are the behavioural means by which we encode the visual information required for linguistic processing. To investigate universality of representation and process across languages we examined eye movement behaviour during reading of very comparable stimuli in three languages, Chinese, English and Finnish. These languages differ in numerous respects (character based vs. alphabetic, visual density, informational density, word spacing, orthographic depth, agglutination, etc.). We used linear mixed modelling techniques to identify variables that captured common variance across languages. Despite fundamental visual and linguistic differences in the orthographies, statistical models of reading behaviour were strikingly similar in a number of respects, and thus, we argue that their composition might reflect universality of representation and process in reading. Copyright © 2015 Elsevier B.V. All rights reserved.

Multimodal doxorubicin loaded magnetic nanoparticles for VEGF targeted theranostics of breast cancer.

Science.gov (United States)

Semkina, Alevtina S; Abakumov, Maxim A; Skorikov, Alexander S; Abakumova, Tatiana O; Melnikov, Pavel A; Grinenko, Nadejda F; Cherepanov, Sergey A; Vishnevskiy, Daniil A; Naumenko, Victor A; Ionova, Klavdiya P; Majouga, Alexander G; Chekhonin, Vladimir P

2018-05-03

In presented paper we have developed new system for cancer theranostics based on vascular endothelial growth factor (VEGF) targeted magnetic nanoparticles. Conjugation of anti-VEGF antibodies with bovine serum albumin coated PEGylated magnetic nanoparticles allows for improved binding with murine breast adenocarcinoma 4T1 cell line and facilitates doxorubicin delivery to tumor cells. It was shown that intravenous injection of doxorubicin loaded VEGF targeted nanoparticles increases median survival rate of mice bearing 4T1 tumors up to 50%. On the other hand magnetic resonance imaging (MRI) of 4T1 tumors 24 h after intravenous injection showed accumulation of nanoparticles in tumors, thus allowing simultaneous cancer therapy and diagnostics. Copyright © 2018. Published by Elsevier Inc.

The endothelial adaptor molecule TSAd is required for VEGF-induced angiogenic sprouting through junctional c-Src activation

NARCIS (Netherlands)

Gordon, Emma J; Fukuhara, Daisuke; Weström, Simone; Padhan, Narendra; Sjöström, Elisabet O; van Meeteren, Laurens|info:eu-repo/dai/nl/299142353; He, Liqun; Orsenigo, Fabrizio; Dejana, Elisabetta; Bentley, Katie; Spurkland, Anne; Claesson-Welsh, Lena

2016-01-01

Activation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by VEGF binding is critical for vascular morphogenesis. In addition, VEGF disrupts the endothelial barrier by triggering the phosphorylation and turnover of the junctional molecule VE-cadherin, a process mediated by the

The experimental study of VEGF antisense oligodeoxynucleotides with lipiodol in arterial embolization of liver cancer in rats

International Nuclear Information System (INIS)

Wu Hanping; Feng Gansheng; Li Xin; Liang Huimin; Zheng Chuansheng

2003-01-01

Objective: To study the inhibitory effects of VEGF antisense oligodeoxynucleotides (asODN) on cultured Walker-256 cells' VEGF expression, and to observe the anti-tumor effects of intraarterial infusion of asODN mixed with lipiodol on rat liver cancer. Methods: VEGF asODN and sense ODN were added to the media of non-serum cultured Walker-256 cells, and the VEGF concentrations of the supernatants were detected by using ELISA 48 hours later. Cells of endothelial cell line ECV-304 were cultured in the supernatants. The growth of ECV-304 cells was observed by MTT method. 30 rats with Walker-256 carcinoma cells implanted into left liver lobe were randomly divided into 3 groups. 0.2 ml ultra-fluid lipiodol (UFLP group, n=10), 3OD asODN mixed with 0.2 ml ultra-fluid lipiodol (UFLP + asODN group, n=10), and 0.2 ml normal saline (control group, n=10) were infused into the hepatic artery. The volumes of tumors were measured by using MRI before and 7 days after the treatment. VEGF mRNA in cancerous and peri-cancerous tissues was detected by RT-PCR. The microvessel density (MVD) and VEGF expression were observed by immunohistochemistry. Results: asODN could inhibit Walker-256 cells' VEGF expression. The tumor growth rate was lower in UFLP + asODN group than that in UFLP and control groups [(140.1±33.8)%, (177.9±64.9)%, and (403.9± 69.4)%, respectively, F=60.02, P 0.05). The MVD in UFLP + asODN group (53.1±18.4) was significantly less than that of control group (73.2±20.4) and UFLP group (80.3±18.5) (F=5.44, P<0.05). Conclusion: VEGF asODN could inhibit VEGF expression of Walker-256 cells. It may be an antiangiogenesis therapy drug in malignant tumor. VEGF asODN mixed with UFLP in embolizing liver cancer could decrease liver cancer growth, VEGF expression, and microvessel density better than UFLP alone

Bone marrow stromal cells with a combined expression of BMP-2 and VEGF-165 enhanced bone regeneration

International Nuclear Information System (INIS)

Xiao Caiwen; Zhou Huifang; Fu Yao; Gu Ping; Fan Xianqun; Liu Guangpeng; Zhang Peng; Hou Hongliang; Tang Tingting

2011-01-01

Bone graft substitutes with osteogenic factors alone often exhibit poor bone regeneration due to inadequate vascularization. Combined delivery of osteogenic and angiogenic factors from biodegradable scaffolds may enhance bone regeneration. We evaluated the effects of bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor (VEGF), combined with natural coral scaffolds, on the repair of critical-sized bone defects in rabbit orbits. In vitro expanded rabbit bone marrow stromal cells (BMSCs) were transfected with human BMP2 and VEGF165 genes. Target protein expression and osteogenic differentiation were confirmed after gene transduction. Rabbit orbital defects were treated with a coral scaffold loaded with BMP2-transduced and VEGF-transduced BMSCs, BMP2-expressing BMSCs, VEGF-expressing BMSCs, or BMSCs without gene transduction. Volume and density of regenerated bone were determined by micro-computed tomography at 4, 8, and 16 weeks after implantation. Neovascularity, new bone deposition rate, and new bone formation were measured by immunostaining, tetracycline and calcein labelling, and histomorphometric analysis at different time points. The results showed that VEGF increased blood vessel formation relative to groups without VEGF. Combined delivery of BMP2 and VEGF increased new bone deposition and formation, compared with any single factor. These findings indicate that mimicking the natural bone development process by combined BMP2 and VEGF delivery improves healing of critical-sized orbital defects in rabbits.

EG-VEGF controls placental growth and survival in normal and pathological pregnancies: case of fetal growth restriction (FGR).

Science.gov (United States)

Brouillet, S; Murthi, P; Hoffmann, P; Salomon, A; Sergent, F; De Mazancourt, P; Dakouane-Giudicelli, M; Dieudonné, M N; Rozenberg, P; Vaiman, D; Barbaux, S; Benharouga, M; Feige, J-J; Alfaidy, N

2013-02-01

Identifiable causes of fetal growth restriction (FGR) account for 30 % of cases, but the remainders are idiopathic and are frequently associated with placental dysfunction. We have shown that the angiogenic factor endocrine gland-derived VEGF (EG-VEGF) and its receptors, prokineticin receptor 1 (PROKR1) and 2, (1) are abundantly expressed in human placenta, (2) are up-regulated by hypoxia, (3) control trophoblast invasion, and that EG-VEGF circulating levels are the highest during the first trimester of pregnancy, the period of important placental growth. These findings suggest that EG-VEGF/PROKR1 and 2 might be involved in normal and FGR placental development. To test this hypothesis, we used placental explants, primary trophoblast cultures, and placental and serum samples collected from FGR and age-matched control women. Our results show that (1) EG-VEGF increases trophoblast proliferation ([(3)H]-thymidine incorporation and Ki67-staining) via the homeobox-gene, HLX (2) the proliferative effect involves PROKR1 but not PROKR2, (3) EG-VEGF does not affect syncytium formation (measurement of syncytin 1 and 2 and β hCG production) (4) EG-VEGF increases the vascularization of the placental villi and insures their survival, (5) EG-VEGF, PROKR1, and PROKR2 mRNA and protein levels are significantly elevated in FGR placentas, and (6) EG-VEGF circulating levels are significantly higher in FGR patients. Altogether, our results identify EG-VEGF as a new placental growth factor acting during the first trimester of pregnancy, established its mechanism of action, and provide evidence for its deregulation in FGR. We propose that EG-VEGF/PROKR1 and 2 increases occur in FGR as a compensatory mechanism to insure proper pregnancy progress.

Eye absence does not regulate planarian stem cells during eye regeneration

OpenAIRE

LoCascio, Samuel A.; Lapan, Sylvain W.; Reddien, Peter W.

2017-01-01

Dividing cells called neoblasts contain pluripotent stem cells and drive planarian flatworm regeneration from diverse injuries. A long-standing question is whether neoblasts directly sense and respond to the identity of missing tissues during regeneration. We used the eye to investigate this question. Surprisingly, eye removal was neither sufficient nor necessary for neoblasts to increase eye progenitor production. Neoblasts normally increase eye progenitor production following decapitation, ...

VEGF-A isoforms differentially regulate ATF-2-dependent VCAM-1 gene expression and endothelial-leukocyte interactions.

Science.gov (United States)

Fearnley, Gareth W; Odell, Adam F; Latham, Antony M; Mughal, Nadeem A; Bruns, Alexander F; Burgoyne, Nicholas J; Homer-Vanniasinkam, Shervanthi; Zachary, Ian C; Hollstein, Monica C; Wheatcroft, Stephen B; Ponnambalam, Sreenivasan

2014-08-15

Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology. VEGF-A stimulates signal transduction pathways that modulate endothelial outputs such as cell migration, proliferation, tubulogenesis, and cell-cell interactions. Multiple VEGF-A isoforms exist, but the biological significance of this is unclear. Here we analyzed VEGF-A isoform-specific stimulation of VCAM-1 gene expression, which controls endothelial-leukocyte interactions, and show that this is dependent on both ERK1/2 and activating transcription factor-2 (ATF-2). VEGF-A isoforms showed differential ERK1/2 and p38 MAPK phosphorylation kinetics. A key feature of VEGF-A isoform-specific ERK1/2 activation and nuclear translocation was increased phosphorylation of ATF-2 on threonine residue 71 (T71). Using reverse genetics, we showed ATF-2 to be functionally required for VEGF-A-stimulated endothelial VCAM-1 gene expression. ATF-2 knockdown blocked VEGF-A-stimulated VCAM-1 expression and endothelial-leukocyte interactions. ATF-2 was also required for other endothelial cell outputs, such as cell migration and tubulogenesis. In contrast, VCAM-1 was essential only for promoting endothelial-leukocyte interactions. This work presents a new paradigm for understanding how soluble growth factor isoforms program complex cellular outputs and responses by modulating signal transduction pathways. © 2014 Fearnley et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

[Eye lens radiation exposure during ureteroscopy with and without a face protection shield: Investigations on a phantom model].

Science.gov (United States)

Zöller, G; Figel, M; Denk, J; Schulz, K; Sabo, A

2016-03-01

Eye lens radiation exposure during radiologically-guided endoscopic procedures may result in radiation-induced cataracts; therefore, we investigated the ocular radiation exposure during ureteroscopy on a phantom model. Using an Alderson phantom model and eye lens dosimeters, we measured the ocular radiation exposure depending on the number of X-ray images and on the duration of fluoroscopic imaging. The measurements were done with and without using a face protection shield. We could demonstrate that a significant ocular radiation exposure can occur, depending on the number of X-ray images and on the duration time of fluoroscopy. Eye lens doses up to 0.025 mSv were recorded even using modern digital X-ray systems. Using face protection shields this ocular radiation exposure can be reduced to a minimum. The International Commission on Radiological Protection (ICRP) recommendations of a mean eye lens dosage of 20 mSv/year may be exceeded during repeated ureteroscopy by a high volume surgeon. Using a face protection shield, the eye lens dose during ureteroscopy could be reduced to a minimum in a phantom model. Further investigations will show whether these results can be transferred to real life ureteroscopic procedures.

EPR investigation of zinc/iodine exchange between propargyl iodides and diethylzinc: detection of propargyl radical by spin trapping.

Science.gov (United States)

Maury, Julien; Jammi, Suribabu; Vibert, François; Marque, Sylvain R A; Siri, Didier; Feray, Laurence; Bertrand, Michèle

2012-10-19

The production of propargyl radicals in the reaction of dialkylzincs with propargyl iodides in nondegassed medium was investigated by EPR using tri-tert-butylnitrosobenzene (TTBNB) as a spin trap. The radical mechanism and the nature of the observed species were confirmed by the trapping of propargyl radicals generated by an alternative pathway: i.e., upon irradiation of propargyl iodides in the presence of hexa-n-butyldistannane. In dialkylzinc-mediated experiments a high concentration of adduct was instantaneously observed, whereas no spontaneous production of spin adduct was detected in a blank experiment performed with the propargylic iodide and TTBNB in the absence of diethylzinc. Under irradiation in the presence of distannane, two different species were observed at the very beginning of the irradiation; the nitroxide resulting from the trapping of propargyl radical at the propargyl carbon remained the only species detected after irradiating for several minutes. The absence of adducts resulting from the trapping of allenyl canonical forms was supported by DFT calculations and by the preparation of an authentic sample.

Overexpression of decorin promoted angiogenesis in diabetic cardiomyopathy via IGF1R-AKT-VEGF signaling.

Science.gov (United States)

Lai, Jinsheng; Chen, Fuqiong; Chen, Jing; Ruan, Guoran; He, Mengying; Chen, Chen; Tang, Jiarong; Wang, Dao Wen

2017-03-14

Microcirculatory dysfunction is believed to play an important role in diabetic cardiomyopathy. The small leucine-rich proteoglycan decorin is generally considered a pro-angiogenic factor. Here, we investigate whether overexpression of decorin ameliorates diabetic cardiomyopathy and its effects on angiogenesis in vivo and in vitro. Diabetes was induced through intraperitoneal injection with streptozotocin combined with a high-fat diet, and decorin was overexpressed via recombinant adeno-associated virus in Wistar rats. Six months later, cardiac function was determined using an echocardiography and cardiac catheter system. The results showed that cardiac function was decreased in diabetic rats and restored by overexpression of decorin. In addition, overexpression of decorin upregulated the expression of VEGF and attenuated the reduction in the cardiac capillary density. In the in vitro study, high glucose induced apoptosis and inhibited the capabilities of tube formation, migration and proliferation, which were all ameliorated by decorin overexpression. Meanwhile, decorin overexpression increased the expression of VEGF and IGF1R, as well as the phosphorylation level of AKT and AP-1. Nonetheless, all of these effects were abolished by pretreatment with the IGF1R antibody or AKT inhibitor. In conclusion, overexpression of decorin ameliorated diabetic cardiomyopathy and promoted angiogenesis through the IGF1R-AKT-VEGF signaling pathway in vivo and in vitro.

Up-regulation of VEGF and its receptor in refractory leukemia cells

OpenAIRE

Wang, Lei; Zhang, Wenjun; Ding, Yi; Xiu, Bing; Li, Ping; Dong, Yan; Zhu, Qi; Liang, Aibin

2015-01-01

Objective: To analyze the causative mechanisms in refractory leukemia cells. Methods: Vascular endothelial growth factor (VEGF) blood plasma concentrations in 35 de novo, 6 relapse, 20 remission leukemia patients and 10 healthy kids were determined via ELISA analyses. Transcription levels of the VEGF receptors (VEGFR) Fms-like tyrosine kinase-1 (Flt-1) and kinase-domain insert containing receptor (KDR) were determined in participants’ leucocytes with RT-PCR. Apoptosis rates as well as Cyt-C a...

Clinical significance of determination of changes of serum EMAb, IL-2, IL-2R and VEGF levels in patients with endometriosis

International Nuclear Information System (INIS)

Min Jieyan

2009-01-01

Objective: To investigate the relationship between the progress of the disease process and changes of serum antiendome-trium antibody (EMAb), interleukin-2 (IL-2), interleukin-2 receptor (IL-2R) and vascular endothelial growth factor (VEGF) levels in patients with endometriosis. Methods: Serum EMAb (with ELISA) and VEGF, IL-2, IL-2R (with RIA) levels were measured in 45 patients with endometriosis both before and after treatment as well as in 35 controls. Results: Before treatment with integrated traditional and western medicine, the positive rate of serum EMAb were significantly higher in patients with endometriosis than that in the controls (P 0.05). Conclusion: Determination of changes of serum EMAb, IL-2, IL-2R and VEGF levels in patients with endometriosis were helpful for assessment of the progress of disease process and outcome prediction. (authors)

The MAPK-dependent regulation of the Jagged/Notch gene expression by VEGF, bFGF or PPAR gamma mediated angiogenesis in HUVEC

DEFF Research Database (Denmark)

Kiec-Wilk, B; Grzybowska-Galuszka, J; Polus, A

2010-01-01

The Jagged-Notch signalling, plays a crucial role in cell differentiation. Angiogenesis, is regulated by VEGF, bFGF as well as by the free fatty acid metabolites , which are regulators of transcription factors such as peroxisome proliferation activating receptors (PPARs). The study analyzed...... the signalling pathways involved in the regulation of Jagged-1/Notch-4 expression in endothelial cells (HUVECs) in response to VEGF, bFGF and PPAR-gamma exogenous activator - ciglitazone. HUVECs were incubated with investigated substances for 24 hours, with or without the presence of the MAP-kinases inhibitors...... were used. Jagged-1 and Notch-4 gene expression was determined using quantitative Real-Time PCR. The Jagged-1/Notch-4 protein expression was compared by flow cytometry, when the phosphorylation-dependent activation of kinases was estimated by Western-blot method. The opposite effect of VEGF, b...

Experimental investigation of the trapping and energy loss mechanisms of intense relativistic electron rings in hydrogen gas and plasma

International Nuclear Information System (INIS)

Smith, A.C. Jr.

1977-01-01

The results of an experimental study on the trapping and energy loss mechanisms of intense, relativistic electron rings confined in Astron-like magnetic field geometries are presented. The work is subdivided into four sections: gas trapping; average ring electron energetics; plasma trapping, and hollow-beam cusp-injection into gas and plasma. The mechanisms by which the injected beam coalesces into a current ring in the existing Cornell RECE-Berta facility are considered. To investigate the nature of ring electron energy loss mechanisms following completion of the trapping process, a diagnostic was developed utilizing multi-foil X-ray absorption spectroscopy to analyze the Bremsstrahlung generated by the electrons as they impinge upon a thin tungsten wire target suspended in the circulating current. Finally, a set of preliminary experimental results is presented in which an annular electron beam was passed through a coaxial, non-adiabatic magnetic cusp located at one end of a magnetic mirror well

Biological variations in plasma VEGF and VEGFR-1 may compromise their biomarker value in colorectal cancer

DEFF Research Database (Denmark)

Svendsen, Mads N.; Brunner, Nils; Christensen, Ib Jarle

2010-01-01

Vascular Endothelial Growth Factor (VEGF) plays a prominent role in tumor angiogenesis and plasma VEGF concentration may carry prognostic information in colorectal cancer. The VEGF receptor 1 (VEGFR-1) is a regulatory receptor which is shredded into plasma of patients with colorectal cancer. For ....... For both molecules, large biological variation and lack of standardization of assay procedures are major challenges....

Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy.

Science.gov (United States)

Woitek, Felix; Zentilin, Lorena; Hoffman, Nicholas E; Powers, Jeffery C; Ottiger, Isabel; Parikh, Suraj; Kulczycki, Anna M; Hurst, Marykathryn; Ring, Nadja; Wang, Tao; Shaikh, Farah; Gross, Polina; Singh, Harinder; Kolpakov, Mikhail A; Linke, Axel; Houser, Steven R; Rizzo, Victor; Sabri, Abdelkarim; Madesh, Muniswamy; Giacca, Mauro; Recchia, Fabio A

2015-07-14

Vascular endothelial growth factor (VEGF)-B activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGF receptors. Therefore, VEGF-B might be an ideal candidate for the treatment of dilated cardiomyopathy, which displays modest microvascular rarefaction and increased rate of apoptosis. This study evaluated VEGF-B gene therapy in a canine model of tachypacing-induced dilated cardiomyopathy. Chronically instrumented dogs underwent cardiac tachypacing for 28 days. Adeno-associated virus serotype 9 viral vectors carrying VEGF-B167 genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure. Moreover, we tested a novel VEGF-B167 transgene controlled by the atrial natriuretic factor promoter. Compared with control subjects, VEGF-B167 markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated heart failure. Atrial natriuretic factor-VEGF-B167 expression was low in normally functioning hearts and stimulated by cardiac pacing; it thus functioned as an ideal therapeutic transgene, active only under pathological conditions. Our results, obtained with a standard technique of interventional cardiology in a clinically relevant animal model, support VEGF-B167 gene transfer as an affordable and effective new therapy for nonischemic heart failure. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Status of THe-Trap

Energy Technology Data Exchange (ETDEWEB)

Streubel, Sebastian; Eronen, Tommi; Hoecker, Martin; Ketter, Jochen; Blaum, Klaus [Max-Planck-Institut fuer Kernphysik, Heidelberg (Germany); Van Dyck, Robert S. Jr. [Department of Physics, University of Washington, Seattle, WA (United States)

2013-07-01

THe-Trap (short for Tritium-{sup 3}He Trap) is a Penning-trap setup dedicated to measure the {sup 3}H to {sup 3}He mass-ratio with a relative uncertainty of better than 10{sup -11}. The ratio is of relevance for the KArlsruhe TRItium Neutrino experiment (KATRIN), which aims to measure the electron anti-neutrino mass, by measuring the shape of the β-decay energy spectrum close to its endpoint. An independent measurement of the {sup 3}H to {sup 3}He mass-ratio pins down this endpoint, and thus will help to determine the systematics of KATRIN. The trap setup consists of two Penning-traps: One trap for precision measurements, the other trap for ion storage. Ideally, the trap content will be periodically switched, which reduces the time between the measurements of the two ions' motional frequencies. In 2012, a mass ratio measurement of {sup 12}C{sup 4+} to {sup 14}N{sup 5+} was performed to characterize systematic effects of the traps. This measurement yielded a accuracy of 10{sup -9}. Further investigations revealed that a major reason for the modest accuracy is the large axial amplitude of ∼100 μm, compared to a ideal case of 3 μm at 4 K. In addition, relative magnetic fluctuations at a 3 x 10{sup -10} level on a 10 h timescale need to be significantly improved. In this contribution, the aforementioned findings and further systematic studies will be presented.

VEGFR1-mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy

DEFF Research Database (Denmark)

Cao, Renhai; Xue, Yuan; Hedlund, Eva-Maria

2010-01-01

. Moreover, blockade of VEGFR1 but not VEGFR2 significantly restores pericyte saturation in mature retinal vessels. Our findings link VEGF and PlGF to cancer-associated retinopathy, reveal the molecular mechanisms of VEGFR1 ligand-mediated retinopathy, and define VEGFR1 as an important target......, and adenoviral vectors ablates pericytes from the mature retinal vasculature through the VEGF receptor 1 (VEGFR1)-mediated signaling pathway, leading to increased vascular leakage. In contrast, we demonstrate VEGF receptor 2 (VEGFR2) is primarily expressed in nonvascular photoreceptors and ganglion cells...

Brain-derived neurotrophic factor promotes VEGF-C-dependent lymphangiogenesis by suppressing miR-624-3p in human chondrosarcoma cells.

Science.gov (United States)

Lin, Chih-Yang; Wang, Shih-Wei; Chen, Yen-Ling; Chou, Wen-Yi; Lin, Ting-Yi; Chen, Wei-Cheng; Yang, Chen-Yu; Liu, Shih-Chia; Hsieh, Chia-Chu; Fong, Yi-Chin; Wang, Po-Chuan; Tang, Chih-Hsin

2017-08-03

Chondrosarcoma is the second most common primary malignancy of bone, and one of the most difficult bone tumors to diagnose and treat. It is well known that increased levels of vascular endothelial growth factor-C (VEGF-C) promote active tumor lymphangiogenesis and lymphatic tumor spread to regional lymph nodes. Brain-derived neurotrophic factor (BDNF) is known to promote metastasis in human chondrosarcoma cells. Knowing more about the mechanism of BDNF in VEGF-C expression and lymphangiogenesis in human chondrosarcoma would improve our understanding as how to prevent chondrosarcoma angiogenesis and metastasis, which currently lacks effective adjuvant treatment. Here, we found that BDNF expression was at least 2.5-fold higher in the highly migratory JJ012(S10) cell line as compared with the primordial cell line (JJ012). In addition, VEGF-C expression and secretion was markedly increased in JJ012(S10) cells. Conditioned medium from JJ012(S10) cells significantly promoted migration and tube formation of human lymphatic endothelial cells (LECs), whereas knockdown of BDNF attenuated LEC migration and tube formation by suppressing VEGF-C production in JJ012(S10) cells. Mechanistic investigations indicated that BDNF facilitated VEGF-C-dependent lymphangiogenesis through the MEK/ERK/mTOR signaling pathway. We also showed that microRNA (miR)-624-3p expression was negatively regulated by BDNF via the MEK/ERK/mTOR cascade. Importantly, BDNF knockdown profoundly inhibited tumor-associated lymphangiogenesis in vivo. Further analyses identified that BDNF promoted tumor lymphangiogenesis by downregulating miR-624-3p in human chondrosarcoma tissues. In conclusion, this study is the first to reveal the mechanism underlying BDNF-induced lymphangiogenesis. We suggest that BDNF may serve as a promising therapeutic target for the restriction of VEGF-C-mediated tumor lymphangiogenesis and lymphatic metastasis.

VEGF-induced Rac1 activation in endothelial cells is regulated by the guanine nucleotide exchange factor Vav2

NARCIS (Netherlands)

Garrett, Tiana A.; van Buul, Jaap D.; Burridge, Keith

2007-01-01

Vascular endothelial growth factor (VEGF) signaling is critical for both normal and disease-associated vascular development. Dysregulated VEGF signaling has been implicated in ischemic stroke, tumor angiogenesis, and many other vascular diseases. VEGF signals through several effectors, including the

Investigation of Trap Sites and Their Roles in Organic Triphenylamine-Based Photorefractive Materials

OpenAIRE

Tsujimura, Sho

2016-01-01

Organic photorefractive (PR) materials have been studied during the last quarter-century, and they have recently received much attention due to their updatable features that allow them to be used in dynamic holographic devices. However, understanding bulk trap sites that drive the PR effect (by inducing a space-charge field) remains a critical issue. In general, the trap site behavior can be controlled from the energetic point of view; however, bulk devices contain not only the energy trap si...

Efficacy of intra-meibomian gland injection of the anti-VEGF agent bevacizumab for the treatment of meibomian gland dysfunction with lid-margin vascularity

Directory of Open Access Journals (Sweden)

Jiang X

2018-05-01

Full Text Available Xiaodan Jiang,* Yuexin Wang,* Huibin Lv, Yan Liu, Mingzhou Zhang, Xuemin Li Department of Ophthalmology, Peking University Third Hospital, Beijing, China *These authors contributed equally to this work Purpose: To investigate the efficacy of a novel treatment – intra-meibomian gland (MG injection of the anti-VEGF agent bevacizumab – for MG dysfunction (MGD with eyelid-margin vascularity. Methods: A total of 26 eyes from 13 patients diagnosed with MGD and eyelid-margin vascularity were included in our study. Patients received intra-meibomian gland injections of bevacizumab (150 µL, 2.5 mg/0.1 mL at multiple sites with a 29 G needle where telangiectasia was severe. The Ocular Surface Disease Index (OSDI, tear film, tear-breakup time (TBUT, eyelid-margin features, MG features, conjunctiva, and corneal staining were assessed at 1 day before injection and 1 week, 1 month, and 3 months after injection. Blood pressure, best-corrected visual acuity, intraocular pressure, and slit lamp examinations were performed to assure the safety of patients at 1 day before and 1 day, 1 week, 1 month, and 3 months after injection. Results: Lid-margin vascularity, conjunctival injection, expressed secretion quality, expressivity of the MG, TBUT, corneal staining, and OSDI were significantly improved 1 week, 1 month, and 3 months after injection compared to baseline values. Lid-margin vascularity, conjunctival injection, meibomian gland expressivity, TBUT, and OSDI continued to improve; the greatest improvements were observed at 1 month and sustained for 3 months. Spearman’s correlation analysis indicated that age and sex significantly influenced TBUT improvement. Females and older patients tended to have shorter baseline TBUT that followed a different trend from that of males and younger patients during postinjection visits, revealed by subgroup analysis. No local or systemic side effects were observed at follow-up visits. Conclusion: This study is the first to

Increased vascular endothelial growth factor (VEGF) expression in ...

African Journals Online (AJOL)

User

2011-05-16

May 16, 2011 ... was quantified by means of western blot and immunohistochemistry technology. ... Key words: Vascular endothelial growth factor (VEGF), spinal cord injury, ... accordance with the National Institute of Health Guide for the Care.

Inhibition of RM-1 prostate carcinoma and eliciting robust immune responses in the mouse model by using VEGF-M2-GnRH3-hinge-MVP vaccine.

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Wang, Yiqin; Alahdal, Murad; Ye, Jia; Jing, Liangliang; Liu, Xiaoxin; Chen, Huan; Jin, Liang; Cao, Rongyue

2018-01-23

GnRH and VEGF have been investigated as prostate carcinoma enhancers that support tumor spread and progression. Although both have documented roles in prostate carcinoma and many cancer types, the weak immunogenicity of these peptides has remained a major challenge for use in immunotherapy. Here, we describe a novel strategy to inhibit GnRH and VEGF production and assess the effect on the immune responses against these hormones using the RM-1 prostate cancer model. We designed a novel recombinant fusion protein which combined GnRH and VEGF as a vaccine against this tumor. The newly constructed fusion protein hVEGF121-M2-GnRH3-hinge-MVP contains the human vascular endothelial growth factor (hVEGF121) and three copies of GnRH in sequential linear alignment and T helper epitope MVP as an immunogenic vaccine. The effectiveness of the vaccine in eliciting an immune response and attenuating the prostate tumor growth was evaluated. Results showed that administration of a new vaccine effectively elicited humoral and cellular immune responses. We found that, a novel fusion protein, hVEGF121-M2-GnRH3-hinge-MVP, effectively inhibited growth of RM-1 prostate model and effectively promoted immune response. In conclusion, hVEGF121-M2-GnRH3-hinge-MVP is an effective dual mechanism tumor vaccine that limits RM-1 prostate growth. This vaccine may be a promising strategy for the treatment of hormone refractory prostate malignancies.

Vitreous vascular endothelial growth factor concentrations in proliferative diabetic retinopathy versus proliferative vitreoretinopathy.

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Citirik, Mehmet; Kabatas, Emrah Utku; Batman, Cosar; Akin, Kadir Okhan; Kabatas, Naciye

2012-01-01

To assess vitreous vascular endothelial growth factor (VEGF) concentrations in proliferative diabetic retinopathy (PDR) in comparison to proliferative vitreoretinopathy (PVR). Vitreous samples were collected from 69 eyes of 69 patients with traumatic lens dislocation (n = 10), grade B PVR with rhegmatogenous retinal detachment (n = 13), grade C PVR with rhegmatogenous retinal detachment (n = 14), PDR with vitreous hemorrhage (n = 18), and PDR with vitreous hemorrhage and tractional retinal detachment (n = 14). Vitreous fluid samples were obtained at vitrectomy, and the levels of VEGF were measured by enzyme-linked immunosorbent assay. The mean vitreous level of VEGF was 15.14 ± 5.22 pg/ml in eyes with grade B PVR, 99.15 ± 38.58 pg/ml in eyes with grade C PVR, 4,534.01 ± 1,193.28 pg/ml in eyes with vitreous hemorrhage secondary to PDR, 5,157.29 ± 969.44 pg/ml in eyes with vitreous hemorrhage and tractional retinal detachment secondary to PDR, and 16.19 ± 5.76 pg/ml in eyes of the control group with traumatic lens dislocation. Vitreous VEGF concentrations were significantly higher in the patients with grade C PVR, PDR with vitreous hemorrhage and PDR with vitreous hemorrhage and tractional retinal detachment in comparison to the control patients (p < 0.05). A significant alteration was not observed in patients with grade B PVR (p = 0.55). Vitreous VEGF concentrations are increased in PDR and grade C PVR. The high VEGF concentrations could suggest a possible effect of VEGF on advanced PVR. Copyright © 2011 S. Karger AG, Basel.

Vascular endothelial growth factor (VEGF-C - a potent risk factor in children diagnosed with stadium 4 neuroblastoma.

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Bogdan Miskowiak

2009-01-01

Full Text Available To evaluate the immunohistochemical expression of VEGF-C, CD34 and VEGFR-2 in cancer tissue of children diagnosed with stadium 4 neuroblastoma (NB and correlate their presence with the survival rate of children diagnosed with that stage of the disease. Eighteen children assigned to stadium 4 composed the study group. Fourteen patients (allocated to stadium 3 formed a control group. VEGF-C, CD34 and VEGFR-2 expressions were evaluated by immunohistochemical assay. Consecutive slides incubated with anti-CD34 and anti-VEGFR-2 antibodies revealed that the two markers were colocalized within endothelial layer of the blood vessels. On the other hand, VEGF-C was expressed exclusively in tumour cells. As demonstrated by Fisher's exact test, the risk of NB treatment failure (progression or relapse as well as tumour related death, when all the patients were considered, was found to be significant in VEGF-C positive patients. VEGF-C expression in NB constitutes a potent risk factor and may direct future anti-angiogenic treatment strategy. The proximity of VEGF-C and CD34/VEGFR-2 of NB could be the equivalent of a potentially interesting VEGF-C fashion involving a tumour cell invasion into the blood vessels in an early phase of metastases promoting.

Thicker carotid intima-media thickness and increased plasma VEGF levels suffered by post-acute thrombotic stroke patients

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Yueniwati Y

2016-12-01

Full Text Available Yuyun Yueniwati,1 Ni Komang Darmiastini,1 Eko Arisetijono2 1Radiology Department, Faculty of Medicine, Brawijaya University, Malang, Indonesia; 2Neurology Department, Faculty of Medicine, Brawijaya University, Malang, Indonesia Background and objectives: Atherosclerosis causes reduction of the oxygen supply to structures in the far arterial wall, provoking the release of factors that drive angiogenesis of vasa vasorum, including VEGF. Other studies have revealed the inflammatory response in atherosclerosis and the role of platelet factor 4 (PF4 as an anti-angiogenic chemokine through the inhibition of VEGF. This cross-sectional study aims at measuring the effect of atherosclerosis assessed through carotid intima-media thickness (CIMT against plasma VEGF levels in patients with post-acute thrombotic stroke. Materials and methods: CIMT was assessed sonographically using GE Logiq S6 with 13 MHz frequency linear probe. VEGF-A plasma levels were measured using enzyme-linked immunosorbent assay (ELISA method. Differences among variables were compared statistically. The data were analyzed using Pearson correlation. Results: A total of 25 patients with post-acute thrombotic stroke were identified in days 7 to 90. CIMT thickening was indicated in 88% of patients (1.202 ± 0.312 mm, while an increase in plasma VEGF was identified in all patients (178.28 ± 93.96 ng/mL. There was no significant correlation between CIMT and plasma VEGF levels in patients with post-acute thrombotic stroke (p=0.741. A significant correlation was recognized between CIMT and total cholesterol (p=0.029 and low-density lipoprotein (p=0.018. Conclusion: There were no significant correlations between CIMT and plasma VEGF levels in patients with post-acute thrombotic stroke. However, plasma VEGF increased in patients with thrombotic stroke. CIMT measurement is a promising noninvasive modality to assess the vascular condition of patients with stroke and diabetes, while plasma VEGF

Poster - 08: Preliminary Investigation into Collapsed-Cone based Dose Calculations for COMS Eye Plaques

International Nuclear Information System (INIS)

Morrison, Hali; Menon, Geetha; Sloboda, Ron

2016-01-01

Purpose: To investigate the accuracy of model-based dose calculations using a collapsed-cone algorithm for COMS eye plaques loaded with I-125 seeds. Methods: The Nucletron SelectSeed 130.002 I-125 seed and the 12 mm COMS eye plaque were incorporated into a research version of the Oncentra® Brachy v4.5 treatment planning system which uses the Advanced Collapsed-cone Engine (ACE) algorithm. Comparisons of TG-43 and high-accuracy ACE doses were performed for a single seed in a 30×30×30 cm 3 water box, as well as with one seed in the central slot of the 12 mm COMS eye plaque. The doses along the plaque central axis (CAX) were used to calculate the carrier correction factor, T(r), and were compared to tabulated and MCNP6 simulated doses for both the SelectSeed and IsoAid IAI-125A seeds. Results: The ACE calculated dose for the single seed in water was on average within 0.62 ± 2.2% of the TG-43 dose, with the largest differences occurring near the end-welds. The ratio of ACE to TG-43 calculated doses along the CAX (T(r)) of the 12 mm COMS plaque for the SelectSeed was on average within 3.0% of previously tabulated data, and within 2.9% of the MCNP6 simulated values. The IsoAid and SelectSeed T(r) values agreed within 0.3%. Conclusions: Initial comparisons show good agreement between ACE and MC doses for a single seed in a 12 mm COMS eye plaque; more complicated scenarios are being investigated to determine the accuracy of this calculation method.

Poster - 08: Preliminary Investigation into Collapsed-Cone based Dose Calculations for COMS Eye Plaques

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Morrison, Hali; Menon, Geetha; Sloboda, Ron [Cross Cancer Institute, Edmonton, AB, and University of Alberta, Edmonton, AB, Cross Cancer Institute, Edmonton, AB, and University of Alberta, Edmonton, AB, Cross Cancer Institute, Edmonton, AB, and University of Alberta, Edmonton, AB (Canada)

2016-08-15

Purpose: To investigate the accuracy of model-based dose calculations using a collapsed-cone algorithm for COMS eye plaques loaded with I-125 seeds. Methods: The Nucletron SelectSeed 130.002 I-125 seed and the 12 mm COMS eye plaque were incorporated into a research version of the Oncentra® Brachy v4.5 treatment planning system which uses the Advanced Collapsed-cone Engine (ACE) algorithm. Comparisons of TG-43 and high-accuracy ACE doses were performed for a single seed in a 30×30×30 cm{sup 3} water box, as well as with one seed in the central slot of the 12 mm COMS eye plaque. The doses along the plaque central axis (CAX) were used to calculate the carrier correction factor, T(r), and were compared to tabulated and MCNP6 simulated doses for both the SelectSeed and IsoAid IAI-125A seeds. Results: The ACE calculated dose for the single seed in water was on average within 0.62 ± 2.2% of the TG-43 dose, with the largest differences occurring near the end-welds. The ratio of ACE to TG-43 calculated doses along the CAX (T(r)) of the 12 mm COMS plaque for the SelectSeed was on average within 3.0% of previously tabulated data, and within 2.9% of the MCNP6 simulated values. The IsoAid and SelectSeed T(r) values agreed within 0.3%. Conclusions: Initial comparisons show good agreement between ACE and MC doses for a single seed in a 12 mm COMS eye plaque; more complicated scenarios are being investigated to determine the accuracy of this calculation method.

Investigating the Construct Measured by Banked Gap-Fill Items: Evidence from Eye-Tracking

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McCray, Gareth; Brunfaut, Tineke

2018-01-01

This study investigates test-takers' processing while completing banked gap-fill tasks, designed to test reading proficiency, in order to test theoretically based expectations about the variation in cognitive processes of test-takers across levels of performance. Twenty-eight test-takers' eye traces on 24 banked gap-fill items (on six tasks) were…

Association of mast cell-derived VEGF and proteases in Dengue shock syndrome.

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Takahisa Furuta

Full Text Available BACKGROUND: Recent in-vitro studies have suggested that mast cells are involved in Dengue virus infection. To clarify the role of mast cells in the development of clinical Dengue fever, we compared the plasma levels of several mast cell-derived mediators (vascular endothelial cell growth factor [VEGF], soluble VEGF receptors [sVEGFRs], tryptase, and chymase and -related cytokines (IL-4, -9, and -17 between patients with differing severity of Dengue fever and healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: The study was performed at Children's Hospital No. 2, Ho Chi Minh City, and Vinh Long Province Hospital, Vietnam from 2002 to 2005. Study patients included 103 with Dengue fever (DF, Dengue hemorrhagic fever (DHF, and Dengue shock syndrome (DSS, as diagnosed by the World Health Organization criteria. There were 189 healthy subjects, and 19 febrile illness patients of the same Kinh ethnicity. The levels of mast cell-derived mediators and -related cytokines in plasma were measured by ELISA. VEGF and sVEGFR-1 levels were significantly increased in DHF and DSS compared with those of DF and controls, whereas sVEGFR-2 levels were significantly decreased in DHF and DSS. Significant increases in tryptase and chymase levels, which were accompanied by high IL-9 and -17 concentrations, were detected in DHF and DSS patients. By day 4 of admission, VEGF, sVEGFRs, and proteases levels had returned to similar levels as DF and controls. In-vitro VEGF production by mast cells was examined in KU812 and HMC-1 cells, and was found to be highest when the cells were inoculated with Dengue virus and human Dengue virus-immune serum in the presence of IL-9. CONCLUSIONS: As mast cells are an important source of VEGF, tryptase, and chymase, our findings suggest that mast cell activation and mast cell-derived mediators participate in the development of DHF. The two proteases, particularly chymase, might serve as good predictive markers of Dengue disease severity.

Combined immunotherapy of breast cancer with EGF and VEGF vaccines from DNA shuffling in a mouse model.

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Jin, Dong; Yu, Xin; Chen, Bing; Li, Zhitao; Ding, Jia; Zhao, Xiuyun; Qi, Gaofu

2017-06-01

Development of EGF and VEGF vaccines with high antigenicity for combined immunotherapy of EGF-EGFR signaling-dependent epithelial tumors such as breast cancer. EGF genes from mouse, human and chicken were randomly assembled to chimeric genes by DNA shuffling, then a chimeric EGF was selected out by PCR, SDS-PAGE and immunization for combined immunotherapy of breast cancer with a previously constructed chimeric VEGF vaccine from shuffling. Combined vaccination with chimeric EGF and VEGF from shuffling could induce high titer of antibodies against EGF and VEGF to inhibit tumor growth and angiogenesis, and improve the survival rate of mice with breast cancer. Combined vaccination with EGF and VEGF from shuffling showed better immunotherapy on EGF-EGFR signaling-dependent epithelial tumors such as breast cancer than the single-agent EGF vaccination.

Increased vascular endothelial growth factor (VEGF) expression in ...

African Journals Online (AJOL)

User

2011-05-16

May 16, 2011 ... Vascular endothelial growth factor (VEGF), a well known angiogenic factor, has been shown to have direct and/or ... Endogenous repair efforts fail to repair ... Spinal cord injury model preparation and intramedullary spinal.

A nanobody directed to a functional epitope on VEGF, as a novel strategy for cancer treatment.

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Farajpour, Zahra; Rahbarizadeh, Fatemeh; Kazemi, Bahram; Ahmadvand, Davoud

2014-03-28

Compelling evidence suggests that vascular endothelial growth factor (VEGF), due to its essential role in angiogenesis, is a critical target for cancer treatment. Neutralizing monoclonal antibodies against VEGF are important class of drugs used in cancer therapy. However, the cost of production, large size, and immunogenicity are main drawbacks of conventional monoclonal therapy. Nanobodies are the smallest antigen-binding antibody fragments, which occur naturally in camelidae. Because of their remarkable features, we decided to use an immune library of nanobody to direct phage display to recognition of novel functional epitopes on VEGF. Four rounds of selection were performed and six phage-displayed nanobodies were obtained from an immune phage library. The most reactive clone in whole-cell ELISA experiments, was purified and assessed in proliferation inhibition assay. Purified ZFR-5 not only blocked interaction of VEGF with its receptor in cell ELISA experiments, but also was able to significantly inhibit proliferation response of human umbilical vein endothelial cells to VEGF in a dose-dependent manner. Taken together, our study demonstrates that by using whole-cell ELISA experiments, nanobodies against antigenic regions included in interaction of VEGF with its receptors can be directed. Because of unique and intrinsic properties of a nanobody and the ability of selected nanobody for blocking the epitope that is important for biological function of VEGF, it represents novel potential drug candidate. Copyright © 2014 Elsevier Inc. All rights reserved.

High expression of SDF-1 and VEGF is associated with poor prognosis in patients with synovial sarcomas.

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Feng, Qi; Guo, Peng; Wang, Jin; Zhang, Xiaoyu; Yang, Hui-Chai; Feng, Jian-Gang

2018-03-01

Stromal cell-derived factor-1 (SDF-1) predicts poor clinical outcomes of certain types of cancer. Furthermore, vascular endothelial growth factor (VEGF) promotes the growth and metastasis of solid tumors. The aim of the present study was to examine the expression of SDF-1 and VEGF in patients with synovial sarcoma and to determine their expression is correlated with unfavorable outcomes. Levels of SDF-1 and VEGF proteins were evaluated in 54 patients with synovial sarcoma using immunohistochemical and immunofluorescence staining. Potential associations between the expression of SDF-1 and VEGF and various clinical parameters were analyzed using Pearson's χ 2 test and the Spearman-rho test. Additionally, univariate and multivariate Cox regression analyses were used to identify potential prognostic factors, and the Kaplan-Meier method was used to analyze the overall survival rates of patients. Low SDF-1 and VEGF expression was detected in 20.4% (11/54) and 22.2% (12/54) of patients with synovial sarcoma; moderate expression was detected in 35.2% (19/54) and 37.0% (20/54) of patients and high expression was detected in 44.4% (24 of 54) and 40.7% (22 of 54) of patients, respectively. Levels of SDF-1 and VEGF proteins were significantly associated with histological grade (P<0.05), metastasis (P<0.05) and American Joint Committee on Cancer staging (P<0.05). In addition, levels of SDF-1 and VEGF expression were positively correlated with each other (P<0.001). Univariate analysis also indicated that VEGF expression was associated with shorter overall survival rates in (P<0.05), whereas multivariate analysis demonstrated that SDF-1 expression was associated with shorter patient survival rates (P<0.05). Finally, both SDF-1 and VEGF expression were associated with various characteristics of synovial sarcoma. Therefore, SDF-1 expression may be a potential independent prognostic indicator in patients with synovial sarcomas.

The impact of KRAS mutations on VEGF-A production and tumour vascular network

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Figueras, Agnès; Arbos, Maria Antonia; Quiles, Maria Teresa; Viñals, Francesc; Germà, Josep Ramón; Capellà, Gabriel

2013-01-01

The malignant potential of tumour cells may be influenced by the molecular nature of KRAS mutations being codon 13 mutations less aggressive than codon 12 ones. Their metabolic profile is also different, with an increased anaerobic glycolytic metabolism in cells harbouring codon 12 KRAS mutations compared with cells containing codon 13 mutations. We hypothesized that this distinct metabolic behaviour could be associated with different HIF-1α expression and a distinct angiogenic profile. Codon13 KRAS mutation (ASP13) or codon12 KRAS mutation (CYS12) NIH3T3 transfectants were analyzed in vitro and in vivo. Expression of HIF-1α, and VEGF-A was studied at RNA and protein levels. Regulation of VEGF-A promoter activity was assessed by means of luciferase assays using different plasmid constructs. Vascular network was assessed in tumors growing after subcutaneous inoculation. Non parametric statistics were used for analysis of results. Our results show that in normoxic conditions ASP13 transfectants exhibited less HIF-1α protein levels and activity than CYS12. In contrast, codon 13 transfectants exhibited higher VEGF-A mRNA and protein levels and enhanced VEGF-A promoter activity. These differences were due to a differential activation of Sp1/AP2 transcription elements of the VEGF-A promoter associated with increased ERKs signalling in ASP13 transfectants. Subcutaneous CYS12 tumours expressed less VEGF-A and showed a higher microvessel density (MVD) than ASP13 tumours. In contrast, prominent vessels were only observed in the latter. Subtle changes in the molecular nature of KRAS oncogene activating mutations occurring in tumour cells have a major impact on the vascular strategy devised providing with new insights on the role of KRAS mutations on angiogenesis

Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes.

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Hagberg, Carolina E; Mehlem, Annika; Falkevall, Annelie; Muhl, Lars; Fam, Barbara C; Ortsäter, Henrik; Scotney, Pierre; Nyqvist, Daniel; Samén, Erik; Lu, Li; Stone-Elander, Sharon; Proietto, Joseph; Andrikopoulos, Sofianos; Sjöholm, Ake; Nash, Andrew; Eriksson, Ulf

2012-10-18

The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts. Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been proposed to contribute to the pathology of type 2 diabetes. However, few treatment options exist that directly target ectopic lipid accumulation. Recently it was found that vascular endothelial growth factor B (VEGF-B) controls endothelial uptake and transport of fatty acids in heart and skeletal muscle. Here we show that decreased VEGF-B signalling in rodent models of type 2 diabetes restores insulin sensitivity and improves glucose tolerance. Genetic deletion of Vegfb in diabetic db/db mice prevented ectopic lipid deposition, increased muscle glucose uptake and maintained normoglycaemia. Pharmacological inhibition of VEGF-B signalling by antibody administration to db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture, improved β-cell function and ameliorated dyslipidaemia, key elements of type 2 diabetes and the metabolic syndrome. The potential use of VEGF-B neutralization in type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart. Our results demonstrate that the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and type 2 diabetes, and that this barrier can be maintained by inhibition of VEGF-B signalling. We propose VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipid-transport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.

Poly(lactic-co-glycolide) polymer constructs cross-linked with human BMP-6 and VEGF protein significantly enhance rat mandible defect repair.

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Das, Anusuya; Fishero, Brian A; Christophel, J Jared; Li, Ching-Ju; Kohli, Nikita; Lin, Yong; Dighe, Abhijit S; Cui, Quanjun

2016-04-01

We have previously shown that the combined delivery of mesenchymal stem cells (MSCs), vascular endothelial growth factor (VEGF) and bone morphogenetic protein 6 (BMP-6) induces significantly more bone formation than that induced by the delivery of any single factor or a combination of any two factors. We now determine whether the exogenous addition of VEGF and BMP-6 is sufficient for bone healing when MSCs are not provided. Poly(lactic-co-glycolic acid) (PLAGA) microsphere-based three-dimensional scaffolds (P) were fabricated by thermal sintering of PLAGA microspheres. The scaffolds were chemically cross-linked with 200 ng recombinant human VEGF (P(VEGF)) or BMP-6 (P(BMP-6)) or both (P(VEGF+BMP-6)) by the EDC-NHS-MES method. Release of the proteins from the scaffolds was detected for 21 days in vitro which confirmed their comparable potential to supply the proteins in vivo. The scaffolds were delivered to a critical-sized mandibular defect created in 32 Sprague Dawley rats. Significant bone regeneration was observed only in rats with P(VEGF+BMP-6) scaffolds at weeks 2, 8 and 12 as revealed by micro-computer tomography. Vascular ingrowth was higher in the P(VEGF+BMP-6) group as seen by microfil imaging than in other groups. Trichrome staining revealed that a soft callus formed in P(VEGF), P(BMP-6) and P(VEGF+BMP-6) but not in P. MSCs isolated from rat femurs displayed expression of the bone-specific marker osteocalcin when cultured with P(VEGF), P(BMP-6), or P(VEGF+BMP-6) but not with P. Robust mineralization and increased alkaline phosphatase gene expression were seen in rat MSCs when cultured on P(VEGF+BMP-6) but not on P, P(VEGF), or P(BMP-6). Thus, unlike the delivery of VEGF or BMP-6 alone, the combined delivery of VEGF and BMP-6 to the bone defect significantly enhanced bone repair through the enhancement of angiogenesis and the differentiation of endogenously recruited MSCs into the bone repair site.

NADPH oxidase 4 mediates insulin-stimulated HIF-1α and VEGF expression, and angiogenesis in vitro.

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Dan Meng

Full Text Available Acute intensive insulin therapy causes a transient worsening of diabetic retinopathy in type 1 diabetes patients and is related to VEGF expression. Reactive oxygen species (ROS have been shown to be involved in HIF-1α and VEGF expression induced by insulin, but the role of specific ROS sources has not been fully elucidated. In this study we examined the role of NADPH oxidase subunit 4 (Nox4 in insulin-stimulated HIF-1α and VEGF expression, and angiogenic responses in human microvascular endothelial cells (HMVECs. Here we demonstrate that knockdown of Nox4 by siRNA reduced insulin-stimulated ROS generation, the tyrosine phosphorylation of IR-β and IRS-1, but did not change the serine phosphorylation of IRS-1. Nox4 gene silencing had a much greater inhibitory effect on insulin-induced AKT activation than ERK1/2 activation, whereas it had little effect on the expression of the phosphatases such as MKP-1 and SHIP. Inhibition of Nox4 expression inhibited the transcriptional activity of VEGF through HIF-1. Overexpression of wild-type Nox4 was sufficient to increase VEGF transcriptional activity, and further enhanced insulin-stimulated the activation of VEGF. Downregulation of Nox4 expression decreased insulin-stimulated mRNA and protein expression of HIF-1α, but did not change the rate of HIF-1α degradation. Inhibition of Nox4 impaired insulin-stimulated VEGF expression, cell migration, cell proliferation, and tube formation in HMVECs. Our data indicate that Nox4-derived ROS are essential for HIF-1α-dependent VEGF expression, and angiogenesis in vitro induced by insulin. Nox4 may be an attractive therapeutic target for diabetic retinopathy caused by intensive insulin treatment.

EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model.

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Reynaud, Déborah; Sergent, Frédéric; Abi Nahed, Roland; Brouillet, Sophie; Benharouga, Mohamed; Alfaidy, Nadia

2018-01-01

During the last decade, multiple animal models have been developed to mimic hallmarks of pregnancy-induced hypertension (PIH) diseases, which include gestational hypertension, preeclampsia (PE), or eclampsia. Converging in vitro, ex vivo, and clinical studies from our group strongly suggested the potential involvement of the new angiogenic factor EG-VEGF (endocrine gland-derived-VEGF) in the development of PIH. Here, we described the protocol that served to demonstrate that maintenance of EG-VEGF production over 11.5 days post coitus (dpc) in the gravid mice caused the development of PIH. The developed model exhibited most hallmarks of preeclampsia.

VEGF, VEGFR-1 and VEGFR-2 immunoreactivity in the porcine arteries of vascular subovarian plexus (VSP during the estrous cycle.

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A Andronowska

2006-04-01

Full Text Available Abstract: Vascular endothelial growth factor (VEGF is an important angiogenic factor in the female reproductive tract. It binds to cell surface through ligand-stimulatable tyrosine kinase receptors, the most important being VEGFR-1 (flt-1 and VEGFR-2 (flk-1. The broad ligament of the uterus is a dynamic organ consisting of specialized complexes of blood vessels connected functionally to the uterus, oviduct and ovary. Endothelial cells form an inner coating of the vessel walls and thus they stay under the influence of various modulators circulating in blood including ovarian steriods involved in developmental changes in the female reproductive system. The aim of the present study was to immunolocalize VEGF and its two receptors: VEGFR-1 and VEGFR-2 in the broad ligament of the uterus in the area of vascular subovarian plexus during different phases of the estrous cycle in pig and to determine the correlation between immunoreactivity of the investigated factors and phases of the estrous cycle. The study was performed on cryostat sections of vascular subovarian plexus stained immunohistochemically by ABC method. Specific polyclonal antibodies: anti-VEGF, anti-VEGFR-1 and anti-VEGFR-2 were used. Data were subjected to one-way analysis of variance. Our study revealed the presence of VEGF and its receptors in endothelial and smooth muscle cells of VSP arteries. All agents displayed phase-related differences in immunoreactivity suggesting the modulatory effect of VEGF, VEGFR-1 and VEGFR-2 on the arteries of the VSP in the porcine broad ligament of the uterus.

DNA binding-independent transcriptional activation of the vascular endothelial growth factor gene (VEGF) by the Myb oncoprotein

International Nuclear Information System (INIS)

Lutwyche, Jodi K.; Keough, Rebecca A.; Hunter, Julie; Coles, Leeanne S.; Gonda, Thomas J.

2006-01-01

Myb is a key transcription factor that can regulate proliferation, differentiation, and apoptosis, predominantly in the haemopoietic system. Abnormal expression of Myb is associated with a number of cancers, both haemopoietic and non-haemopoietic. In order to better understand the role of Myb in normal and tumorigenic processes, we undertook a cDNA array screen to identify genes that are regulated by this factor. In this way, we identified the gene encoding vascular endothelial growth factor (VEGF) as being potentially regulated by the Myb oncoprotein in myeloid cells. To determine whether this was a direct effect on VEGF gene transcription, we examined the activity of the murine VEGF promoter in the presence of either wild-type (WT) or mutant forms of Myb. It was found that WT Myb was able to activate the VEGF promoter and that a minimal promoter region of 120 bp was sufficient to confer Myb responsiveness. Surprisingly, activation of the VEGF promoter was independent of DNA binding by Myb. This was shown by the use of DNA binding-defective Myb mutants and by mutagenesis of a potential Myb-binding site in the minimal promoter. Mutation of Sp1 sites within this region abolished Myb-mediated regulation of a reporter construct, suggesting that Myb DNA binding-independent activation of VEGF expression occurs via these Sp1 binding elements. Regulation of VEGF production by Myb has implications for the potential role of Myb in myeloid leukaemias and in solid tumours where VEGF may be functioning as an autocrine growth factor

Inhibition of prostate cancer osteoblastic progression with VEGF121/rGel, a single agent targeting osteoblasts, osteoclasts, and tumor neovasculature.

Science.gov (United States)

Mohamedali, Khalid A; Li, Zhi Gang; Starbuck, Michael W; Wan, Xinhai; Yang, Jun; Kim, Sehoon; Zhang, Wendy; Rosenblum, Michael G; Navone, Nora M

2011-04-15

A hallmark of prostate cancer (PCa) progression is the development of osteoblastic bone metastases, which respond poorly to available therapies. We previously reported that VEGF(121)/rGel targets osteoclast precursors and tumor neovasculature. Here we tested the hypothesis that targeting nontumor cells expressing these receptors can inhibit tumor progression in a clinically relevant model of osteoblastic PCa. Cells from MDA PCa 118b, a PCa xenograft obtained from a bone metastasis in a patient with castrate-resistant PCa, were injected into the femurs of mice. Osteoblastic progression was monitored following systemic administration of VEGF(121)/rGel. VEGF(121)/rGel was cytotoxic in vitro to osteoblast precursor cells. This cytotoxicity was specific as VEGF(121)/rGel internalization into osteoblasts was VEGF(121) receptor driven. Furthermore, VEGF(121)/rGel significantly inhibited PCa-induced bone formation in a mouse calvaria culture assay. In vivo, VEGF(121)/rGel significantly inhibited the osteoblastic progression of PCa cells in the femurs of nude mice. Microcomputed tomographic analysis revealed that VEGF(121)/rGel restored the bone volume fraction of tumor-bearing femurs to values similar to those of the contralateral (non-tumor-bearing) femurs. VEGF(121)/rGel significantly reduced the number of tumor-associated osteoclasts but did not change the numbers of peritumoral osteoblasts. Importantly, VEGF(121)/rGel-treated mice had significantly less tumor burden than control mice. Our results thus indicate that VEGF(121)/rGel inhibits osteoblastic tumor progression by targeting angiogenesis, osteoclastogenesis, and bone formation. Targeting VEGF receptor (VEGFR)-1- or VEGFR-2-expressing cells is effective in controlling the osteoblastic progression of PCa in bone. These findings provide the basis for an effective multitargeted approach for metastatic PCa. ©2011 AACR.

Results of Paleomagnetic Investigation of Angara - Taseeva Depression and Central Part of Tunguska Syncline (Siberian Trap Province, Russia)

Science.gov (United States)

Latyshev, A.; Veselovskiy, R. V.; Pavlov, V.

2014-12-01

Results of paleomagnetic investigation of two regions of Siberian Trap province (Angara - Taseeva depression and central part of Tunguska syncline) are performed here. Our work was dedicated to the estimation of dynamics and duration of magmatic activity during Siberian Traps emplacement. The conclusions are based on paleomagnetic study of large dolerite sills in the periphery of Siberian Trap province, tuffaceous deposits, small intrusions and lava flows of Tunguska syncline, and on geochronological data (Ivanov et al., 2013; Reichow et al., 2009). The presented data show that formation of Siberian Traps in these regions took place as several short bursts of magmatic activity led to large sill intrusions and eruptions of tuffs. This data are in agreement with the pulsating character of magmatic activity in the Northern part of Siberian platform (Pavlov et al., 2014). The most powerful burst of magmatic activity in Angara-Taseeva syncline is supposed to be synchronous to the main phase of volcanic eruptions in the Northern part of Siberian platform and emplacement of ore-bearing intrusions in Noril'sk district. This study was funded by grant RFBR # 14-05-31447.

A survey of prosthetic eye wearers to investigate mucoid discharge

Directory of Open Access Journals (Sweden)

Pine K

2012-05-01

Full Text Available Keith Pine1, Brian Sloan2, Joanna Stewart3, Robert J Jacobs11Department of Optometry and Vision Science, 2Department of Ophthalmology, New Zealand National Eye Centre, 3Section of Epidemiology and Biostatistics, School of Population Health, University of Auckland, Auckland, New ZealandBackground: This study aimed to better understand the causes and treatments of mucoid discharge associated with prosthetic eye wear by reviewing the literature and surveying anophthalmic patients.Methods: An anonymous questionnaire was completed by 429 prosthetic eye wearers who used visual analog scales to self-measure their discharge experience for four discharge characteristics: frequency, color, volume, and viscosity. These characteristics were analyzed with age, ethnicity, years wearing a prosthesis, eye loss cause, removal and cleaning regimes, hand-washing behavior, age of current prosthesis, and professional repolishing regimes as explanatory variables. Eighteen ocularists’ Web sites containing comments on the cause and treatment of discharge were surveyed.Results: Associations were found between discharge frequency and cleaning regimes with more frequent cleaning accompanying more frequent discharge. Color was associated with years of wearing and age, with more years of wearing and older people having less colored discharge. Volume was associated with cleaning regimes with more frequent cleaners having more volume. Viscosity was associated with cleaning regimes and years of wearing with more frequent cleaning and shorter wearing time accompanying more viscous discharge. No associations were found between discharge characteristics and ethnicity, eye loss cause, hand washing, age of current prosthesis, or repolishing regimes. Forty-seven percent of ocularists’ Web sites advised that discharge was caused by surface deposits on the prosthesis, 29% by excessive handling of the prosthesis, and 24% by other causes.Conclusions: A standardized treatment

Extra virgin olive oil rich in polyphenols modulates VEGF-induced angiogenic responses by preventing NADPH oxidase activity and expression.

Science.gov (United States)

Calabriso, Nadia; Massaro, Marika; Scoditti, Egeria; D'Amore, Simona; Gnoni, Antonio; Pellegrino, Mariangela; Storelli, Carlo; De Caterina, Raffaele; Palasciano, Giuseppe; Carluccio, Maria Annunziata

2016-02-01

Previous studies have shown the antiinflammatory, antioxidant and antiangiogenic properties by pure olive oil polyphenols; however, the effects of olive oil phenolic fraction on the inflammatory angiogenesis are unknown. In this study, we investigated the effects of the phenolic fraction (olive oil polyphenolic extract, OOPE) from extra virgin olive oil and related circulating metabolites on the VEGF-induced angiogenic responses and NADPH oxidase activity and expression in human cultured endothelial cells. We found that OOPE (1-10 μg/ml), at concentrations achievable nutritionally, significantly reduced, in a concentration-dependent manner, the VEGF-induced cell migration, invasiveness and tube-like structure formation through the inhibition of MMP-2 and MMP-9. OOPE significantly (Pextra virgin olive oil, with high polyphenol content, decreased VEGF-induced NADPH oxidase activity and Nox4 expression, as well as, MMP-9 expression, as compared with fasting control serum. Overall, native polyphenols and serum metabolites of extra virgin olive oil rich in polyphenols are able to lower the VEGF-induced angiogenic responses by preventing endothelial NADPH oxidase activity and decreasing the expression of selective NADPH oxidase subunits. Our results provide an alternative mechanism by which the consumption of olive oil rich in polyphenols may account for a reduction of oxidative stress inflammatory-related sequelae associated with chronic degenerative diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype

International Nuclear Information System (INIS)

Nagy, Janice A.; Senger, Donald R.

2006-01-01

Normal angiogenesis is a complex process involving the organization of proliferating and migrating endothelial cells (ECs) into a well-ordered and highly functional vascular network. In contrast, pathological angiogenesis, which is a conspicuous feature of tumor growth, ischemic diseases, and chronic inflammation, is characterized by vessels with aberrant angioarchitecture and compromised barrier function. Herein we review the subject of pathological angiogenesis, particularly that driven by vascular endothelial growth factor (VEGF-A), from a new perspective. We propose that the serious structural and functional anomalies associated with VEGF-A-elicited neovessels, reflect, at least in part, imbalances in the internal molecular cues that govern the ordered assembly of ECs into three dimensional vascular networks and preserve vessel barrier function. Adopting such a viewpoint widens the focus from solely on specific pro-angiogenic stimuli such as VEGF-A to include a key set of cytoskeletal regulatory molecules, the Rho GTPases, which are known to direct multiple aspects of vascular morphogenesis including EC motility, alignment, multi-cellular organization, as well as intercellular junction integrity. We offer this perspective to draw attention to the importance of endothelial cytoskeletal dynamics for proper neovascularization and to suggest new therapeutic strategies with the potential to improve the pathological vascular phenotype

Characteristics of single-atom trapping in a magneto-optical trap with a high magnetic-field gradient

International Nuclear Information System (INIS)

Yoon, Seokchan; Choi, Youngwoon; Park, Sangbum; Ji, Wangxi; Lee, Jai-Hyung; An, Kyungwon

2007-01-01

A quantitative study on characteristics of a magneto-optical trap with a single or a few atoms is presented. A very small number of 85 Rb atoms were trapped in a micron-size magneto-optical trap with a high magnetic-field gradient. In order to find the optimum condition for a single-atom trap, we have investigated how the number of atoms and the size of atomic cloud change as various experimental parameters, such as a magnetic-field gradient and the trapping laser intensity and detuning. The averaged number of atoms was measured very accurately with a calibration procedure based on the single-atom saturation curve of resonance fluorescence. In addition, the number of atoms in a trap could be controlled by suppressing stochastic loading events by means of a real-time active feedback on the magnetic-field gradient

The development of eye tracking in aviation (ETA) technique to investigate pilot's cognitive processes of attention and decision-making

OpenAIRE

Li, Wen-Chin; Lin, John J. H.; Braithwaite, Graham; Greaves, Matt

2016-01-01

Eye tracking device had provided researchers a promising way to investigate what pilot‘s cognitive processes when they see information present on the flight deck. There are 35 participants consisted by pilots and avionics engineers participated in current research. The research apparatus include an eye tracker and a flight simulator divided by five AOIs for data collection. The research aims are to develop cost-efficiency of eye tracking technique in order to facilitate scientific research of...

Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis.

Science.gov (United States)

Weidemann, Anja K; Crawshaw, Ania A; Byrne, Emily; Young, Helen S

2013-09-26

Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF)-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation) and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased cardiovascular risk.

Interleukin-6 secreted by oral cancer- associated fibroblast accelerated VEGF expression in tumor and stroma cells.

Science.gov (United States)

Mirkeshavarz, M; Ganjibakhsh, M; Aminishakib, P; Farzaneh, P; Mahdavi, N; Vakhshiteh, F; Karimi, A; Gohari, N S; Kamali, F; Kharazifard, M J; Shahzadeh Fazeli, S A; Nasimian, A

2017-10-31

Oral cancer represents the sixth most common cancer type worldwide. Patients with oral cancer express high levels of IL-6 which is associated with very poor prognosis. Previous studies illustrated that IL-6 cytokine induces angiogenesis. It has also been reported that the presence of Cancer- Associated Fibroblasts (CAFs) is essential for angiogenesis. In this study, we examined the correlation between IL-6 and CAF and the role of this correlation on VEGF production. In this study, quantitative expression level of IL-6 and VEGF in CAF and Oral Cancer Cells (OCCs) examined through Real Time PCR and ELISA and western blot analysis. In addition, maintenance and retention of IL-6 and VEGF checked out in co-culture experiment of CAF and OCC cells. These experiments demonstrated that in oral cancer, CAF cell line secretes significantly more IL-6 than OCC. Also IL-6 is a factor that causes VEGF secretion in CAF cell line. CAF is the basic and the most essential source for producing IL-6 in patients with oral cancer. Secreted IL-6 is able to induce VEGF production in both CAF and OCCs. Correlation between CAF, IL-6 and VEGF could be considered as an approach for cancer therapy.

Mechanism of selective VEGF-A binding by neuropilin-1 reveals a basis for specific ligand inhibition.

Directory of Open Access Journals (Sweden)

Matthew W Parker

Full Text Available Neuropilin (Nrp receptors function as essential cell surface receptors for the Vascular Endothelial Growth Factor (VEGF family of proangiogenic cytokines and the semaphorin 3 (Sema3 family of axon guidance molecules. There are two Nrp homologues, Nrp1 and Nrp2, which bind to both overlapping and distinct members of the VEGF and Sema3 family of molecules. Nrp1 specifically binds the VEGF-A(164/5 isoform, which is essential for developmental angiogenesis. We demonstrate that VEGF-A specific binding is governed by Nrp1 residues in the b1 coagulation factor domain surrounding the invariant Nrp C-terminal arginine binding pocket. Further, we show that Sema3F does not display the Nrp-specific binding to the b1 domain seen with VEGF-A. Engineered soluble Nrp receptor fragments that selectively sequester ligands from the active signaling complex are an attractive modality for selectively blocking the angiogenic and chemorepulsive functions of Nrp ligands. Utilizing the information on Nrp ligand binding specificity, we demonstrate Nrp constructs that specifically sequester Sema3 in the presence of VEGF-A. This establishes that unique mechanisms are used by Nrp receptors to mediate specific ligand binding and that these differences can be exploited to engineer soluble Nrp receptors with specificity for Sema3.

Deuterium trapping in tungsten

Science.gov (United States)

Poon, Michael

Tungsten is one of the primary material candidates being investigated for use in the first-wall of a magnetic confinement fusion reactor. An ion accelerator was used to simulate the type of ion interaction that may occur at a plasma-facing material. Thermal desorption spectroscopy (TDS) was the primary tool used to analyze the effects of the irradiation. Secondary ion mass spectroscopy (SIMS) was used to determine the distribution of trapped D in the tungsten specimen. The tritium migration analysis program (TMAP) was used to simulate thermal desorption profiles from the D depth distributions. Fitting of the simulated thermal desorption profiles with the measured TDS results provided values of the D trap energies. Deuterium trapping in single crystal tungsten was studied as a function of the incident ion fluence, ion flux, irradiation temperature, irradiation history, and surface impurity levels during irradiation. The results show that deuterium was trapped at vacancies and voids. Two deuterium atoms could be trapped at a tungsten vacancy, with trapping energies of 1.4 eV and 1.2 eV for the first and second D atoms, respectively. In a tungsten void, D is trapped as atoms adsorbed on the inner walls of the void with a trap energy of 2.1 eV, or as D2 molecules inside the void with a trap energy of 1.2 eV. Deuterium trapping in polycrystalline tungsten was also studied as a function of the incident fluence, irradiation temperature, and irradiation history. Deuterium trapping in polycrystalline tungsten also occurs primarily at vacancies and voids with the same trap energies as in single crystal tungsten; however, the presence of grain boundaries promotes the formation of large surface blisters with high fluence irradiations at 500 K. In general, D trapping is greater in polycrystalline tungsten than in single crystal tungsten. To simulate mixed materials comprising of carbon (C) and tungsten, tungsten specimens were pre-irradiated with carbon ions prior to D

Deuterium trapping in tungsten

International Nuclear Information System (INIS)

Poon, M.

2004-01-01

Tungsten is one of the primary material candidates being investigated for use in the first-wall of a magnetic confinement fusion reactor. An ion accelerator was used to simulate the type of ion interaction that may occur at a plasma-facing material. Thermal desorption spectroscopy (TDS) was the primary tool used to analyze the effects of the irradiation Secondary ion mass spectroscopy (SIMS) was used to determine the distribution of trapped D in the tungsten specimen. The tritium migration analysis program (TMAP) was used to simulate thermal desorption profiles from the D depth distributions. Fitting of the simulated thermal desorption profiles with the measured TDS results provided values of the D trap energies. . Deuterium trapping in single crystal tungsten was studied as a function of the incident ion fluence, ion flux, irradiation temperature, irradiation history, and surface impurity levels during irradiation The results show that deuterium was trapped at vacancies and voids. Two deuterium atoms could be trapped at a tungsten vacancy, with trapping energies of 1.4 eV and 1.2 eV for the first and second D atoms, respectively. In a tungsten void, D is trapped as atoms adsorbed on the inner walls of the void with a trap energy of 2.1 eV, or as D 2 molecules inside the void with a trap energy of 1.2 eV. . Deuterium trapping in polycrystalline tungsten was also studied as a function of the incident fluence, irradiation temperature, and irradiation history. Deuterium trapping in polycrystalline tungsten also occurs primarily at vacancies and voids with the same trap energies as in single crystal tungsten; however, the presence of grain boundaries promotes the formation of large surface blisters with high fluence irradiations at 500 K. In general, D trapping is greater in polycrystalline tungsten than in single crystal tungsten. To simulate mixed materials comprising of carbon (C) and tungsten, tungsten specimens were pre-irradiated with carbon ions prior to D

Deuterium trapping in tungsten

Energy Technology Data Exchange (ETDEWEB)

Poon, M

2004-07-01

Tungsten is one of the primary material candidates being investigated for use in the first-wall of a magnetic confinement fusion reactor. An ion accelerator was used to simulate the type of ion interaction that may occur at a plasma-facing material. Thermal desorption spectroscopy (TDS) was the primary tool used to analyze the effects of the irradiation Secondary ion mass spectroscopy (SIMS) was used to determine the distribution of trapped D in the tungsten specimen. The tritium migration analysis program (TMAP) was used to simulate thermal desorption profiles from the D depth distributions. Fitting of the simulated thermal desorption profiles with the measured TDS results provided values of the D trap energies. . Deuterium trapping in single crystal tungsten was studied as a function of the incident ion fluence, ion flux, irradiation temperature, irradiation history, and surface impurity levels during irradiation The results show that deuterium was trapped at vacancies and voids. Two deuterium atoms could be trapped at a tungsten vacancy, with trapping energies of 1.4 eV and 1.2 eV for the first and second D atoms, respectively. In a tungsten void, D is trapped as atoms adsorbed on the inner walls of the void with a trap energy of 2.1 eV, or as D{sub 2} molecules inside the void with a trap energy of 1.2 eV. . Deuterium trapping in polycrystalline tungsten was also studied as a function of the incident fluence, irradiation temperature, and irradiation history. Deuterium trapping in polycrystalline tungsten also occurs primarily at vacancies and voids with the same trap energies as in single crystal tungsten; however, the presence of grain boundaries promotes the formation of large surface blisters with high fluence irradiations at 500 K. In general, D trapping is greater in polycrystalline tungsten than in single crystal tungsten. To simulate mixed materials comprising of carbon (C) and tungsten, tungsten specimens were pre-irradiated with carbon ions prior to D

Investigation of HIV-1 infected and uninfected cells using the optical trapping technique

CSIR Research Space (South Africa)

Ombinda-Lemboumba, Saturnin

2017-02-01

Full Text Available Optical trapping has emerged as an essential tool for manipulating single biological material and performing sophisticated spectroscopy analysis on individual cell. The optical trapping technique has been used to grab and immobilize cells from a...

Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer

Science.gov (United States)

Willett, Christopher G; Boucher, Yves; di Tomaso, Emmanuelle; Duda, Dan G; Munn, Lance L; Tong, Ricky T; Chung, Daniel C; Sahani, Dushyant V; Kalva, Sanjeeva P; Kozin, Sergey V; Mino, Mari; Cohen, Kenneth S; Scadden, David T; Hartford, Alan C; Fischman, Alan J; Clark, Jeffrey W; Ryan, David P; Zhu, Andrew X; Blaszkowsky, Lawrence S; Chen, Helen X; Shellito, Paul C; Lauwers, Gregory Y; Jain, Rakesh K

2009-01-01

The effects of vascular endothelial growth factor (VEGF) blockade on the vascular biology of human tumors are not known. Here we show here that a single infusion of the VEGF-specific antibody bevacizumab decreases tumor perfusion, vascular volume, microvascular density, interstitial fluid pressure and the number of viable, circulating endothelial and progenitor cells, and increases the fraction of vessels with pericyte coverage in rectal carcinoma patients. These data indicate that VEGF blockade has a direct and rapid antivascular effect in human tumors. PMID:14745444

Angiogenic activity of bFGF and VEGF suppressed by proteolytic cleavage by neutrophil elastase

International Nuclear Information System (INIS)

Ai, Shingo; Cheng Xianwu; Inoue, Aiko; Nakamura, Kae; Okumura, Kenji; Iguchi, Akihisa; Murohara, Toyoaki; Kuzuya, Masafumi

2007-01-01

Neutrophil elastase (NE), a serine protease released from the azurophil granules of activated neutrophil, proteolytically cleaves multiple cytokines, and cell surface proteins. In the present study, we examined whether NE affects the biological abilities of angiogenic growth factors such as basic-fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). NE degraded bFGF and VEGF in a time- and concentration-dependent manner, and these degradations were suppressed by sivelestat, a synthetic inhibitor of NE. The bFGF- or VEGF-mediated proliferative activity of human umbilical vein endothelial cells was inhibited by NE, and the activity was recovered by sivelestat. Furthermore, NE reduced the bFGF- or VEGF-induced tubulogenic response of the mice aortas, ex vivo angiogenesis assay, and these effects were also recovered by sivelestat. Neutrophil-derived NE degraded potent angiogenic factors, resulting in loss of their angiogenic activity. These findings provide additional insight into the role played by neutrophils in the angiogenesis process at sites of inflammation

Albendazole inhibits HIF-1α-dependent glycolysis and VEGF expression in non-small cell lung cancer cells.

Science.gov (United States)

Zhou, Fang; Du, Jin; Wang, Jianjun

2017-04-01

Albendazole (ABZ) has an anti-tumor ability and inhibits HIF-1α activity. HIF-1α is associated with glycolysis and vascular endothelial cell growth factor (VEGF) expression, which plays an important role in cancer progression. These clues indicate that ABZ exerts an anti-cancer effect by regulating glycolysis and VEGF expression. The aim of this study is to clarify the effects of ABZ on non-small cell lung cancer (NSCLC) cells and explore the underlying molecular mechanisms. The expression levels of HIF-1α and VEGF were detected using western blot analysis, and the effect of ABZ on glycolysis was evaluated by measuring the relative activities of hexokinase (HK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) and detecting the production of lactate in A549 and H1299 cells. The results showed that ABZ decreased the expression levels of HIF-1α and VEGF and suppressed glycolysis in under hypoxia, but not normoxic condition. Inhibiting HIF-1α also suppressed glycolysis and VEGF expression. Additionally, ABZ inhibited the volume and weight, decreased the relative activities of HK, PK, and LDH, and reduced the levels of HIF-1α and VEGF of A549 xenografts in mouse models. In conclusion, ABZ inhibited growth of NSCLC cells by suppressing HIF-1α-dependent glycolysis and VEGF expression.

Alternative splicing of TIA-1 in human colon cancer regulates VEGF isoform expression, angiogenesis, tumour growth and bevacizumab resistance.

Science.gov (United States)

Hamdollah Zadeh, Maryam A; Amin, Elianna M; Hoareau-Aveilla, Coralie; Domingo, Enric; Symonds, Kirsty E; Ye, Xi; Heesom, Katherine J; Salmon, Andrew; D'Silva, Olivia; Betteridge, Kai B; Williams, Ann C; Kerr, David J; Salmon, Andrew H J; Oltean, Sebastian; Midgley, Rachel S; Ladomery, Michael R; Harper, Steven J; Varey, Alexander H R; Bates, David O

2015-01-01

The angiogenic capability of colorectal carcinomas (CRC), and their susceptibility to anti-angiogenic therapy, is determined by expression of vascular endothelial growth factor (VEGF) isoforms. The intracellular protein T-cell Intracellular Antigen (TIA-1) alters post-transcriptional RNA processing and binds VEGF-A mRNA. We therefore tested the hypothesis that TIA-1 could regulate VEGF-A isoform expression in colorectal cancers. TIA-1 and VEGF-A isoform expression was measured in colorectal cancers and cell lines. We discovered that an endogenous splice variant of TIA-1 encoding a truncated protein, short TIA-1 (sTIA-1) was expressed in CRC tissues and invasive K-Ras mutant colon cancer cells and tissues but not in adenoma cell lines. sTIA-1 was more highly expressed in CRC than in normal tissues and increased with tumour stage. Knockdown of sTIA-1 or over-expression of full length TIA-1 (flTIA-1) induced expression of the anti-angiogenic VEGF isoform VEGF-A165b. Whereas flTIA-1 selectively bound VEGF-A165 mRNA and increased translation of VEGF-A165b, sTIA-1 prevented this binding. In nude mice, xenografted colon cancer cells over-expressing flTIA-1 formed smaller, less vascular tumours than those expressing sTIA-1, but flTIA-1 expression inhibited the effect of anti-VEGF antibodies. These results indicate that alternative splicing of an RNA binding protein can regulate isoform specific expression of VEGF providing an added layer of complexity to the angiogenic profile of colorectal cancer and their resistance to anti-angiogenic therapy. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Effects of hyperthyroidism on expression of vascular endothelial growth factor (VEGF and apoptosis in fetal adrenal glands

Directory of Open Access Journals (Sweden)

T. Karaca

2015-11-01

Full Text Available This study investigated the expression of vascular endothelial growth factor (VEGF, vascular density, and apoptosis in fetal rat adrenal glands with hyperthyroidism in late gestation. Twelve mature female Wistar albino rats with the same biological and physiological features were used for this study. Rats were divided into two groups: control and hyperthyroidism. Hyperthyroidism was induced by daily subcutaneous injections of L-thyroxine (250 μg/kg before pregnancy for 21 days and during pregnancy. Rats in the control and hyperthyroidism groups were caged according to the number of male rats. Zero day of pregnancy (Day 0 was indicated when the animals were observed to have microscopic sperm in vaginal smears. Pregnant rats were sacrificed on the 20th day of pregnancy; blood from each animal was collected to determine the concentrations of maternal adrenocorticotropic hormone and thyroxine. Rat fetuses were then quickly removed from the uterus, and the adrenal glands of the fetuses were dissected. VEGF expression, vascular density, and apoptosis were analyzed in fetal rat adrenal glands. Maternal serum levels of the adrenocorticotropic hormone and free thyroxine were significantly higher in the hyperthyroidism group than in the control group. Immunohistochemistry revealed that the number of VEGF positive cells and vessel density significantly increased in the hyperthyroidism rat fetal adrenal group compared with the control group. Hyperthyroidism did not change the fetal and placental weights and the number of fetuses. This study demonstrates that hyperthyroidism may have an effect on the development of rat adrenal glands mediated by VEGF expression, angiogenesis, and apoptosis. 

Effects of hyperthyroidism on expression of vascular endothelial growth factor (VEGF) and apoptosis in fetal adrenal glands.

Science.gov (United States)

Karaca, T; Hulya Uz, Y; Karabacak, R; Karaboga, I; Demirtas, S; Cagatay Cicek, A

2015-11-26

This study investigated the expression of vascular endothelial growth factor (VEGF), vascular density, and apoptosis in fetal rat adrenal glands with hyperthyroidism in late gestation. Twelve mature female Wistar albino rats with the same biological and physiological features were used for this study. Rats were divided into two groups: control and hyperthyroidism. Hyperthyroidism was induced by daily subcutaneous injections of L-thyroxine (250 μg/kg) before pregnancy for 21 days and during pregnancy. Rats in the control and hyperthyroidism groups were caged according to the number of male rats. Zero day of pregnancy (Day 0) was indicated when the animals were observed to have microscopic sperm in vaginal smears. Pregnant rats were sacrificed on the 20th day of pregnancy; blood from each animal was collected to determine the concentrations of maternal adrenocorticotropic hormone and thyroxine. Rat fetuses were then quickly removed from the uterus, and the adrenal glands of the fetuses were dissected. VEGF expression, vascular density, and apoptosis were analyzed in fetal rat adrenal glands. Maternal serum levels of the adrenocorticotropic hormone and free thyroxine were significantly higher in the hyperthyroidism group than in the control group. Immunohistochemistry revealed that the number of VEGF positive cells and vessel density significantly increased in the hyperthyroidism rat fetal adrenal group compared with the control group. Hyperthyroidism did not change the fetal and placental weights and the number of fetuses. This study demonstrates that hyperthyroidism may have an effect on the development of rat adrenal glands mediated by VEGF expression, angiogenesis, and apoptosis.

Semaphorin SEMA3F and VEGF Have Opposing Effects on Cell Attachment and Spreading

Directory of Open Access Journals (Sweden)

Patrick Nasarre

2003-01-01

Full Text Available SEMA3F, isolated from a 3p21.3 deletion, has antitumor activity in transfected cells, and protein expression correlates with tumor stage and histology. In primary tumors, SEMA3F and VEGF surface staining is inversely correlated. Coupled with SEMA3F at the leading edge of motile cells, we previously suggested that both proteins competitively regulate cell motility and adhesion. We have investigated this using the breast cancer cell line, MCF7. SEMA3F inhibited cell attachment and spreading as evidenced by loss of lamellipodia extensions, membrane ruffling, and cell-cell contacts, with cells eventually rounding-up and detaching. In contrast, VEGF had opposite effects. Although SEMA3F binds NRP2 with 10-fold greater affinity than NRP1, the effects in MCF7 were mediated by NRP1. This was determined by receptor expression and blocking of anti-NRP1 antibodies. Similar effects, but through NRP2, were observed in the C100 breast cancer cell line. Although we were unable to demonstrate changes in total GTPbound Rac1 or RhoA, we did observe changes in the localization of Rac1-GFP using time lapse microscopy. Following SEMA3F, Rac1 moved to the base of lamellipodia and — with their collapse — to the membrane. These results support the concept that SEMA3F and VEGF have antagonistic actions affecting motility in primary tumor cell.

Análise da relação entre a expressão da proteína VEGF e o estadiamento do câncer colorretal Analysis of relationship between VEGF protein expression and colorectal câncer staging

Directory of Open Access Journals (Sweden)

Leandro Mutschall

2009-03-01

Full Text Available Os estudos em biologia molecular desenvolvidos nas últimas décadas, possibilitaram grandes avanços para uma maior compreensão da carcinogênese colorretal. Na década de 80 pesquisadores descobriram uma proteína com a capacidade de aumentar a permeabilidade dos vasos sangüíneos. Inicialmente esta proteína foi denominada como fator de permeabilidade vascular. Estudos posteriores correlacionaram esta proteína com o crescimento de novos vasos sangüíneos (angiogênese, quando passou a ser chamada de fator de crescimento endotelial vascular (VEGF. A proteína VEGF tem sido apontada como o principal fator promotor da angiogênese, dentre os vários já conhecidos. Neste trabalho o objetivo foi quantificar a proteína VEGF, e correlacionar os resultados com o estadiamento tumoral em amostras de adenocarcinoma colorretal. Foram incluídos 56 adenocarcinomas colorretais, nos quais a detecção da proteína VEGF foi realizada por imunoistoquímica através da construção de uma matriz tecidual e sua quantificação com análise digital de imagens assistida por computador. Nossos resultados não evidenciaram relação estatisticamente significativa entre a expressão da proteína VEGF e o estadiamento tumoral, ou presença e número de linfonodos comprometidos. Baseado no nível de expressão da proteína VEGF não foi possível inferir a presença de linfonodos comprometidos nas amostras analisadas.Development of studies in molecular biology over the last decades has contributed for better knowledge about colorectal carcinogenesis. An important landmark in this process was the identification of a protein with effect on vascular permeability eventually named as vascular endothelial growth factor (VEGF, which seems to be essential for the angiogenesis activation of tumor development. The aim of this study was to assess the VEGF expression and correlate to tumor staging in colorectal cancer. Surgical specimens from 56 colorectal cancer patients

Response of eyes with age-related macular degeneration to anti-VEGF drugs and implications for therapy planning

Directory of Open Access Journals (Sweden)

Miyamoto N

2017-04-01

Full Text Available Noriko Miyamoto,1,2 Michiko Mandai,1,3 Hiroshi Kojima,1,2 Takanori Kameda,1,2 Masataka Shimozono,1,2 Akihiro Nishida,1,2 Yasuo Kurimoto1,2 1Department of Ophthalmology, Kobe City Medical Center General Hospital, 2Department of Ophthalmology, Institute of Biomedical Research and Innovation, 3Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Japan Purpose: To evaluate the response to and dependence on aflibercept or ranibizumab in patients with age-related macular degeneration (AMD.Methods: We retrospectively reviewed AMD patients who received induction therapy with aflibercept or ranibizumab for the following parameters: whether complete resolution of the retinal fluid (“good response” was achieved and whether recurrence was observed within 3 months (“dependent” after the induction treatment. With aflibercept treatment, treatment-naïve eyes with a good response/non-dependence were recommended a pro re nata regimen, and other eyes were recommended a proactive bimonthly regimen, followed by monitoring of visual acuity (VA for 12 months. The measured values of the groups were compared using one-way analysis of variance with Tukey’s test to evaluate the difference between baseline and postinjection VA.Results: Among the treatment-naïve eyes, 76% had a good response to aflibercept and 37% of these were aflibercept-dependent, while 58% had a good response to ranibizumab but 51% of these were ranibizumab-dependent. Among the eyes that converted from ranibizumab treatment, 92% of the good responders to ranibizumab with dependence and 76% of the poor responders on ranibizumab had a good response to aflibercept. With aflibercept treatment, the mean VA of treatment-naïve patients was significantly better than the baseline VA over 12 months (P<0.001, and the VA of the converted group improved significantly with proactive treatment and the improvement was continuously maintained from 6 to 12 months

Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis

DEFF Research Database (Denmark)

Cao, Renhai; Ji, Hong; Feng, Ninghan

2012-01-01

Interplay between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis remains poorly understood. Here we show that FGF-2 and VEGF-C, two lymphangiogenic factors, collaboratively promote angiogenesis and lymphangiogenesis in the tumor microenvironment, leading...... endothelial cell tip cell formation is a prerequisite for FGF-2-stimulated lymphangiogenesis. In the tumor microenvironment, the reciprocal interplay between FGF-2 and VEGF-C collaboratively stimulated tumor growth, angiogenesis, intratumoral lymphangiogenesis, and metastasis. Thus, intervention and targeting...

Eye exposure to optical radiation in the glassblowing industry: an investigation in southern Ontario.

Science.gov (United States)

Oriowo, O M; Chou, B R; Cullen, A P

2000-01-01

To investigate if the levels of optical radiation hazards in glassblowing are well classified according to the hazard types defined in the Canadian Standards Association (CSA) standard for industrial eye protectors. We carried out radiometric measurements, and questionnaire survey in 4 university glassblowing laboratories, and 3 private studios. There is exposure to low levels of UV and IR radiation in all glassblowing operations. A supra-threshold IR radiation level exists in the craft glassblowing. The use of eye protectors is based on past experience regardless of the level of ocular exposure. Optical radiation hazards exist in both craft and scientific glassblowing. There seems to be an inadequate understanding about radiation types encountered by glassblowers.

Increased plasma levels of soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1) in women by moderate exercise and increased plasma levels of VEGF in overweight/obese women

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Makey, Kristina L.; Patterson, Sharla G.; Robinson, James; Loftin, Mark; Waddell, Dwight E.; Miele, Lucio; Chinchar, Edmund; Huang, Min; Smith, Andrew D.; Weber, Mark; Gu, Jian-Wei

2012-01-01

The incidence of breast cancer is increasing worldwide, and this seems to be related to an increase in lifestyle risk factors, including physical inactivity, and overweight/obesity. We previously reported that exercise induced a circulating angiostatic phenotype characterized by increased sFlt-1 and endostatin and decreased unbound-VEGF in men. However, there is no data on women. The present study determines the following: 1) whether moderate exercise increased sFlt-1 and endostatin and decreased unbound-VEGF in the circulation of adult female volunteers; 2) whether overweight/obese women have a higher plasma level of unbound-VEGF than lean women. 72 African American and Caucasian adult women volunteers aged from 18–44 were enrolled into the exercise study. All the participants walked on a treadmill for 30 minutes at a moderate intensity (55–59% heart rate reserve), and oxygen consumption (VO2) was quantified by utilizing a metabolic cart. We had the blood samples before and immediately after exercise from 63 participants. ELISA assays (R&D Systems) showed that plasma levels of sFlt-1 were 67.8±3.7 pg/ml immediately after exercise (30 minutes), significantly higher than basal levels, 54.5±3.3 pg/ml, before exercise (P < 0.01; n=63). There was no significant difference in the % increase of sFlt-1 levels after exercise between African American and Caucasian (P=0.533) or between lean and overweight/obese women (P=0.892). There was no significant difference in plasma levels of unbound VEGF (35.28±5.47 vs. 35.23±4.96 pg/ml; P=0.99) or endostatin (111.12±5.48 vs. 115.45±7.15 ng/ml; P=0.63) before and after exercise. Basal plasma levels of unbound-VEGF in overweight/obese women were 52.26±9.6 pg/ml, significantly higher than basal levels of unbound-VEGF in lean women, 27.34±4.99 pg/ml (P < 0.05). The results support our hypothesis that exercise-induced plasma levels of sFlt-1 could be an important clinical biomarker to explore the mechanisms of exercise

Trapping and dark current in plasma-based accelerators

International Nuclear Information System (INIS)

Schroder, C.B.; Esarey, E.; Shadwick, B.A.; Leemans, W.P.

2004-01-01

The trapping of thermal electrons in a nonlinear plasma wave of arbitrary phase velocity is investigated. The threshold plasma wave amplitude for trapping plasma electrons is calculated, thereby determining the fraction trapped and the expected dark current in a plasma-based accelerator. It is shown that the presence of a laser field (e.g., trapping in the self-modulated regime of the laser wakefield accelerator) increases the trapping threshold. Implications for experimental and numerical laser-plasma studies are discussed

Design of a variant of vascular endothelial growth factor-A (VEGF-A) antagonizing KDR/Flk-1 and Flt-1.

NARCIS (Netherlands)

Leenders, W.P.J.; Lubsen, N.H.; Altena, M.C. van; Clauss, M.; Deckers, M.; Lowik, C.W.G.M.; Breier, G.; Ruiter, D.J.; Waal, R.M.W. de

2002-01-01

Because of its central role in pathological angiogenesis, vascular endothelial growth factor (VEGF) has become a major target for anti-angiogenic therapies. We report here the construction of a heterodimeric antagonistic VEGF variant (HD-VEGF). In this antagonist, binding domains for the

Superparamagnetic iron oxide nanoparticles mediated 131I-hVEGF siRNA inhibits hepatocellular carcinoma tumor growth in nude mice

International Nuclear Information System (INIS)

Chen, Jing; Zhu, Shu; Tong, Liangqian; Li, Jiansha; Chen, Fei; Han, Yunfeng; Zhao, Ming; Xiong, Wei

2014-01-01

Hepatocellular carcinoma (HCC) is a primary liver tumor and is the most difficult human malignancy to treat. In this study, we sought to develop an integrative approach in which real-time tumor monitoring, gene therapy, and internal radiotherapy can be performed simultaneously. This was achieved through targeting HCC with superparamagnetic iron oxide nanoparticles (SPIOs) carrying small interfering RNA with radiolabled iodine 131 ( 131 I) against the human vascular endothelial growth factor (hVEGF). hVEGF siRNA was labeled with 131 I by the Bolton-Hunter method and conjugated to SilenceMag, a type of SPIOs. 131 I-hVEGF siRNA/SilenceMag was then subcutaneously injected into nude mice with HCC tumors exposed to an external magnetic field (EMF). The biodistribution and cytotoxicity of 131 I-hVEGF siRNA/SilenceMag was assessed by SPECT (Single-Photon Emission Computed Tomography) and MRI (Magnetic Resonance Imaging) studies and blood kinetics analysis. The body weight and tumor size of nude mice bearing HCC were measured daily for the 4-week duration of the experiment. 131 I-hVEGF siRNA/SilenceMag was successfully labeled; with a satisfactory radiochemical purity (>80%) and biological activity in vitro. External application of an EMF successfully attracted and retained more 131 I-hVEGF siRNA/SilenceMag in HCC tumors as shown by SPECT, MRI and biodistribution studies. The tumors treated with 131 I-hVEGF siRNA/SilenceMag grew nearly 50% slower in the presence of EMF than those without EMF and the control. Immunohistochemical assay confirmed that the tumor targeted by 131 I-hVEGF siRNA/SilenceMag guided by an EMF had a lower VEGF protein level compared to that without EMF exposure and the control. EMF-guided 131 I-hVEGF siRNA/SilenceMag exhibited an antitumor effect. The synergic therapy of 131 I-hVEGF siRNA/SilenceMag might be a promising future treatment option against HCC with the dual functional properties of tumor therapy and imaging

Deleterious effects of progestagen treatment in VEGF expression in corpora lutea of pregnant ewes.

Science.gov (United States)

Letelier, C A; Sanchez, M A; Garcia-Fernandez, R A; Sanchez, B; Garcia-Palencia, P; Gonzalez-Bulnes, A; Flores, J M

2011-06-01

The aim of the current study was to determine the possible effects of progestagen oestrous synchronization on vascular endothelial growth factor (VEGF) expression during sheep luteogenesis and the peri-implantation period and the relationship with luteal function. At days 9, 11, 13, 15, 17 and 21 of pregnancy, the ovaries from 30 progestagen treated and 30 ewes cycling after cloprostenol injection were evaluated by ultrasonography and, thereafter, collected and processed for immunohistochemical evaluation of VEGF; blood samples were drawn for evaluating plasma progesterone. The progestagen-treated group showed smaller corpora lutea than cloprostenol-treated and lower progesterone secretion. The expression of VEGF in the luteal cells increased with time in the cloprostenol group, but not in the progestagen-treated group, which even showed a decrease between days 11 and 13. In progestagen-treated sheep, VEGF expression in granulosa-derived parenchymal lobule capillaries was correlated with the size of the luteal tissue, larger corpora lutea had higher expression, and tended to have a higher progesterone secretion. In conclusion, the current study indicates the existence of deleterious effects from exogenous progestagen treatments on progesterone secretion from induced corpora lutea, which correlate with alterations in the expression of VEGF in the luteal tissue and, this, presumably in the processes of neoangiogenesis and luteogenesis. © 2010 Blackwell Verlag GmbH.

Albendazole inhibits endothelial cell migration, tube formation, vasopermeability, VEGF receptor-2 expression and suppresses retinal neovascularization in ROP model of angiogenesis

Energy Technology Data Exchange (ETDEWEB)

Pourgholami, Mohammad H., E-mail: mh.pourgholami@unsw.edu.au [University of New South Wales, Department of Surgery, St George Hospital (SESIAHS), Sydney (Australia); Khachigian, Levon M.; Fahmy, Roger G. [Centre for Vascular Research, The University of New South Wales, Department of Haematology, The Prince of Wales Hospital, Sydney (Australia); Badar, Samina; Wang, Lisa; Chu, Stephanie Wai Ling; Morris, David Lawson [University of New South Wales, Department of Surgery, St George Hospital (SESIAHS), Sydney (Australia)

2010-07-09

The angiogenic process begins with the cell proliferation and migration into the primary vascular network, and leads to vascularization of previously avascular tissues and organs as well to growth and remodeling of the initially homogeneous capillary plexus to form a new microcirculation. Additionally, an increase in microvascular permeability is a crucial step in angiogenesis. Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis. We have previously reported that albendazole suppresses VEGF levels and inhibits malignant ascites formation, suggesting a possible effect on angiogenesis. This study was therefore designed to investigate the antiangiogenic effect of albendazole in non-cancerous models of angiogenesis. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with albendazole led to inhibition of tube formation, migration, permeability and down-regulation of the VEGF type 2 receptor (VEGFR-2). In vivo albendazole profoundly inhibited hyperoxia-induced retinal angiogenesis in mice. These results provide new insights into the antiangiogenic effects of albendazole.

Albendazole inhibits endothelial cell migration, tube formation, vasopermeability, VEGF receptor-2 expression and suppresses retinal neovascularization in ROP model of angiogenesis

International Nuclear Information System (INIS)

Pourgholami, Mohammad H.; Khachigian, Levon M.; Fahmy, Roger G.; Badar, Samina; Wang, Lisa; Chu, Stephanie Wai Ling; Morris, David Lawson

2010-01-01

The angiogenic process begins with the cell proliferation and migration into the primary vascular network, and leads to vascularization of previously avascular tissues and organs as well to growth and remodeling of the initially homogeneous capillary plexus to form a new microcirculation. Additionally, an increase in microvascular permeability is a crucial step in angiogenesis. Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis. We have previously reported that albendazole suppresses VEGF levels and inhibits malignant ascites formation, suggesting a possible effect on angiogenesis. This study was therefore designed to investigate the antiangiogenic effect of albendazole in non-cancerous models of angiogenesis. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with albendazole led to inhibition of tube formation, migration, permeability and down-regulation of the VEGF type 2 receptor (VEGFR-2). In vivo albendazole profoundly inhibited hyperoxia-induced retinal angiogenesis in mice. These results provide new insights into the antiangiogenic effects of albendazole.

Inhibition of prostate cancer osteoblastic progression with VEGF121/rGel, a single agent targeting osteoblasts, osteoclasts, and tumor neovasculature

Science.gov (United States)

Mohamedali, Khalid A.; Li, Zhi Gang; Starbuck, Michael W.; Wan, Xinhai; Yang, Jun; Kim, Sehoon; Zhang, Wendy; Rosenblum, Michael G.; Navone, Nora M.

2011-01-01

Purpose A hallmark of prostate cancer (PCa) progression is the development of osteoblastic bone metastases, which respond poorly to available therapies. We previously reported that VEGF121/rGel targets osteoclast precursors and tumor neovasculature. Here we tested the hypothesis that targeting non-tumor cells expressing these receptors can inhibit tumor progression in a clinically relevant model of osteoblastic PCa. Experimental Design Cells from MDA PCa 118b, a PCa xenograft obtained from a bone metastasis in a patient with castrate-resistant PCa, were injected into the femurs of mice. Osteoblastic progression was monitored following systemic administration of VEGF121/rGel. Results VEGF121/rGel was cytotoxic in vitro to osteoblast precursor cells. This cytotoxicity was specific as VEGF121/rGel internalization into osteoblasts was VEGF121 receptor driven. Furthermore, VEGF121/rGel significantly inhibited PCa-induced bone formation in a mouse calvaria culture assay. In vivo, VEGF121/rGel significantly inhibited the osteoblastic progression of PCa cells in the femurs of nude mice. Microcomputed tomography analysis revealed that VEGF121/rGel restored the bone volume fraction of tumor-bearing femurs to values similar to those of the contralateral (non–tumor bearing) femurs. VEGF121/rGel significantly reduced the number of tumor-associated osteoclasts but did not change the numbers of peritumoral osteoblasts. Importantly, VEGF121/rGel-treated mice had significantly less tumor burden than control mice. Our results thus indicate that VEGF121/rGel inhibits osteoblastic tumor progression by targeting angiogenesis, osteoclastogenesis, and bone formation. Conclusions Targeting VEGFR-1 – or VEGFR-2–expressing cells is effective in controlling the osteoblastic progression of PCa in bone. These findings provide the basis for an effective multitargeted approach for metastatic PCa. PMID:21343372

Vitamin D Decreases Serum VEGF Correlating with Clinical Improvement in Vitamin D-Deficient Women with PCOS: A Randomized Placebo-Controlled Trial.

Science.gov (United States)

Irani, Mohamad; Seifer, David B; Grazi, Richard V; Irani, Sara; Rosenwaks, Zev; Tal, Reshef

2017-03-28

Vascular endothelial growth factor (VEGF) has been suggested to play a role in the pathophysiology of polycystic ovary syndrome (PCOS) and may contribute to increased risk of ovarian hyperstimulation syndrome (OHSS) in affected individuals. Vitamin D (VitD) supplementation improves multiple clinical parameters in VitD-deficient women with PCOS and decreases VEGF levels in several other pathologic conditions. Unveiling the basic mechanisms underlying the beneficial effects of vitamin D on PCOS may enhance our understanding of the pathophysiology of this syndrome. It may also suggest a new treatment for PCOS that can improve it through the same mechanism as vitamin D and can be given regardless of vitamin D levels. Therefore, we aimed to explore the effect of VitD supplementation on serum VEGF levels and assess whether changes in VEGF correlate with an improvement in characteristic clinical abnormalities of PCOS. This is a randomized placebo-controlled trial conducted between October 2013 and March 2015. Sixty-eight VitD-deficient women with PCOS were recruited. Women received either 50,000 IU of oral VitD3 or placebo once weekly for 8 weeks. There was a significant decrease in serum VEGF levels (1106.4 ± 36.5 to 965.3 ± 42.7 pg·mL -1 ; p PCOS. This is a novel molecular explanation for the beneficial effects of VitD treatment. It also suggests the need to investigate a potential role of VitD treatment in reducing the incidence or severity of OHSS in VitD-deficient women with PCOS.

Inhibition of protein kinase C delta attenuates allergic airway inflammation through suppression of PI3K/Akt/mTOR/HIF-1 alpha/VEGF pathway.

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Yun Ho Choi

Full Text Available Vascular endothelial growth factor (VEGF is supposed to contribute to the pathogenesis of allergic airway disease. VEGF expression is regulated by a variety of stimuli such as nitric oxide, growth factors, and hypoxia-inducible factor-1 alpha (HIF-1α. Recently, inhibition of the mammalian target of rapamycin (mTOR has been shown to alleviate cardinal asthmatic features, including airway hyperresponsiveness, eosinophilic inflammation, and increased vascular permeability in asthma models. Based on these observations, we have investigated whether mTOR is associated with HIF-1α-mediated VEGF expression in allergic asthma. In studies with the mTOR inhibitor rapamycin, we have elucidated the stimulatory role of a mTOR-HIF-1α-VEGF axis in allergic response. Next, the mechanisms by which mTOR is activated to modulate this response have been evaluated. mTOR is known to be regulated by phosphoinositide 3-kinase (PI3K/Akt or protein kinase C-delta (PKC δ in various cell types. Consistent with these, our results have revealed that suppression of PKC δ by rottlerin leads to the inhibition of PI3K/Akt activity and the subsequent blockade of a mTOR-HIF-1α-VEGF module, thereby attenuating typical asthmatic attack in a murine model. Thus, the present data indicate that PKC δ is necessary for the modulation of the PI3K/Akt/mTOR signaling cascade, resulting in a tight regulation of HIF-1α activity and VEGF expression. In conclusion, PKC δ may represent a valuable target for innovative therapeutic treatment of allergic airway disease.