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  1. VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer.

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    Waldner, Maximilian J; Wirtz, Stefan; Jefremow, André; Warntjen, Moritz; Neufert, Clemens; Atreya, Raja; Becker, Christoph; Weigmann, Benno; Vieth, Michael; Rose-John, Stefan; Neurath, Markus F

    2010-12-20

    Whereas the inhibition of vascular endothelial growth factor (VEGF) has shown promising results in sporadic colon cancer, the role of VEGF signaling in colitis-associated cancer (CAC) has not been addressed. We found that, unlike sporadic colorectal cancer and control patients, patients with CAC show activated VEGFR2 on intestinal epithelial cells (IECs). We then explored the function of VEGFR2 in a murine model of colitis-associated colon cancer characterized by increased VEGFR2 expression. Epithelial cells in tumor tissue expressed VEGFR2 and responded to VEGF stimulation with augmented VEGFR2-mediated proliferation. Blockade of VEGF function via soluble decoy receptors suppressed tumor development, inhibited tumor angiogenesis, and blocked tumor cell proliferation. Functional studies revealed that chronic inflammation leads to an up-regulation of VEGFR2 on IECs. Studies in conditional STAT3 mutant mice showed that VEGFR signaling requires STAT3 to promote epithelial cell proliferation and tumor growth in vivo. Thus, VEGFR-signaling acts as a direct growth factor for tumor cells in CAC, providing a molecular link between inflammation and the development of colon cancer.

  2. Evaluation of the efficacy of excimer laser ablation of cross-linked porcine cornea.

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    Shihao Chen

    Full Text Available BACKGROUND: Combination of riboflavin/UVA cross-linking (CXL and excimer laser ablation is a promising therapy for treating corneal ectasia. The cornea is strengthened by cross-linking, while the irregular astigmatism is reduced by laser ablation. This study aims to compare the efficacy of excimer laser ablation on porcine corneas with and without cross-linking. METHODS AND FINDINGS: The porcine cornea was de-epithelialized and treated with 0.1% riboflavin solution for 30 minutes. A half of the cornea was exposed to UVA-radiation for another 30 minutes while the controlled half of the cornea was protected from the UVA using a metal shield. Photo therapeutic keratectomy (PTK was then performed on the central cornea. Corneal thickness of 5 paired locations on the horizontal line, ± 0.5, ± 1.0, ± 1.5, ± 2.0, and ± 2.5 mm from the central spot, were measured using optical coherence tomography prior to and after PTK. The ablation depth was then determined by the corneal thickness. There was a 9% difference (P<0.001 in the overall ablation depth between the CXL-half corneas (158 ± 22 µm and the control-half corneas (174 ± 26 µm. The ablation depths of all 5 correspondent locations on the CXL-half were significantly smaller (P<0.001. CONCLUSION: The efficacy of the laser ablation seems to be lower in cross-linked cornea. Current ablation algorithms may need to be modified for cross-linked corneas.

  3. Lymphangiogenesis linked to VEGF-C from tumor-associated macrophages: accomplices to metastasis by cutaneous squamous cell carcinoma?

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    Kluger, Martin S; Colegio, Oscar R

    2011-01-01

    During wound healing, dermal macrophages secrete lymphangiogenic vascular endothelial growth factor (VEGF)-C, and lymphatic vessels transport cytokines and cells to draining lymph nodes. In this issue, Moussai et al. show that macrophages in peritumoral nonlesional skin near squamous cell carcinoma secrete prolymphangiogenic VEGF-C. Their study suggests how tumor-associated macrophages and neolymphatic vessels may coordinate metastasis starting early in cutaneous squamous cell carcinoma.

  4. Laser-induced corneal cross-linking upon photorefractive ablation with riboflavin

    OpenAIRE

    Kornilovskiy IM; Kasimov EM; Sultanova AI; Burtsev AA

    2016-01-01

    Igor M Kornilovskiy,1 Elmar M Kasimov,2 Ayten I Sultanova,2 Alexander A Burtsev1 1Department of Eye Diseases, Federal State Budgetary Institution “National Pirogov Medical Surgical Centre”, Ministry of Health, Moscow, Russia; 2Department of Eye Diseases, Zarifa Aliyeva National Ophthalmology Center, Ministry of Health, Baku, Azerbaijan Aim: To estimate the biomechanical effect of the laser-induced cross-linking resulting from photorefractive ablation of the cornea with r...

  5. Endometrial ablation

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    Hysteroscopy - endometrial ablation; Laser thermal ablation; Endometrial ablation - radiofrequency; Endometrial ablation - thermal balloon ablation; Rollerball ablation; Hydrothermal ablation; Novasure ...

  6. Laser-induced corneal cross-linking upon photorefractive ablation with riboflavin.

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    Kornilovskiy, Igor M; Kasimov, Elmar M; Sultanova, Ayten I; Burtsev, Alexander A

    2016-01-01

    To estimate the biomechanical effect of the laser-induced cross-linking resulting from photorefractive ablation of the cornea with riboflavin. Excimer laser ablation studies were performed ex vivo (32 eyes of 16 rabbits) by phototherapeutic keratectomy (PTK) and in vivo (24 eyes of 12 rabbits) by transepithelial photorefractive keratectomy (TransPRK), with and without riboflavin saturation of the stroma. Then, we performed corneal optical coherence tomography on 36 eyes of 18 patients with varying degrees of myopia at different times after the TransPRK was performed with riboflavin saturation of the stroma. Biomechanical testing of corneal samples saturated with riboflavin revealed cross-linking effect accompanied by the increase in tensile strength and maximum strength. PTK showed increase in tensile strength from 5.1±1.4 to 7.2±1.6 MPa (P=0.001), while Trans-PRK showed increase in tensile strength from 8.8±0.9 to 12.8±1.3 MPa (P=0.0004). Maximum strength increased from 8.7±2.5 to 12.0±2.8 N (P=0.005) in PTK and from 12.8±1.6 to 18.3±1.2 N (P=0.0004) in TransPRK. Clinical optical coherence tomography studies of the biomicroscopic transparent cornea at different times after TransPRK showed increased density in the surface layers of the stroma and membrane-like structure beneath the epithelium. Photorefractive ablation of the preliminary corneal stroma saturation with riboflavin causes the effect of laser-induced cross-linking, which is attended with an increase in corneal tensile strength, maximum strength, increased density in the surface layers of the stroma, and formation of a membrane-like structure beneath the epithelium after TransPRK.

  7. Laser-induced corneal cross-linking upon photorefractive ablation with riboflavin

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    Kornilovskiy IM

    2016-04-01

    Full Text Available Igor M Kornilovskiy,1 Elmar M Kasimov,2 Ayten I Sultanova,2 Alexander A Burtsev1 1Department of Eye Diseases, Federal State Budgetary Institution “National Pirogov Medical Surgical Centre”, Ministry of Health, Moscow, Russia; 2Department of Eye Diseases, Zarifa Aliyeva National Ophthalmology Center, Ministry of Health, Baku, Azerbaijan Aim: To estimate the biomechanical effect of the laser-induced cross-linking resulting from photorefractive ablation of the cornea with riboflavin.Methods: Excimer laser ablation studies were performed ex vivo (32 eyes of 16 rabbits by phototherapeutic keratectomy (PTK and in vivo (24 eyes of 12 rabbits by transepithelial photorefractive keratectomy (TransPRK, with and without riboflavin saturation of the stroma. Then, we performed corneal optical coherence tomography on 36 eyes of 18 patients with varying degrees of myopia at different times after the TransPRK was performed with riboflavin saturation of the stroma.Results: Biomechanical testing of corneal samples saturated with riboflavin revealed cross-linking effect accompanied by the increase in tensile strength and maximum strength. PTK showed increase in tensile strength from 5.1±1.4 to 7.2±1.6 MPa (P=0.001, while TransPRK showed increase in tensile strength from 8.8±0.9 to 12.8±1.3 MPa (P=0.0004. Maximum strength increased from 8.7±2.5 to 12.0±2.8 N (P=0.005 in PTK and from 12.8±1.6 to 18.3±1.2 N (P=0.0004 in TransPRK. Clinical optical coherence tomography studies of the biomicroscopic transparent cornea at different times after TransPRK showed increased density in the surface layers of the stroma and membrane-like structure beneath the epithelium.Conclusion: Photorefractive ablation of the preliminary corneal stroma saturation with riboflavin causes the effect of laser-induced cross-linking, which is attended with an increase in corneal tensile strength, maximum strength, increased density in the surface layers of the stroma, and formation of

  8. [Riboflavin photoprotection with cross-linking effect in photorefractive ablation of the cornea].

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    Kornilovskiy, I M; Sultanova, A I; Burtsev, A A

    2016-01-01

    Photorefractive ablation is inevitably accompanied by oxidative stress of the cornea and weakening of its biomechanical and photoprotective properties. To validate the expediency of riboflavin use in photorefractive ablation for photoprotection of the cornea and cross-linking. The effects of riboflavin use in photorefractive ablation was first studied in a series of in vitro and in vivo experiments performed on 56 eyes of 28 rabbits, and then on 232 eyes of 142 patients with different degrees of myopia. Biomechanical testing of corneal samples was performed with Zwick/RoellВZ 2.5/TN1S tensile-testing machine. Transepithelial photorefractive keratectomy (TransPRK) and femtosecond laser-assisted in situ keratomileusis (Femto-LASIK) were performed on Wavelight-Allegretto200, MEL-80, and WaveLight-EX500 excimer laser systems and also VisuMax and WaveLight-FS200 femtosecond lasers. For preliminary examinations, an appropriate set of diagnostic tools was used. In vivo experiments have proved that, in the absence of conservative therapy, riboflavin is able to produce both photoprotective and cross-linking effects to the cornea. Corneal syndrome was thus reduced and re-epithelialization after TransPRK accelerated. Biomechanical testing of corneal samples revealed an increase in tolerated load from 12.9±1.4 N to 18.3±1.2 N (p=0.0002) and tensile strength from 8.6±1.7 MPa to 12.4±1.7 MPa (p=0.007). Clinical studies conducted in a group of patients with mild to moderate myopia have also confirmed the photoprotective effect of riboflavin at months 1-12 after TransPRK. There were no significant differences in uncorrected visual acuity (ranged from 0.80±0.16 to 0.85±0.15) and corrected visual acuity at baseline (0.83±0.14). Evaluation of the optical and refractive effect achieved after Femto-LASIK with riboflavin photoprotection in the fellow eye has shown that this technique is not inferior to the traditional one as to its refractive accuracy, but provides better

  9. Analysis of VEGF--a regulated gene expression in endothelial cells to identify genes linked to angiogenesis.

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    Corban G Rivera

    Full Text Available Angiogenesis is important for many physiological processes, diseases, and also regenerative medicine. Therapies that inhibit the vascular endothelial growth factor (VEGF pathway have been used in the clinic for cancer and macular degeneration. In cancer applications, these treatments suffer from a "tumor escape phenomenon" where alternative pathways are upregulated and angiogenesis continues. The redundancy of angiogenesis regulation indicates the need for additional studies and new drug targets. We aimed to (i identify novel and missing angiogenesis annotations and (ii verify their significance to angiogenesis. To achieve these goals, we integrated the human interactome with known angiogenesis-annotated proteins to identify a set of 202 angiogenesis-associated proteins. Across endothelial cell lines, we found that a significant fraction of these proteins had highly perturbed gene expression during angiogenesis. After treatment with VEGF-A, we found increasing expression of HIF-1α, APP, HIV-1 tat interactive protein 2, and MEF2C, while endoglin, liprin β1 and HIF-2α had decreasing expression across three endothelial cell lines. The analysis showed differential regulation of HIF-1α and HIF-2α. The data also provided additional evidence for the role of endothelial cells in Alzheimer's disease.

  10. Analysis of VEGF--a regulated gene expression in endothelial cells to identify genes linked to angiogenesis.

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    Rivera, Corban G; Mellberg, Sofie; Claesson-Welsh, Lena; Bader, Joel S; Popel, Aleksander S

    2011-01-01

    Angiogenesis is important for many physiological processes, diseases, and also regenerative medicine. Therapies that inhibit the vascular endothelial growth factor (VEGF) pathway have been used in the clinic for cancer and macular degeneration. In cancer applications, these treatments suffer from a "tumor escape phenomenon" where alternative pathways are upregulated and angiogenesis continues. The redundancy of angiogenesis regulation indicates the need for additional studies and new drug targets. We aimed to (i) identify novel and missing angiogenesis annotations and (ii) verify their significance to angiogenesis. To achieve these goals, we integrated the human interactome with known angiogenesis-annotated proteins to identify a set of 202 angiogenesis-associated proteins. Across endothelial cell lines, we found that a significant fraction of these proteins had highly perturbed gene expression during angiogenesis. After treatment with VEGF-A, we found increasing expression of HIF-1α, APP, HIV-1 tat interactive protein 2, and MEF2C, while endoglin, liprin β1 and HIF-2α had decreasing expression across three endothelial cell lines. The analysis showed differential regulation of HIF-1α and HIF-2α. The data also provided additional evidence for the role of endothelial cells in Alzheimer's disease.

  11. Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells

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    Chuang, Cheng-Hung, E-mail: chchuang@hk.edu.tw [Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, 1018 Sec. 6 Taiwan Boulevard, Taichung 43302, Taiwan, ROC (China); Liu, Chia-Hua [Department of Food Science and Biotechnology, National Chung-Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan, ROC (China); Lu, Ta-Jung [Department of Chemistry, Institute of Technology and Innovation Management, National Chung-Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan, ROC (China); Hu, Miao-Lin, E-mail: mlhuhu@dragon.nchu.edu.tw [Department of Food Science and Biotechnology, National Chung-Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan, ROC (China)

    2014-12-15

    Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30 μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression. - Graphical abstract: Possible mechanisms of α-TEA on inhibited angiogenesis of human umbilical vein endothelial cells. Brief summary In the present study, we have demonstrated that VEGF-mediated angiogenesis is significantly inhibited by α-TEA, and that this effect involves inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways related to invasion and migration. - Highlights: • The anti-angiogenic effect and the mechanistic action of α-TEA were investigated. • α-TEA significantly inhibited VEGF-mediated angiogenesis both in vitro and ex vivo. • α-TEA down

  12. Combined targeting of EGFR-dependent and VEGF-dependent pathways: rationale, preclinical studies and clinical applications.

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    Tortora, Giampaolo; Ciardiello, Fortunato; Gasparini, Giampietro

    2008-09-01

    Cellular heterogeneity, redundancy of molecular pathways and effects of the microenvironment contribute to the survival, motility and metastasis of cells in solid tumors. It is unlikely that tumors are entirely dependent on only one abnormally activated signaling pathway; consequently, treatment with an agent that interferes with a single target may be insufficient. Combined blockade of functionally linked and relevant multiple targets has become an attractive therapeutic strategy. The EGFR and ERBB2 (HER2) pathways and VEGF-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and has demonstrated a suggested role for VEGF in the acquired resistance to anti-ERBB drugs when these receptors are pharmacologically blocked. Combined inhibition of ERBB and VEGF signaling interferes with a molecular feedback loop responsible for acquired resistance to anti-ERBB agents and promotes apoptosis while ablating tumor-induced angiogenesis. To this aim, either two agents highly selective against VEGF and ERBB respectively, or, alternatively, a single multitargeted agent, can be used. Preclinical studies have proven the efficacy of both these approaches and early clinical studies have provided encouraging results. This Review discusses the experimental rationale for, preclinical studies of and clinical trials on combined blockade of ERBB and VEGF signaling.

  13. 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.

  14. Alginate hydrogels allow for bioactive and sustained release of VEGF-C and VEGF-D for lymphangiogenic therapeutic applications.

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    Campbell, Kevin T; Hadley, Dustin J; Kukis, David L; Silva, Eduardo A

    2017-01-01

    Lymphatic dysfunction is associated with the progression of many cardiovascular disorders due to their role in maintaining tissue fluid homeostasis. Promoting new lymphatic vessels (lymphangiogenesis) is a promising strategy to reverse these cardiovascular disorders via restoring lymphatic function. Vascular endothelial growth factor (VEGF) members VEGF-C and VEGF-D are both potent candidates for stimulating lymphangiogenesis, though maintaining spatial and temporal control of these factors represents a challenge to developing efficient therapeutic lymphangiogenic applications. Injectable alginate hydrogels have been useful for the controlled delivery of many angiogenic factors, including VEGF-A, to stimulate new blood vasculature. However, the utility of these tunable hydrogels for delivering lymphangiogenic factors has never been closely examined. Thus, the objective of this study was to utilize ionically cross-linked alginate hydrogels to deliver VEGF-C and VEGF-D for potential lymphangiogenic applications. We demonstrated that lymphatic endothelial cells (LECs) are sensitive to temporal presentation of VEGF-C and VEGF-D but with different responses between the factors. The greatest LEC mitogenic and sprouting response was observed for constant concentrations of VEGF-C and a high initial concentration that gradually decreased over time for VEGF-D. Additionally, alginate hydrogels provided sustained release of radiolabeled VEGF-C and VEGF-D. Finally, VEGF-C and VEGF-D released from these hydrogels promoted a similar number of LEC sprouts as exogenously added growth factors and new vasculature in vivo via a chick chorioallantoic membrane (CAM) assay. Overall, these findings demonstrate that alginate hydrogels can provide sustained and bioactive release of VEGF-C and VEGF-D which could have applications for therapeutic lymphangiogenesis.

  15. Current biology of VEGF-B and VEGF-C.

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    Olofsson, B; Jeltsch, M; Eriksson, U; Alitalo, K

    1999-12-01

    Endothelial growth factors and their receptors may provide important therapeutic tools for the treatment of pathological conditions characterised by defective or aberrant angiogenesis. Vascular endothelial growth factor (VEGF) is pivotal for vasculogenesis and for angiogenesis in normal and pathological conditions. VEGF-B and VEGF-C provide this gene family with additional functions, for example, VEGF-C also regulates lymphangiogenesis.

  16. [VEGF as an angiogenic, neurotrophic, and neuroprotective factor].

    Science.gov (United States)

    Namiecińska, Magdalena; Marciniak, Katarzyna; Nowak, Jerzy Z

    2005-01-01

    Vascular endothelial growth factor (VEGF, occurring in several isoforms: VEGF-A, -B, -C, -D) is a well-known endothelial cell mitogen and vascular growth and permeability factor. Recent work done over the last few years has elucidated the important role of VEGF, which participates in the regulation of normal (physiological or therapeutic) and pathological angiogenesis (VEGF-A, VEGF-B) and lymphangiogenesis (VEGF-C, VEGF-D). VEGF has also been implicated in practically every stage of angiogenesis, yet its role in the initiation of new blood vessel creation appears to be the most important. In addition to its role as a key angiogenic factor, VEGF also possesses neurotrophic and neuroprotective activity both in the peripheral and in the central nervous system, exerting a direct action on neurons, Schwann cells, astrocytes, neural stem cells, and microglia. VEGF interacts with three subtypes of VEGF receptors occurring on the cellular membrane known as VEGFR-1 (Flt-1), VEGFR-2 (Flk-1/KDR), and VEGFR-3 (Flt-4). All these receptor types possess an internal tyrosin kinase domain. Interaction of VEGF with particular subtypes of receptors activates a circuit of signaling pathways, e.g. PI3K/Akt, Ras/Raf-MEK/Erk, eNOS/NO, and IP3/Ca2+. These participate in the generation of specific biological responses connected with proliferation, migration, increasing vascular permeability, or promoting endothelial cell survival. Recent findings from experiments performed on animals with experimentally evoked focal cerebral ischemia suggest that the neuroprotective activity of VEGF runs in parallel with its ability to promote neurogenesis and angiogenesis and that these effects may operate independently through multiple mechanisms. The above-mentioned three major features characterizing the neurobiological activity of VEGF, i.e. neuroprotection, neurogenesis, and angiogenesis, together with their possible functional link(s), provide the rationale for considering VEGF-based therapy as a

  17. Targeting VEGF-A with a vaccine decreases inflammation and joint destruction in experimental arthritis.

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    Semerano, Luca; Duvallet, Emilie; Belmellat, Nadia; Marival, Nicolas; Schall, Nicolas; Monteil, Maëlle; Grouard-Vogel, Géraldine; Bernier, Emilie; Lecouvey, Marc; Hlawaty, Hanna; Muller, Sylviane; Boissier, Marie-Christophe; Assier, Eric

    2016-01-01

    Inflammation and angiogenesis are two tightly linked processes in arthritis, and therapeutic targeting of pro-angiogenic factors may contribute to control joint inflammation and synovitis progression. In this work, we explored whether vaccination against vascular endothelial growth factor (VEGF) ameliorates collagen-induced arthritis (CIA). Anti-VEGF vaccines were heterocomplexes consisting of the entire VEGF cytokine (or a VEGF-derived peptide) linked to the carrier protein keyhole limpet hemocyanin (KLH). Two kinds of vaccines were separately tested in two independent experiments of CIA. In the first, we tested a kinoid of the murine cytokine VEGF (VEGF-K), obtained by conjugating VEGF-A to KLH. For the second, we selected two VEGF-A-derived peptide sequences to produce heterocomplexes (Vpep1-K and Vpep2-K). DBA/1 mice were immunized with either VEGF-K, Vpep1-K, or Vpep2-K, before CIA induction. Clinical and histological scores of arthritis, anti-VEGF, anti-Vpep Ab titers, and anti-VEGF Abs neutralizing capacity were determined. Both VEGF-K and Vpep1-K significantly ameliorated clinical arthritis scores and reduced synovial inflammation and joint destruction at histology. VEGF-K significantly reduced synovial vascularization. None of the vaccines reduced anti-collagen Ab response in mice. Both VEGF-K and Vpep1-K induced persistently high titers of anti-VEGF Abs capable of inhibiting VEGF-A bioactivity. Vaccination against the pro-angiogenic factor VEGF-A leads to the production of anti-VEGF polyclonal Abs and has a significant anti-inflammatory effect in CIA. Restraining Ab response to a single peptide sequence (Vpep1) with a peptide vaccine effectively protects immunized mice from joint inflammation and destruction.

  18. Post-LASIK keratectasia triggered by eye rubbing and treated with topography-guided ablation and collagen cross-linking--a case report.

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    Padmanabhan, Prema; Aiswaryah, R; Abinaya Priya, V

    2012-05-01

    To report a case of unilateral post-laser-assisted in situ keratomileusis (LASIK) keratectasia in a 35-year-old woman who had no known predisposing risk factors but who rubbed her affected eye frequently and vigorously in response to allergic conjunctivitis. Case report with relevant literature review. A 35-year-old woman, with a cumulative risk scale score of 0 (according to the Randleman criteria), who underwent bilateral LASIK developed unilateral post-LASIK keratectasia 32 months later. She presented with a history of vigorous eye rubbing of the affected eye since about a year after allergic conjunctivitis. The fellow eye, which was not rubbed, remained normal. She complained of glare, halos, and ghost images in her affected eye. She underwent transepithelial topography-guided customized ablation with simultaneous UV-A corneal collagen cross-linking, after which she improved symptomatically and topographically. Eye rubbing could contribute to the development of keratectasia, even in an eye that has no subclinical features of the disease. When detected early, a simultaneous combined topography-guided customized ablation treatment and collagen cross-linking is effective in improving the irregular corneal contour and restoring biomechanical stability.

  19. VEGF121b and VEGF165b are weakly angiogenic isoforms of VEGF-A

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    Pio Ruben

    2010-12-01

    Full Text Available Abstract Background Different isoforms of VEGF-A (mainly VEGF121, VEGF165 and VEGF189 have been shown to display particular angiogenic properties in the generation of a functional tumor vasculature. Recently, a novel class of VEGF-A isoforms, designated as VEGFxxxb, generated through alternative splicing, have been described. Previous studies have suggested that these isoforms may inhibit angiogenesis. In the present work we have produced recombinant VEGF121/165b proteins in the yeast Pichia pastoris and constructed vectors to overexpress these isoforms and assess their angiogenic potential. Results Recombinant VEGF121/165b proteins generated either in yeasts or mammalian cells activated VEGFR2 and its downstream effector ERK1/2, although to a lesser extent than VEGF165. Furthermore, treatment of endothelial cells with VEGF121/165b increased cell proliferation compared to untreated cells, although such stimulation was lower than that induced by VEGF165. Moreover, in vivo angiogenesis assays confirmed angiogenesis stimulation by VEGF121/165b isoforms. A549 and PC-3 cells overexpressing VEGF121b or VEGF165b (or carrying the PCDNA3.1 empty vector, as control and xenotransplanted into nude mice showed increased tumor volume and angiogenesis compared to controls. To assess whether the VEGFxxxb isoforms are differentially expressed in tumors compared to healthy tissues, immunohistochemical analysis was conducted on a breast cancer tissue microarray. A significant increase (p xxxb and total VEGF-A protein expression in infiltrating ductal carcinomas compared to normal breasts was observed. A positive significant correlation (r = 0.404, p = 0.033 between VEGFxxxb and total VEGF-A was found. Conclusions Our results demonstrate that VEGF121/165b are not anti-angiogenic, but weakly angiogenic isoforms of VEGF-A. In addition, VEGFxxxb isoforms are up-regulated in breast cancer in comparison with non malignant breast tissues. These results are to be taken

  20. One-Year Results of Simultaneous Topography-Guided Photorefractive Keratectomy and Corneal Collagen Cross-Linking in Keratoconus Utilizing a Modern Ablation Software

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    A. M. Sherif

    2015-01-01

    Full Text Available Purpose. To evaluate effectiveness of simultaneous topography-guided photorefractive keratectomy and corneal collagen cross-linking in mild and moderate keratoconus. Methods. Prospective nonrandomized interventional study including 20 eyes of 14 patients with grade 1-2 keratoconus that underwent topography-guided PRK using a Custom Ablation Transition Zone (CATz profile with 0.02% MMC application immediately followed by standard 3 mw/cm2 UVA collagen cross-linking. Maximum ablation depth did not exceed 58 μm. Follow-up period: 12 months. Results. Progressive statistically significant improvement of UCVA from 0.83±0.37 logMAR preoperative, reaching 0.25±0.26 logMAR at 12 months (P<0.001. Preoperative BCVA (0.27±0.31 logMAR showed a progressive improvement reaching 0.08±0.12 logMAR at 12 months (P=0.02. Mean Kmax reduced from 48.9±2.8 to 45.4±3.1 D at 12 months (P<0.001, mean Kmin reduced from 45.9±2.8 D to 44.1±3.2 D at 12 months (P<0.003, mean keratometric asymmetry reduced from 3.01±2.03 D to 1.25±1.2 D at 12 months (P<0.001. The safety index was 1.39 at 12 months and efficacy index 0.97 at 12 months. Conclusion. Combined topography-guided PRK and corneal collagen cross-linking are a safe and effective option in the management of mild and moderate keratoconus. Precis. To our knowledge, this is the first published study on the use of the CATz ablation system on the Nidek Quest excimer laser platform combined with conventional cross-linking in the management of mild keratoconus.

  1. Cardiac ablation procedures

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    Catheter ablation; Radiofrequency catheter ablation; Cryoablation - cardiac ablation; AV nodal reentrant tachycardia - cardiac ablation; AVNRT - cardiac ablation; Wolff-Parkinson-White Syndrome - cardiac ablation; Atrial fibrillation - cardiac ablation; Atrial flutter - ...

  2. 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.

  3. 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.

  4. Genetic ablation of PRAS40 improves glucose homeostasis via linking the AKT and mTOR pathways.

    Science.gov (United States)

    Malla, Ritu; Wang, Yu; Chan, William K; Tiwari, Amit K; Faridi, Jesika S

    2015-07-01

    Alterations in PI3K-AKT-mTOR signaling have been implicated in diabetes. This study assessed whether disruption of PRAS40, a substrate of AKT and component of mTORC1, would alter glucose homeostasis and prevent hyperglycemia in the streptozotocin (STZ)-induced diabetes mouse model. PRAS40 ablation resulted in a mild lowering of blood glucose levels and glycated hemoglobin (HbA1C), a lowered insulin requirement, and improved glucose tolerance in untreated PRAS40 gene knockout (PRAS40(-/-)) as compared to wild-type (PRAS40(+/+)) mice. Diabetes was then induced in these mice using STZ at 50mg/kg/day over five days. Following STZ-treatment, PRAS40(-/-) mice exhibited significantly lower blood glucose and HbA1C levels than PRAS40(+/+) mice. Liver tissue of PRAS40(-/-) mice and shPRAS40 Hep3B cells showed increased activation of AKT (p-AKT T308) and mTORC1 (p-p70S6K) signaling as well as decreased p-AKT (S473) and increased p-IRS1 (S612) protein levels. Altered tissue gene expression of several glucose transporters (GLUT) and increased hepatic GLUT4 protein levels were observed in PRAS40(-/-) as compared to PRAS40(+/+) mice. In summary, PRAS40 deletion significantly attenuates hyperglycemia in STZ-induced PRAS40(-/-) mice through increased hepatic AKT and mTORC1 signaling, a lowered serum insulin requirement, and altered hepatic GLUT4 levels. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. The Effect of Depression on Serum VEGF Level in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    JaeHoon Jung

    2015-01-01

    Full Text Available Objective. Growing evidence suggests that angiogenesis might represent a new pathogenic mechanism involved in the progression of Alzheimer’s disease (AD. Among angiogenic cytokines, vascular endothelial growth factor (VEGF levels in AD patients have been evaluated, but the results are controversial among studies. We investigated serum levels of VEGF in AD patients with depression, AD patients without depression, and the controls, respectively. The aim of this study is to elucidate the relationship between VEGF, depression, and cognitive impairment in AD. Methods. The CDR (Clinical Dementia Rating, MMSE-KC (the Mini-Mental Status Examination-Korean version, and SGDS-K (the Korean version of the Geriatric Depression Scale-Short Form were measured in the subjects. Serum VEGF levels were measured in 24 AD patients with depression, 25 AD patients without depression, and 26 controls, using an enzyme-linked immunosorbent assay kit. Results. Serum VEGF levels in AD patients with depression were significantly higher than AD patients without depression or the control. A correlation was observed between VEGF and scores on SGDS-K, but no correlation was detected between VEGF and MMSE-KC scores. Conclusion. Serum VEGF levels in AD patients with depression were higher than those without depression. Depression might be associated with changes in serum levels of VEGF in AD patients.

  6. VEGFR2-mediated vascular dilation as a mechanism of VEGF-induced anemia and bone marrow cell mobilization.

    Science.gov (United States)

    Lim, Sharon; Zhang, Yin; Zhang, Danfang; Chen, Fang; Hosaka, Kayoko; Feng, Ninghan; Seki, Takahiro; Andersson, Patrik; Li, Jingrong; Zang, Jingwu; Sun, Baocun; Cao, Yihai

    2014-10-23

    Molecular mechanisms underlying tumor VEGF-induced host anemia and bone marrow cell (BMC) mobilization remain unknown. Here, we report that tumor VEGF markedly induced sinusoidal vasculature dilation in bone marrow (BM) and BMC mobilization to tumors and peripheral tissues in mouse and human tumor models. Unexpectedly, anti-VEGFR2, but not anti-VEGFR1, treatment completely blocked VEGF-induced anemia and BMC mobilization. Genetic deletion of Vegfr2 in endothelial cells markedly ablated VEGF-stimulated BMC mobilization. Conversely, deletion of the tyrosine kinase domain from Vegfr1 gene (Vegfr1(TK-/-)) did not affect VEGF-induced BMC mobilization. Analysis of VEGFR1(+)/VEGFR2(+) populations in peripheral blood and BM showed no significant ratio difference between VEGF- and control tumor-bearing animals. These findings demonstrate that vascular dilation through the VEGFR2 signaling is the mechanism underlying VEGF-induced BM mobilization and anemia. Thus, our data provide mechanistic insights on VEGF-induced BMC mobilization in tumors and have therapeutic implications by targeting VEGFR2 for cancer therapy. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Specific imaging of VEGF-A expression with radiolabeled anti-VEGF monoclonal antibody.

    NARCIS (Netherlands)

    Stollman, T.H.; Scheer, M.G.W.; Leenders, W.P.J.; Verrijp, K.C.; Soede, A.C.; Oyen, W.J.G.; Ruers, T.J.M.; Boerman, O.C.

    2008-01-01

    Vascular endothelial growth factor-A (VEGF-A) is one of the most important angiogenic factors. Here, we studied in a nude mouse model whether the expression of VEGF-A in a tumor could be imaged with a radiolabeled anti-VEGF antibody. The humanized anti-VEGF-A antibody A.4.6.1. (bevacizumab), which

  8. Medium- to Long-Term Results of Corneal Cross-Linking for Keratoconus Using Phototherapeutic Keratectomy for Epithelial Removal and Partial Stromal Ablation.

    Science.gov (United States)

    Chen, Xiangjun; Stojanovic, Aleksandar; Xu, Yangyang; Zhou, Wen; Raeder, Sten; Enayati, Sam; Utheim, Tor Paaske

    2017-07-01

    To evaluate the medium- to long-term outcomes of corneal cross-linking in treatment of keratoconus using transepithelial phototherapeutic keratectomy (PTK-CXL) for epithelial removal and partial stromal ablation to stabilize the cornea, reduce corneal irregularity, and improve corrected vision. Retrospective analysis of 46 keratoconic eyes that underwent PTK-CXL. Corrected distance visual acuity (CDVA), manifest refraction, steep and flat simulated keratometry (Kmax and Kmin), corneal irregularity index (IRI), corneal higher order aberrations (HOAs), epithelial thickness profile, and corneal biomechanical characteristics were evaluated preoperatively and postoperatively. At a mean follow-up time of 21.0 ± 7.6 months (range: 10 to 43 months) postoperatively, CDVA improved from 0.25 ± 0.24 to 0.18 ± 0.22 logMAR (P = .002). CDVA remained unchanged in 32.6% (15 eyes) and 56.5% (26 eyes) gained up to five Snellen lines of CDVA, whereas 6.5% (3 eyes) lost two or more lines of CDVA, respectively. Postoperatively, flattening of Kmax from 50.58 ± 5.26 to 48.96 ± 4.00 diopters (D) and Kmin from 45.80 ± 3.11 to 44.77 ± 2.63 D (P biomechanical measurements did not show statistically significant change. Two eyes demonstrated slight topographic regression. PTK-CXL seems to be effective in arresting the progression of keratoconus, improving CDVA, flattening the cornea, regularizing corneal surface, and reducing corneal HOAs. [J Refract Surg. 2017;33(7):488-495.]. Copyright 2017, SLACK Incorporated.

  9. Serum VEGF levels as predictive marker of bisphosphonate-related osteonecrosis of the jaw

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    Vincenzi Bruno

    2012-09-01

    Full Text Available Abstract Recent studies have been reported that angiogenesis suppression may play a role in developing bisphosphonate-related osteonecrosis of the jaw (B-ONJ. According to these evidence we evaluated the role of VEGF as predictive marker of B-ONJ onset. Of the 81 patients, 6 developed B-ONJ following bisphosphonate treatment. These patients showed a strongest decrease in VEGF circulating levels at day 7 and at day 21 after the first administration. These data demonstrated for the first time that the anti-angiogenic properties of bisphosphonates are directly linked to B-ONJ pathogenesis and serum VEGF levels could represent an effective early predictive marker.

  10. Pericardial fluid and serum VEGF in response to different types of heparin treatment.

    Science.gov (United States)

    Gerrah, Rabin; Tshori, Sagi; Gilon, Dan

    2004-04-01

    Heparin is an important medication in the treatment of patients with unstable angina pectoris. We designed an observational study to compare the effects of standard heparin (SH) with low molecular weight heparin (LMWH) on vascular endothelial growth factor (VEGF) levels in patients undergoing coronary artery bypass grafting (CABG). Thirty-two patients with unstable angina pectoris undergoing CABG were prospectively categorized into two groups according to the type of heparin administration before surgery. VEGF levels determined by enzyme linked immunosorbent assay (ELISA) were compared between the two groups' blood samples obtained before the surgery and pericardial fluid after pericardial opening. There was no difference in preoperative characteristics between the two groups. Serum VEGF levels were similar (P=0.3) in patients treated by SH (85+/-55 pg/ml) compared to those treated with LMWH (105+/-64 pg/ml). VEGF levels in the pericardial fluid were significantly raised (P<0.0001) in patients of LMWH group (36+/-13 pg/ml) compared to SH group (13+/-6 pg/ml). A good correlation was observed between VEGF in the serum and platelet count in both SH group (r=0.8) and LMWH group (r=0.7). Local response of the ischemic myocardium, as expressed by VEGF levels, differs in patients treated with SH compared to patients treated with LMWH. VEGF levels in pericardial fluid of patients receiving LMWH were 2-3-folds higher than patients in SH group.

  11. The correlation analysis of the expression of VEGF and the DCs’ infiltration density of gastric cancer tissues

    Institute of Scientific and Technical Information of China (English)

    Feng Yang; Ai-Mei Li; De-Huai Jing

    2016-01-01

    Objective:To investigate the correlation of the expression of vascular endothecial growth factor (VEGF) and the dendritic cells (DCs) infiltration density of tumor tissues in patients with gastric cancer and the correlation of the frequency of DCs of VEGF in gastric cancer tissues and the clinic stages; and to analyze the expressions of HLA-DR and CD86 on peripheral blood monocyte-derived DCs.Methods:Immuno fluorescence method was applied to test the expressions of CD11c and VEGF in gastric cancer tissues and para-carcinoma tissues and enzyme-linked immune sorbent assay was used to detect the concentration of serum VEGF. Peripheral blood mononuclear cells of the gastric cancer patients and healthy people were separated and induced DCs by GM-CSF and IL-4in vitro. Then, the expressions of HLA-DR and CD86 on DCs were tested by flow cytometry. Finally, the recombinant VEGF protein was added into DCs cultures to explore how VEGF affected the expression of CD86. Results: There was a negative correlation between the expression intensity of VEGF on gastric cancer cells and the tumor-infiltrating density of DCs; while there was a certain positive correlation between the frequency of DCs of VEGF and the development of the disease. The concentration of serum VEGF had no association with the density of tumor-infiltrating DCs. As for peripheral blood mononuclear cell, it had a certain induced effect on the decrease of DCs, the expressions of HLA-DR and CD86 and the expression of CD86 on DCs’ cell surface by VEGF.Conclusions:The activities of DCs were inhibited by VEGF secretion of gastric cancer tissues so as to mediate immune escape of the cancer cells. In addition, DCs infiltrated in gastric cancer tissues may secrete VEGF to participate the development of the disease.

  12. (-)-Epigallocatechin-3-gallate inhibits VEGF expression induced by IL-6 via Stat3 in gastric cancer

    Science.gov (United States)

    Zhu, Bao-He; Chen, Hua-Yun; Zhan, Wen-Hua; Wang, Cheng-You; Cai, Shi-Rong; Wang, Zhao; Zhang, Chang-Hua; He, Yu-Long

    2011-01-01

    AIM: To demonstrate that (-)-Epigallocatechin-3-gallate (EGCG) inhibits vascular endothelial growth factor (VEGF) expression and angiogenesis induced by interleukin-6 (IL-6) via suppressing signal transducer and activator of transcription 3 (Stat3) activity in gastric cancer. METHODS: Human gastric cancer (AGS) cells were treated with IL-6 (50 ng/mL) and EGCG at different concentrations. VEGF, total Stat3 and activated Stat3 protein levels in the cell lyses were examined by Western blotting, VEGF protein level in the conditioned medium was measured by enzyme-linked immunosorbent assay, and the level of VEGF mRNA was evaluated by reverse transcription polymerase chain reaction (RT-PCR). Stat3 nuclear translocation was determined by Western blotting with nuclear extract, and Stat3-DNA binding activity was examined with Chromatin immunoprecipitation (ChIP) assay. IL-6 induced endothelial cell proliferation was measured with 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazoliumbromide assay, in vitro angiogenesis was determined with endothelial cell tube formation assay in Matrigel, and IL-6-induced angiogenesis in vitro was measured with Matrigel plug assay. RESULTS: There was a basal expression and secretion of VEGF in AGS cells. After stimulation with IL-6, VEGF expression was apparently up-regulated and a 2.4-fold increase was observed. VEGF secretion in the conditioned medium was also increased by 2.8 folds. When treated with EGCG, VEGF expression and secretion were dose-dependently decreased. IL-6 also increased VEGF mRNA expression by 3.1 folds. EGCG treatment suppressed VEGF mRNA expression in a dose-dependent manner. EGCG dose-dependently inhibited Stat3 activation induced by IL-6, but did not change the total Stat3 expression. When treated with EGCG or AG490, VEGF expressions were reduced to the level or an even lower level in the tumor cells not stimulated with IL-6. However, PD98059 and LY294002 did not change VEGF expression induced by IL-6. EGCG

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

    Science.gov (United States)

    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.

  14. Using Anti-VEGF in Diabetic Retinopathy

    OpenAIRE

    Marashi, Ameen

    2016-01-01

    Vascular endothelium growth factor is the main pathological factor in diabetic retinopathy and diabetic macular edema (DME), Anti-VEGF agents are safe and effective in DME treatment, there are multiple Anti-VEGF agents, choosing between them is essential to individualize treatment for each patient to achieve the optimum results.

  15. 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.

  16. The therapeutic role of VEGF-expressing muscle-derived stem cells in acute penile cavernosal injury.

    Science.gov (United States)

    An, Geng; Ji, Chenyang; Wei, Zhe; Chen, Hao; Zhang, Jinming

    2012-08-01

    Traumatic penile injury is one of the urological emergencies. Surgery and conservative management are major treatment methods but are always accompanied by many complications. To investigate the feasibility of repairing cavernous tissues in acute rabbit penile cavernosal injury model with vascular endothelial growth factor (VEGF)-expressing muscle-derived stem cells (MDSCs). MDSCs were isolated and transfected with hVEGF165 lentiviral gene vector in vitro. The expression of VEGF was confirmed using enzyme-linked immunosorbent assay (ELISA), Western blot, and real-time polymerase chain reaction (PCR) analyses. After animal models were constructed, animals were randomly divided into four groups, which were administrated with MDSCs/VEGF, MDSCs/vector, MDSCs, and normal saline, respectively. A month later, magnetic resonance imaging (MRI) and intracavernosal pressures (ICP) were performed on the animals. Then penile tissues were harvested and assayed with Western blot and immunohistochemistry. Real-time PCR, Western blot, ELISA, immunohistochemistry, MRI, and ICP were performed in our experiments. The expression of VEGF significantly increased in the VEGF-expressing MDSCs group compared with those in the MDSCs/vector and MDSCs groups. VEGF protein expression in the injury sites of cavernous tissues were significantly higher in the MDSCs/VEGF group compared with those in other three groups. Immunohistochemical staining showed that α-smooth muscle actin-positive cells, von Willebrand factor-positive cells and capillary density markedly increased in the MDSCs/VEGF group. Animals receiving MDSCs/VEGF showed a significant improvement in cavernosal contractile function and structural repair. The transplantation of VEGF-expressing MDSCs could repair the actuely injured cavernous tissue. We believed that it could be a novel therapeutic strategy for acute rabbit penile cavernosal injury. © 2012 International Society for Sexual Medicine.

  17. Covalent immobilisation of VEGF on plasma-coated electrospun scaffolds for tissue engineering applications.

    Science.gov (United States)

    Guex, A G; Hegemann, D; Giraud, M N; Tevaearai, H T; Popa, A M; Rossi, R M; Fortunato, G

    2014-11-01

    Recent findings in the field of biomaterials and tissue engineering provide evidence that surface immobilised growth factors display enhanced stability and induce prolonged function. Cell response can be regulated by material properties and at the site of interest. To this end, we developed scaffolds with covalently bound vascular endothelial growth factor (VEGF) and evaluated their mitogenic effect on endothelial cells in vitro. Nano- (254±133 nm) or micro-fibrous (4.0±0.4 μm) poly(ɛ-caprolactone) (PCL) non-wovens were produced by electrospinning and coated in a radio frequency (RF) plasma process to induce an oxygen functional hydrocarbon layer. Implemented carboxylic acid groups were converted into amine-reactive esters and covalently coupled to VEGF by forming stable amide bonds (standard EDC/NHS chemistry). Substrates were analysed by X-ray photoelectron spectroscopy (XPS), enzyme-linked immuno-assays (ELISA) and immunohistochemistry (anti-VEGF antibody and VEGF-R2 binding). Depending on the reaction conditions, immobilised VEGF was present at 127±47 ng to 941±199 ng per substrate (6mm diameter; concentrations of 4.5 ng mm(-2) or 33.3 ng mm(-2), respectively). Immunohistochemistry provided evidence for biological integrity of immobilised VEGF. Endothelial cell number of primary endothelial cells or immortalised endothelial cells were significantly enhanced on VEGF-functionalised scaffolds compared to native PCL scaffolds. This indicates a sustained activity of immobilised VEGF over a culture period of nine days. We present a versatile method for the fabrication of growth factor-loaded scaffolds at specific concentrations. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. VEGF and endothelial guidance in angiogenic sprouting.

    Science.gov (United States)

    Gerhardt, Holger

    2008-10-01

    The cellular actions of VEGF need to be coordinated to guide vascular patterning during sprouting angiogenesis. Individual endothelial tip cells lead and guide the blood vessel sprout, while neighbouring stalk cells proliferate and form the vascular lumen. Recent studies illustrate how endothelial DLL4/NOTCH signalling, stimulated by VEGF, regulates the sprouting response by limiting tip cell formation in the stalk. The spatial distribution of VEGF, in turn, regulates the shape of the ensuing sprout by directing tip cell migration and determining stalk cell proliferation.

  19. Expressions of hypoxia-inducible factor-1 and epithelial cell adhesion molecule are linked with aggressive local recurrence of hepatocellular carcinoma after radiofrequency ablation therapy.

    Science.gov (United States)

    Yamada, Shinichiro; Utsunomiya, Tohru; Morine, Yuji; Imura, Satoru; Ikemoto, Tetsuya; Arakawa, Yusue; Kanamoto, Mami; Iwahashi, Shuichi; Saito, Yu; Takasu, Chie; Ishikawa, Daichi; Shimada, Mitsuo

    2014-06-01

    Radiofrequency ablation (RFA) is a widely used therapy for hepatocellular carcinoma (HCC). Several reports have demonstrated the aggressive local recurrence of HCC after RFA, suggesting that induction of further malignant transformation of HCC has occurred. Eighty-eight (88) patients with HCC who underwent hepatic resection were included in this study. Hepatectomy was indicated for local recurrence of HCC after RFA (n = 10, RFA group) and for HCC without prior RFA (n = 78, non-RFA group). Clinicopathological data and the patient's prognosis after hepatectomy were compared between the two groups. Expression levels of hypoxia-inducible factor-1 (HIF-1), epithelial cell adhesion molecule (EpCAM), CD44, and vascular endothelial growth factor messenger RNA (mRNA) in the tumor tissues were also examined. The RFA group showed higher frequency of portal vein invasion and less tumor differentiation compared with the non-RFA group (p treatment by RFA.

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  1. Expression of HIF-1A/VEGF/ING-4 Axis in Pulmonary Sarcoidosis.

    Science.gov (United States)

    Piotrowski, W J; Kiszałkiewicz, J; Pastuszak-Lewandoska, D; Górski, P; Antczak, A; Migdalska-Sęk, M; Górski, W; Czarnecka, K H; Domańska, D; Nawrot, E; Brzeziańska-Lasota, E

    2015-01-01

    Angiogenesis/angiostasis regulated by hypoxia inducible factor-1A (HIF-1A)/vascular endothelial growth factor (VEGF)/inhibitor of growth protein 4 (ING-4) axis may be crucial for the course and outcome of sarcoidosis. Overexpression of angiogenic factors (activation of VEGF through HIF-1A) may predispose to chronic course and lung fibrosis, whereas immunoangiostasis (related to an overexpression of inhibitory ING-4) may be involved in granuloma formation in early sarcoid inflammation, or sustained or recurrent formation of granulomas. In this work we investigated gene expression of HIF-1A, VEGF and ING-4 in bronchoalveolar fluid (BALF) cells and in peripheral blood (PB) lymphocytes of sarcoidosis patients (n=94), to better understand mechanisms of the disease and to search for its biomarkers. The relative gene expression level (RQ value) was analyzed by qPCR. The results were evaluated according to the presence of lung parenchymal involvement (radiological stage I vs. II-IV), acute vs. insidious onset, lung function tests, calcium metabolism parameters, percentage of lymphocytes (BALL%) and BAL CD4+/CD8+ in BALF, age, and gender. In BALF cells, the ING-4 and VEGF RQ values were increased, while HIF-1A expression was decreased. In PB lymphocytes all studied genes were overexpressed. Higher expression of HIF-1A in PB lymphocytes of patients with abnormal spirometry, and in BALF cells of patients with lung volume restriction was found. VEGF gene expression in BALF cells was also higher in patients with abnormal spirometry. These findings were in line with previous data on the role of HIF-1A/VEGF/ING-4 axis in the pathogenesis of sarcoidosis. Up-regulated HIF-1A and VEGF genes are linked to acknowledged negative prognostics.

  2. Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform.

    Directory of Open Access Journals (Sweden)

    Liangxian Cao

    Full Text Available Current anti-VEGF (Vascular Endothelial Growth Factor A therapies to treat various cancers indiscriminately block VEGF function in the patient resulting in the global loss of VEGF signaling which has been linked to dose-limiting toxicities as well as treatment failures due to acquired resistance. Accumulating evidence suggests that this resistance is at least partially due to increased production of compensatory tumor angiogenic factors/cytokines. VEGF protein production is differentially controlled depending on whether cells are in the normal "homeostatic" state or in a stressed state, such as hypoxia, by post-transcriptional regulation imparted by elements in the 5' and 3' untranslated regions (UTR of the VEGF mRNA. Using the Gene Expression Modulation by Small molecules (GEMS™ phenotypic assay system, we performed a high throughput screen to identify low molecular weight compounds that target the VEGF mRNA UTR-mediated regulation of stress-induced VEGF production in tumor cells. We identified a number of compounds that potently and selectively reduce endogenous VEGF production under hypoxia in HeLa cells. Medicinal chemistry efforts improved the potency and pharmaceutical properties of one series of compounds resulting in the discovery of PTC-510 which inhibits hypoxia-induced VEGF expression in HeLa cells at low nanomolar concentration. In mouse xenograft studies, oral administration of PTC-510 results in marked reduction of intratumor VEGF production and single agent control of tumor growth without any evident toxicity. Here, we show that selective suppression of stress-induced VEGF production within tumor cells effectively controls tumor growth. Therefore, this approach may minimize the liabilities of current global anti-VEGF therapies.

  3. Endobronchial ablative therapies.

    Science.gov (United States)

    Seaman, Joseph C; Musani, Ali I

    2013-09-01

    Endobronchial ablative therapies are used to address a variety of malignant and benign airway lesions. By utilizing endobronchial ablative techniques patients with symptomatic airway lesions may receive significant symptom improvement, improved quality of life, and improved life expectancy. Endobronchial ablative therapies include laser, electrocautery, argon plasma coagulation, cryotherapy, brachytherapy, and photodynamic therapy. The choice to use one therapy versus another depends on technical and patient specific factors. This article reviews indications and contraindications for each therapy, discusses details related to each endobronchial ablative therapy, complications of endobronchial ablative therapies, and briefly discusses practical consideration with endobronchial ablative therapies. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Quantification of plasma and bone marrow VEGF and angiopoietin-2 levels in pediatric malignancies.

    Science.gov (United States)

    Hintsala, Emilia; Bono, Petri; Andersson, Sture; Kivivuori, Sanna-Maria

    2012-10-01

    Data on angiogenesis in pediatric patients with malignancy are scarce. Our aim was to study angiogenic growth factors vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang2) in pediatric oncological patients at diagnosis and a few months after the beginning of the therapy. Eighty-four consecutive patients with malignancy were included in this study. The levels of plasma and bone marrow VEGF and Ang2 were analyzed by enzyme-linked immunosorbent assay. The levels of VEGF were higher in patients with solid tumors than in patients with leukemias (P=0.003), whereas Ang2 concentrations showed the opposite (P=0.003). Interestingly, the plasma concentrations of both VEGF and Ang2 correlated with concentrations in the bone marrow (Ppatients with lower VEGF level and patients with higher Ang2 level at follow-up had longer event-free survival than other patients (P=0.032 and 0.053, respectively). The results of our study enlighten the behavior of 2 different angiogenic factors in pediatric patients with malignancy. An interesting finding was the connection between survival of pediatric leukemia patients and angiogenic factor levels a few months after the beginning of therapy. Pathophysiology and clinical applications of these findings need further studies.

  5. Release kinetics of VEGF165 from a collagen matrix and structural matrix changes in a circulation model

    Directory of Open Access Journals (Sweden)

    Fischer Carsten

    2010-07-01

    Full Text Available Abstract Background Current approaches in bone regeneration combine osteoconductive scaffolds with bioactive cytokines like BMP or VEGF. The idea of our in-vitro trial was to apply VEGF165 in gradient concentrations to an equine collagen carrier and to study pharmacological and morphological characteristics of the complex in a circulation model. Methods Release kinetics of VEGF165 complexed in different quantities in a collagen matrix were determined in a circulation model by quantifying protein concentration with ELISA over a period of 5 days. The structural changes of the collagen matrix were assessed with light microscopy, native scanning electron microscopy (SEM as well as with immuno-gold-labelling technique in scanning and transmission electron microscopy (TEM. Results We established a biological half-life for VEGF165 of 90 minutes. In a half-logarithmic presentation the VEGF165 release showed a linear declining gradient; the release kinetics were not depending on VEGF165 concentrations. After 12 hours VEGF release reached a plateau, after 48 hours VEGF165 was no longer detectable in the complexes charged with lower doses, but still measurable in the 80 μg sample. At the beginning of the study a smear layer was visible on the surface of the complex. After the wash out of the protein in the first days the natural structure of the collagen appeared and did not change over the test period. Conclusions By defining the pharmacological and morphological profile of a cytokine collagen complex in a circulation model our data paves the way for further in-vivo studies where additional biological side effects will have to be considered. VEGF165 linked to collagen fibrils shows its improved stability in direct electron microscopic imaging as well as in prolonged release from the matrix. Our in-vitro trial substantiates the position of cytokine collagen complexes as innovative and effective treatment tools in regenerative medicine and and may initiate

  6. VEGF, sVEGFR-1 and Endostatin Serum Levels and VEGF Polymorphisms in Recurrent Aphthous Stomatitis

    Directory of Open Access Journals (Sweden)

    Salim Yuce

    2016-09-01

    Full Text Available Aim: Recurrent aphthous stomatitis (RAS is one of the most frequent diseases of the oral mucosa, characterized by chronic, painful, recurrent, and necrotizing ulcerations. The precise etiology and pathogenesis of RAS have not been clarified. Therefore, we aimed to investigate serum levels of VEGF, sVEGFR-1, and endostatin as well as the frequencies of VEGF 936 C/T and -1154 G/A single nucleotide polymorphisms (SNPs in Turkish patients with recurrent aphthous stomatitis. Material and Method: Forty-two patients with RAS (24 minor RAS and 18 major RAS and 37 healthy subjects were included in the study. Serum levels of VEGF, sVEGFR-1, and endostatin were measured using the ELISA method. VEGF 936 C/T and -1154 G/A SNPs were determined by the PCR-RFLP method. Results: The mean serum level of VEGF was found higher in bearing CC genotype of 936 C/T SNP compared with CT genotype (639.5 ± 309.1 vs 442.1 ± 197.8; p = 0.032. VEGF -1154 GA genotype was found to be more frequent in patients with minor RAS and GG genotype was more frequent in patients with major RAS (p = 0.022. There was a significant difference between minor RAS and major RAS with regard to mean VEGF serum levels (677.1 ± 316.7 vs 492.9 ± 242.7; p = 0.032.Discussion: The T allele of 936 C/T SNP is associated with decreased serum VEGF level, and this decrease may have a contributory role in impaired neovascularization and re-epithelialization in the etiology and pathogenesis of RAS. Further studies are needed to determine the role of VEGF in RAS susceptibility and its clinical manifestations.

  7. Ablative skin resurfacing.

    Science.gov (United States)

    Chwalek, Jennifer; Goldberg, David J

    2011-01-01

    Ablative skin resurfacing has remained the gold standard for treating photodamage and acne scars since the development of the first CO(2) lasers. CO(2) and Er:YAG lasers emit infrared light, which targets water resulting in tissue contraction and collagen formation. The first ablative laser systems created significant thermal damage resulting in unacceptably high rates of scarring and prolonged healing. Newer devices, such as high-energy pulsed lasers and fractional ablative lasers, are capable of achieving significant improvements with fewer side effects and shorter recovery times. While ablative resurfacing has become safer, careful patient selection is still important to avoid post-treatment scarring, dyspigmentation, and infections. Clinicians utilizing ablative devices need to be aware of possible side effects in order to maximize results and patient satisfaction. This chapter reviews the background of ablative lasers including the types of ablative lasers, mechanism of action, indications for ablative resurfacing, and possible side effects. Copyright © 2011 S. Karger AG, Basel.

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

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    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

  9. Comparing protein VEGF inhibitors: In vitro biological studies

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Lanlan; Liang, Xiao Huan [Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 (United States); Ferrara, Napoleone, E-mail: nf@gene.com [Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 (United States)

    2011-05-06

    Highlights: {yields} VEGF is a mediator of angiogenesis. {yields} VEGF inhibitors have clinical applications in cancer and eye disorders. {yields} Five protein VEGF inhibitors were compared for their ability to inhibit. {yields} VEGF-induced activities in cultured endothelial cells. -- Abstract: VEGF inhibitors are widely used as a therapy for tumors and intravascular neovascular disorders, but limited and conflicting data regarding their relative biological potencies are available. The purpose of the study is to compare different protein VEGF inhibitors for their ability to inhibit VEGF-stimulated activities. We tested ranibizumab, the full-length variant of ranibizumab (Mab Y0317), bevacizumab, the VEGF-TrapR1R2 and Flt(1-3)-IgG in bioassays measuring VEGF-stimulated proliferation of bovine retinal microvascular endothelial cells or chemotaxis of human umbilical vein endothelial cells (HUVEC). The inhibitors were also compared for their ability to inhibit MAP kinase activation in HUVECs following VEGF addition. Ranibizumab, VEGF-TrapR1R2 and Flt(1-3)-IgG had very similar potencies in the bioassays tested. Bevacizumab was over 10-fold less potent than these molecules. Mab Y0317 was over 30-fold more potent than bevacizumab. The findings reported in this manuscript describe important intrinsic characteristics of several VEGF inhibitors that may be useful to design and interpret preclinical or clinical studies.

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

    Science.gov (United States)

    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.

  11. Autocrine VEGF isoforms differentially regulate endothelial cell behavior

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    Hideki Yamamoto

    2016-09-01

    Full Text Available Vascular endothelial growth factor A (VEGF is involved in all the essential biology of endothelial cells, from proliferation to vessel function, by mediating intercellular interactions and monolayer integrity. It is expressed as three major alternative spliced variants. In mice, these are VEGF120, VEGF164, and VEGF188, each with different affinities for extracellular matrices and cell surfaces, depending on the inclusion of heparin-binding sites, encoded by exons 6 and 7. To determine the role of each VEGF isoform in endothelial homeostasis, we compared phenotypes of primary endothelial cells isolated from lungs of mice expressing single VEGF isoforms in normoxic and hypoxic conditions. The differential expression and distribution of VEGF isoforms affect endothelial cell functions, such as proliferation, adhesion, migration and integrity, which are dependent on the stability of and affinity to VEGF receptor 2 (VEGFR2. We found a correlation between autocrine VEGF164 and VEGFR2 stability, which is also associated with increased expression of proteins involved in cell adhesion. Endothelial cells expressing only VEGF188, which localizes to extracellular matrices or cell surfaces, presented a mesenchymal morphology and weakened monolayer integrity. Cells expressing only VEGF120 lacked stable VEGFR2 and dysfunctional downstream processes, rendering the cells unviable. Endothelial cells expressing these different isoforms in isolation also had differing rates of apoptosis, proliferation, and signaling via nitric oxide (NO synthesis. These data indicate that autocrine signaling of each VEGF isoform has unique functions on endothelial homeostasis and response to hypoxia, due to both distinct VEGF distribution and VEGFR2 stability, which appears to be, at least partly, affected by differential NO production. This study demonstrates that each autocrine VEGF isoform has a distinct effect on downstream functions, namely VEGFR2-regulated endothelial cell

  12. Physical disruption of cell-cell contact induces VEGF expression in RPE cells.

    Science.gov (United States)

    Farjood, Farhad; Vargis, Elizabeth

    2017-01-01

    To investigate the role of RPE cell-cell contact in vascular endothelial growth factor (VEGF) protein expression in cultures of primary human RPE (hRPE) cells and a human RPE cell line (ARPE-19). Two in vitro methods, scratching and micropatterning, were used to control the physical dissociation of RPE cell-cell junctions. Scratching was performed by scoring monolayers of RPE cells with a cell scraper. Micropatterning was achieved by using a stencil patterning method. Extracellular VEGF expression was assessed by using an enzyme-linked immunosorbent assay (ELISA) kit. Immunocytochemistry (ICC) was performed to visualize the expression and localization of VEGF and intercellular proteins zonula occludens-1 (ZO-1), N-cadherin, β-catenin, and claudin-1 in RPE cultures. Higher expression of VEGF protein by cells on the edges of the scratched RPE layers was confirmed with ICC in short-term (1 day after confluency) and long-term (4 weeks after confluency) cultures. According to the ICC results, ZO-1, N-cadherin, β-catenin, and claudin-1 successfully localized to cell-cell junctions in long-term cultures of ARPE-19 and hRPE cells. However, unlike N-cadherin, β-catenin, and claudin-1, only ZO-1 localized junctionally in short-term cultures of both cell types. Moreover, removing cell-cell junctions by scratching resulted in the delocalization of ZO-1 from tight junctions to the cytoplasm. The loss of tight junction formation and the accumulation of ZO-1 in the cytoplasm correlated with increased VEGF expression. Micropatterning RPE cells on different sized circular patterns produced varying concentrations of cells with lost cell-cell junctions. When fewer cells formed intercellular junctions, increased extracellular VEGF secretion was observed from the ARPE-19 and hRPE cells. VEGF expression increases after physical disruption of RPE cell-cell connections. This increase in VEGF expression correlates with the loss of intercellular junctions and the localization of ZO-1 in

  13. Pazopanib and anti-VEGF therapy

    Directory of Open Access Journals (Sweden)

    Harry A Drabkin

    2010-03-01

    Full Text Available Harry A DrabkinMedical University of South Carolina and Hollings Cancer Center, Charleston, SC, USAAbstract: Pazopanib (VotrientTM, GlaxoSmithKline, a multi-kinase inhibitor with activity against VEGFR and other receptors, was recently approved by the FDA for the treatment of advanced renal cell carcinoma (RCC. Here, we review the history of its development, together with an overview of VEGF and its receptors and co-receptors. Results from selected clinical trial data in RCC and other malignant diseases are presented. Based on available evidence, pazopanib is an effective VEGFR inhibitor with demonstrable clinical activity in metastatic RCC and promising activity in other diseases. Like most kinase inhibitors, its activity is not restricted to VEGF receptors, which is reflected in its side-effect profile.Keywords: pazopanib, VEGFR, renal cell carcinoma

  14. 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.

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

    Science.gov (United States)

    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.

  16. Prognosis of VEGF inhibitors combined with laser therapy in patients with diabetic retinopathy

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    Wei-Xiong Zhou

    2017-02-01

    Full Text Available AIM: To discuss the prognosis effects of vascular endothelial growth factor(VEGFinhibitors combined with laser therapy in patients with diabetic retinopathy. METHODS: Totally 120 patients(129 eyeswith diabetic retinopathy were selected from September 2014 to December 2015 in our Hospital. According to the random distribution, all patients were divided into inhibitor-laser group(60 case with 65 eyesand laser group(60 case with 64 eyes. The laser group was treated with conventional laser treatments. Inhibitor-laser group patients were given VEGF inhibitors treatment besides laser. The international standard was used to charted the visual acuity and enzyme-linked immunosorbent(ELISAwas used to detect the plasma VEGF levels. All patients were followed up for 6mo, analyzed before and after the treatment for curative effect, the lesion center concave thickness(CMT, retinal neovascularization leakage area(RNV, plasma VEGF levels and adverse reactions, and the best corrected visual acuity(BCVAbefore and 1, 3, 6mo after treatment.RESULTS: Efficient rate of inhibitor-laser group was obviously higher than that of the laser group, with statistical difference(PPPP>0.05. CONCLUSION: VEGF inhibitors combined with laser therapy can effectively improve the curative effect of patients with diabetic retinopathy. It can effectively improve the retinal thickness and leakage of new blood vessels, and the patient's vision, with good security.

  17. The relationship between synovial fluid VEGF and serum leptin with ultrasonographic findings in knee osteoarthritis.

    Science.gov (United States)

    Kim, Hae-Rim; Lee, Jung-Hwa; Kim, Kyoung-Woon; Kim, Bo-Mi; Lee, Sang-Heon

    2016-03-01

    This study aimed to determine synovial fluid and serum biomarkers which could accord with radiological and ultrasonographic findings in knee osteoarthritis. Thirty-four patients with knee osteoarthritis were detected with joint effusion by clinical examination. Both knee joints were examined using plain radiographs and ultrasonography. Questions were obtained for visual analog scale (VAS), Western Ontario McMaster Universities Osteoarthritis Index and Health Assessment Questionnaire (HAQ). Synovial fluid (SF) and serum levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-13, leptin, resistin and cartilage oligomeric matrix protein (COMP) were measured using enzyme-linked immunosorbent assay. Synovial fluid VEGF level was positively correlated with Kellgren-Lawrence (KL) grades and it was higher in patients with KL grade 4 than those with KL grade 2. SF VEGF correlated with ultrasonographic findings, such as the length of medial osteophytes. The amount of effusion was positively correlated with SF resistin. Serum leptin level had positive correlation with HAQ and the length of medial osteophytes. MMP-13 or COMP levels were not correlated with radiographic or ultrasonographic findings. Synovial fluid VEGF level was correlated with radiographic grading, ultrasonographic findings and functional statues in knee osteoarthritis, and serum leptin level also correlated with the ultrasonographic findings and functional status of knee osteoarthritis. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  18. VEGF Expression in Patellar Tendinopathy: A Preliminary Study

    Science.gov (United States)

    Lian, Øystein; Bahr, Roald; Hart, David A.; Duronio, Vincent

    2008-01-01

    Vascular function and angiogenesis are regulated by vascular endothelial growth factor-A (VEGF). The purpose of this preliminary study was to address the following questions: Is VEGF expression in the patellar tendon more prevalent in patients with patellar tendinopathy than in individuals with normal, pain-free patellar tendons? Which cell populations express VEGF in normal and tendinopathic tendon? Is there a difference in symptom duration between VEGF+ and VEGF− tendons? We collected patellar tendon tissue from 22 patients undergoing open débridement of the patellar tendon and from 10 patients undergoing intramedullary nailing of the tibia. VEGF expression was assessed immunohistochemically. Relevant inflammatory and repair cell types were immunolabeled. VEGF expression was absent from control tendons, but was present in a subset of patients with histopathological evidence of angiofibroblastic tendinosis. VEGF was expressed in the intimal layer of tendon vessels, but was absent in other cell types. Patients demonstrating VEGF expression in the patellar tendon had a shorter symptom duration (12 ± 7.8 months) than patients with no detectable VEGF (32.8 ± 23.5 months). VEGF may contribute to the vascular hyperplasia that is a cardinal feature of symptomatic tendinosis, particularly in cases with more recent onset. PMID:18459027

  19. Ablative Thermal Protection System Fundamentals

    Science.gov (United States)

    Beck, Robin A. S.

    2013-01-01

    This is the presentation for a short course on the fundamentals of ablative thermal protection systems. It covers the definition of ablation, description of ablative materials, how they work, how to analyze them and how to model them.

  20. Comparative integromics on VEGF family members.

    Science.gov (United States)

    Katoh, Yuriko; Katoh, Masaru

    2006-06-01

    VEGF, Hedgehog, FGF, Notch, and WNT signaling pathways network together for vascular remodeling during embryogenesis, tissue regeneration, and carcinogenesis. VEGFA (VEGF), VEGFB, VEGFC, VEGFD (FIGF) and PGF (PlGF) are VEGF family ligands for receptor tyrosine kinases, including VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4). Bevacizumab (Avastin), Sunitinib (Sutent) and Sorafenib (Nexavar) are anti-cancer drugs targeted to VEGF signaling pathway. TCF/LEF binding sites within the promoter region of human VEGF family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the 5'-promoter region of human VEGFD gene within AC095351.5 genome sequence, comparative genomics analyses on VEGFD orthologs were further performed. ASB9-ASB11-VEGFD locus at human chromosome Xp22.2 and ASB5-VEGFC locus at human chromosome 4q34 were paralogous regions within the human genome. Human VEGFD mRNA was expressed in lung, small intestine, uterus, breast, neural tissues, and neuroblastoma. Mouse Vegfd mRNA was expressed in kidney, pregnant oviduct, and neural tissues. Chimpanzee VEGFD promoter, cow Vegfd promoter, mouse Vegfd promoter and rat Vegfd promoter were identified within NW_121675.1, AC161065.2, AL732475.6 and AC130036.3 genome sequences, respectively. Three out of four TCF/LEF-binding sites within human VEGFD promoter were conserved in chimpanzee VEGFD promoter, and one in cow Vegfd promoter. TCF/LEF-binding site, not conserved in human VEGFD promoter, occurred in cow, mouse and rat Vegfd promoters. At least five out of six bHLH-binding sites within human VEGFD proximal promoter region were conserved in chimpanzee VEGFD proximal promoter region, while only one in cow Vegfd proximal promoter region. Together these facts indicate that relatively significant promoter evolution occurred among mammalian VEGFD orthologs. Human VEGFD was characterized as a potent target gene of WNT

  1. Laser ablation principles and applications

    CERN Document Server

    1994-01-01

    Laser Ablation provides a broad picture of the current understanding of laser ablation and its many applications, from the views of key contributors to the field. Discussed are in detail the electronic processes in laser ablation of semiconductors and insulators, the post-ionization of laser-desorbed biomolecules, Fourier-transform mass spectroscopy, the interaction of laser radiation with organic polymers, laser ablation and optical surface damage, laser desorption/ablation with laser detection, and laser ablation of superconducting thin films.

  2. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188.

    Science.gov (United States)

    Maes, Christa; Carmeliet, Peter; Moermans, Karen; Stockmans, Ingrid; Smets, Nico; Collen, Désiré; Bouillon, Roger; Carmeliet, Geert

    2002-02-01

    Vascular endothelial growth factor (VEGF)-mediated angiogenesis is an important part of bone formation. To clarify the role of VEGF isoforms in endochondral bone formation, we examined long bone development in mice expressing exclusively the VEGF120 isoform (VEGF120/120 mice). Neonatal VEGF120/120 long bones showed a completely disturbed vascular pattern, concomitant with a 35% decrease in trabecular bone volume, reduced bone growth and a 34% enlargement of the hypertrophic chondrocyte zone of the growth plate. Surprisingly, embryonic hindlimbs at a stage preceding capillary invasion exhibited a delay in bone collar formation and hypertrophic cartilage calcification. Expression levels of marker genes of osteoblast and hypertrophic chondrocyte differentiation were significantly decreased in VEGF120/120 bones. Furthermore, inhibition of all VEGF isoforms in cultures of embryonic cartilaginous metatarsals, through the administration of a soluble receptor chimeric protein (mFlt-1/Fc), retarded the onset and progression of ossification, suggesting that osteoblast and/or hypertrophic chondrocyte development were impaired. The initial invasion by osteoclasts and endothelial cells into VEGF120/120 bones was retarded, associated with decreased expression of matrix metalloproteinase-9. Our findings indicate that expression of VEGF164 and/or VEGF188 is important for normal endochondral bone development, not only to mediate bone vascularization but also to allow normal differentiation of hypertrophic chondrocytes, osteoblasts, endothelial cells and osteoclasts.

  3. Anti-VEGF Therapy for Diabetic Eye Diseases.

    Science.gov (United States)

    Bahrami, Bobak; Hong, Thomas; Gilles, Mark C; Chang, Andrew

    2017-01-01

    Diabetic retinopathy (DR) is a leading cause of vision impairment and blindness in the working-age population. The identification of vascular endothelial growth factor (VEGF) as a key mediator in the pathogenesis of DR has revolutionized the management of this vision-threatening disease. There is now strong evidence supporting intravitreal anti-VEGF therapy as first line in the management of sight-threatening diabetic macular edema (DME), along with a growing body of evidence to support the use of anti-VEGF drugs for proliferative DR. This review summarizes the role of VEGF in DR, the evidence for anti-VEGF therapy, safety considerations, and the future of anti-VEGF therapy for the management of DR. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

  4. Thicker carotid intima-media thickness and increased plasma VEGF levels suffered by post-acute thrombotic stroke patients

    Directory of Open Access Journals (Sweden)

    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

  5. Engineered microenvironments for synergistic VEGF - Integrin signalling during vascularization.

    Science.gov (United States)

    Moulisová, Vladimíra; Gonzalez-García, Cristina; Cantini, Marco; Rodrigo-Navarro, Aleixandre; Weaver, Jessica; Costell, Mercedes; Sabater I Serra, Roser; Dalby, Matthew J; García, Andrés J; Salmerón-Sánchez, Manuel

    2017-05-01

    We have engineered polymer-based microenvironments that promote vasculogenesis both in vitro and in vivo through synergistic integrin-growth factor receptor signalling. Poly(ethyl acrylate) (PEA) triggers spontaneous organization of fibronectin (FN) into nanonetworks which provide availability of critical binding domains. Importantly, the growth factor binding (FNIII12-14) and integrin binding (FNIII9-10) regions are simultaneously available on FN fibrils assembled on PEA. This material platform promotes synergistic integrin/VEGF signalling which is highly effective for vascularization events in vitro with low concentrations of VEGF. VEGF specifically binds to FN fibrils on PEA compared to control polymers (poly(methyl acrylate), PMA) where FN remains in a globular conformation and integrin/GF binding domains are not simultaneously available. The vasculogenic response of human endothelial cells seeded on these synergistic interfaces (VEGF bound to FN assembled on PEA) was significantly improved compared to soluble administration of VEGF at higher doses. Early onset of VEGF signalling (PLCγ1 phosphorylation) and both integrin and VEGF signalling (ERK1/2 phosphorylation) were increased only when VEGF was bound to FN nanonetworks on PEA, while soluble VEGF did not influence early signalling. Experiments with mutant FN molecules with impaired integrin binding site (FN-RGE) confirmed the role of the integrin binding site of FN on the vasculogenic response via combined integrin/VEGF signalling. In vivo experiments using 3D scaffolds coated with FN and VEGF implanted in the murine fat pad demonstrated pro-vascularization signalling by enhanced formation of new tissue inside scaffold pores. PEA-driven organization of FN promotes efficient presentation of VEGF to promote vascularization in regenerative medicine applications. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. VEGF-targeted magnetic nanoparticles for MRI visualization of brain tumor.

    Science.gov (United States)

    Abakumov, Maxim A; Nukolova, Natalia V; Sokolsky-Papkov, Marina; Shein, Sergey A; Sandalova, Tatiana O; Vishwasrao, Hemant M; Grinenko, Nadezhda F; Gubsky, Iliya L; Abakumov, Artem M; Kabanov, Alexander V; Chekhonin, Vladimir P

    2015-05-01

    This work is focused on synthesis and characterization of targeted magnetic nanoparticles as magnetic resonance imaging (МRI) agents for in vivo visualization of gliomas. Ferric oxide (Fe3O4) cores were synthesized by thermal decomposition and coated with bovine serum albumin (BSA) to form nanoparticles with Deff of 53±9nm. The BSA was further cross-linked to improve colloidal stability. Monoclonal antibodies against vascular endothelial growth factor (mAbVEGF) were covalently conjugated to BSA through a polyethyleneglycol linker. Here we demonstrate that 1) BSA coated nanoparticles are stable and non-toxic to different cells at concentration up to 2.5mg/mL; 2) conjugation of monoclonal antibodies to nanoparticles promotes their binding to VEGF-positive glioma С6 cells in vitro; 3) targeted nanoparticles are effective in MRI visualization of the intracranial glioma. Thus, mAbVEGF-targeted BSA-coated magnetic nanoparticles are promising MRI contrast agents for glioma visualization. This work focuses on synthesis and characterization of targeted magnetic nanoparticles as magnetic resonance imaging (МRI) agents for in vivo visualization of gliomas. The authors utilize the fact that high-grade gliomas have extensive areas of necrosis and hypoxia, which results in increased secretion of angiogenesis vascular endothelial growth factor (VEGF). Monoclonal antibodies against vascular endothelial growth factor (mAbVEGF) were covalently conjugated to crosslinked BSA coated ferric oxide (Fe3O4) nanoparticles. The results show that these targeted nanoparticles are effective in MRI visualization of the intracranial glioma and may provide a new and promising contrast agent. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. VEGF, HIF-1α and PEDF expression in the retina of streptozotocin-induced diabetics rats treated with ozone

    Directory of Open Access Journals (Sweden)

    Ting-Yu Xie

    2016-02-01

    Full Text Available AIM:To study vascular endothelial growth factor(VEGF, pigment epithelium derived factor(PEDFand hypoxia inducible factor-1α(HIF-1αexpression in retinal and serum in ozone-treated streptozotocin(STZ-induced diabetic rats and to determine the possible efficacy of ozone therapy for diabetic retinopathy(DR.METHODS:Seventy male Sprague-Dawley rats were used. Group A(n=10received a normal diet, diabetic molding established by intraperitoneal injection of STZ(50mg/ml, then divided into three groups, group B without any intervene; and groups C and D given oxygen and ozone clyster treatment respectively, twice per week for 1mo. Retina and blood were taken under general anesthesia. Reverse transcription-polymerase chain reaction(RT-PCRand enzyme-linked immunosorbent assay(ELISAmethods were used to study retinal and serum VEGF, HIF-1α and PEDF expression.RESULTS:VEGF occurred mostly in the inner layer of the retina; the difference of VEGF in the retina among each group has statistical difference(F=23.923; P=0.000; in which, group D closer to group A, but still has statistical difference(PP>0.05except for no difference between group A and D(P>0.05, others as same result as retinal VEGF expression.HIF-1α expression decreased in ozone-treated rats(group Dcompared with control group(PPP>0.05. Overall, PEDF expression was lower than VEGF and HIF-1α, and groups A and D showed more expression than groups B and C, but the differences were not significant(P >0.05.CONCLUSION: Ozone administration can reduce the VEGF and HIF-1α expression and ozone may have potential uses in its treatment.

  8. Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164.

    Science.gov (United States)

    Sacchi, Veronica; Mittermayr, Rainer; Hartinger, Joachim; Martino, Mikaël M; Lorentz, Kristen M; Wolbank, Susanne; Hofmann, Anna; Largo, Remo A; Marschall, Jeffrey S; Groppa, Elena; Gianni-Barrera, Roberto; Ehrbar, Martin; Hubbell, Jeffrey A; Redl, Heinz; Banfi, Andrea

    2014-05-13

    Clinical trials of therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery failed to show efficacy. Major challenges include the need to precisely control in vivo distribution of growth factor dose and duration of expression. Recombinant VEGF protein delivery could overcome these issues, but rapid in vivo clearance prevents the stabilization of induced angiogenesis. Here, we developed an optimized fibrin platform for controlled delivery of recombinant VEGF, to robustly induce normal, stable, and functional angiogenesis. Murine VEGF164 was fused to a sequence derived from α2-plasmin inhibitor (α2-PI1-8) that is a substrate for the coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. An α2-PI1-8-fused variant of the fibrinolysis inhibitor aprotinin was used to control the hydrogel degradation rate, which determines both the duration and effective dose of factor release. An optimized aprotinin-α2-PI1-8 concentration ensured ideal degradation over 4 wk. Under these conditions, fibrin-α2-PI1-8-VEGF164 allowed exquisitely dose-dependent angiogenesis: concentrations ≥25 μg/mL caused widespread aberrant vascular structures, but a 500-fold concentration range (0.01-5.0 μg/mL) induced exclusively normal, mature, nonleaky, and perfused capillaries, which were stable after 3 mo. Optimized delivery of fibrin-α2-PI1-8-VEGF164 was therapeutically effective both in ischemic hind limb and wound-healing models, significantly improving angiogenesis, tissue perfusion, and healing rate. In conclusion, this optimized platform ensured (i) controlled and highly tunable delivery of VEGF protein in ischemic tissue and (ii) stable and functional angiogenesis without introducing genetic material and with a limited and controllable duration of treatment. These findings suggest a strategy to improve safety and efficacy of therapeutic angiogenesis.

  9. Construction, expression, purification, and characterization of a dual-targeting PD-1/VEGF-A fusion protein (P-V).

    Science.gov (United States)

    Qian, Niliang; Gao, Liucun; Dong, Lihou; Liu, Hongchuan; Fu, Jie; Meng, Dan; Gao, Xin; Zhang, Jing; Gao, Yucai; Song, Haifeng

    2015-05-01

    Targeting programmed death-1 (PD-1) is regarded as a novel and promising means for the treatment of many types of solid tumor. In the tumor microenvironment (TME), VEGF expression is dramatically up-regulated, and compounds that neutralize VEGF or block the interaction of VEGF with its receptors exhibit potent antitumor activity, and blocking PD-1 might promote T cell infiltration into TME and significantly enhance local immune activation. Thus, we fused domain II and domain III of kinase-insert domain receptor (KDR), the receptor of VEGF-A, to the Fc side of an anti-PD-1 monoclonal antibody with a (Gly4Ser)3 linker to generate a dual targeting fusion protein. The recombinant plasmid was successfully constructed and the fusion protein was expressed in 293E cells. Protein purification was performed in a single step by using protein A affinity chromatography. The molecular weight of the fusion protein was approximately 220kDa, and the yield was approximately 2.97g/L. Specific binding of recombinant protein to PD-1 and VEGF was detected by enzyme-linked immunosorbent assay (ELISA) analysis. Half maximal effective concentration (EC50) values were 0.561nM for PD-1 and 0.682nM for VEGF-A; accordingly, half maximal inhibitory concentration (IC50) values were 0.914nM and 0.583nM, respectively. Proliferation inhibition assays indicated that the fusion protein could inhibit the growth of human umbilical vein endothelial cells effectively. Taken together, the results indicate that this novel fusion protein can simultaneously target PD-1 and VEGF and may be beneficial for combining anti-angiogenesis with immunotherapeutic approaches for the treatment of patients with cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Hypoxia promotes adipose-derived stem cell proliferation via VEGF

    Directory of Open Access Journals (Sweden)

    Phuc Van Pham

    2016-01-01

    Full Text Available Adipose-derived stem cells (ADSCs are a promising mesenchymal stem cell source with therapeutic applications. Recent studies have shown that ADSCs could be expanded in vitro without phenotype changes. This study aimed to evaluate the effect of hypoxia on ADSC proliferation in vitro and to determine the role of vascular endothelial growth factor (VEGF in ADSC proliferation. ADSCs were selectively cultured from the stromal vascular fraction obtained from adipose tissue in DMEM/F12 medium supplemented with 10% fetal bovine serum and 1% antibiotic-antimycotic. ADSCs were cultured under two conditions: hypoxia (5% O2 and normal oxygen (21% O2. The effects of the oxygen concentration on cell proliferation were examined by cell cycle and doubling time. The expression of VEGF was evaluated by the ELISA assay. The role of VEGF in ADSC proliferation was studied by neutralizing VEGF with anti-VEGF monoclonal antibodies. We found that the ADSC proliferation rate was significantly higher under hypoxia compared with normoxia. In hypoxia, ADSCs also triggered VEGF expression. However, neutralizing VEGF with anti-VEGF monoclonal antibodies significantly reduced the proliferation rate. These results suggest that hypoxia stimulated ADSC proliferation in association with VEGF production. [Biomed Res Ther 2016; 3(1.000: 476-482

  11. Molecular Imaging of VEGF Receptors in Graft Arteriosclerosis

    Science.gov (United States)

    Zhang, Jiasheng; Razavian, Mahmoud; Tavakoli, Sina; Nie, Lei; Tellides, George; Backer, Joseph M.; Backer, Marina V.; Bender, Jeffrey R.; Sadeghi, Mehran M.

    2012-01-01

    Objectives Vascular endothelial growth factor (VEGF) signaling plays a key role in the pathogenesis of vascular remodeling, including graft arteriosclerosis (GA). GA is the major cause of late organ failure in cardiac transplantation. We used molecular near-infrared fluorescent (NIRF) imaging with an engineered Cy5.5-labeled single-chain VEGF tracer (scVEGF/Cy) to detect VEGF receptors (VEGFRs) and vascular remodeling in human coronary artery grafts by molecular imaging. Methods and Results VEGFR-specificity of probe uptake was shown by flow cytometry in endothelial cells. In severe combined immunodeficiency mice, transplantation of human coronary artery segments into the aorta followed by adoptive transfer of allogeneic human peripheral blood mononuclear cells (PBMCs) led to significant neointima formation in the grafts over a period of 4 weeks. NIRF imaging of transplant recipients at 4 weeks demonstrated focal uptake of scVEGF/Cy in remodeling artery grafts. Uptake specificity was demonstrated using an inactive homologue of scVEGF/Cy. scVEGF/Cy uptake predominantly localized in the neointima of remodeling coronary arteries and correlated with VEGFR-1, but not VEGFR-2 expression. There was a significant correlation between scVEGF/Cy uptake and transplanted artery neointima area. Conclusions Molecular imaging of VEGF receptors may provide a non-invasive tool for detection of GA in solid organ transplantation. PMID:22723442

  12. The production of VEGF involving MAP kinase activation by low level laser therapy in human granulosa cells

    Science.gov (United States)

    Utsunomiya-Kai, Yufuko; Kai, Kentaro; Miyakawa, Isao; Ohshiro, Toshio; Narahara, Hisashi

    2012-01-01

    Objective: The function of granulosa cells is regulated by various hormones and growth factors. Our aim is to clarify the regulation of vascular endothelial growth factor (VEGF) production via mitogen-activated protein kinase (MAPK) induced by low level laser therapy (LLLT) in human granulosa cells. Methods: A human granulosa cell line, KGN cells, were cultured and incubated after LLLT (60mW, GaAlAs 830nm). The levels of VEGF in the culture media were determined by an enzyme-linked immunosorbent assay. The activation of MAP kinase in KGN cells was detected by western blot analysis. Results: VEGF production was significantly increased by LLLT in a time-dependent manner. MAP kinase activity was increased by LLLT. In addition it was enhanced by LLLT and follicle-stimulating hormone (FSH) stimulation. Conclusions: The results suggested that VEGF is induced by LLLT through mechanisms involving MAPK. The increase in VEGF may contribute to neovascularization, which in turn would promote various ovulation phenomena as well as follicular growth. PMID:24511196

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Pancreatic duct cells as a source of VEGF in mice.

    Science.gov (United States)

    Xiao, Xiangwei; Prasadan, Krishna; Guo, Ping; El-Gohary, Yousef; Fischbach, Shane; Wiersch, John; Gaffar, Iljana; Shiota, Chiyo; Gittes, George K

    2014-05-01

    Vascular endothelial growth factor (VEGF) is essential for proper pancreatic development, islet vascularisation and insulin secretion. In the adult pancreas, VEGF is thought to be predominantly secreted by beta cells. Although human duct cells have previously been shown to secrete VEGF at angiogenic levels in culture, an analysis of the kinetics of VEGF synthesis and secretion, as well as elucidation of an in vivo role for this ductal VEGF in affecting islet function and physiology, has been lacking. We analysed purified duct cells independently prepared by flow cytometry, surgical isolation or laser-capture microdissection. We infected duct cells in vivo with Vegf (also known as Vegfa) short hairpin RNA (shRNA) in an intrapancreatic ductal infusion system and examined the effect of VEGF knockdown in duct cells in vitro and in vivo. Pancreatic duct cells express high levels of Vegf mRNA. Compared with beta cells, duct cells had a much higher ratio of secreted to intracellular VEGF. As a bioassay, formation of tubular structures by human umbilical vein endothelial cells was essentially undetectable when cultured alone and was substantially increased when co-cultured with pancreatic duct cells but significantly reduced when co-cultured with duct cells pretreated with Vegf shRNA. Compared with islets transplanted alone, improved vascularisation and function was detected in the islets co-transplanted with duct cells but not in islets co-transplanted with duct cells pretreated with Vegf shRNA. Human islet preparations for transplantation typically contain some contaminating duct cells and our findings suggest that the presence of duct cells in the islet preparation may improve transplantation outcomes.

  15. Identification and characterization of VEGF and FGF from Hydra.

    Science.gov (United States)

    Krishnapati, Lakshmi-Surekha; Ghaskadbi, Surendra

    2013-01-01

    Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) play important roles in the formation of the blood vascular system and in axon guidance, nervous system development and function. Here, we report isolation and characterization of VEGF and FGF homologues from Hydra vulgaris Ind-Pune, a Cnidarian which exhibits an organized nervous system and primitive epithelio-muscular cells. VEGF expression was prominent in the endoderm of the peduncle region and tentacles, as evident from in situ hybridization of whole polyps and its transverse sections. High levels of FGF were detected in the ectoderm of the budding region. The expression of VEGF in endodermal and FGF in interstitial cells was confirmed using sf-1 hydra, a temperature-sensitive mutant strain of Hydra magnipapillata. Tissue-specific expression of VEGF and FGF was confirmed by semi quantitative RT-PCR for ectodermal and endodermal tissues in H. vulgaris Ind-Pune. Treatment with SU5416, a specific inhibitor of the VEGF receptor, did not affect the whole polyp, but did delay both budding and head regeneration, suggesting a possible role of VEGF in nerve cell development, tube formation and/or in branching. FGF expression in the ectoderm of budding region, where the majority of interstitial stem cells reside suggests its role in interstitial stem cell maintenance. Further, activation of canonical Wnt signalling with the glycogen synthase kinase-3β (GSK-3β) inhibitor alsterpaullone caused down-regulation of VEGF and FGF, suggesting an antagonistic relationship between the Wnt and VEGF/FGF pathways. Our results indicate that VEGF and FGF evolved early in evolution, before the development of the blood vascular system, and open up the possibility of elucidating the evolutionarily ancient functions of VEGF and FGF.

  16. Aberrant, ectopic expression of VEGF and VEGF receptors 1 and 2 in malignant colonic epithelial cells. Implications for these cells growth via an autocrine mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Ahluwalia, Amrita [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Jones, Michael K. [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Department of Medicine, University of California, Irvine, CA (United States); Szabo, Sandor [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Department of Pathology, University of California, Irvine, CA (United States); Tarnawski, Andrzej S., E-mail: amrita.ahluwalia@va.gov [Veterans Affairs Long Beach Healthcare System, Long Beach, CA (United States); Department of Medicine, University of California, Irvine, CA (United States)

    2013-08-09

    Highlights: •Malignant colonic epithelial cells express VEGF and its receptors. •Cultured colon cancer cells secrete VEGF into the medium. •Inhibition of VEGF receptor significantly decreases colon cancer cell proliferation. •VEGF is critical for colon cancer cell growth. -- Abstract: Vascular endothelial growth factor A (referred to as VEGF) is implicated in colon cancer growth. Currently, the main accepted mechanism by which VEGF promotes colon cancer growth is via the stimulation of angiogenesis, which was originally postulated by late Judah Folkman. However, the cellular source of VEGF in colon cancer tissue; and, the expression of VEGF and its receptors VEGF-R1 and VEGF-R2 in colon cancer cells are not fully known and are subjects of controversy. Material and methods: We examined and quantified expression of VEGF, VEGF-R1 and VEGF-R2 in three different human colonic tissue arrays containing sections of adenocarcinoma (n = 43) and normal mucosa (n = 41). In human colon cancer cell lines HCT116 and HT29 and normal colon cell lines NCM356 and NCM460, we examined expression of VEGF, VEGF-R1 and VEGF-R2 mRNA and protein, VEGF production and secretion into the culture medium; and, the effect of a potent, selective inhibitor of VEGF receptors, AL-993, on cell proliferation. Results: Human colorectal cancer specimens had strong expression of VEGF in cancer cells and also expressed VEGF-R1 and VEGF-R2.In vitro studies showed that human colon cancer cell lines, HCT116 and HT29, but not normal colonic cell lines, express VEGF, VEGF-R1 and VEGF-R2 and secrete VEGF into the medium up to a concentration 2000 pg/ml within 48 h. Furthermore, we showed that inhibition of VEGF receptors using a specific VEGF-R inhibitor significantly reduced proliferation (by >50%) of cultured colon cancer cell lines. Conclusions: Our findings support the contention that VEGF generated by colon cancer cells stimulates their growth directly through an autocrine mechanism that is

  17. Radiofrequency ablation in dermatology

    Directory of Open Access Journals (Sweden)

    Sachdeva Silonie

    2007-01-01

    Full Text Available Radiofreqeuency ablation is a versatile dermatosurgical procedure used for surgical management of skin lesions by using various forms of alternating current at an ultra high frequency. The major modalities in radiofrequency are electrosection, electrocoagulation, electrodessication and fulguration. The use of radiofrequency ablation in dermatosurgical practice has gained importance in recent years as it can be used to treat most of the skin lesions with ease in less time with clean surgical field due to adequate hemostasis and with minimal side effects and complications. This article focuses on the major tissue effects and factors influencing radiofrequency ablation and its application for various dermatological conditions.

  18. Matrix metalloproteinase-2 ablation in dystrophin-deficient mdx muscles reduces angiogenesis resulting in impaired growth of regenerated muscle fibers.

    Science.gov (United States)

    Miyazaki, Daigo; Nakamura, Akinori; Fukushima, Kazuhiro; Yoshida, Kunihiro; Takeda, Shin'ichi; Ikeda, Shu-ichi

    2011-05-01

    Matrix metalloproteases (MMPs) are a family of endopeptidases classified into subgroups based on substrate preference in normal physiological processes such as embryonic development and tissue remodeling, as well as in various disease processes via degradation of extracellular matrix components. Among the MMPs, MMP-9 and MMP-2 have been reported to be up-regulated in skeletal muscles in the lethal X-linked muscle disorder Duchenne muscular dystrophy (DMD), which is caused by loss of dystrophin. A recent study showed that deletion of the MMP9 gene in mdx, a mouse model for DMD, improved skeletal muscle pathology and function; however, the role of MMP-2 in the dystrophin-deficient muscle is not well known. In this study, we aimed at verifying the role of MMP-2 in the dystrophin-deficient muscle by using mdx mice with genetic ablation of MMP-2 (mdx/MMP-2(-/-)). We found impairment of regenerated muscle fiber growth with reduction of angiogenesis in mdx/MMP-2(-/-) mice at 3 months of age. Expression of vascular endothelial growth factor-A (VEGF-A), an important angiogenesis-related factor, decreased in mdx/MMP-2(-/-) mice at 3 months of age. MMP-2 had not a critical role in the degradation of dystrophin-glycoprotein complex (DGC) components such as β-dystroglycan and β-sarcoglycan in the regeneration process of the dystrophic muscle. Accordingly, MMP-2 may be essential for growth of regenerated muscle fibers through VEGF-associated angiogenesis in the dystrophin-deficient skeletal muscle.

  19. Elevated serum and tissue VEGF associated with poor outcome in ...

    African Journals Online (AJOL)

    Enas Mohamed Ali

    Abstract Vascular endothelial growth factor (VEGF) has a potent angiogenesis functions in experimental models, although their role in the progression of human breast cancer is unclear. The aim of the current study was to examine the expression pattern of VEGF in serum and tissues of breast cancer patients, examine the ...

  20. Increased vascular endothelial growth factor (VEGF) expression in ...

    African Journals Online (AJOL)

    Vascular endothelial growth factor (VEGF), a well known angiogenic factor, has been shown to have direct and/or indirect influence on spinal cord injury (SCI). The purpose of this study is to observe VEGF expression changes in rats with SCI by bone marrow stromal cells (BMSCs) treatment. The mRNA expression of VEGF ...

  1. VEGF, the underlying factor for metabolic syndrome; fact or fiction?

    Science.gov (United States)

    Mazidi, Mohsen; Rezaie, Peyman; Kengne, A P; Stathopoulou, Maria G; Azimi-Nezhad, Mohsen; Siest, Sophie

    2017-11-01

    Metabolic syndrome (MetS) is currently diagnosed by the co-presence of at least three of the five following abnormalities: abdominal obesity, dysglycaemia, elevated serum triglycerides, low high-density cholesterol (HDL) and finally elevated blood pressure. Metabolic syndrome increases the risk of developing cardiovascular disease and diabetes. This review is on the associations between MetS and vascular endothelial growth factor (VEGF). VEGF induces migration and proliferation of endothelial cells (ECs), increases vascular permeability and has a role in tumor growth, adipose tissue expansion, age-related macular degeneration and diabetic retinopathy. Circulating levels of VEGFs are elevated in obese individuals and it has also been suggested that VEGF is secreted from adipose tissues, especially from intra-abdominal adipose tissue. There is abundant evidence to support that poor glycemic control in diabetic patients is associated with increased plasma VEGF, which in turn may cause hypertension and several vascular complications in diabetic patients. Circulating VEGF levels are increased in children and young adults with type 1 diabetes mellitus and middle-aged diabetic patients with proliferative retinopathy. It has been revealed that plasma VEGF increases in patients with hyperlipidemia and may trigger the development of atherosclerosis. It can be concluded that there is a positive association between VEGF and components of MetS. Because of the importance of this relationship, more investigations are needed in this field. Copyright © 2016. Published by Elsevier Ltd.

  2. Ginsenoside Rg3 attenuates hepatoma VEGF overexpression after hepatic artery embolization in an orthotopic transplantation hepatocellular carcinoma rat model

    Directory of Open Access Journals (Sweden)

    Zhou B

    2014-10-01

    Full Text Available Bo Zhou, Jianhua Wang, Zhiping Yan Department of Interventional Radiology, Zhongshan Hospital, Shanghai Medical College, Fudan University, People's Republic of China Background: Hypoxia-induced vascular endothelial growth factor (VEGF upregulation and angiogenesis following treatment of hepatocellular carcinoma (HCC with transarterial embolization (TAE or transarterial chemoembolization (TACE may be mediated by ginsenoside Rg3, an anti-angiogenic saponin extracted from ginseng. Objective: To access the synergistic action of Rg3 and TAE treatment on HCC by VEGF and it's receptor expressions decreasing in a rat model of HCC. Methods: An orthotopic transplantation HCC model was established in Buffalo rats. HCC rats were treated with hepatic artery infusions of normal saline or iodized oil (0.1 mL with or without Rg3 (1 mg/kg (each n=15 in control, Rg3, TAE, and TAE + Rg3 groups. At 1, 2, 4, and 8 weeks, performance status (body weight, tumor progression (longest tumor diameter, metastasis rate, microvessel density (MVD, and overall survival rate were assessed. Additionally, cluster of differentiation 31 (CD31, VEGF, VEGF receptor 2 (VEGF-R2 and VEGF-R2 phosphorylation levels were assessed by immunohistochemistry, enzyme-linked immunosorbent assay (ELISA, and Western blot. Results: Combined Rg3 and TAE treatment reduced tumor progression, body weight loss, angiogenesis, and metastasis rate, and led to better overall survival in the HCC rat model. ELISA results showing VEGF expression in the control, Rg3, TAE, and TAE + Rg3 groups at 4 weeks following treatment were 132.6±2.38, 37.9±0.8, 87.4±0.7, and 45.3±0.4 pg/mL, respectively. Combined Rg3 and TAE reduced the protein expression of CD31 and VEGF-R2 phosphorylation, compared with those in the TAE group at 4 weeks of treatment. Conclusion: Combined Rg3 and TAE treatment limited metastasis and promoted survival by downregulating VEGF overexpression in HCC tumors. Thus, this treatment may have

  3. Changing paradigms of anti-VEGF in the Indian scenario

    Directory of Open Access Journals (Sweden)

    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.

  4. [Role of VEGF in diseases of the retina].

    Science.gov (United States)

    Barquet, Luis Arias

    2015-03-01

    Angiogenesis is the process through which new blood vessels are formed, based on preexisting vessels, and is the paradigm of diseases such as cancer and exudative ageassociated macular degeneration (ARMD). Several proangiogenic factors have been identified, such as vascular endothelial growth factor (VEGF), especially VEGF-A, which activates endothelial cells and promotes cell proliferation, migration, and an increase in vascular permeability. VEGF is also involved in the etiopathogenesis of other retinal diseases, such as diabetic macular edema and macular edema secondary to retinal vein occlusion. Likewise, there is increasing evidence that placental growth factor (PIGF) acts recepsynergetically with VEGF in promoting these diseases. Currently, the main treatment for these diseases are the anti-VEGF drugs, aflibercept, ranibizumab and bevacizumab. These agents differ in their molecular structure and mechanism of action. Copyright © 2015 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  5. Differential expression of VEGF ligands and receptors in prostate cancer.

    Science.gov (United States)

    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.

  6. Laser ablation of concrete.

    Energy Technology Data Exchange (ETDEWEB)

    Savina, M.

    1998-10-05

    Laser ablation is effective both as an analytical tool and as a means of removing surface coatings. The elemental composition of surfaces can be determined by either mass spectrometry or atomic emission spectroscopy of the atomized effluent. Paint can be removed from aircraft without damage to the underlying aluminum substrate, and environmentally damaged buildings and sculptures can be restored by ablating away deposited grime. A recent application of laser ablation is the removal of radioactive contaminants from the surface and near-surface regions of concrete. We present the results of ablation tests on concrete samples using a high power pulsed Nd:YAG laser with fiber optic beam delivery. The laser-surface interaction was studied on various model systems consisting of Type I Portland cement with varying amounts of either fine silica or sand in an effort to understand the effect of substrate composition on ablation rates and mechanisms. A sample of non-contaminated concrete from a nuclear power plant was also studied. In addition, cement and concrete samples were doped with non-radioactive isotopes of elements representative of cooling waterspills, such as cesium and strontium, and analyzed by laser-resorption mass spectrometry to determine the contamination pathways. These samples were also ablated at high power to determine the efficiency with which surface contaminants are removed and captured. The results show that the neat cement matrix melts and vaporizes when little or no sand or aggregate is present. Surface flows of liquid material are readily apparent on the ablated surface and the captured aerosol takes the form of glassy beads up to a few tens of microns in diameter. The presence of sand and aggregate particles causes the material to disaggregate on ablation, with intact particles on the millimeter size scale leaving the surface. Laser resorption mass spectrometric analysis showed that cesium and potassium have similar chemical environments in the

  7. Impact of Alendronate and VEGF- antisense combined treatment on highly VEGF-expressing A431 cells

    OpenAIRE

    Mongerard-Coulanges, Medge; Migianu-Griffoni, Evelyne; Lecouvey, Marc; Jolles, Béatrice

    2009-01-01

    Abstract Bisphosphonates, and more specially nitrogen- containing bisphosphonates, which are in current use for the treatment of bone diseases, demonstrate proapoptotic, antiproliferative, antiangiogenic and anti-invasive properties on tumor cells. The amino- bisphosphonate alendronate is considered as a potential anticancer drug. In the case of A431 cells, which express high levels of VEGF, it had a two-step effect. At 24h, the antitumor properties of alendronate were counterbalan...

  8. Correlation between the expression of vegf and survival in osteosarcoma.

    Science.gov (United States)

    Baptista, André Mathias; Camargo, André Ferrari De França; Filippi, Renée Zon; Oliveira, Cláudia Regina Gomes Cardim Mendes De; Azevedo Neto, Raymundo Soares De; Camargo, Olavo Pires De

    2014-01-01

    To present a series of 50 consecutive patients with non-metastatic extremity osteosarcoma, and attempt to correlate expression of the vascular endothelial growth factor (VEGF) protein in biopsy tissue to their prognosis regarding overall survival, disease-free survival and local recurrence. Fifty cases of non-metastatic osteosarcoma of the extremities treated between 1986 and 2006 at Instituto de Ortopedia e Traumatologia da Universidade de São Paulo, São Paulo, Brasil, were evaluated regarding expression of the VEGF protein. There were 19 females and 31 males. The mean age was 16 years old (range 5-28 years old) and the mean follow-up was 60.6 months (range 25-167 months). The variables studied were age, gender, anatomic location, type of surgery, surgical margins, tumor size, post chemotherapy necrosis, local recurrence, pulmonary metastasis and death. Thirty-six patients showed VEGF expression on 30% or less cells (low), and the remaining 14 cases had VEGF expression above 30% (high). Among the 36 patients with low VEGF expression, nine developed pulmonary metastasis and four died (11.1%). Among the 14 patients with high VEGF expression, six developed pulmonary metastasis and three died (21.4%). There was no statistically significant correlation between the expression of VEGF and any of the variables studied. Level of Evidence IV, Therapeutic Study.

  9. Amphiregulin enhances VEGF-A production in human chondrosarcoma cells and promotes angiogenesis by inhibiting miR-206 via FAK/c-Src/PKCδ pathway.

    Science.gov (United States)

    Wang, Chao-Qun; Huang, Yu-Wen; Wang, Shih-Wei; Huang, Yuan-Li; Tsai, Chun-Hao; Zhao, Yong-Ming; Huang, Bi-Fei; Xu, Guo-Hong; Fong, Yi-Chin; Tang, Chih-Hsin

    2017-01-28

    Chondrosarcoma is the second most common primary malignancy of bone after myeloma and osteosarcoma. Chondrosarcoma development may be linked to angiogenesis, which is principally elicited by vascular endothelial growth factor-A (VEGF-A). The expression of VEGF-A has been recognized as a prognostic marker in angiogenesis. Amphiregulin (AR), an epidermal growth factor receptor ligand, promotes tumor proliferation, metastasis and angiogenesis. However, the role of AR in VEGF-A expression and angiogenesis in human chondrosarcoma remains largely unknown. This current study shows that AR promoted VEGF-A production and induced angiogenesis of human endothelial progenitor cells. Moreover, AR-enhanced VEGF-A expression and angiogenesis involved the FAK, c-Src and PKCδ signaling pathways, while miR-206 expression was negatively mediated by AR via the FAK, c-Src and PKCδ pathways. Our results illustrate the clinical significance between AR, VEGF-A and miR-206, as well as tumor stage, in human chondrosarcoma. AR may represent a novel therapeutic target in the metastasis and angiogenesis of chondrosarcoma. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. WISP-3 inhibition of miR-452 promotes VEGF-A expression in chondrosarcoma cells and induces endothelial progenitor cells angiogenesis.

    Science.gov (United States)

    Lin, Chih-Yang; Tzeng, Huey-En; Li, Te-Mao; Chen, Hsien-Te; Lee, Yi; Yang, Yi-Chen; Wang, Shih-Wei; Yang, Wei-Hung; Tang, Chih-Hsin

    2017-06-13

    Chondrosarcoma is the second most prevalent general primary tumor of bone following osteosarcoma. Chondrosarcoma development may be linked to angiogenesis, which is principally elicited by vascular endothelial growth factor-A (VEGF-A). VEGF-A level has been recognized as a prognostic marker in angiogenesis. WNT1-inducible signaling pathway protein-3 (WISP)-3/CCN6 belongs to the CCN family and is involved in regulating several cellular functions, including cell proliferation, differentiation, and migration. Nevertheless, the effect of WISP-3 on VEGF-A production and angiogenesis in human chondrosarcoma remains largely unknown. This current study shows that WISP-3 promoted VEGF-A production and induced angiogenesis of human endothelial progenitor cells. Moreover, WISP-3-enhanced VEGF-A expression and angiogenesis involved the c-Src and p38 signaling pathways, while miR-452 expression was negatively affected by WISP-3 via the c-Src and p38 pathways. Our results illustrate the clinical significance of WISP-3, VEGF-A and miR-452 in human chondrosarcoma patients. WISP-3 may illustrate a novel therapeutic target in the metastasis and angiogenesis of chondrosarcoma.

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

    African Journals Online (AJOL)

    Yomi

    2012-01-16

    Jan 16, 2012 ... human VEGF165 (hVEGF165) gene based on overlap PCR method and recombinant expressed in Chinese's hamster ovary (CHO) ... recombinant human VEGF165 (rhVEGF165) protein in CHO cells. Key words: Overlap .... Stable transfected positive clones appeared after 14 days when the. CHO cells not ...

  12. Joint Effect of Urinary Total Arsenic Level and VEGF-A Genetic Polymorphisms on the Recurrence of Renal Cell Carcinoma.

    Directory of Open Access Journals (Sweden)

    Shu-Mei Yang

    Full Text Available The results of our previous study suggested that high urinary total arsenic levels were associated with an increased risk of renal cell carcinoma (RCC. Germline genetic polymorphisms might also affect cancer risk and clinical outcomes. Vascular endothelial growth factor (VEGF plays an important role in vasculogenesis and angiogenesis, but the combined effect of these factors on RCC remains unclear. In this study, we explored the association between the VEGF-A -2578C>A, -1498T>C, -1154G>A, -634G>C, and +936C>T gene polymorphisms and RCC. We also evaluated the combined effects of the VEGF-A haplotypes and urinary total arsenic levels on the prognosis of RCC. This case-control study was conducted with 191 RCC patients who were diagnosed with renal tumors on the basis of image-guided biopsy or surgical resections. An additional 376 age- and gender-matched controls were recruited. Concentrations of urinary arsenic species were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Genotyping was investigated using fluorescent-based TaqMan allelic discrimination. We observed no significant associations between VEGF-A haplotypes and RCC risk. However, the VEGF-A ACGG haplotype from VEGF-A -2578, -1498, -1154, and -634 was significantly associated with an increased recurrence of RCC (OR = 3.34, 95% CI = 1.03-10.91. Urinary total arsenic level was significantly associated with the risk of RCC in a dose-response manner, but it was not related to the recurrence of RCC. The combination of high urinary total arsenic level and VEGF-A risk haplotypes affected the OR of RCC recurrence in a dose-response manner. This is the first study to show that joint effect of high urinary total arsenic and VEGF-A risk haplotypes may influence the risk of RCC recurrence in humans who live in an area without obvious arsenic exposure.

  13. What is the contribution of two genetic variants regulating VEGF levels to type 2 diabetes risk and to microvascular complications?

    Directory of Open Access Journals (Sweden)

    Amélie Bonnefond

    impact on the variance in circulating VEGF, we did not find any association between SNPs rs6921438 and rs10738760, and the risk of T2D, diabetic nephropathy or retinopathy. The link between VEGF and T2D and its complications might be indirect and more complex than expected.

  14. Ablative Thermal Protection Systems Fundamentals

    Science.gov (United States)

    Beck, Robin A. S.

    2017-01-01

    This is a presentation of the fundamentals of ablative TPS materials for a short course at TFAWS 2017. It gives an overall description of what an ablator is, the equations that define it, and how to model it.

  15. Power Laser Ablation Symposia

    CERN Document Server

    Phipps, Claude

    2007-01-01

    Laser ablation describes the interaction of intense optical fields with matter, in which atoms are selectively driven off by thermal or nonthermal mechanisms. The field of laser ablation physics is advancing so rapidly that its principal results are seen only in specialized journals and conferences. This is the first book that combines the most recent results in this rapidly advancing field with authoritative treatment of laser ablation and its applications, including the physics of high-power laser-matter interaction. Many practical applications exist, ranging from inertial confinement fusion to propulsion of aerostats for pollution monitoring to laser ignition of hypersonic engines to laser cleaning nanoscale contaminants in high-volume computer hard drive manufacture to direct observation of the electronic or dissociative states in atoms and molecules, to studying the properties of materials during 200kbar shocks developed in 200fs. Selecting topics which are representative of such a broad field is difficu...

  16. Advanced Ablative TPS

    Science.gov (United States)

    Gasch, Matthew J.

    2011-01-01

    Early NASA missions (Gemini, Apollo, Mars Viking) employed new ablative TPS that were tailored for the entry environment. After 40 years, heritage ablative TPS materials using Viking or Pathfinder era materials are at or near their performance limits and will be inadequate for future exploration missions. Significant advances in TPS materials technology are needed in order to enable any subsequent human exploration missions beyond Low Earth Orbit. This poster summarizes some recent progress at NASA in developing families of advanced rigid/conformable and flexible ablators that could potentially be used for thermal protection in planetary entry missions. In particular the effort focuses technologies required to land heavy (approx.40 metric ton) masses on Mars to facilitate future exploration plans.

  17. Therapeutic lymphangiogenesis using stem cell and VEGF-C hydrogel.

    Science.gov (United States)

    Hwang, Ji Hye; Kim, In Gul; Lee, Ji Young; Piao, Shuyu; Lee, David S; Lee, Tae Seung; Ra, Jeong Chan; Lee, Ji Youl

    2011-07-01

    Lymphedema is a manifestation of lymphatic system insufficiency. It arises from primary lymphatic dysplasia or secondary obliteration after lymph node dissection or irradiation. Although improvement of swelling can be achieved by comprehensive non-operative therapy, treatment of this condition requires lifelong care and good compliance. Recently molecular-based treatments using VEGF-C have been investigated by several researchers. We designed the present study to determine whether the therapeutic efficacy of implanted human adipose-derived stem cells (hADSCs) could be improved by applying a gelatin hydrogel containing VEGF-C (VEGF-C hydrogel) to the site of tissue injury in a lymphedema mouse model. Four weeks after the operation, we evaluated edema and determined lymphatic vessel density at various post-operative time points. Mice treated with hADSCs and VEGF-C hydrogel showed a significantly decreased dermal edema depth compared to the groups of mice that received hADSCs only or VEGF-C hydrogel only. Immunohistochemical analysis also revealed that the hADSC/VEGF-C hydrogel group showed significantly greater lymphatic vessel regeneration than all the other groups. hADSCs were detected in the implantation sites of all mice in the hADSC/VEGF-C group, and exhibited a lymphatic endothelial differentiation phenotype as determined by co-staining PKH-labeled hADSCs for the lymphatic marker LYVE-1. Our results suggest that co-administration of hADSCs and VEGF-C hydrogel has a substantial positive effect on lymphangiogenesis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. Thrombospondin-1 and VEGF in inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    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.

  19. Advanced Rigid Ablative TPS

    Science.gov (United States)

    Gasch, Matthew J.

    2011-01-01

    NASA Exploration Systems Mission Directorate s (ESMD) Entry, Descent, and Landing (EDL) Technology Development Project (TDP) and the NASA Aeronautics Research Mission Directorate s (ARMD) Hypersonics Project are developing new advanced rigid ablators in an effort to substantially increase reliability, decrease mass, and reduce life cycle cost of rigid aeroshell-based entry systems for multiple missions. Advanced Rigid Ablators combine ablation resistant top layers capable of high heat flux entry and enable high-speed EDL with insulating mass-efficient bottom that, insulate the structure and lower the areal weight. These materials may benefit Commercial Orbital Transportation Services (COTS) vendors and may potentially enable new NASA missions for higher velocity returns (e.g. asteroid, Mars). The materials have been thermally tested to 400-450 W/sq cm at the Laser Hardened Materials Evaluation Lab (LHMEL), Hypersonics Materials Evaluation Test System (HyMETS) and in arcjet facilities. Tested materials exhibit much lower backface temperatures and reduced recession over the baseline materials (PICA). Although the EDL project is ending in FY11, NASA in-house development of advanced ablators will continue with a focus on varying resin systems and fiber/resin interactions.

  20. Basal and apical regulation of VEGF-A and placenta growth factor in the RPE/choroid and primary RPE.

    Science.gov (United States)

    Klettner, Alexa; Kaya, Leyla; Flach, Janina; Lassen, Jens; Treumer, Felix; Roider, Johann

    2015-01-01

    Members of the vascular endothelial growth factor (VEGF) family are strongly involved in pathological processes in the retina, such as age-related macular degeneration and diabetic retinopathy. Cells of the retinal pigment epithelium (RPE) constitutively secrete VEGF-A, and the secretion of placental growth factor (PlGF) has also been described. RPE cells are strongly polarized cells with different secretome at the apical and basal side. In this study, we evaluated the basal and apical regulation of VEGF-A and PlGF secretion in RPE/choroid explants and primary RPE cells. RPE/choroid tissue explants were prepared from porcine eyes and cultivated in modified Ussing chambers, separating apical (RPE) and basal (choroid) supernatant. Primary RPE cells were also prepared from porcine eyes and cultivated on Transwell plates. Explants and cells were treated with inhibitors for VEGFR-2 (SU1498), p38 (SB203580), and the transcription factors nuclear factor-kappa B (NF-κB) and SP-1 (mithramycin), respectively. VEGF-A and PlGF content was evaluated with enzyme-linked immunosorbent assay (ELISA). In addition, western blots were performed. In the RPE/choroid, VEGF-A can initially be found on the apical and basal sides with significantly more pronounced secretion on the basal side. VEGF-A secretion is differentially regulated on the apical and basal sides, with the inhibition of SP-1 and NF-κB showing strong effects apically and basally after 24 h and 48 h, the inhibition of p38 displaying its effect mainly on the basal side with some effect apically after 48 h, and the inhibition of VEGFR-2 reducing the secretion of VEGF only on the apical side at 24 h and 48 h. In the RPE cell culture, similar effects were found, with inhibition of NF-κB or SP-1 displaying a strong decrease in VEGF-A on both sides, and p38 inhibition displaying only an inhibitory effect on the basal side. In contrast, an apical effect of VEGFR-2 inhibition was not found. However, the western blot experiments

  1. SREBP inhibits VEGF expression in human smooth muscle cells.

    Science.gov (United States)

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

    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.

  2. Anti-VEGF Agents for Ocular Angiogenesis and Vascular Permeability

    Directory of Open Access Journals (Sweden)

    Kenichi Kimoto

    2012-01-01

    Full Text Available We review articles describing intravitreal injection of anti-VEGF drug trials, while discussing the mechanisms of the action of anti-VEGF antibodies, and also evaluating their outcomes. Intraocular injections of anti-VEGF drug are considered to be an effective treatment for macular edema after retinal vein occlusion, however, recurrent/persistent edema is common. The recent reports may lead to a shift in treatment paradigm for DME, from laser photocoagulation, to newer approaches using anti-VEGF drugs. There have been several well-publicized prospective, randomized studies that demonstrated the efficacy of intravitreal injection of anti-VEGF drugs for patients with AMD. Adjuvant bevacizumab for neovascular glaucoma may prevent further PAS formation, and it is likely to open up a therapeutic window for a panretinal photocoagulation and trabeculectomy. Intravitreal injection of bevacizumab (IVB results in a substantial decrease in bleeding from the retinal vessels or new vessels during a standard vitrectomy. IVB has also been reported to be effective for inducing the regression of new vessels in proliferative diabetic retinopathy. The use of bevacizumab in stage 4 or 5 retinopahty of permaturity (ROP is to reduce the plus sign to help reduce hemorrhage during the subsequent vitrectomy. Some authors reported cases of resolution of stage 4 A ROP after bevacizumab injection.

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

    DEFF Research Database (Denmark)

    Høier, Birgitte; Hellsten, Ylva

    2014-01-01

    , these VEGF containing vesicles are redistributed towards the sarcolemma where the contents are secreted into the extracellular fluid. VEGF mRNA expression is increased primarily after exercise, which allows for a more rapid replenishment of VEGF stores lost through secretion during exercise. Future studies...... 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...

  4. Investigation of Antiangiogenic Tumor Therapy Potential of Microencapsulated HEK293 VEGF165b Producing Cells

    Directory of Open Access Journals (Sweden)

    Fatemeh Afkhami

    2010-01-01

    encapsulated and non-encapsulated cells was similar. The effect of VEGF165b harvested from encapsulated cells on Human Umbilical Vein Endothelial cells (HUVECs proliferation were also examined.The same inhibitory effects on HUVECs proliferation was seen when the cells were incubated with a mixture of VEGF165b and a 2-fold VEGF165b or with VEGF165b and 2-fold excess VEGF165b released from encapsulated cells. Subcutaneous injection of microencapsulated VEGF165b producing cells in tumor site of nude mice resulted in the reduction of the number of vessels around the tumors.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  6. VEGF gene polymorphisms and outcome of epithelial ovarian cancer patients.

    Science.gov (United States)

    Camerin, Gabriela Ribeiro; Brito, Angelo Borsarelli Carvalho; Vassallo, José; Derchain, Sophie Françoise Mauricette; Lima, Carmen Silvia Passos

    2017-02-01

    Since VEGF polymorphisms were associated with variable protein production, we analyzed herein their roles in outcome of epithelial ovarian cancer (EOC) patients. Genotypes of 85 patients with primary EOC were identified in DNA by real-time PCR. Progression-free survival and overall survival were analyzed using Kaplan-Meier method, univariate Cox model and bootstrap resampling study. At 60 months of follow-up, progression-free survival was shorter in patients with VEGF c.-2578 CC genotype compared with others (52.7 vs 82.2%; p = 0.04). Those patients had 2.15 more chance of presenting disease progression than others (p = 0.04); bootstrap study validated the result (p = 0.03). Our data suggest that VEGF c.-2578C>A polymorphism acts as a prognostic factor in EOC.

  7. Field enhancement induced laser ablation

    DEFF Research Database (Denmark)

    Fiutowski, Jacek; Maibohm, Christian; Kjelstrup-Hansen, Jakob

    . The accompanying field enhancement substantially lowers the ablation threshold of the polymer film and thus creates local ablation spots and corresponding topographic modifications of the polymer film. Such modifications are quantified straightforwardly via scanning electron and atomic force microscopy. Thickness......Sub-diffraction spatially resolved, quantitative mapping of strongly localized field intensity enhancement on gold nanostructures via laser ablation of polymer thin films is reported. Illumination using a femtosecond laser scanning microscope excites surface plasmons in the nanostructures...

  8. Advanced Ablation Characterization and Modelling

    OpenAIRE

    Gülhan, Ali

    2016-01-01

    Ablative thermal protection materials are a key technology for current and future space exploration missions. However, the mission feasibility is determined by the materials available, and the development of new materials is performed, essentially, by an iterative trial-and-error process. This is due to the absence of validated predictive models for ablative material behaviour. Models are tuned to bulk material properties from tests. In order to describe physical processes of the ablation cor...

  9. Pulsed laser ablation of copper

    Science.gov (United States)

    Jordan, R.; Cole, D.; Lunney, J. G.; Mackay, K.; Givord, D.

    1995-02-01

    The laser ablation of copper with a 532 nm, 6 ns laser has been investigated in the regime normally used for pulsed laser deposition. The ablation depth per pulse and the flux and energy distribution of the ions in the plume were measured and compared to the deposition rate as measured by a quartz microbalance. These measurements were compared with an analytic model of ablation via a laser sustained plasma. It is shown that self-sputtering of the growing film is significant.

  10. Radiofrequency ablation of pulmonary tumors

    Energy Technology Data Exchange (ETDEWEB)

    Crocetti, Laura, E-mail: l.crocetti@med.unipi.i [Division of Diagnostic Imaging and Intervention, Department of Liver Transplants, Hepatology and Infectious Diseases, Pisa University School of Medicine (Italy); Lencioni, Riccardo [Division of Diagnostic Imaging and Intervention, Department of Liver Transplants, Hepatology and Infectious Diseases, Pisa University School of Medicine (Italy)

    2010-07-15

    The development of image-guided percutaneous techniques for local tumor ablation has been one of the major advances in the treatment of solid tumors. Among these methods, radiofrequency (RF) ablation is currently established as the primary ablative modality at most institutions. RF ablation is accepted as the best therapeutic choice for patients with early-stage hepatocellular carcinoma when liver transplantation or surgical resection are not suitable options and is considered as a viable alternate to surgery for inoperable patients with limited hepatic metastatic disease, especially from colorectal cancer. Recently, RF ablation has been demonstrated to be a safe and valuable treatment option for patients with unresectable or medically inoperable lung malignancies. Resection should remain the standard therapy for non-small cell lung cancer (NSCLC) but RF ablation may be better than conventional external-beam radiation for the treatment of the high-risk individual with NSCLC. Initial favourable outcomes encourage combining radiotherapy and RF ablation, especially for treating larger tumors. In the setting of colorectal cancer lung metastases, survival rates provided by RF ablation in selected patients, are substantially higher than those obtained with any chemotherapy regimens and provide indirect evidence that RF ablation therapy improves survival in patients with limited lung metastatic disease.

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

    NARCIS (Netherlands)

    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

  12. Recombinant Goat VEGF164 Increases Hair Growth by Painting Process on the Skin of Shaved Mouse

    Directory of Open Access Journals (Sweden)

    Wenlei Bao

    2014-09-01

    Full Text Available To detect goat vascular endothelial growth factor (VEGF-mediated regrowth of hair, full-length VEGF164 cDNA was cloned from Inner Mongolia cashmere goat (Capra hircus into the pET-his prokaryotic expression vector, and the recombinant plasmid was transferred into E. coli BL21 cells. The expression of recombinant 6×his-gVEGF164 protein was induced by 0.5 mM isopropyl thio-β-D-galactoside at 32°C. Recombinant goat VEGF164 (rgVEGF164 was purified and identi ed by western blot using monoclonal anti-his and anti-VEGF antibodies. The rgVEGF164 was smeared onto the dorsal area of a shaved mouse, and we noted that hair regrowth in this area was faster than in the control group. Thus, rgVEGF164 increases hair growth in mice.

  13. Cryoballoon ablation versus radiofrequency ablation for atrial fibrillation.

    Science.gov (United States)

    Reissmann, Bruno; Metzner, Andreas; Kuck, Karl-Heinz

    2017-05-01

    Catheter ablation (CA) provides the most effective treatment option for patients suffering from symptomatic atrial fibrillation (AF). The procedural cornerstone of all ablation strategies and for all entities of AF is the electrical isolation of the pulmonary veins (PV). CA with the use of radiofrequency (RF) in conjunction with a 3-dimensional electroanatomical mapping system is the most established ablation approach, but it demands a long learning curve and recurrences of AF are commonly the result of recovered PV conduction. As a consequence, novel ablation systems such as the Cryoballoon (CB) have been evolved aiming at facilitation and increased efficacy of pulmonary vein isolation (PVI). CB ablation is characterized by a short learning curve as well as short procedure times and demonstrated non-inferiority with regard to safety and efficacy when being directly compared to RF ablation for treatment of paroxysmal AF. However, RF ablation is first choice for treatment of persistent AF, in particular when expanded ablation strategies beyond PVI are intended in order to improve clinical outcomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Pharmacokinetics and tolerability of cediranib, a potent VEGF signalling inhibitor, in cancer patients with hepatic impairment

    DEFF Research Database (Denmark)

    van Herpen, Carla M L; Lassen, Ulrik; Desar, Ingrid M E

    2013-01-01

    Vascular endothelial growth factor (VEGF) signalling plays a key role in tumour angiogenesis. Cediranib (AZD2171) is a small-molecule VEGF signalling inhibitor with potent activity against all three VEGF receptors. In this phase I, open-label, parallel-group study, adults with advanced solid...

  15. 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 ...

  16. 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

  17. VEGF Polymorphisms Are Associated With Endocardial Cushion Defects : A Family-Based Case-Control Study

    NARCIS (Netherlands)

    Smedts, Huberdina P. M.; Isaacs, Aaron; de Costa, Dominique; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Gittenberger-de Groot, Adriana C.; Helbing, Willem A.; Steegers, Eric A. P.; Steegers-Theunissen, Regina P. M.

    Endocardial cushion defects (ECDs) of the cardiac outflow tract are among the most common congenital heart disease phenotypes. VEGF is essential for endocardial cushion formation and derangements in VEGF synthesis lead to ECD. Three functional single nucleotide polymorphisms (SNPs) in the VEGF gene

  18. VEGF expression and microvascular density in relation to high-risk ...

    African Journals Online (AJOL)

    VEGF expression and microvascular density in relation to high-risk-HPV infection in cervical carcinoma – An immunohistochemical study. ... Eleven cases were low grade and 19 were high-grade cases. VEGF expression was detected in 100% of cases. The relation between carcinoma grade and VEGF expression and ...

  19. Good practice with endometrial ablation.

    Science.gov (United States)

    Garry, R

    1995-07-01

    To provide clear guidelines for the safe and effective performance of endometrial ablation. Representatives of American, Australian, British, and Canadian hysteroscopists were brought together to produce a consensus document of good practice in endometrial ablation. The guidelines were produced after researching the literature, combining the extensive experience of the group, and debating the relevant issues. Endometrial ablation is a new procedure. Correct patient selection is essential in producing good results. Patients must be counseled carefully about the advantages, disadvantages, and potential complications of this approach to the management of menstrual disorders. The main indication for endometrial ablation is heavy menstrual loss in the absence of organic disease. Excessive uterine size, the presence of active pelvic infection, and evidence of malignant and premalignant endometrium are absolute contraindications. Ablation can be produced by electrosurgical resection, rollerball or rollerbarrel ablation and Nd-YAG laser ablation. Severe complications can occur, and techniques should be adopted to avoid uterine perforation, hemorrhage, and excessive fluid absorption. In skilled hands, endometrial ablation can be a safe and effective treatment for menorrhagia.

  20. Radiofrequency ablation of osteoid osteoma

    NARCIS (Netherlands)

    Vanderschueren, Geert Maria Joris Michael

    2009-01-01

    The main purpose of this thesis was to evaluate the effectiveness and safety of CT-guided radiofrequency ablation for the treatment of spinal and non-spinal osteoid osteomas. Furthermore, the technical requirements needed for safe radiofrequency ablation and the clinical outcome after radiofrequency

  1. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    DEFF Research Database (Denmark)

    Sjöström, S; Wibom, C; Andersson, U

    2011-01-01

    significantly associated to survival, namely rs2071559 and rs12502008. However, these results are likely to be false positives due to multiple testing and could not be confirmed in a separate dataset. Overall, this study provides little evidence that VEGF and VEGFR2 polymorphisms are important for glioblastoma...

  2. Genetic variations in VEGF and VEGFR2 and glioblastoma outcome

    DEFF Research Database (Denmark)

    Sjöström, S; Wibom, C; Andersson, U

    2010-01-01

    significantly associated to survival, namely rs2071559 and rs12502008. However, these results are likely to be false positives due to multiple testing and could not be confirmed in a separate dataset. Overall, this study provides little evidence that VEGF and VEGFR2 polymorphisms are important for glioblastoma...

  3. Elevated serum and tissue VEGF associated with poor outcome in ...

    African Journals Online (AJOL)

    Serum and tissue vascular endothelial growth factor was strongly associated with grade III tumor, large tumor size, positive lymph node, negative hormone receptor status, +ve HER2 neu and poor survival, the data of the present study showed significant increase in mean serum level of VEGF in patients with positive ...

  4. (VEGF) expression in rats with spinal cord injury by transplantation ...

    African Journals Online (AJOL)

    User

    2011-05-16

    May 16, 2011 ... was quantified by means of western blot and immunohistochemistry technology. It was found that .... 0.6× volume of isopropyl alcohol and a 0.1× volume of 3 M sodium ... To detect expression and localization of VEGF in spinal cord tissue, .... ischemic brain (Chen et al., 2003) have provided their beneficial ...

  5. Thrombospondin-1 and VEGF in inflammatory bowel disease | Alkim ...

    African Journals Online (AJOL)

    Background and aim: 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, ...

  6. Acoustic signal characteristics during IR laser ablation and their consequences for acoustic tissue discrimination

    Science.gov (United States)

    Nahen, Kester; Vogel, Alfred

    2000-06-01

    IR laser ablation of skin is accompanied by acoustic signals the characteristics of which are closely linked to the ablation dynamics. A discrimination between different tissue layers, for example necrotic and vital tissue during laser burn debridement, is therefore possible by an analysis of the acoustic signal. We were able to discriminate tissue layers by evaluating the acoustic energy. To get a better understanding of the tissue specificity of the ablation noise, we investigated the correlation between sample water content, ablation dynamics, and characteristics of the acoustic signal. A free running Er:YAG laser with a maximum pulse energy of 2 J and a spot diameter of 5 mm was used to ablate gelatin samples with different water content. The ablation noise in air was detected using a piezoelectric transducer with a bandwidth of 1 MHz, and the acoustic signal generated inside the ablated sample was measured simultaneously ba a piezoelectric transducer in contact with the sample. Laser flash Schlieren photography was used to investigate the expansion velocity of the vapor plume and the velocity of the ejected material. We observed large differences between the ablation dynamics and material ejection velocity for gelatin samples with 70% and 90% water content. These differences cannot be explained by the small change of the gelatin absorption coefficient, but are largely related to differences of the mechanical properties of the sample. The different ablation dynamics are responsible for an increase of the acoustic energy by a factor of 10 for the sample with the higher water content.

  7. Laboratory Simulations of Micrometeoroid Ablation

    Science.gov (United States)

    Thomas, Evan Williamson

    Each day, several tons of meteoric material enters Earth's atmosphere, the majority of which consist of small dust particles (micrometeoroids) that completely ablate at high altitudes. The dust input has been suggested to play a role in a variety of phenomena including: layers of metal atoms and ions, nucleation of noctilucent clouds, effects on stratospheric aerosols and ozone chemistry, and the fertilization of the ocean with bio-available iron. Furthermore, a correct understanding of the dust input to the Earth provides constraints on inner solar system dust models. Various methods are used to measure the dust input to the Earth including satellite detectors, radar, lidar, rocket-borne detectors, ice core and deep-sea sediment analysis. However, the best way to interpret each of these measurements is uncertain, which leads to large uncertainties in the total dust input. To better understand the ablation process, and thereby reduce uncertainties in micrometeoroid ablation measurements, a facility has been developed to simulate the ablation of micrometeoroids in laboratory conditions. An electrostatic dust accelerator is used to accelerate iron particles to relevant meteoric velocities (10-70 km/s). The particles are then introduced into a chamber pressurized with a target gas, and they partially or completely ablate over a short distance. An array of diagnostics then measure, with timing and spatial resolution, the charge and light that is generated in the ablation process. In this thesis, we present results from the newly developed ablation facility. The ionization coefficient, an important parameter for interpreting meteor radar measurements, is measured for various target gases. Furthermore, experimental ablation measurements are compared to predictions from commonly used ablation models. In light of these measurements, implications to the broader context of meteor ablation are discussed.

  8. [Antitumor effect of recombinant Xenopus laevis vascular endothelial growth factor (VEGF) as a vaccine combined with adriamycin on EL4 lymphoma in mice].

    Science.gov (United States)

    Niu, Ting; Liu, Ting; Jia, Yong-Qian; Liu, Ji-Yan; Wu, Yang; Hu, Bing; Tian, Ling; Yang, Li; Kan, Bing; Wei, Yu-Quan

    2005-09-01

    To explore the antitumor effect of immunotherapy with recombinant Xenopus laevis vascular endothelial growth factor (xVEGF) as a vaccine combined with adriamycin on lymphoma model in mice. EL4 lymphoma model was established in C57BL/6 mice. Mice were randomized into four groups: combination therapy, adriamycin alone, xVEGF alone and normal saline (NS) groups, and then were given relevant treatments. The growth of tumor, the survival rate of tumor-bearing mice, and the potential toxicity of regimens above were observed. Anti-VEGF antibody-producing B cells (APBCs) were detected by enzyme-linked immunospot (ELISPOT) assay. In addition, microvessel density (MVD) of tumor was detected by immunohistochemistry, and tumor cell apoptosis was also detected by TUNEL staining. The tumor volumes of mice were significantly smaller in combination group than those in other three groups (P < 0.05). Complete regression of tumor was observed in 3 of 10 mice in combination group. Forty-eight days after inoculation of tumor cells, the survival rate of mice was significantly higher in combination group than in NS group (P < 0.01). The anti-VEGF APBC count in combination group or xVEGF group was significantly higher, compared with that in adriamycin group or NS group (P < 0.01). MVD in tumor tissues was significantly lower in combination group than those in other three groups (P < 0.05). Moreover, tumor cell apoptosis was significantly higher in combination group than those in other three groups (P < 0.05). In this experimental study, the use of xVEGF vaccine and adriamycin as a combination of immunotherapy with chemotherapy has sucessfully produced synergistic antitumor effect on lymphoma in mice.

  9. ScVEGF-PEG-HBED-CC and scVEGF-PEG-NOTA conjugates: comparison of easy-to-label recombinant proteins for [{sup 68}Ga]PET imaging of VEGF receptors in angiogenic vasculature

    Energy Technology Data Exchange (ETDEWEB)

    Eder, Matthias [German Cancer Research Center (DKFZ), 69120 Heidelberg (Germany)], E-mail: m.eder@dkfz.de; Krivoshein, Arcadius V.; Backer, Marina; Backer, Joseph M. [SibTech, Inc., Brookfield, CT 06804 (United States); Haberkorn, Uwe [Department of Nuclear Medicine, University of Heidelberg, 69120 Heidelberg (Germany); Eisenhut, Michael [German Cancer Research Center (DKFZ), 69120 Heidelberg (Germany)

    2010-05-15

    Introduction: VEGF receptors play a key role in angiogenesis and are important targets for several approved and many experimental drugs. Imaging of VEGF receptor expression in malignant tumors would provide important information, which can influence patient management. The aim of this study was the development of an easy-to-label positron-emitting tracer for imaging VEGF receptors. The tracer is based on engineered single-chain VEGF (scVEGF), expressed with cysteine-containing fusion tag (Cys-tag) for site-specific conjugation of PEGylated bifunctional chelating agents, HBED-CC or NOTA, suitable for labeling with {sup 68}Ga at ambient temperature. Methods: scVEGF-PEG-HBED-CC was synthesized by activating a single carboxyl group of the [Fe(HBED-CC)]{sup -} complex with N-hydroxysuccinimide. Reaction of the activated complex with NH{sub 2}-PEG-maleimide was followed by site-specific conjugation of PEGylated chelator to a thiol group in Cys-tag of scVEGF. The scVEGF-PEG-NOTA conjugate was synthesized using NHS-PEG-maleimide and p-NH{sub 2}-Bn-NOTA. {sup 68}Ga complexation was performed in HEPES buffer (pH 4.2) at room temperature. The functional activity after labeling was tested by radioligand cell binding assays. Biodistribution and PET studies in tumor-bearing mice were performed after 1, 2, 3 and 4 h postinjection. Results: The radiolabeling of scVEGF-PEG-HBED-CC proved more efficient than scVEGF-PEG-NOTA allowing to stop the reaction after 4 min (>97% radiochemical yield). Radioligand cell binding assays performed on HEK-293 cells overexpressing VEGFR-2 revealed no change in the binding properties of {sup 68}Ga-radiolabeled scVEGF relative to other scVEGF-based tracers. Both tracers showed comparable results in biodistribution, such as tumor accumulation and low liver uptake. The tracers were stable in 50% human serum for at least 72 h. Conclusions: The conjugates scVEGF-PEG-HBED-CC and scVEGF-PEG-NOTA revealed comparable in vivo characteristics and allowed easy

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

    Science.gov (United States)

    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.

  11. Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF-VEGF receptors.

    Science.gov (United States)

    Guan, Xiao-Jun; Song, Lin; Han, Feng-Feng; Cui, Zhi-Lei; Chen, Xi; Guo, Xue-Jun; Xu, Wei-Guo

    2013-02-01

    Progressive pulmonary inflammation and emphysema have been implicated in the progression of chronic obstructive pulmonary disease (COPD), while current pharmacological treatments are not effective. Transplantation of bone marrow mesenchymal stem cells (MSCs) has been identified as one such possible strategy for treatment of lung diseases including acute lung injury (ALI) and pulmonary fibrosis. However, their role in COPD still requires further investigation. The aim of this study is to test the effect of administration of rat MSCs (rMSCs) on emphysema and pulmonary function. To accomplish this study, the rats were exposed to cigarette smoke (CS) for 11 weeks, followed by administration of rMSCs into the lungs. Here we show that rMSCs infusion mediates a down-regulation of pro-inflammatory mediators (TNF-α, IL-1β, MCP-1, and IL-6) and proteases (MMP9 and MMP12) in lung, an up-regulation of vascular endothelial growth factor (VEGF), VEGF receptor 2, and transforming growth factor (TGFβ-1), while reducing pulmonary cell apoptosis. More importantly, rMSCs administration improves emphysema and destructive pulmonary function induced by CS exposure. In vitro co-culture system study of human umbilical endothelial vein cells (EA.hy926) and human MSCs (hMSCs) provides the evidence that hMSCs mediates an anti-apoptosis effect, which partly depends on an up-regulation of VEGF. These findings suggest that MSCs have a therapeutic potential in emphysematous rats by suppressing the inflammatory response, excessive protease expression, and cell apoptosis, as well as up-regulating VEGF, VEGF receptor 2, and TGFβ-1. Copyright © 2012 Wiley Periodicals, Inc.

  12. Cancer-Associated Systemic Syndrome (CASS:The Mechanism of VEGF in Tumor-Bearing Mice

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    Fang CHEN

    2009-04-01

    Full Text Available Background and objective VEGF plays an important role in the development of cancer. The aim of this study is to observe the structural alterations in multiple organs of high VEGF expression mice, and insight into the role of tumor-derived VEGF in the development of CASS. Methods Murine fibrosarcoma of T241-VEGF and T241- Vector tumor cells were transplanted subcutaneously in mice to construct the xenograft tumor model. The mice gross examinations were observed and the percentage of survival animals in each group is presented. The level of hemoglobin, the numbers of erythrocytes and serum concentration of VEGF in peripheral blood were analyzed. Histological analysis of liver, spleen, adrenal gland and bone-marrow were applied. Vascular networks in tumors were analyzed under a confocal microscope. Results The VEGF-expressing tumor bearing mice manifested CASS by severe anemia, hepatosplenomegaly and loss of body weight. The survival rate of mice was decreased. The level of hemoglobin and erythrocytes in circulating blood were significantly reduced (P<0.01, with the increased serum concentration of VEGF. The blood vessels of tumorappeared as primitive and dilated sinusoidal vascular structures. Conclusion The tumor-produced VEGF affect multiple tissues, organs and resulted in CASS in mice model. It suggest that VEGF might be involved in the occurrence and development of CASS. It might be helpful for anti-VEGF therapy in clinical CASS and combing anti-VEGF therapy in advanced cancer patients.

  13. VEGF increases the permeability of sheep pleura ex vivo through VEGFR2 stimulation.

    Science.gov (United States)

    Peppa, Vasiliki I; Arsenopoulou, Zoi V; Zarogiannis, Sotirios G; Deligiorgi, Triantafyllia; Jagirdar, Rajesh; Makantasis, Ioannis; Stefanidis, Ioannis; Liakopoulos, Vassilios; Molyvdas, Paschalis-Adam; Gourgoulianis, Konstantinos I; Hatzoglou, Chrissi

    2014-10-01

    Vascular endothelial growth factor (VEGF), a cytokine that increases vascular permeability to water and proteins and induces angiogenesis, has been implicated in the development of pleural effusions. Inflammatory and malignant pleural effusions are rich in VEGF content while mesothelial cells produce and excrete VEGF. In this report we aimed at investigating by means of electrophysiology the direct effects of VEGF on the parietal and visceral sheep pleura as well as the type of receptors that mediate this effect. Our findings show that VEGF has a direct effect on the pleural mesothelium rendering it more permeable and this effect is mediated through the stimulation of VEGF receptor 2. Our findings shed more light to the role of VEGF in the pathogenesis of pleural effusions and provide functional evidence for a role of VEGFR2 on the pleural mesothelium that has never been studied before. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Is VF an Ablatable Rhythm?

    Science.gov (United States)

    Cheniti, Ghassen; Hocini, Meleze; Martin, Ruairidh; Sacher, Frederic; Dubois, Remi; Haissaguerre, Michel; Jais, Pierre

    2017-02-01

    Ventricular fibrillation (VF) has traditionally been considered to be a disorganized arrhythmia not amenable to catheter ablation. However, a better understanding of the VF pathophysiology has allowed identification of targets for ablation. Ablation targeting the premature ventricular complexes which trigger VF was proven to be associated with high success rates and long-term freedom from VF recurrence. Recent mapping data has identified rotors, focal breakthroughs, and figure of eight re-entries as main drivers maintaining human VF. Most interestingly, the type and the spatiotemporal behavior of these drivers are reproducible between different VF episodes. In addition, drivers are usually clustered at the scar borders. This has ushered in a new era of ablation targeting the VF substrate and the drivers maintaining VF with promising results.

  15. Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies.

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    Seung Hoan Choi

    2016-02-01

    Full Text Available Vascular endothelial growth factor (VEGF is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3 and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13, rs74506613 (JMJD1C, P = 1.17 x 10(-19, rs4782371 (ZFPM1, P = 1.59 x 10(-9 and rs2639990 (ZADH2, P = 1.72 x 10(-8, respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18; rs7043199, VLDLR-AS1, P = 5.12 x 10(-14 at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467; rs1740073, C6orf223, P = 2.34 x 10(-17; rs6993770, ZFPM2, P = 2.44 x 10(-60; rs2375981, KCNV2, P = 1.48 x 10(-100. These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis

  16. The impact of hyperbaric oxygen therapy on serological values of vascular endothelial growth factor (VEGF and basic fibroblast growth factor (bFGF

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    Ziebura Thomas

    2010-12-01

    Full Text Available Abstract Background Hyperbaric oxygen (HBO therapy is an effective adjunct treatment for ischemic disorders such as chronic infection or chronic wounds. It combines hyperoxic effects with the stimulating potential of post-therapeutic reactive hypoxia. As its crucial effects, stimulation of fibroblast growth, induction of collagen synthesis and the initiation of angiogenesis are discussed. Angiogenesis is a multistage process resulting in the growth of blood vessels. It includes degradation of extracellular matrix, proliferation and migration of different cell populations and finally formation of new vessel structures. This complex chain of procedures is orchestrated by different cytokines and growth factors. Crucial mediators of angiogenesis are basic fibroblast growth factor (bFGF and vascular endothelial growth factor (VEGF; their in-vivo function is still not fully understood. Methods Forty-three patients suffering from sudden sensorineural hearing loss or tinnitus were treated with HBO. The therapy included 10 sessions of 90 minutes each, one session a day. Serological levels of bFGF and VEGF were assessed by enzyme-linked immunosorbent assays performed according to the manufacturer's instructions on day 1, 2, 5 and 10 of HBO therapy and were compared to mean values of the control group, related to the patient's age and sex, and their development observed over the ten days of HBO. Results There was no sex- or age dependency of bFGF observed in the present study, whereas under HBO our results showed a significant mitigation of the bFGF concentration. In the present data, there was no connection between the VEGF concentration and the patients' ages. Women showed significantly higher levels of VEGF. There was no significant change of VEGF concentration or the VEGF/bFGF ratio during HBO. All scored results varied within the range of standard values as described in the current literature. Conclusions A significant effect of HBO on serum

  17. Neural crest cell-derived VEGF promotes embryonic jaw extension

    Science.gov (United States)

    Wiszniak, Sophie; Mackenzie, Francesca E.; Anderson, Peter; Kabbara, Samuela; Ruhrberg, Christiana; Schwarz, Quenten

    2015-01-01

    Jaw morphogenesis depends on the growth of Meckel’s cartilage during embryogenesis. However, the cell types and signals that promote chondrocyte proliferation for Meckel’s cartilage growth are poorly defined. Here we show that neural crest cells (NCCs) and their derivatives provide an essential source of the vascular endothelial growth factor (VEGF) to enhance jaw vascularization and stabilize the major mandibular artery. We further show in two independent mouse models that blood vessels promote Meckel’s cartilage extension. Coculture experiments of arterial tissue with NCCs or chondrocytes demonstrated that NCC-derived VEGF promotes blood vessel growth and that blood vessels secrete factors to instruct chondrocyte proliferation. Computed tomography and X-ray scans of patients with hemifacial microsomia also showed that jaw hypoplasia correlates with mandibular artery dysgenesis. We conclude that cranial NCCs and their derivatives provide an essential source of VEGF to support blood vessel growth in the developing jaw, which in turn is essential for normal chondrocyte proliferation, and therefore jaw extension. PMID:25922531

  18. VEGF Promotes Malaria-Associated Acute Lung Injury in Mice

    Science.gov (United States)

    Carapau, Daniel; Pena, Ana C.; Ataíde, Ricardo; Monteiro, Carla A. A.; Félix, Nuno; Costa-Silva, Artur; Marinho, Claudio R. F.; Dias, Sérgio; Mota, Maria M.

    2010-01-01

    The spectrum of the clinical presentation and severity of malaria infections is broad, ranging from uncomplicated febrile illness to severe forms of disease such as cerebral malaria (CM), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pregnancy-associated malaria (PAM) or severe anemia (SA). Rodent models that mimic human CM, PAM and SA syndromes have been established. Here, we show that DBA/2 mice infected with P. berghei ANKA constitute a new model for malaria-associated ALI. Up to 60% of the mice showed dyspnea, airway obstruction and hypoxemia and died between days 7 and 12 post-infection. The most common pathological findings were pleural effusion, pulmonary hemorrhage and edema, consistent with increased lung vessel permeability, while the blood-brain barrier was intact. Malaria-associated ALI correlated with high levels of circulating VEGF, produced de novo in the spleen, and its blockage led to protection of mice from this syndrome. In addition, either splenectomization or administration of the anti-inflammatory molecule carbon monoxide led to a significant reduction in the levels of sera VEGF and to protection from ALI. The similarities between the physiopathological lesions described here and the ones occurring in humans, as well as the demonstration that VEGF is a critical host factor in the onset of malaria-associated ALI in mice, not only offers important mechanistic insights into the processes underlying the pathology related with malaria but may also pave the way for interventional studies. PMID:20502682

  19. Role of VEGF family members and receptors in coronary vessel formation.

    Science.gov (United States)

    Tomanek, Robert J; Holifield, Jennifer S; Reiter, Rebecca S; Sandra, Alexander; Lin, Jim J-C

    2002-11-01

    The specific roles of vascular endothelial growth factor (VEGF) family members and their receptors (VEGFRs) in coronary vessel formation were studied. By using the quail heart explant model, we found that neutralizing antibodies to VEGF-B or VEGF-C inhibited tube formation on the collagen gel more than anti-VEGF-A. Soluble VEGFR-1, a receptor for VEGF-A and -B, inhibited tube formation by 87%, a finding consistent with that of VEGF-B inhibition. In contrast, addition of soluble VEGFR-2, a receptor for VEGF family members A, C, D, and E, inhibited tube formation by only 43%. Acidic FGF-induced tube formation dependency on VEGF was demonstrated by the attenuating effect of a soluble VEGFR-1 and -2 chimera. The localization of VEGF R-2 and R-3 was demonstrated by in situ hybridization of serial sections, which documented marked accumulations of transcripts for both receptors at the base of the truncus arteriosus coinciding with the temporal and spatial formation of the coronary arteries by means of ingrowth of capillary plexuses. This finding suggests that both VEGFR-2 and R-3 may play a role in the formation of the coronary artery roots. In summary, these experiments document a role for multiple members of the VEGF family and their receptors in formation of the coronary vascular bed. Copyright 2002 Wiley-Liss, Inc.

  20. 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.

  1. Chronic hypoxia attenuates VEGF signaling and angiogenic responses by downregulation of KDR in human endothelial cells.

    Science.gov (United States)

    Olszewska-Pazdrak, Barbara; Hein, Travis W; Olszewska, Paulina; Carney, Darrell H

    2009-05-01

    Coronary artery disease results in progressive vascular stenosis associated with chronic myocardial ischemia. Vascular endothelial growth factor (VEGF) stimulates endothelial cell angiogenic responses to revascularize ischemic tissues; however, the effect of chronic hypoxia on the responsiveness of endothelial cells to VEGF remains unclear. We, therefore, investigated whether hypoxia alters VEGF-stimulated signaling and angiogenic responses in primary human coronary artery endothelial (HCAE) cells. Exposure of HCAE cells to hypoxia (1% O(2)) for 24 h decreased VEGF-stimulated endothelial cell migration ( approximately 82%), proliferation ( approximately 30%), and tube formation. Hypoxia attenuated VEGF-stimulated activation of endothelial nitric oxide (NO) synthase (eNOS) ( approximately 72%) and reduced NO production in VEGF-stimulated cells from 237 +/- 38.8 to 61.3 +/- 28.4 nmol/l. Moreover, hypoxia also decreased the ratio of phosphorylated eNOS to total eNOS in VEGF-stimulated cells by approximately 50%. This effect was not observed in thrombin-stimulated cells, suggesting that hypoxia specifically inhibited VEGF signaling upstream of eNOS phosphorylation. VEGF-induced activation of Akt, ERK1/2, p38, p70S6 kinases, and S6 ribosomal protein was also attenuated in hypoxic cells. Moreover, VEGF-stimulated phosphorylation of VEGF receptor-2 (KDR) at Y996 and Y1175 was decreased by hypoxia. This decrease correlated with a 70 +/- 12% decrease in KDR protein expression. Analysis of mRNA from these cells showed that hypoxia reduced steady-state levels of KDR mRNA by 52 +/- 16% and decreased mRNA stability relative to normoxic cells. Our findings demonstrate that chronic hypoxia attenuates VEGF-stimulated signaling in HCAE cells by specific downregulation of KDR expression. These data provide a novel explanation for the impaired angiogenic responses to VEGF in endothelial cells exposed to chronic hypoxia.

  2. Relationship between LIBS Ablation and Pit Volume for Geologic Samples: Applications for in situ Absolute Geochronology

    Science.gov (United States)

    Devismes, D.; Cohen, Barbara A.

    2014-01-01

    In planetary sciences, in situ absolute geochronology is a scientific and engineering challenge. Currently, the age of the Martian surface can only be determined by crater density counting. However this method has significant uncertainties and needs to be calibrated with absolute ages. We are developing an instrument to acquire in situ absolute geochronology based on the K-Ar method. The protocol is based on the laser ablation of a rock by hundreds of laser pulses. Laser Induced Breakdown Spectroscopy (LIBS) gives the potassium content of the ablated material and a mass spectrometer (quadrupole or ion trap) measures the quantity of 40Ar released. In order to accurately measure the quantity of released 40Ar in cases where Ar is an atmospheric constituent (e.g., Mars), the sample is first put into a chamber under high vacuum. The 40Arquantity, the concentration of K and the estimation of the ablated mass are the parameters needed to give the age of the rocks. The main uncertainties with this method are directly linked to the measures of the mass (typically some µg) and of the concentration of K by LIBS (up to 10%). Because the ablated mass is small compared to the mass of the sample, and because material is redeposited onto the sample after ablation, it is not possible to directly measure the ablated mass. Our current protocol measures the ablated volume and estimates the sample density to calculate ablated mass. The precision and accuracy of this method may be improved by using knowledge of the sample's geologic properties to predict its response to laser ablation, i.e., understanding whether natural samples have a predictable relationship between laser energy deposited and resultant ablation volume. In contrast to most previous studies of laser ablation, theoretical equations are not highly applicable. The reasons are numerous, but the most important are: a) geologic rocks are complex, polymineralic materials; b) the conditions of ablation are unusual (for example

  3. Guided bone regeneration (GBR) utilizing injectable Vascular Endothelial Growth Factor (VEGF) delivery gel

    Science.gov (United States)

    Kaigler, Darnell; Silva, Eduardo A.; Mooney, David J.

    2013-01-01

    Background Vascularization underlies the success of guided bone regeneration (GBR) procedures. This study evaluated the regenerative potential of GBR in combination with Vascular Endothelial Growth Factor (VEGF) delivery, via an injectable hydrogel system. Methods Critical-sized defects were created in rat calvariae and GBR procedures were performed with a collagen membrane either alone (control), plus bolus delivery of VEGF, or plus application of VEGF releasing hydrogels (VEGF - Alg). Four and eight weeks following treatment, defect sites were evaluated with microcomputed tomographic and histomorphometric analyses for blood vessel and bone formation. Results At four weeks, relative to the control condition, the bolus addition of VEGF did not affect blood vessel density within the defect site; yet, the application of the VEGF+ Alg significantly (pGBR may be a promising strategy for enhancing outcomes of GBR. PMID:22668339

  4. Sanguinarine is a novel VEGF inhibitor involved in the suppression of angiogenesis and cell migration

    Science.gov (United States)

    XU, JIA-YING; MENG, QING-HUI; CHONG, YU; JIAO, YANG; ZHAO, LIN; ROSEN, ELIOT M.; FAN, SAIJUN

    2013-01-01

    Vascular endothelial growth factor (VEGF) is a main angiogenic factor which is known to be upregulated in lung cancer. In the present study, it was demonstrated that sanguinarine, an alkaloid obtained from the bloodroot plant, markedly repressed the VEGF-induced tube formation of human microvascular endothelial cells (HMVECs) and the migration of human A549 lung cancer cells. Furthermore, sanguinarine decreased VEGF secretion and expression in HMVECs and A549 lung cancer cells in a dose- and time-dependent manner. Additionally, sanguinarine inhibited the activation of serum starvation- and hypoxia-induced VEGF promoter activity. Sanguinarine also inhibited the VEGF-mediated Akt and p38 activation, as well as VE-cadherin protein phosphorylation. To the best of our knowledge, this is the first study demonstrating that VEGF inhibition appears to be an important mechanism involved in the antiangiogenic and anti-invasive activities of sanguinarine in lung cancer treatment. PMID:24649171

  5. 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

  6. VEGF family members regulate myocardial tubulogenesis and coronary artery formation in the embryo.

    Science.gov (United States)

    Tomanek, Robert J; Ishii, Yasuo; Holifield, Jennifer S; Sjogren, Christina L; Hansen, Heidi K; Mikawa, Takashi

    2006-04-14

    This study tested the hypothesis that coronary tubulogenesis and coronary artery formation require VEGF family members. Quail embryos were injected with soluble vascular endothelial growth factor (VEGF) receptors R1 (Flt-1), R2 (Flk-1), R3 (Flt-4), VEGF-Trap (a chimera of R1 and R2), or neutralizing antibodies to VEGF-A, VEGF-B, or fibroblast growth factor (FGF)-2. Our data document that tubulogenesis is temporally dependent on multiple VEGF family members, because the early stage of tubulogenesis was markedly inhibited by VEGF-Trap and to a lesser extent by soluble VEGFR-1. Some inhibition of tubulogenesis was documented when anti-FGF-2, but not anti-VEGF-A, antibodies were injected at embryonic day 6 (E6). Most importantly, we found that VEGF-Trap injected at either E6 or E7 prevented the formation of coronary arteries. Soluble VEGFR-1 and soluble VEGFR-2 modified the formation of coronary arteries, whereas soluble VEGFR-3 was without effect. Antibodies to VEGF-B, but not VEGF-A, had a strong inhibitory effect on coronary artery development. The absence of coronary artery stems, and thus a functional coronary circulation, in the embryos injected with VEGF-Trap caused an accumulation of erythrocytes in the subepicardium and muscular interventricular septum. Using retroviral cell tagging, we showed that some of the erythrocytes in blood islands and small vascular tubes were progeny of the proepicardium. Thus, another salient finding of this study is the first definitive documentation of proepicardially derived hemangioblasts, which can differentiate into erythrocytes.

  7. VEGF Polymorphisms Related to Higher Serum Levels of Protein Identify Patients with Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Maria Eduarda Lopes Baitello

    2016-01-01

    Full Text Available Hepatocellular carcinoma (HCC is the most common primary neoplasia of the liver. Major risk factors for hepatocellular carcinoma include chronic liver diseases, carcinogenic agents, and genetic alterations as well as vascular endothelial growth factor (VEGF involved in angiogenesis process. The aim of this study was to evaluate the association of VEGF-A (C936T and A1154G with HCC and cirrhosis, in addition to serum levels of VEGF, clinical profile, lifestyle habits, and comorbidities. A total of 346 individuals were studied: 102 with HCC (G1, 117 with cirrhosis (G2, and 127 controls (G3. Polymorphisms were analysed by PCR/RFLP and serum levels of VEGF by ELISA. Alpha error was set at 5%. The wild-type genotype of both polymorphisms prevailed (P>0.05. In G1, 23% of the patients died, with no relation to genetic profile (P>0.05. Increased VEGF level was observed in G1 and G3, related to the mutant allele of VEGF-C936T and VEGF-A1154G, respectively, and compared with the wild-type genotype (P=0.0285; P=0.0284, resp. as well as G1 versus G2 and G3 for VEGF-C936T and G1 versus G2 for VEGF-A1154G (P<0.05 for both. In conclusion, there is a relationship between mutant alleles of VEGF-C936T and VEGF-A1154G polymorphisms and higher VEGF level, making them potential markers for HCC.

  8. Circulating VEGF as a biological marker in patients with rheumatoid arthritis? Preanalytical and biological variability in healthy persons and in patients

    DEFF Research Database (Denmark)

    Hetland, Merete Lund; Christensen, Ib Jarle; Lottenburger, Tine

    2008-01-01

    and contamination of plasma with cellular elements lead to significant increases in VEGF levels, whereas storage for up to 2 years at -80 degrees C or up to 10 freeze/thaw cycles did not affect VEGF levels. Serum VEGF levels were 7-10 fold higher than plasma VEGF levels. Reference intervals for VEGF (plasma: 45 pg...

  9. Dual targeting of Bcl-2 and VEGF: a potential strategy to improve therapy for prostate cancer.

    Science.gov (United States)

    Anai, Satoshi; Sakamoto, Noboru; Sakai, Yoshihisa; Tanaka, Motoyoshi; Porvasnik, Stacy; Urbanek, Cydney; Cao, Wengang; Goodison, Steve; Rosser, Charles J

    2011-01-01

    We previously demonstrated that Bcl-2 overexpression stimulates angiogenesis in PC-3 human prostate cancer cells, thus giving these tumors a growth advantage. To further elucidate the relationship between Bcl-2 and vascular endothelial growth factor (VEGF) in PC-3-Bcl-2 cells, tumorigenicity and angiogenesis were evaluated in our in vitro and in vivo model treated with antisense Bcl-2 oligodeoxynucleotide (ASO) and bevacizumab. In vitro and in vivo angiogenesis assays, as well as a xenograft tumor model of the human prostate cancer cell line PC-3-Bcl-2, were subjected to ASO alone, bevacizumab alone, or the combination of ASO and bevacizumab. Protein-based assays (e.g., immunohistochemical staining and enzyme-linked immunosorbent assay [ELISA]) were utilized to detect molecular changes. Interestingly, targeting Bcl-2 with ASO resulted in the inhibition of in vitro tube formation and inhibition of angiogenesis in Matrigel plugs similar to treatment with bevacizumab. In our PC-3-Bcl-2 xenograft model, ASO alone resulted in 41% reduction in tumor size, bevacizumab alone resulted in a 50% reduction in tumor size, whereas the combination of ASO with bevacizumab was associated with >95% reduction in tumor volume. Reduction in tumor size in all groups was associated with reduction in Bcl-2 and VEGF expression, induction of apoptosis, and inhibition of angiogenesis and its associated chemokine production. These findings confirm that Bcl-2 is a pivotal target for cancer therapy and thus, further study of this novel combination of Bcl-2 reduction and angiogenic targeting in human tumors is warranted. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Up-Regulation of ENO1 by HIF-1α in Retinal Pigment Epithelial Cells after Hypoxic Challenge Is Not Involved in the Regulation of VEGF Secretion.

    Directory of Open Access Journals (Sweden)

    Feihui Zheng

    Full Text Available Alpha-enolase (ENO1, a major glycolytic enzyme, is reported to be over-expressed in various cancer tissues. It has been demonstrated to be regulated by the Hypoxia-inducible factor 1-α (HIF-1α, a crucial transcriptional factor implicated in tumor progression and cancer angiogenesis. Choroidal neovascularization (CNV, which is a leading cause of severe vision loss caused by newly formed blood vessels in the choroid, is also engendered by hypoxic stress. In this report, we investigated the expression of ENO1 and the effects of its down-regulation upon cobalt (II chloride-induced hypoxia in retinal pigment epithelial cells, identified as the primary source of ocular angiogenic factors.HIF-1α-diminished retinal pigment epithelial cells were generated by small interfering RNA (siRNA technology in ARPE-19 cells, a human retinal pigment epithelial cell line. Both normal and HIF-1α-diminished ARPE-19 cells were then subjected to hypoxic challenge using cobalt (II chloride (CoCl2 or anaerobic chamber. The relation between ENO1 expression and vascular endothelial growth factor (VEGF secretion by retinal pigment epithelial cells were examined. Protein levels of HIF-1α and ENO1 were analyzed using Western Blot, while VEGF secretion was essayed by enzyme-linked immunosorbent assay (ELISA. Cytotoxicity after hypoxia was detected by Lactate Dehydrogenase (LDH Assay.Upon 24 hr of CoCl2-induced hypoxia, the expression levels of ENO1 and VEGF were increased along with HIF-1α in ARPE-19 cells, both of which can in turn be down-regulated by HIF-1α siRNA application. However, knockdown of ENO1 alone or together with HIF-1α did not help suppress VEGF secretion in hypoxic ARPE-19 cells.ENO1 was demonstrated to be up-regulated by HIF-1α in retinal pigment epithelial cells in response to hypoxia, without influencing VEGF secretion.

  11. WISP-1 promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-300 in human oral squamous cell carcinoma cells.

    Science.gov (United States)

    Lin, Ching-Chia; Chen, Po-Chun; Lein, Ming-Yu; Tsao, Ching-Wen; Huang, Chiu-Chen; Wang, Shih-Wei; Tang, Chih-Hsin; Tung, Kwong-Chung

    2016-03-01

    Oral squamous cell carcinoma (OSCC), which accounts for nearly 90% of head and neck cancers, is characterized by a poor prognosis and a low survival rate. Vascular endothelial growth factor-C (VEGF-C) has been implicated in lymphangiogenesis and is correlated with cancer metastasis. WNT1-inducible signaling pathway protein-1 (WISP)-1/CCN4 is an extracellular matrix-related protein that belongs to the CCN family and stimulates many biological functions. Our previous studies showed that WISP-1 plays an important role in OSCC migration and angiogenesis. However, the effect of WISP-1 on VEGF-C regulation and lymphangiogenesis in OSCC is poorly understood. Here, we showed a correlation between WISP-1 and VEGF-C in tissue specimens from patients with OSCC. To examine the lymphangiogenic effect of WISP-1, we used human lymphatic endothelial cells (LECs) to mimic lymphatic vessel formation. The results showed that conditioned media from WISP-1-treated OSCC cells promoted tube formation and cell migration in LECs. We also found that WISP-1-induced VEGF-C is mediated via the integrin αvβ3/integrin-linked kinase (ILK)/Akt signaling pathway. In addition, the expression of microRNA-300 (miR-300) was inhibited by WISP-1 via the integrin αvβ3/ILK/Akt cascade. Collectively, these results reveal the detailed mechanism by which WISP-1 promotes lymphangiogenesis via upregulation of VEGF-C expression in OSCC. Therefore, WISP-1 could serve as therapeutic target to prevent metastasis and lymphangiogenesis in OSCC.

  12. Fragmentation and ablation during entry

    Energy Technology Data Exchange (ETDEWEB)

    Canavan, G.H.

    1997-09-01

    This note discusses objects that both fragment and ablate during entry, using the results of previous reports to describe the velocity, pressure, and fragmentation of entering objects. It shows that the mechanisms used there to describe the breakup of non-ablating objects during deceleration remain valid for most ablating objects. It treats coupled fragmentation and ablation during entry, building on earlier models that separately discuss the entry of objects that are hard, whose high heat of ablation permits little erosion, and those who are strong whose strength prevents fragmentation, which are discussed in ``Radiation from Hard Objects,`` ``Deceleration and Radiation of Strong, Hard, Asteroids During Atmospheric Impact,`` and ``Meteor Signature Interpretation.`` This note provides a more detailed treatment of the further breakup and separation of fragments during descent. It replaces the constraint on mass per unit area used earlier to determine the altitude and magnitude of peak power radiation with a detailed analytic solution of deceleration. Model predictions are shown to be in agreement with the key features of numerical calculations of deceleration. The model equations are solved for the altitudes of maximum radiation, which agree with numerical integrations. The model is inverted analytically to infer object size and speed from measurements of peak power and altitude to provide a complete model for the approximate inversion of meteor data.

  13. 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...... whole tumor sections for VEGF-A, -B, and VEGFR-1 of invasive ductal carcinomas of the breast and scored the tumors manually with staining intensity as the only parameter and by a combination of qualitative and quantitative information. We also introduce an automated method for analyzing VEGF expression...

  14. Modified VEGF targets the ischemic myocardium and promotes functional recovery after myocardial infarction.

    Science.gov (United States)

    Yang, Yun; Shi, Chunying; Hou, Xianglin; Zhao, Yannan; Chen, Bing; Tan, Bo; Deng, Zongwu; Li, Qingguo; Liu, Jianzhou; Xiao, Zhifeng; Miao, Qi; Dai, Jianwu

    2015-09-10

    Vascular endothelial growth factor (VEGF) promotes angiogenesis and improves cardiac function after myocardial infarction (MI). However, the non-targeted delivery of VEGF decreases its therapeutic efficacy due to an insufficient local concentration in the ischemic myocardium. In this study, we used a specific peptide to modify VEGF and determined that this modified VEGF (IMT-VEGF) localized to the ischemic myocardium through intravenous injection by interacting with cardiac troponin I (cTnI). When IMT-VEGF was used to mediate cardiac repair in a rat model of ischemia-reperfusion (I-R) injury, we observed a decreased scar size, enhanced angiogenesis and improved cardiac function. Moreover, an alternative treatment using the repeated administration of a low-dose IMT-VEGF also promoted angiogenesis and functional recovery. The therapeutic effects of IMT-VEGF were further confirmed in a pig model of MI as the result of the conserved properties of its interacting protein, cTnI. These results suggest a promising therapeutic strategy for MI based on the targeted delivery of IMT-VEGF. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. An increase of VEGF plasma levels is associated with restenosis of drug-eluting stents.

    Science.gov (United States)

    Katsaros, Katharina M; Kastl, Stefan P; Krychtiuk, Konstantin A; Hutter, Randolph; Zorn, Gerlinde; Maurer, Gerald; Huber, Kurt; Wojta, Johann; Christ, Günter; Speidl, Walter S

    2014-06-01

    Drug-eluting stents (DES) reduce late lumen loss compared to bare metal stents but were not able to eradicate in-stent restenosis (ISR) fully. Vascular endothelial growth factor (VEGF) may inhibit late lumen loss through accelerated reendothelialisation, but may also promote neointima formation by proinflammatory effects. The aim of this study was to evaluate whether endogenous plasma levels of VEGF are associated with development of ISR after implantation of DES. We studied 85 patients who were treated with 159 DES. VEGF plasma levels were determined before and 24 hours after PCI. During the eight-month follow-up period, two patients (2.4%) died of cardiovascular causes and 12 patients (14.5% of patients, 7.6% of stents) developed angiographic ISR. Basal VEGF plasma levels were not different in patients with and without ISR at follow-up. In contrast to patients without ISR, VEGF increased significantly upon PCI in patients with ISR (p<0.005). Patients with a decrease of VEGF after PCI had a restenosis rate of 2.4% compared to a restenosis rate of 26.2% in patients with an increase of VEGF after the procedure (p<0.05). This was independent from clinical and angiographic risk factors. Basal plasma levels of VEGF are not associated with the development of ISR. However, an increase of VEGF after PCI is associated with a dramatically increased ISR rate after implantation of DES.

  16. A Biomimic Reconstituted High Density Lipoprotein Nanosystem for Enhanced VEGF Gene Therapy of Myocardial Ischemia

    Directory of Open Access Journals (Sweden)

    Xiaotian Sun

    2015-01-01

    Full Text Available A biomimic reconstituted high density lipoprotein (rHDL based system, rHDL/Stearic-PEI/VEGF complexes, was fabricated as an advanced nanovector for delivering VEGF plasmid. Here, Stearic-PEI was utilized to effectively condense VEGF plasmid and to incorporate the plasmid into rHDL. The rHDL/Stearic-PEI/VEGF complexes with diameter under 100 nm and neutral surface charge demonstrated enhanced stability under the presence of bovine serum albumin. Moreover, in vitro cytotoxicity and transfection assays on H9C2 cells further revealed their superiority, as they displayed lower cytotoxicity with much higher transfection efficiency when compared to PEI 10K/VEGF and Lipos/Stearic-PEI/VEGF complexes. In addition, in vivo investigation on ischemia/reperfusion rat model implied that rHDL/Stearic-PEI/VEGF complexes possessed high transgene capacity and strong therapeutic activity. These findings indicated that rHDL/Stearic-PEI/VEGF complexes could be an ideal gene delivery system for enhanced VEGF gene therapy of myocardial ischemia, which might be a new promising strategy for effective myocardial ischemia treatment.

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

    Science.gov (United States)

    Hoier, Birgitte; Hellsten, Ylva

    2014-05-01

    In skeletal muscle, growth of capillaries is an important adaptation to exercise training that secures adequate diffusion capacity for oxygen and nutrients even at high-intensity exercise when increases in muscle blood flow are profound. Mechanical forces present during muscle activity, such as shear stress and passive stretch, lead to cellular signaling, enhanced expression of angiogenic factors, and initiation of capillary growth. The most central angiogenic factor in skeletal muscle capillary growth is 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, these VEGF-containing vesicles are redistributed toward the sarcolemma where the contents are secreted into the extracellular fluid. VEGF mRNA expression is increased primarily after exercise, which allows for a more rapid replenishment of VEGF stores lost through secretion during exercise. Future studies should focus on elucidating mechanisms and regulation of VEGF secretion. © 2014 John Wiley & Sons Ltd.

  18. Cellular and molecular mechanisms involved in the neuroprotective effects of VEGF on motoneurons

    Directory of Open Access Journals (Sweden)

    Jerònia eLladó

    2013-10-01

    Full Text Available Vascular endothelial growth factor (VEGF, originally described as a factor with a regulatory role in vascular growth and development, it is also known for its direct effects on neuronal cells. The discovery in the past decade that transgenic mice expressing reduced levels of VEGF developed late-onset motoneuron pathology, reminiscent of amyotrophic lateral sclerosis (ALS, opened a new field of research on this disease. VEGF has been shown to protect motoneurons from excitotoxic death, which is a relevant mechanism involved in motoneuron degeneration in ALS. Thus, VEGF delays motoneuron degeneration and increases survival in animal models of ALS. VEGF exerts its anti-excitotoxic effects on motoneurons through molecular mechanisms involving the VEGF receptor-2 resulting in the activation of the PI3-K/Akt signaling pathway, upregulation of GluR2 subunit of AMPA receptors, inhibition of p38MAPK and induction of the anti-apoptotic molecule Bcl-2. In addition, VEGF acts on astrocytes to reduce astroglial activation and to induce the release of growth factors. The potential use of VEGF as a therapeutic tool in ALS is counteracted by its vascular effects and by its short effective time frame. More studies are needed to assess the optimal isoform, route of administration and time frame for using VEGF in the treatment of ALS.

  19. SFRP2 Is Associated with Increased Adiposity and VEGF Expression.

    Science.gov (United States)

    Crowley, Rachel K; O'Reilly, Michael W; Bujalska, Iwona J; Hassan-Smith, Zaki K; Hazlehurst, Jonathan M; Foucault, Danielle R; Stewart, Paul M; Tomlinson, Jeremy W

    The aim of this study was to assess depot-specific expression and secretion of secreted frizzled-related protein 2 (sFRP2) by adipose tissue and its effect on adipocyte biology. We measured serum sFRP2 concentrations in 106 patients in vivo to explore its relationship to fat mass, glycaemia and insulin resistance. Expression of sFRP2 in mouse and human tissues was assessed using polymerase chain reaction and Western blot. Western blot confirmed secretion of sFRP2 by adipose tissue into cell culture medium. Effects of recombinant sFRP2 on lipogenesis and preadipocyte proliferation were measured. Preadipocyte expression of the angiogenic genes vascular endothelial growth factor (VEGF) and nuclear factor of activated T-cells 3 (NFATC3) was measured after recombinant sFRP2 exposure. Complementary clinical studies correlating human serum sFRP2 with age, gender, adiposity and insulin secretion were also performed. sFRP2 messenger RNA (mRNA) was expressed in mouse and human adipose tissue. In humans, sFRP2 mRNA expression was 4.2-fold higher in omental than subcutaneous adipose. Omental adipose tissue secreted 63% more sFRP2 protein than subcutaneous. Treatment with recombinant sFRP2 did not impact on lipogenesis or preadipocyte proliferation but was associated with increased VEGF mRNA expression. In human subjects, circulating insulin levels positively correlated with serum sFRP2, and levels were higher in patients with abnormal glucose tolerance (34.2ng/ml) compared to controls (29.5ng/ml). A positive correlation between sFRP2 and BMI was also observed. Circulating sFRP2 is associated with adipose tissue mass and has a potential role to drive adipose angiogenesis through enhanced VEGF expression.

  20. Corneal avascularity is due to soluble VEGF receptor-1.

    Science.gov (United States)

    Ambati, Balamurali K; Nozaki, Miho; Singh, Nirbhai; Takeda, Atsunobu; Jani, Pooja D; Suthar, Tushar; Albuquerque, Romulo J C; Richter, Elizabeth; Sakurai, Eiji; Newcomb, Michael T; Kleinman, Mark E; Caldwell, Ruth B; Lin, Qing; Ogura, Yuichiro; Orecchia, Angela; Samuelson, Don A; Agnew, Dalen W; St Leger, Judy; Green, W Richard; Mahasreshti, Parameshwar J; Curiel, David T; Kwan, Donna; Marsh, Helene; Ikeda, Sakae; Leiper, Lucy J; Collinson, J Martin; Bogdanovich, Sasha; Khurana, Tejvir S; Shibuya, Masabumi; Baldwin, Megan E; Ferrara, Napoleone; Gerber, Hans-Peter; De Falco, Sandro; Witta, Jassir; Baffi, Judit Z; Raisler, Brian J; Ambati, Jayakrishna

    2006-10-26

    Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice and Pax6+/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.

  1. Musculoskeletal interventional radiology: radiofrequency ablation.

    Science.gov (United States)

    Ward, Emily; Munk, Peter L; Rashid, Faisal; Torreggiani, William C

    2008-05-01

    Radiofrequency ablation is the use of low-voltage high-frequency electrical energy to heat and destroy abnormal tissues within the human body. It has gained increasing acceptance as both a primary and secondary form of treatment in the musculoskeletal system because of its excellent safety profile, ease of use, and technical success. In the musculoskeletal system, radiofrequency ablation may be used to treat a wide range of lesions that include primary lesions such as osteoid osteomas and a variety of metastases both within the osseous skeleton as well as those lying within the muscles and soft tissues. In this chapter, a background to the principles, physics, and indications of radiofrequency is presented as well as an in-depth description of radiofrequency ablation techniques that may be utilized in the musculoskeletal system.

  2. Laser ablation studies of nanocomposites

    Directory of Open Access Journals (Sweden)

    Oleg V. Mkrtychev

    2015-03-01

    Full Text Available The first experimental measurements of the threshold energy density values for the laser ablation of glass nanocomposites with nanodimensional coatings have been carried out under the action of the YAG–Nd laser power pulse radiation. The coatings in question were of different compositions and had been created by the sol–gel technology. The procedure for determining the laser ablation threshold energy density values was worked out on the base of the breakdown probability level of 0.5. The statistical processing of the measurement data over all the samples allowed obtaining the dependence of the ablation destruction threshold energy parameters on the coating physical and chemical properties such as the sample transmission in the visible region of the spectrum, coating thickness, the chemical composition of the film-forming solution, and on the pulse duration of laser radiation.

  3. Potent small molecule Hedgehog agonists induce VEGF expression in vitro.

    Science.gov (United States)

    Seifert, Katrin; Büttner, Anita; Rigol, Stephan; Eilert, Nicole; Wandel, Elke; Giannis, Athanassios

    2012-11-01

    Here, we describe the synthesis, SAR studies as well as biological investigations of the known Hedgehog signaling agonist SAG and a small library of its analogues. The SAG and its derivatives were analyzed for their potency to activate the expression of the Hh target gene Gli1 in a reporter gene assay. By analyzing SAR important molecular descriptors for Gli1 activation have been identified. SAG as well as compound 10c proven to be potent activators of VEGF expression in cultivated dermal fibroblasts. Importantly and in contrast to SAG, derivative 10c displayed no toxicity in concentrations up to 250 μm. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. Radiofrequency Catheter Ablation of Parahisian Accessory Pathway

    Directory of Open Access Journals (Sweden)

    Korodi Szilamér

    2016-06-01

    Full Text Available Radiofrequency catheter ablation of parahisian accessory pathways in pre-excitation syndrome is a challenging task, due to the extremely high risk of complete atrioventricular block. In this brief report we describe the case of a 32 year-old man presenting a parahisian accessory pathway, who has been successfully treated by radiofrequency ablation. Radiofrequency catheter ablation using low-power radiofrequency current is considered to be the most appropiate method of ablation in adult patients.

  5. Femtosecond laser ablation of dentin

    Science.gov (United States)

    Alves, S.; Oliveira, V.; Vilar, R.

    2012-06-01

    The surface morphology, structure and composition of human dentin treated with a femtosecond infrared laser (pulse duration 500 fs, wavelength 1030 nm, fluences ranging from 1 to 3 J cm-2) was studied by scanning electron microscopy, x-ray diffraction, x-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. The average dentin ablation threshold under these conditions was 0.6 ± 0.2 J cm-2 and the ablation rate achieved in the range 1 to 2 µm/pulse for an average fluence of 3 J cm-2. The ablation surfaces present an irregular and rugged appearance, with no significant traces of melting, deformation, cracking or carbonization. The smear layer was entirely removed by the laser treatment. For fluences only slightly higher than the ablation threshold the morphology of the laser-treated surfaces was very similar to the dentin fracture surfaces and the dentinal tubules remained open. For higher fluences, the surface was more porous and the dentin structure was partially concealed by ablation debris and a few resolidified droplets. Independently on the laser processing parameters and laser processing method used no sub-superficial cracking was observed. The dentin constitution and chemical composition was not significantly modified by the laser treatment in the processing parameter range used. In particular, the organic matter is not preferentially removed from the surface and no traces of high temperature phosphates, such as the β-tricalcium phosphate, were observed. The achieved results are compatible with an electrostatic ablation mechanism. In conclusion, the high beam quality and short pulse duration of the ultrafast laser used should allow the accurate preparation of cavities, with negligible damage of the underlying material.

  6. Catheter ablation for paroxysmal atrial fibrillation: segmental pulmonary vein ostial ablation versus left atrial ablation.

    Science.gov (United States)

    Oral, Hakan; Scharf, Christoph; Chugh, Aman; Hall, Burr; Cheung, Peter; Good, Eric; Veerareddy, Srikar; Pelosi, Frank; Morady, Fred

    2003-11-11

    Segmental ostial catheter ablation (SOCA) to isolate the pulmonary veins (PVs) and left atrial catheter ablation (LACA) to encircle the PVs both may eliminate paroxysmal atrial fibrillation (PAF). The relative efficacy of these 2 techniques has not been directly compared. Of 80 consecutive patients with symptomatic PAF (age, 52+/-10 years), 40 patients underwent PV isolation by SOCA and 40 patients underwent LACA to encircle the PVs. During SOCA, ostial PV potentials recorded with a ring catheter were targeted. LACA was performed by encircling the left- and right-sided PVs 1 to 2 cm from the ostia and was guided by an electroanatomic mapping system; ablation lines also were created in the mitral isthmus and posterior left atrium. The mean procedure and fluoroscopy times were 156+/-45 and 50+/-17 minutes for SOCA and 149+/-33 and 39+/-12 minutes for LACA, respectively. At 6 months, 67% of patients who underwent SOCA and 88% of patients who underwent LACA were free of symptomatic PAF when not taking antiarrhythmic drug therapy (P=0.02). Among the variables of age, sex, duration and frequency of PAF, ejection fraction, left atrial size, structural heart disease, and the ablation technique, only an increased left atrial size and the SOCA technique were independent predictors of recurrent PAF. The only complication was left atrial flutter in a patient who underwent LACA. In patients undergoing catheter ablation for PAF, LACA to encircle the PVs is more effective than SOCA.

  7. Ablation of Solid Hydrogen in a Plasma

    DEFF Research Database (Denmark)

    Jørgensen, L. W.; Sillesen, Alfred Hegaard

    1979-01-01

    Several hydrogen pellet ablation models based on the formation of a shielding neutral cloud have been reported by different authors. The predicted ablation rates are shown to follow almost the same scaling law and this is used to explain the authors' ablation experiment....

  8. Delineating multiple functions of VEGF-A in the adult brain.

    Science.gov (United States)

    Licht, Tamar; Keshet, Eli

    2013-05-01

    Vascular endothelial growth factor-A (abbreviated throughout this review as VEGF) is mostly known for its angiogenic activity, for its activity as a vascular permeability factor, and for its vascular survival activity [1]. There is a growing body of evidence, however, that VEGF fulfills additional less 'traditional' functions in multiple organs, both during development, as well as homeostatic functions in fully developed organs. This review focuses on the multiple roles of VEGF in the adult brain and is less concerned with the roles played by VEGF during brain development, functions described elsewhere in this review series. Most functions of VEGF that are essential for proper brain development are, in fact, dispensable in the adult brain as was clearly demonstrated using a conditional brain-specific VEGF loss-of-function (LOF) approach. Thus, in contrast to VEGF LOF in the developing brain, a process which is detrimental for the growth and survival of blood vessels and leads to massive neuronal apoptosis [2-4], continued signaling by VEGF in the mature brain is no longer required for maintaining already established cerebral vasculature and its inhibition does not cause appreciable vessel regression, hypoxia or apoptosis [4-7]. Yet, VEGF continues to be expressed in the adult brain in a constitutive manner. Moreover, VEGF is expressed in the adult brain in a region-specific manner and in distinctive spatial patterns incompatible with an angiogenic role (see below), strongly suggesting angiogenesis-independent and possibly also perfusion-independent functions. Here we review current knowledge on some of these 'non-traditional', often unexpected homeostatic VEGF functions, including those unrelated to its effects on the brain vasculature. These effects could be mediated directly (on non-vascular cells expressing cognate VEGF receptors) or indirectly (via the endothelium). Experimental approaches aimed at distinguishing between these possibilities for each particular

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

    Science.gov (United States)

    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.

  10. Evaluation of anticancer peptide VEGF111b secretion in HEK293 human cells

    Directory of Open Access Journals (Sweden)

    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.

  11. Epithelial membrane protein 2 controls VEGF expression in ARPE-19 cells.

    Science.gov (United States)

    Morales, Shawn A; Telander, David G; Leon, Deanna; Forward, Krisztina; Braun, Jonathan; Wadehra, Madhuri; Gordon, Lynn K

    2013-03-28

    VEGF production by RPE cells has been shown to be important in regulating aberrant angiogenesis in the retina, which is responsible for multiple types of ocular pathology. EMP2 is highly expressed in the RPE and has been shown to regulate FAK activation, which is implicated in VEGF expression in other cell lines. The purpose of this study was to determine whether EMP2 regulates VEGF expression in the RPE cell line, ARPE-19. ARPE-19 cells were engineered to overexpress EMP2. EMP2 siRNA was used to decrease EMP2 expression. The small molecule inhibitor PP2 was used to inhibit FAK activation. VEGF levels were measured by Western blot and ELISA. Functional differences in secreted VEGF were assayed using HUVEC migration. VEGF expression levels correlated with levels of EMP2. An increase of VEGF by 150% was observed in EMP2 overexpressing cells as compared with ARPE-19 cells. Concordantly, EMP2 knockdown resulted in a 57% decrease in VEGF expression. HUVEC migration (P = 0.01) and vessel tube formation (P < 0.01) were significantly increased when exposed to cell culture supernatants from EMP2 overexpressing cells. This study establishes a novel connection between EMP2 and VEGF and may reflect either a direct effect through the tetraspan web or an indirect change through FAK activation. This connection is functionally significant. In addition to the direct use of anti-VEGF antibodies, modulation of EMP2 with impact on VEGF is potentially a distinct therapeutic target for the treatment of neovascularization associated with retinal diseases that involve pathologic angiogenesis.

  12. MicroRNA-199b Modulates Vascular Cell Fate During iPS Cell Differentiation by Targeting the Notch Ligand Jagged1 and Enhancing VEGF Signaling.

    Science.gov (United States)

    Chen, Ting; Margariti, Andriana; Kelaini, Sophia; Cochrane, Amy; Guha, Shaunta T; Hu, Yanhua; Stitt, Alan W; Zhang, Li; Xu, Qingbo

    2015-05-01

    Recent ability to derive endothelial cells (ECs) from induced pluripotent stem (iPS) cells holds a great therapeutic potential for personalized medicine and stem cell therapy. We aimed that better understanding of the complex molecular signals that are evoked during iPS cell differentiation toward ECs may allow specific targeting of their activities to enhance cell differentiation and promote tissue regeneration. In this study, we have generated mouse iPS cells from fibroblasts using established protocol. When iPS cells were cultivated on type IV mouse collagen-coated dishes in differentiation medium, cell differentiation toward vascular lineages were observed. To study the molecular mechanisms of iPS cell differentiation, we found that miR-199b is involved in EC differentiation. A step-wise increase in expression of miR-199 was detected during EC differentiation. Notably, miR-199b targeted the Notch ligand JAG1, resulting in vascular endothelial growth factor (VEGF) transcriptional activation and secretion through the transcription factor STAT3. Upon shRNA-mediated knockdown of the Notch ligand JAG1, the regulatory effect of miR-199b was ablated and there was robust induction of STAT3 and VEGF during EC differentiation. Knockdown of JAG1 also inhibited miR-199b-mediated inhibition of iPS cell differentiation toward smooth muscle markers. Using the in vitro tube formation assay and implanted Matrigel plugs, in vivo, miR-199b also regulated VEGF expression and angiogenesis. This study indicates a novel role for miR-199b as a regulator of the phenotypic switch during vascular cell differentiation derived from iPS cells by regulating critical signaling angiogenic responses. Stem Cells 2015;33:1405-1418. © 2015 AlphaMed Press.

  13. Molecular Analysis of Vascular Endothelial Growth Factor (VEGF) Receptors in EUS-guided Samples Obtained from Patients with Pancreatic Adenocarcinoma.

    Science.gov (United States)

    Costache, Madalin Ionut; Iordache, Sevastita; Costache, Cornelia Alexandra; Dragos, Ene; Dragos, Alexandru; Saftoiu, Adrian

    2017-03-01

    Vascular endothelial growth factor (VEGF) and its receptors (VEGF-R1 and VEGF-R2) are the most important angiogenesis stimulating factors in pancreatic cancer. This study aims to assess VEGF-R1 and VEGF-R2 gene expression in EUS-FNA samples and identify prognostic markers in pancreatic adenocarcinoma. This was a retrospective study of prospectively collected data of 88 consecutive patients, with clinical and imaging suspicion of pancreatic neoplasms, based on samples obtained through endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). EUS had an accuracy of 93.2% for the diagnosis of pancreatic cancer. Based on real-time qPCR analysis, VEGF-R1 and VEGF-R2 expressions were present in 90% and 65% of the analysed malignant samples, respectively; 89% of the patients died during the study, with a median survival rate of only 9 months. The survival was correlated with the initial stage and with the presence of VEGF-R1 and VEGF-R2 gene expression. We found that there are significant correlations between death/survival and T stage, N stage, resectability status, VEGF-R1, VEGF-R2 and VEGF-R1/VEGF-R2 coexpression. Using a Cox model regression our study demonstrates that VEGF-R1/VEGF-R2 coexpression might be considered as a poor prognostic factor in pancreatic cancer. EUS is a very effective technique for the diagnosis and staging of pancreatic adenocarcinoma in patients with clinical and imaging suspicion of pancreatic neoplasm, with an accuracy of 93.2%. Furthermore, the role of molecular analysis of EUS-guided FNA samples was established by the assessment of VEGF-R1, VEGF-R2 gene expression, which might be considered prognostic markers in pancreatic cancer.

  14. Ablative zone size created by radiofrequency ablation with and without chemoembolization in small hepatocellular carcinomas.

    Science.gov (United States)

    Yamanaka, Takashi; Yamakado, Koichiro; Takaki, Haruyuki; Nakatsuka, Atsuhiro; Shiraki, Katsuya; Hasegawa, Hiroshi; Takei, Yoshiyuki; Takeda, Kan

    2012-08-01

    We retrospectively evaluated whether combined use of chemoembolization expands ablative zone sizes created by radiofrequency (RF) ablation in patients with small hepatocellular carcinomas (HCCs). Fifty-seven patients treated with single RF ablation for solitary HCC measuring ≤2 cm were assessed. RF ablation alone was done in nine patients and in 48 patients following chemoembolization, with an interval of 0 days in 6, 1-14 days in 27, 15-28 days in 6, and ≥4 weeks in 9. Ablative zone sizes, disappearance of tumor enhancement, and creation of sufficient ablative margins (>5 mm) were evaluated on contrast-enhanced computed tomography (CT) images. Both mean long-axis (4.2-4.7 vs. 3.6 ± 0.4 cm, p ablation was done until 4 weeks after chemoembolization than with RF ablation alone. Tumor enhancement disappeared in all patients. Frequency of achieving sufficient ablative margins was significantly higher when RF ablation was done until 4 weeks after chemoembolization than with RF ablation alone (74.0-83.3 vs. 22.2 %, p Ablative zones created by RF ablation with chemoembolization become larger than RF ablation alone, leading to secure ablative margins.

  15. [Macular Edema in Uveitis - Steroids or VEGF Inhibitors?

    Science.gov (United States)

    Heinz, Carsten; Heiligenhaus, Arnd

    2017-06-09

    Macular edema in uveitis patients is certainly the most frequent complication leading to a permanent and irreversible reduction in vision during the course of the disease. Thanks to optical coherence tomography (OCT) technology and fluorescein angiography (FAG), significantly more macular edemas are detected. Macular edema can be found in various uveitis varieties and can show different clinical patterns. All macular edema should be treated. Macular edema with active inflammation usually reacts very well to general uveitis treatment. In the case of eyes without visible inflammation, however, the response to such therapy is usually less effective. According to the latest treatment recommendations, dexamethasone implants should be used as the first intravitreal therapy. Vascular endothelial growth factor inhibitors (VEGF inhibitors) are second-line treatment regimens. The choice of therapy is, therefore, primarily based on the degree of inflammation and the individual complications, such as glaucoma, lens situation or previous increase in IOP after steroid administration. These individual complications may allow using VEGF inhibitors as first line treatment. An improvement in the macular edema can be achieved with both groups of active substances. Georg Thieme Verlag KG Stuttgart · New York.

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

    Directory of Open Access Journals (Sweden)

    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

  17. A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap.

    Directory of Open Access Journals (Sweden)

    Florence T H Wu

    Full Text Available Vascular endothelial growth factor (VEGF, through its activation of cell surface receptor tyrosine kinases including VEGFR1 and VEGFR2, is a vital regulator of stimulatory and inhibitory processes that keep angiogenesis--new capillary growth from existing microvasculature--at a dynamic balance in normal physiology. Soluble VEGF receptor-1 (sVEGFR1--a naturally-occurring truncated version of VEGFR1 lacking the transmembrane and intracellular signaling domains--has been postulated to exert inhibitory effects on angiogenic signaling via two mechanisms: direct sequestration of angiogenic ligands such as VEGF; or dominant-negative heterodimerization with surface VEGFRs. In pre-clinical studies, sVEGFR1 gene and protein therapy have demonstrated efficacy in inhibiting tumor angiogenesis; while in clinical studies, sVEGFR1 has shown utility as a diagnostic or prognostic marker in a widening array of angiogenesis-dependent diseases. Here we developed a novel computational multi-tissue model for recapitulating the dynamic systemic distributions of VEGF and sVEGFR1. Model features included: physiologically-based multi-scale compartmentalization of the human body; inter-compartmental macromolecular biotransport processes (vascular permeability, lymphatic drainage; and molecularly-detailed binding interactions between the ligand isoforms VEGF(121 and VEGF(165, signaling receptors VEGFR1 and VEGFR2, non-signaling co-receptor neuropilin-1 (NRP1, as well as sVEGFR1. The model was parameterized to represent a healthy human subject, whereupon we investigated the effects of sVEGFR1 on the distribution and activation of VEGF ligands and receptors. We assessed the healthy baseline stability of circulating VEGF and sVEGFR1 levels in plasma, as well as their reliability in indicating tissue-level angiogenic signaling potential. Unexpectedly, simulated results showed that sVEGFR1 - acting as a diffusible VEGF sink alone, i.e., without sVEGFR1-VEGFR heterodimerization

  18. Investigation of excimer laser ablation of iron

    Science.gov (United States)

    Jordan, R.; Lunney, J. G.

    1998-05-01

    The excimer ablation of iron at 248 nm has been investigated by measuring the ablation depth and average ion energy as a function of laser fluence. Measurements have also been made of the laser transmission through the ablated vapour above the target. The absolute spectral intensity of the emission from the ablation plasma has been measured in both the vacuum ultraviolet and the visible. All results were compared with a simple numerical model describing the main physical processes involved in laser ablation of metal targets.

  19. Modern Advances in Ablative TPS

    Science.gov (United States)

    Venkatapathy, Ethiraj

    2013-01-01

    Topics covered include: Physics of Hypersonic Flow and TPS Considerations. Destinations, Missions and Requirements. State of the Art Thermal Protection Systems Capabilities. Modern Advances in Ablative TPS. Entry Systems Concepts. Flexible TPS for Hypersonic Inflatable Aerodynamic Decelerators. Conformal TPS for Rigid Aeroshell. 3-D Woven TPS for Extreme Entry Environment. Multi-functional Carbon Fabric for Mechanically Deployable.

  20. Fractional ablative erbium YAG laser

    DEFF Research Database (Denmark)

    Taudorf, Elisabeth H; Haak, Christina S; Erlendsson, Andrés M

    2014-01-01

    BACKGROUND AND OBJECTIVES: Treatment of a variety of skin disorders with ablative fractional lasers (AFXL) is driving the development of portable AFXLs. This study measures micropore dimensions produced by a small 2,940 nm AFXL using a variety of stacked pulses, and determines a model correlating...

  1. Microwave ablation of lung tissue: impact of single-lung ventilation on ablation size.

    Science.gov (United States)

    Santos, Ricardo S; Gan, Jianmin; Ohara, Carl J; Daly, Benedict; Ebright, Michael I; Desimone, Michael; Fernando, Hiran C

    2010-10-01

    Thermal ablation is increasingly used to treat pulmonary tumors in medically inoperable patients. Most procedures are performed with sedation in the radiology suite. Ideally, the ablation should encompass the entire tumor volume with a surrounding margin of necrosis; however, ablation may not be as effective in the normal aerated lung surrounding a denser tumor. Inducing atelectasis of the lung may potentially increase ablation volumes and increase local cancer control. This study examines the effect of single-lung ventilation on ablation size using a microwave system. Twenty microwave ablation procedures were performed in the lungs of 10 swine. Bilateral thoracotomy using a clamshell approach was used. In one lung, ablation was performed with continuous ventilation. In the contralateral lung, single-lung ventilation was achieved by clamping the bronchus before ablation. The ablated lobes were resected and sent for pathologic analysis. Routine and supravital staining was performed. The ablation zone was clearly demarcated on gross examination, and in all cases 100% ablation occurred, without skip areas of viability. The ablation zones were elliptical with the long axis parallel to the axis of the ablation probes (active tip, 3.7 cm). Ablation diameters and volume were compared between the ventilated and nonventilated lungs. Ablation volume was superior in nonventilated lungs (10.74 cm(3) versus 7.35 cm(3); p = 0.039) primarily because of differences in the short axis of the ablation zone. Microwave energy can effectively ablate normal pulmonary parenchyma without skip areas of viable tissue within the gross ablation field. The volume of necrosis is increased in nonventilated lungs, suggesting that ablation results can be improved in patients by using general anesthesia with single-lung ventilation. Future studies will be required to confirm this hypothesis. Copyright © 2010 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  2. 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 litterm...

  3. Increased VEGF-A promotes multiple distinct aging diseases of the eye through shared pathomechanisms.

    Science.gov (United States)

    Marneros, Alexander G

    2016-03-01

    While increased VEGF-A has been associated with neovascular age-related macular degeneration (AMD), it is not known whether VEGF-A may also promote other age-related eye diseases. Here, we show that an increase in VEGF-A is sufficient to cause multiple distinct common aging diseases of the eye, including cataracts and both neovascular and non-exudative AMD-like pathologies. In the lens, increased VEGF-A induces age-related opacifications that are associated with ERK hyperactivation, increased oxidative damage, and higher expression of the NLRP3 inflammasome effector cytokine IL-1β. Similarly, increased VEGF-A induces oxidative stress and IL-1β expression also in the retinal pigment epithelium (RPE). Targeting NLRP3 inflammasome components or Il1r1 strongly inhibited not only VEGF-A-induced cataract formation, but also both neovascular and non-exudative AMD-like pathologies. Moreover, increased VEGF-A expression specifically in the RPE was sufficient to cause choroidal neovascularization (CNV) as in neovascular AMD, which could be inhibited by RPE-specific inactivation of Flk1, while Tlr2 inactivation strongly reduced CNV. These findings suggest a shared pathogenic role of VEGF-A-induced and NLRP3 inflammasome-mediated IL-1β activation for multiple distinct ocular aging diseases. © 2016 The Author. Published under the terms of the CC BY 4.0 license.

  4. 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.

    for immunhistochemistry using polyclonal antibodies against VEGF, VEGFR-1, VEGFR-2 and Tie-2. Results: In the present study the VEGF-system exhibited intense staining in the uterine epithelium, uterine glandular epithelium and trophoblast. The endothelial cells and smooth muscle cells of the vessels in the maternal...

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

    DEFF Research Database (Denmark)

    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...

  6. Synthesis of the human VEGF 165 gene based on overlap PCR and ...

    African Journals Online (AJOL)

    Synthesis of the human VEGF165 gene based on overlap PCR and recombinant expression in stable transfected CHO cells. J Zhang, T Wang, B Yang, Y Lin, Z Li. Abstract. Vascular endothelial growth factors (VEGFs) are a member of a family of structurally related proteins that mediate angiogenesis, and vascular ...

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

    Directory of Open Access Journals (Sweden)

    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

  8. Differential actions of VEGF-A isoforms on perichondrial angiogenesis during endochondral bone formation.

    Science.gov (United States)

    Takimoto, Aki; Nishizaki, Yuriko; Hiraki, Yuji; Shukunami, Chisa

    2009-08-15

    During endochondral bone formation, vascular invasion initiates the replacement of avascular cartilage by bone. We demonstrate herein that the cartilage-specific overexpression of VEGF-A(164) in mice results in the hypervascularization of soft connective tissues away from cartilage. Unexpectedly, perichondrial tissue remained avascular in addition to cartilage. Hypervascularization of tissues similarly occurred when various VEGF-A isoforms were overexpressed in the chick forelimb, but also in this case perichondrial tissue and cartilage were completely devoid of vasculature. However, following bony collar formation, anti-angiogenic properties in perichondrial tissue were lost and perichondrial angiogenesis was accelerated by VEGF-A(146), VEGF-A(166), or VEGF-A(190). Once the perichondrium was vascularized, osteoclast precursors were recruited from the circulation and the induction of MMP9 and MMP13 can be observed in parallel with the activation of TGF-beta signaling. Neither perichondrial angiogenesis nor the subsequent cartilage vascularization was found to be accelerated by the non-heparin-binding VEGF-A(122) or by the VEGF-A(166)DeltaE(162)-R(166) mutant lacking a neuropilin-binding motif. Hence, perichondrial angiogenesis is a prerequisite for subsequent cartilage vascularization and is differentially regulated by VEGF-A isoforms.

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

    DEFF Research Database (Denmark)

    Farajpour, Zahra; Rahbarizadeh, Fatemeh; Kazemi, Bahram

    2014-01-01

    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...

  10. Activation of protease-activated receptor 2 induces VEGF independently of HIF-1.

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    Jeppe Grøndahl Rasmussen

    Full Text Available BACKGROUND: 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 factor 1(HIF-1. The present study hypothesized that PAR2 stimulation through activation of kinase signaling cascades lead to induction of HIF-1 and secretion of VEGF. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemistry revealed the expression of PAR2 receptors on the surface of hASCs. Blocking the PAR2 receptors with a specific antibody prior to trypsin treatment showed these receptors are involved in trypsin-evoked increase in VEGF secretion from hASCs. Blocking with specific kinase inhibitors suggested that that activation of MEK/ERK and PI3-kinase/Akt pathways are involved in trypsin-eveoked induction of VEGF. The effect of the trypsin treatment on the transcription of VEGF peaked at 6 hours after the treatment and was comparable to the activation observed after keeping hASCs for 24 hours at 1% oxygen. In contrast to hypoxia, trypsin alone failed to induce HIF-1 measured with ELISA, while the combination of trypsin and hypoxia had an additive effect on both VEGF transcription and secretion, results which were confirmed by Western blot. CONCLUSION: In hASCs trypsin and hypoxia induce VEGF expression through separate pathways.

  11. 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...

  12. A proteomic study of potential VEGF-C-associated proteins in bladder cancer T24 cells.

    Science.gov (United States)

    Zhang, Hui-hui; Qi, Fan; Zu, Xiong-bing; Cao, You-han; Miao, Jian-guang; Xu, Liang; Qi, Lin

    2012-11-01

    Overexpression of vascular endothelial growth factor-C (VEGF-C) has been found to play an important role in malignant progression of various cancer cells, in addition to lymphangiogenesis. However, the mechanisms involved are still largely unknown. Our early research has confirmed that the expression of VEGF-C in bladder cancer was markedly higher than that in normal bladder tissues. VEGF-C can also obviously promote proliferation and invasion of bladder cancer T24 cells. In the present work, we attempted to use proteomic analysis to screen out potential VEGF-C-associated proteins involved in malignant progression of the bladder cancer T24 cells. Lentivirus vector-based RNA interference (RNAi) was employed to diminish VEGF-C expression of bladder cancer T24 cells. Then we performed comparative proteome analysis to explore differentially expressed proteins in T24 cells with and without VEGF-C siRNA, by two-dimensional difference gel electrophoresis (2D-DIGE). Twenty-three proteins were identified. Some proteins (matrix metalloproteinase-9, Keratin 8, Serpin B5, Annexin A8) with significant differences were further confirmed by Western blotting. The 23 potential VEGF-C-associated proteins identified in our study provide us with further insights into the mechanism of VEGF-C promoting malignant progression of bladder cancer cells.

  13. Platelet activation determines angiopoietin-1 and VEGF levels in malaria: implications for their use as biomarkers

    NARCIS (Netherlands)

    Brouwers, J.; Noviyanti, R.; Fijnheer, R.; Groot, P.G. de; Trianty, L.; Mudaliana, S.; Roest, M.; Syafruddin, D.; Ven, A. van der; Mast, Q. de

    2013-01-01

    INTRODUCTION: The angiogenic proteins angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF) are regulators of endothelial inflammation and integrity. Since platelets store large amounts of Ang-1 and VEGF, measurement of circulation levels of these proteins is sensitive to

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

    Directory of Open Access Journals (Sweden)

    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

  15. Interstitial ablative techniques for hepatic tumours.

    Science.gov (United States)

    Erce, C; Parks, R W

    2003-03-01

    Most patients with liver tumours are not suitable for surgery but interstitial ablative techniques may control disease progression and improve survival rates. A review was undertaken using Medline of all reported studies of cryoablation, radiofrequency ablation, microwave ablation, interstitial laser photocoagulation, high-intensity focused ultrasound and ethanol ablation of primary liver tumours and hepatic metastases. Although there are no randomized clinical trials, cryoablation, thermal ablation and ethanol ablation have all been shown to be associated with improved palliation in patients with primary and secondary liver cancer. The techniques can be undertaken safely with minimal morbidity and mortality. Although surgical resection remains the first line of treatment for selected patients with primary and secondary liver malignancies, interstitial ablative techniques are promising therapies for patients not suitable for hepatic resection or as an adjunct to liver surgery. Copyright 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

  16. Moving Past Anti-VEGF: Novel Therapies for Treating Diabetic Retinopathy.

    Science.gov (United States)

    Bolinger, Mark T; Antonetti, David A

    2016-09-07

    Diabetic retinopathy is the leading cause of blindness in working age adults, and is projected to be a significant future health concern due to the rising incidence of diabetes. The recent advent of anti-vascular endothelial growth factor (VEGF) antibodies has revolutionized the treatment of diabetic retinopathy but a significant subset of patients fail to respond to treatment. Accumulating evidence indicates that inflammatory cytokines and chemokines other than VEGF may contribute to the disease process. The current review examines the presence of non-VEGF cytokines in the eyes of patients with diabetic retinopathy and highlights mechanistic pathways in relevant animal models. Finally, novel drug targets including components of the kinin-kallikrein system and emerging treatments such as anti-HPTP (human protein tyrosine phosphatase) β antibodies are discussed. Recognition of non-VEGF contributions to disease pathogenesis may lead to novel therapeutics to enhance existing treatments for patients who do not respond to anti-VEGF therapies.

  17. 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....... Material and methods: We immunostained whole tumor sections for VEGF-A, -B, and VEGFR-1 of invasive ductal carcinomas of the breast and scored the tumors manually by staining intensity as the only parameter and by a combination of qualitative and quantitative staining information. We also introduced...... measurements of VEGF-A, VEGF-B and VEGFR-1 when analyzing whole tumor sections of invasive ductal breast carcinomas....

  18. Interferon decreases VEGF levels in patients with chronic myeloid leukemia treated with imatinib.

    Science.gov (United States)

    Legros, L; Guilhot, J; Huault, S; Mahon, F X; Preudhomme, C; Guilhot, F; Hueber, A O

    2014-06-01

    In chronic myeloid leukemia (CML), evidence is supporting the role of VEGF in growth, and survival of leukemia cells. The evaluation of plasma VEGF levels in 403 CML patients randomized within SPIRIT study to received imatinib-400mg versus imatinib+cytarabine versus imatinib+interferon (IFN) versus imatinib-600mg demonstrated that VEGF is an independent factor of BCR-ABL burden. VEGF low levels at diagnosis were associated with a progression-free survival of 100% at 48 months. Under treatment, significant lowest levels were observed in imatinib+IFN arm. These results support the use of VEGF as a parameter to predict CML evolution and let us to speculate about antiangiogenic properties of IFN. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. VEGF may contribute to macrophage recruitment and M2 polarization in the decidua.

    Directory of Open Access Journals (Sweden)

    Karen C Wheeler

    Full Text Available It is increasingly evident that cytokines and growth factors produced in the decidua play a pivotal role in the regulation of the local immune microenvironment and the establishment of pregnancy. One of the major growth factors produced in the decidua is vascular endothelial growth factor (VEGF, which acts not only on endothelial cells, but also on multiple other cell types, including macrophages. We sought to determine whether decidua-derived VEGF affects macrophage recruitment and polarization using human endometrial/decidual tissue samples, primary human endometrial stromal cells (ESCs, and the human monocyte cell line THP1. In situ hybridization was used for assessment of local VEGF expression and immunohistochemistry was used for identification and localization of CD68-positive endometrial macrophages. Macrophage migration in culture was assessed using a transwell migration assay, and the various M1/M2 phenotypic markers and VEGF expression were assessed using quantitative real-time PCR (qRT-PCR. We found dramatic increases in both VEGF levels and macrophage numbers in the decidua during early pregnancy compared to the secretory phase endometrium (non-pregnant, with a significant increase in M2 macrophage markers, suggesting that M2 is the predominant macrophage phenotype in the decidua. However, decidual samples from preeclamptic pregnancies showed a significant shift in macrophage phenotype markers, with upregulation of M1 and downregulation of M2 markers. In THP1 cultures, VEGF treatment significantly enhanced macrophage migration and induced M1 macrophages to shift to an M2 phenotype. Moreover, treatment with conditioned media from decidualized ESCs induced changes in macrophage migration and polarization similar to that of VEGF treatment. These effects were abrogated by the addition of a potent VEGF inhibitor. Together these results suggest that decidual VEGF plays a significant role in macrophage recruitment and M2 polarization, and

  20. VEGF and IL-18 in induced sputum of lung cancer patients.

    Science.gov (United States)

    Rovina, Nikoletta; Hillas, Georgios; Dima, Efrossini; Vlastos, Fotis; Loukides, Stylianos; Veldekis, Dimitrios; Roussos, Charis; Alhanatis, Manos; Bakakos, Petros

    2011-06-01

    Cytokines are key players in the biological processes of malignant tumors and special interest has been focused on cytokines exerting tumor and anti-tumor properties, such as vascular endothelial growth factor (VEGF) and Interleukin-18 (IL-18). Aim of this study was to assess IL-18 and VEGF levels in induced sputum of lung cancer patients at diagnosis, and assess their possible association with the histological type of cancer, the stage and the overall patient survival. Seventy six patients with a diagnosis of lung cancer were recruited and were followed up for 48months. Thirteen healthy smokers and 16 healthy non-smokers were used as control groups. VEGF and IL-18 were measured by ELISA in sputum supernatants at the time of diagnosis. Lung cancer patients had significantly higher baseline IL-18 and VEGF levels compared to healthy controls (p<0.001). No difference was found in IL-18 and VEGF levels between the various stages in non-small cell lung cancer (NSCLC) and between limited and extended small cell lung cancer (SCLC). However, the ratio of VEGF/IL-18 was significantly higher in NSCLC compared to SCLC patients (p=0.018). In extended SCLC overall survival was inversely associated with baseline sputum VEGF levels (p=0.034) and estimated mortality risk was 1.14 (95% CI 1.006-1.283) for an increase of 100pg/ml in VEGF levels. Such association was not found regarding baseline IL-18 levels. VEGF levels in induced sputum may have a prognostic role in the survival of SCLC. The ratio VEGF/IL-18 in induced sputum differs between NSCLC and SCLC, indicating differences in angiogenesis mechanisms and/or immunological response in these two major histological types of lung cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. The treatment of femoral neck fracture using VEGF-loaded nanographene coated internal fixation screws.

    Science.gov (United States)

    Li, Shuo; Yuan, Hengfeng; Pan, Jianfeng; Fan, Wenshuai; Zhu, Liang; Yan, Zuoqin; Guo, Changan

    2017-01-01

    Previous studies have proved that vascular endothelial growth factor (VEGF) has a dual role in the promotion of new bone formation and blood vessel repair during fracture healing. However, how to introduce VEGF to a fracture site safely and effectively is still a challenge. This study aimed to prepare a VEGF-loaded nanographene coated internal fixation screw and to evaluate its effects in the treatment of femoral neck fracture. Nanographene coated screws were prepared by direct liquid-phase exfoliation of the graphite method, and the surface characteristics were observed through scanning electron microscopy (SEM). VEGF was loaded on nanographene coatings through physical adsorption, and the VEGF controlled release was examined by ELISA. Then a canine femoral neck fracture model was built to examine both the angiogenic and osteogenic properties of the VEGF-loaded coated screws. X-ray, micro-CT-based microangiography, and histopathologic evaluation were used to assess the fracture healing progress. The results demonstrated that nanographene could load VEGF effectively, and the accumulative release of VEGF clearly increased during the entire testing period (9 days) without burst release. In canine fracture models, the results of X-ray, microangiography, and histopathologic examination proved that the speed of fracture healing, new bone formation area, and revascularization of the fractured femoral heads in the VEGF-loaded coated screws groups were significantly higher than in the control groups. Our study proved that VEGF-loaded nanographene coated screws were effective in the treatment of femoral neck fracture and prevention of avascular necrosis of femoral head.

  2. Sustained delivery of VEGF from designer self-assembling peptides improves cardiac function after myocardial infarction

    Energy Technology Data Exchange (ETDEWEB)

    Guo, Hai-dong [Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Cui, Guo-hong; Yang, Jia-jun [Department of Neurology, Shanghai No. 6 People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200233 (China); Wang, Cun [Institutes of Biomedical Sciences, Fudan University, Shanghai 200032 (China); Zhu, Jing; Zhang, Li-sheng; Jiang, Jun [Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China); Shao, Shui-jin, E-mail: shaoshuijin@163.com [Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203 (China)

    2012-07-20

    Highlights: Black-Right-Pointing-Pointer The designer peptide LRKKLGKA could self-assemble into nanofibers. Black-Right-Pointing-Pointer Injection of LRKKLGKA peptides could promote the sustained delivery of VEGF. Black-Right-Pointing-Pointer Injection of VEGF with LRKKLGKA peptides lead to sufficient angiogenesis. Black-Right-Pointing-Pointer Injection of VEGF with LRKKLGKA peptides improves heart function. -- Abstract: Poor vascularization and insufficient oxygen supply are detrimental to the survival of residual cardiomyocytes or transplanted stem cells after myocardial infarction. To prolong and slow the release of angiogenic factors, which stimulate both angiogenesis and vasculogenesis, we constructed a novel self-assembling peptide by attaching the heparin-binding domain sequence LRKKLGKA to the self-assembling peptide RADA16. This designer self-assembling peptide self-assembled into nanofiber scaffolds under physiological conditions, as observed by atomic force microscopy. The injection of designer self-assembling peptides can efficiently provide the sustained delivery of VEGF for at least 1 month. At 4 weeks after transplantation, cardiac function was improved, and scar size and collagen deposition were markedly reduced in the group receiving VEGF with the LRKKLGKA scaffolds compared with groups receiving VEGF alone, LRKKLGKA scaffolds alone or VEGF with RADA16 scaffolds. The microvessel density in the VEGF with LRKKLGKA group was higher than that in the VEGF with RADA16 group. TUNEL and cleaved caspase-3 expression assays showed that the transplantation of VEGF with LRKKLGKA enhanced cell survival in the infarcted heart. These results present the tailor-made peptide scaffolds as a new generation of sustained-release biomimetic biomaterials and suggest that the use of angiogenic factors along with designer self-assembling peptides can lead to myocardial protection, sufficient angiogenesis, and improvement in cardiac function.

  3. Profiling of microRNAs in AML cells following overexpression or silencing of the VEGF gene.

    Science.gov (United States)

    Li, Li; Zhu, Lixia; Wang, Yungui; Zhou, De; Zhu, Jingjing; Xie, Wanzhuo; Ye, Xiujin

    2017-01-01

    Acute myeloid leukemia (AML) is a disease of the hematopoietic progenitor cells associated with heterogeneous clonal proliferation. Vascular endothelial growth factor (VEGF) and its receptors play important roles in the regulation of angiogenesis during physiological and pathological processes. It is thought that AML cells have an autocrine VEGF pathway that contributes to the development and progression of AML. In addition, growing evidence has suggested that numerous microRNAs are involved in AML. The present study aimed to investigate the relationship between VEGF dysregulation and microRNA profiles in AML cells and patients. VEGF-overexpressing and VEGF-knockdown leukemia cells were constructed and changes in the patterns of microRNA expression were analyzed using a microRNA array. Subsequently, mononuclear cells from the blood of patients with AML showing high or low expression levels of VEGF were obtained and were used to assess the patterns of microRNA expression by reverse transcription-quantitative polymerase chain reaction. The results of the present study suggested that downregulation of VEGF markedly altered the profile of microRNAs in AML cells, while upregulation of VEGF did not. Examination of clinical samples from patients with AML showed that several microRNAs were closely associated with the expression level of VEGF, including miR-20a, miR-93, miR-16-5p, miR-17-5p, miR-124-5p and miR-17-3p. These results suggested that VEGF may be a pivotal protein that can both receive and initiate signals in leukemia cells.

  4. Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System.

    Science.gov (United States)

    Cutroneo, Paola Maria; Giardina, Claudia; Ientile, Valentina; Potenza, Simona; Sottosanti, Laura; Ferrajolo, Carmen; Trombetta, Costantino J; Trifirò, Gianluca

    2017-11-01

    Anti-vascular endothelial growth factor (anti-VEGF) drugs are widely used for the treatment of several cancers and retinal diseases. The systemic use of anti-VEGF drugs has been associated with an increased risk of serious adverse reactions. Whether this risk is also related to intravitreal administration of anti-VEGF drugs is unclear. The aim of this study was to provide an overview of the safety of anti-VEGF drugs in oncology and ophthalmology settings using the Italian Spontaneous Reporting System (SRS). We selected all suspected adverse drug reaction (ADR) reports attributed to anti-VEGF drugs and conducted descriptive frequency analyses stratified by indication of use. As a measure of disproportionality, we calculated the proportional reporting ratio with 95% confidence intervals at the level of standardized Medical Dictionary for Regulatory Activities (MedDRA ® ) queries (SMQs). Of a total of 2472 anti-VEGF drug-related reports, 2173 (87.9%) and 299 (12.1%) were attributed to systemic and intravitreal use of these drugs, respectively. The frequency of serious ADRs reported was higher for intravitreal administration of anti-VEGF drugs than for systemic use in patients with cancer (58.9 vs. 34.1%) (p < 0.001) and were disproportionally associated with ischemic heart disease and thromboembolic and cerebrovascular events. Most serious ADRs related to anti-VEGF drugs in patients with cancer are known and clinically relevant (e.g., gastrointestinal and vascular disorders). This study documented that serious ADRs and systemic toxicity may occur not only with systemic use of anti-VEGF drugs in patients with cancer but also with intravitreal administration. Close monitoring of cardio/cerebrovascular adverse events should be considered during treatment with all anti-VEGF drugs.

  5. [Catheter ablation in supraventricular tachycardia].

    Science.gov (United States)

    Pitschner, H F; Neuzner, J

    1996-01-01

    The first report about successful radio frequency ablation of a right-posterior-septal accessory pathway appeared in 1986. Since then, the technology of both guidable ablation catheters and radio frequency generators has been considerably improved in an initially clinical-experimental phase. At the same time, electrophysiologists were equally able to enlarge their knowledge in the field of signal characteristics of arrhythmogenic substrates. This included the discovery of action potentials of accessory pathways (preexcitation syndromes), the location of fast and slow AV node conduction (AV nodal reentrant tachycardia, AVNRT), the functional importance of the anatomical isthmus between the os of the coronary sinus, the tricuspid valve and the inferior caval vein (atrial flutter). Mapping techniques such as transient and concealed entrainment became, among others, significant tools in finding the best localization for radio frequency catheter ablation. Thus, technical development and the increased knowledge of clinical electrophysiologists resulted in firmly establishing the procedure of catheter ablation as the method of first choice in the curative treatment of supraventricular tachycardias in a potential collective of about 5 per mill of the normal population (without atrial fibrillation). Supraventricular tachycardias with a reentry mechanism in the broadest sense (> 95% of all pts. with SVT) and those with focal automaticity ( 90% versus uncommon type 90%). Atrial reentrant tachycardias are rather rare (with the exception of atrial fibrillation/flutter). The literature suggests medical therapy to be successful in about 60% of these patients. Those patients who are presently proposed to receive radio frequency catheter ablation usually continue to be symptomatic despite pharmacological therapy and/or have a potential risk for sudden cardiac death due to atrial fibrillation in WPW syndrome, or rate-dependent hemodynamic compromise secondary to cardiac disease

  6. Basic fibroblast growth factor induces VEGF expression in chondrosarcoma cells and subsequently promotes endothelial progenitor cell-primed angiogenesis.

    Science.gov (United States)

    Tzeng, Huey-En; Chen, Po-Chun; Lin, Kai-Wei; Lin, Chih-Yang; Tsai, Chun-Hao; Han, Shao-Min; Teng, Chieh-Lin; Hwang, Wen-Li; Wang, Shih-Wei; Tang, Chih-Hsin

    2015-07-01

    Chondrosarcoma, a common malignant tumour, develops in bone. Effective adjuvant therapy remains inadequate for treatment, meaning poor prognosis. It is imperative to explore novel remedies. Angiogenesis is a rate-limiting step in progression that explains neovessel formation for blood supply in the tumour microenvironment. Numerous studies indicate that EPCs (endothelial progenitor cells) promote angiogenesis and contribute to tumour growth. bFGF (basic fibroblast growth factor), a secreted cytokine, regulates biological activity, including angiogenesis, and correlates with tumorigenesis. However, the role of bFGF in angiogenesis-related tumour progression by recruiting EPCs in human chondrosarcoma is rarely discussed. In the present study, we found that bFGF induced VEGF (vascular endothelial growth factor) expression via the FGFR1 (fibroblast growth factor receptor 1)/c-Src/p38/NF-κB (nuclear factor κB) signalling pathway in chondrosarcoma cells, thereby triggering angiogenesis of endothelial progenitor cells. Our in vivo data revealed that tumour-secreted bFGF promotes angiogenesis in both mouse plug and chick CAM (chorioallantoic membrane) assays. Xenograft mouse model data, due to bFGF-regulated angiogenesis, showed the bFGF regulates angiogenesis-linked tumour growth. Finally, bFGF was highly expressed in chondrosarcoma patients compared with normal cartilage, positively correlating with VEGF expression and tumour stage. The present study reveals a novel therapeutic target for chondrosarcoma progression.

  7. Comparison of lymphatic vessel density and expression of VEGF-C and VEGF-D lymphangiogenic factors in Warthin's tumours and oncocytic adenomas.

    Science.gov (United States)

    Hoza, Jiri; Salzman, Richard; Bakaj, Tomas; Kucerova, Ladislava; Starek, Ivo

    2017-11-02

    To compare the density of lymphatic vessels and VEGF-C and VEGF-D expression in Warthin's tumours (WTs) and oncocytic adenomas (OCAs). Twenty three WTs and 13 OCAs of the parotid gland were analyzed. Lymphatic vessels were detected using the D2-40 antibody. For evaluation of the intratumour and peritumour lymphatic vessel density (iLVD and pLVD, respectively) the area of greatest vascularisation (hot spots) was chosen, using a ×40 field, and the number of vessels per square millimeter was counted in a ×200 field. The staining intensity for VEGF-C and VEGF-D immunoreaction in the tumour cells was graded from 0 to 3. The mean iLVD and pLVD values in WTs was 4.7 (range 1-8) and 6.9 (range 3-10), those in the OCAs 1.0 (range 0-3) and 5.8 (range 2-8), respectively. The differences in the iLVD, but not pLVD between the two tumour groups were statistically significant. In both entities, the pLVD markedly outnumbered the iLVD. The intratumour vessels in the WTs were present exclusively in the lymphoid stroma. In the group of 23 WTs, 13 (56.6%), 17 (73.9%) and 10 (43.4%) samples revealed positive VEGF-C, VEGF-D and both immunoreactions, respectively. 10 of 13 (77%) cases revealed VEGF-D immunoreaction and in none of them was the VEGF-C reaction present. The tumours had a comparable high density of peritumorous lymphatic network. However, WTs markedly differed from OCAs in the number of the intratumorous vessels. These were abundant solely in the stroma of WT, while practically lacking in the neoplastic epithelium of the WT and relatively rare in OCAs. We suggest that homeostasis in both entities is mediated mainly by peritumorous lymphatics. The lymphatic drainage in WTs is also fostered exclusively by stromal lymphatics, whereas in stroma poor OCAs by the vessels present in their neoplastic epithelium. We also believe that WTs stimulate proliferation of pre-existing lymphatic capillaries by means of the paracrine secretion of VEGF-C and VEGF-D in the neoplastic as well

  8. Post-radiation increase in VEGF enhances glioma cell motility in vitro

    Directory of Open Access Journals (Sweden)

    Kil Whoon

    2012-02-01

    Full Text Available Abstract Background Glioblastoma multiforme (GBM is among the most lethal of all human tumors, with frequent local recurrences after radiation therapy (RT. The mechanism accounting for such a recurrence pattern is unclear. It has classically been attributed to local recurrence of treatment-resistant cells. However, accumulating evidence suggests that additional mechanisms exist that involve the migration of tumor or tumor stem cells from other brain regions to tumor bed. VEGFs are well-known mitogens and can be up-regulated after RT. Here, we examine the effect of irradiation-induced VEGF on glioma cell motility. Materials and methods U251 and LN18 cell lines were used to generate irradiated-conditioned medium (IR-CM. At 72 h after irradiation, the supernatants were harvested. VEGF level in IR-CM was quantified by ELISA, and expression levels for VEGF mRNA were detected by RT-PCR. In vitro cancer cell motility was measured in chambers coated with/without Matrigel and IR-CM as a cell motility enhancer and a VEGF antibody as a neutralizer of VEGF bioactivity. Immunoblots were performed to evaluate the activity of cell motility-related kinases. Proliferation of GBM cells after treatment was measured by flow cytometry. Results Irradiation increased the level of VEGF mRNA that was mitigated by pre-RT exposure to Actinomycin D. U251 glioma cell motility (migration and invasion was enhanced by adding IR-CM to un-irradiated cells (174.9 ± 11.4% and 334.2 ± 46% of control, respectively. When we added VEGF antibody to IR-CM, this enhanced cell motility was negated (110.3 ± 12.0% and 105.7 ± 14.0% of control, respectively. Immunoblot analysis revealed that IR-CM increased phosphorylation of VEGF receptor-2 (VEGFR2 secondary to an increase in VEGF, with a concomitant increase of phosphorylation of the downstream targets (Src and FAK. Increased phosphorylation was mitigated by adding VEGF antibody to IR-CM. There was no difference in the mitotic index of

  9. Glue septal ablation: A promising alternative to alcohol septal ablation

    Directory of Open Access Journals (Sweden)

    Sercan Okutucu

    2016-03-01

    Full Text Available Hypertrophic cardiomyopathy (HCM is defined as myocardial hypertrophy in the absence of another cardiac or systemic disease capable of producing the magnitude of present hypertrophy. In about 70% of patients with HCM, there is left ventricular outflow tract (LVOT obstruction (LVOTO and this is known as obstructive type of hypertrophic cardiomyopathy (HOCM. Cases refractory to medical treatment have had two options either surgical septal myectomy or alcohol septal ablation (ASA to alleviate LVOT gradient. ASA may cause some life-threatening complications including conduction disturbances and complete heart block, hemodynamic compromise, ventricular arrhythmias, distant and massive myocardial necrosis. Glue septal ablation (GSA is a promising technique for the treatment of HOCM. Glue seems to be superior to alcohol due to some intrinsic advantageous properties of glue such as immediate polymerization which prevents the leak into the left anterior descending coronary artery and it is particularly useful in patients with collaterals to the right coronary artery in whom alcohol ablation is contraindicated. In our experience, GSA is effective and also a safe technique without significant complications. GSA decreases LVOT gradient immediately after the procedure and this reduction persists during 12 months of follow-up. It improves New York Heart Association functional capacity and decrease interventricular septal wall thickness. Further studies are needed in order to assess the long-term efficacy and safety of this technique.

  10. Integrin-specific hydrogels functionalized with VEGF for vascularization and bone regeneration of critical-size bone defects

    Science.gov (United States)

    García, José R.; Clark, Amy Y.; García, Andrés J.

    2016-01-01

    Vascularization of bone defects is considered a crucial component to the successful regeneration of large bone defects. Although vascular endothelial growth factor (VEGF) has been delivered to critical-size bone defect models to augment blood vessel infiltration into the defect area, its potential to increase bone repair remains ambiguous. In this study, we investigated whether integrin-specific biomaterials modulate the effects of VEGF on bone regeneration. We engineered protease-degradable, VEGF-loaded polyethylene glycol (PEG) hydrogels functionalized with either a triple-helical, α2β1 integrin-specific peptide (GFOGER) or an αvβ3 integrin-targeting peptide (RGD). Covalent incorporation of VEGF into the PEG hydrogel allowed for protease degradation-dependent release of the protein while maintaining VEGF bioactivity. When applied to critical-size segmental defects in the murine radius, GFOGER-functionalized VEGF-free hydrogels exhibited significantly increased vascular volume and density and resulted in a larger number of thicker blood vessels compared to RGD-functionalized VEGF-free hydrogels. VEGF-loaded RGD hydrogels increased vascularization compared to VEGF-free RGD hydrogels, but the levels of vascularization for these VEGF-containing RGD hydrogels were similar to those of VEGF-free GFOGER hydrogels. VEGF transiently increased bone regeneration in RGD hydrogels but had no effect at later time points. In GFOGER hydrogels, VEGF did not show an effect on bone regeneration. However, VEGF-free GFOGER hydrogels resulted in increased bone regeneration compared to VEGF-free RGD hydrogels. These findings demonstrate the importance of integrin-specificity in engineering constructs for vascularization and associated bone regeneration. PMID:26662727

  11. Advanced Coats’ disease treated with intravitreal bevacizumab combined with laser vascular ablation

    Directory of Open Access Journals (Sweden)

    Villegas VM

    2014-05-01

    for advanced Coats’ disease presenting with exudative retinal detachment.Keywords: Coats’ disease, bevacizumab, anti-VEGF, laser ablation, retina

  12. Laser Ablation for Medical Applications

    Science.gov (United States)

    Hayashi, Ken-Ichi

    Medical applications of laser are measurement, laser surgery, in-situ monitoring, and processing of medical devices. In this paper, author briefly reviews the trends of medical applications, describes some new applications, and then discuss about the future trends and problems of medical applications. At present, the domestic market of laser equipment for medical applications is nearly 1/10 of that for industrial applications, which has registered significant growth continuously. Laser surgery as a minimum invasive surgery under arthroscope is expected to decrease the pain of patients. Precise processing such as cutting and welding is suitable for manufacturing medical devices. Pulsed laser deposition has been successfully applied to the thin film coating. The corneal refractive surgery by ArF excimer laser has been widely accepted for its highly safe operation. Laser ablation for retinal implant in the visual prosthesis is one of the promising applications of laser ablation in medicine. New applications with femtosecond laser are expected in the near future.

  13. Serum VEGF levels are related to the presence of pulmonary arterial hypertension in systemic sclerosis

    Directory of Open Access Journals (Sweden)

    Sakkas Lazaros

    2009-05-01

    Full Text Available Abstract Background The association between systemic sclerosis and pulmonary arterial hypertension (PAH is well recognized. Vascular endothelial growth factor (VEGF has been reported to play an important role in pulmonary hypertension. The aim of the present study was to examine the relationship between systolic pulmonary artery pressure, clinical and functional manifestations of the disease and serum VEGF levels in systemic sclerosis. Methods Serum VEGF levels were measured in 40 patients with systemic sclerosis and 13 control subjects. All patients underwent clinical examination, pulmonary function tests and echocardiography. Results Serum VEGF levels were higher in systemic sclerosis patients with sPAP ≥ 35 mmHg than in those with sPAP LCO were independent predictors of systolic pulmonary artery pressure. Conclusion Serum VEGF levels are increased in systemic sclerosis patients with sPAP ≥ 35 mmHg. The correlation between VEGF levels and systolic pulmonary artery pressure may suggest a possible role of VEGF in the pathogenesis of PAH in systemic sclerosis.

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

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Jinqiao, E-mail: jinqiao1977@163.com [Institute of Pediatrics, Children' s Hospital of Fudan University (China); Sha, Bin [Department of Neonatology, Children' s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102 (China); Zhou, Wenhao, E-mail: zhou_wenhao@yahoo.com.cn [Department of Neonatology, Children' s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102 (China); Yang, Yi [Institute of Pediatrics, Children' s Hospital of Fudan University (China)

    2010-03-26

    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.

  15. Development of VEGF-loaded PLGA matrices in association with mesenchymal stem cells for tissue engineering

    Directory of Open Access Journals (Sweden)

    A.R. Rosa

    Full Text Available The association of bioactive molecules, such as vascular endothelial growth factor (VEGF, with nanofibers facilitates their controlled release, which could contribute to cellular migration and differentiation in tissue regeneration. In this research, the influence of their incorporation on a polylactic-co-glycolic acid (PLGA scaffold produced by electrospinning on cell adhesion and viability and cytotoxicity was carried out in three groups: 1 PLGA/BSA/VEGF; 2 PLGA/BSA, and 3 PLGA. Morphology, fiber diameter, contact angle, loading efficiency and controlled release of VEGF of the biomaterials, among others, were measured. The nanofibers showed smooth surfaces without beads and with interconnected pores. PLGA/BSA/VEGF showed the smallest water contact angle and VEGF released for up to 160 h. An improvement in cell adhesion was observed for the PLGA/BSA/VEGF scaffolds compared to the other groups and the scaffolds were non-toxic for the cells. Therefore, the scaffolds were shown to be a good strategy for sustained delivery of VEGF and may be a useful tool for tissue engineering.

  16. Rapamycin Inhibits Proliferation of Hemangioma Endothelial Cells by Reducing HIF-1-Dependent Expression of VEGF

    Science.gov (United States)

    Medici, Damian; Olsen, Bjorn R.

    2012-01-01

    Hemangiomas are tumors formed by hyper-proliferation of vascular endothelial cells. This is caused by elevated vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2 (VEGFR2). Here we show that elevated VEGF levels produced by hemangioma endothelial cells are reduced by the mTOR inhibitor rapamycin. mTOR activates p70S6K, which controls translation of mRNA to generate proteins such as hypoxia inducible factor-1 (HIF-1). VEGF is a known HIF-1 target gene, and our data show that VEGF levels in hemangioma endothelial cells are reduced by HIF-1α siRNA. Over-expression of HIF-1α increases VEGF levels and endothelial cell proliferation. Furthermore, both rapamycin and HIF-1α siRNA reduce proliferation of hemangioma endothelial cells. These data suggest that mTOR and HIF-1 contribute to hemangioma endothelial cell proliferation by stimulating an autocrine loop of VEGF signaling. Furthermore, mTOR and HIF-1 may be therapeutic targets for the treatment of hemangiomas. PMID:22900063

  17. Experimental studies of a vaccine formulation of recombinant human VEGF antigen with aluminum phosphate.

    Science.gov (United States)

    Pérez Sánchez, Lincidio; Morera Díaz, Yanelys; Bequet-Romero, Mónica; Ramses Hernández, Gerardo; Rodríguez, Yadira; Castro Velazco, Jorge; Puente Pérez, Pedro; Ayala Avila, Marta; Gavilondo, Jorge V

    2015-01-01

    CIGB-247 is a cancer vaccine that is a formulation of a recombinant protein antigen representative of the human vascular endothelial growth factor (VEGF) with a bacterially-derived adjuvant (VSSP). The vaccine has shown an excellent safety profile in mice, rats, rabbits, not-human primates and in recent clinical trials in cancer patients. Response to the vaccine is characterized by specific antibody titers that neutralize VEGF/VEGFR2 binding and a cytotoxic tumor-specific response. To expand our present anti-VEGF active immunotherapy strategies, we have now studied in mice and non-human primates the effects of vaccination with a formulation of our recombinant VEGF antigen and aluminum phosphate adjuvant (hereafter denominated CIGB-247-A). Administered bi-weekly, CIGB-247-A produces high titers of anti-VEGF IgG blocking antibodies in 2 mice strains. Particularly in BALB/c, the treatment impaired subcutaneous F3II mammary tumor growth and reduced the number of spontaneous lung macro metastases, increasing animals' survival. Spleen cells from specifically immunized mice directly killed F3II tumor cells in vitro. CIGB-247-A also showed to be immunogenic in non-human primates, which developed anti-VEGF blocking antibodies and the ability for specific direct cell cytotoxic responses, all without impairing the healing of deep skin wounds or other side effect. Our results support consideration of aluminum phosphate as a suitable adjuvant for the development of new vaccine formulations using VEGF as antigen.

  18. WISP-1 positively regulates angiogenesis by controlling VEGF-A expression in human osteosarcoma.

    Science.gov (United States)

    Tsai, Hsiao-Chi; Tzeng, Huey-En; Huang, Chun-Yin; Huang, Yuan-Li; Tsai, Chun-Hao; Wang, Shih-Wei; Wang, Po-Chuan; Chang, An-Chen; Fong, Yi-Chin; Tang, Chih-Hsin

    2017-04-13

    In recent years, much research has focused on the role of angiogenesis in osteosarcoma, which occurs predominantly in adolescents and young adults. The vascular endothelial growth factor-A (VEGF-A) pathway is the key regulator of angiogenesis and in osteosarcoma. VEGF-A expression has been recognized as a prognostic marker in angiogenesis. Aberrant WNT1-inducible signaling pathway protein-1 (WISP-1) expression is associated with various cancers. However, the function of WISP-1 in osteosarcoma angiogenesis is poorly understood. We demonstrate a positive correlation between WISP-1 and VEGF-A expression in human osteosarcoma. Moreover, we show that WISP-1 promotes VEGF-A expression in human osteosarcoma cells, subsequently inducing human endothelial progenitor cell (EPC) migration and tube formation. The focal adhesion kinase (FAK), Jun amino-terminal kinase (JNK), and hypoxia-inducible factor (HIF)-1α signaling pathways were activated after WISP-1 stimulation, while FAK, JNK, and HIF-1α inhibitors or small interfering RNA (siRNA) abolished WISP-1-induced VEGF-A expression and angiogenesis. In vitro and in vivo studies revealed down-regulation of microRNA-381 (miR-381) in WISP-1-induced VEGF-A expression and angiogenesis. Our findings reveal that WISP-1 enhances VEGF-A expression and angiogenesis through the FAK/JNK/HIF-1α signaling pathways, as well as via down-regulation of miR-381 expression. WISP-1 may be a promising target in osteosarcoma angiogenesis.

  19. Mussel-inspired immobilization of vascular endothelial growth factor (VEGF) for enhanced endothelialization of vascular grafts.

    Science.gov (United States)

    Shin, Young Min; Lee, Yu Bin; Kim, Seok Joo; Kang, Jae Kyeong; Park, Jong-Chul; Jang, Wonhee; Shin, Heungsoo

    2012-07-09

    Most polymeric vascular prosthetic materials have low patency rate for replacement of small diameter vessels (polydopamine-mediated immobilization of growth factors on the surface of polymeric materials as a versatile tool to modify surface characteristics of vascular grafts potentially for accelerated endothelialization. Polydopamine was deposited on the surface of biocompatible poly(L-lactide-co-ε-caprolactone) (PLCL) elastomer, on which vascular endothelial growth factor (VEGF) was subsequently immobilized by simple dipping. Surface characteristics and composition were investigated by using scanning electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. Immobilization of VEGF on the polydopamine-deposited PLCL films was effective (19.8 ± 0.4 and 197.4 ± 19.7 ng/cm(2) for DPv20 and DPv200 films, respectively), and biotin-mediated labeling of immobilized VEGF revealed that the fluorescence intensity increased as a function of the concentration of VEGF solution. The effect of VEGF on adhesion of HUVECs was marginal, which may have been masked by polydopamine layer that also enhanced cell adhesion. However, VEGF-immobilized substrate significantly enhanced proliferation of HUVECs for over 7 days of in vitro culture and also improved their migration. In addition, immobilized VEGF supported robust cell to cell interactions with strong expression of CD 31 marker. The same process was effective for immobilization of basic fibroblast growth factor, demonstrating the robustness of polydopamine layer for secondary ligation of growth factors as a simple and novel surface modification strategy for vascular graft materials.

  20. Rapamycin inhibits proliferation of hemangioma endothelial cells by reducing HIF-1-dependent expression of VEGF.

    Directory of Open Access Journals (Sweden)

    Damian Medici

    Full Text Available Hemangiomas are tumors formed by hyper-proliferation of vascular endothelial cells. This is caused by elevated vascular endothelial growth factor (VEGF signaling through VEGF receptor 2 (VEGFR2. Here we show that elevated VEGF levels produced by hemangioma endothelial cells are reduced by the mTOR inhibitor rapamycin. mTOR activates p70S6K, which controls translation of mRNA to generate proteins such as hypoxia inducible factor-1 (HIF-1. VEGF is a known HIF-1 target gene, and our data show that VEGF levels in hemangioma endothelial cells are reduced by HIF-1α siRNA. Over-expression of HIF-1α increases VEGF levels and endothelial cell proliferation. Furthermore, both rapamycin and HIF-1α siRNA reduce proliferation of hemangioma endothelial cells. These data suggest that mTOR and HIF-1 contribute to hemangioma endothelial cell proliferation by stimulating an autocrine loop of VEGF signaling. Furthermore, mTOR and HIF-1 may be therapeutic targets for the treatment of hemangiomas.

  1. An electrochemical biosensor to simultaneously detect VEGF and PSA for early prostate cancer diagnosis based on graphene oxide/ssDNA/PLLA nanoparticles.

    Science.gov (United States)

    Pan, Lung-Hsuan; Kuo, Shin-Hung; Lin, Tzu-Yang; Lin, Chih-Wen; Fang, Po-Yu; Yang, Hung-Wei

    2017-03-15

    Early diagnosis of prostate cancer (PCa) is critical for the prevention of metastasis and for early treatment; therefore, a simple and accurate device must be developed for this purpose. In this study, we reported a novel fabrication method for producing a dual-modality biosensor that can simultaneously detect vascular endothelial growth factor (VEGF) and prostate-specific antigen (PSA) in human serum for early diagnosis of PCa. This biosensor was constructed by coating graphene oxide/ssDNA (GO-ssDNA) on an Au-electrode for VEGF detection, and incorporated with poly-L-lactide nanoparticles (PLLA NPs) for signal amplification and PSA detection. The results showed that this biosensor has wide liner detection ranges (0.05-100ng/mL for VEGF and 1-100ng/mL for PSA), as well as high levels of sensitivity and selectivity (i.e., resisting interference from external factors, such as glucose, ascorbic acid human serum protein, immunoglobulin G, and immunoglobulin M), and demonstrated a high correlation with an enzyme-linked immunosorbent assay for sample detection in patients. Therefore, this biosensor could be utilized for early clinical diagnosis of PCa in the future. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. 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.

  4. VEGF and Id-1 in pancreatic adenocarcinoma: prognostic significance and impact on angiogenesis.

    Science.gov (United States)

    Georgiadou, D; Sergentanis, T N; Sakellariou, S; Filippakis, G M; Zagouri, F; Vlachodimitropoulos, D; Psaltopoulou, T; Lazaris, A C; Patsouris, E; Zografos, G C

    2014-10-01

    The significance of vascular endothelial growth factor (VEGF) and inhibitor of differentiation/DNA synthesis (Id-1) in tumor neoangiogenesis and tumor progression in pancreatic ductal adenocarcinoma (PDAC) is still unclear. Given the central role of VEGF in cancer angiogenesis and the inconclusive results on Id-1 expression in PDAC, it is of great interest to investigate whether Id-1 and VEGF expression are associated with angiogenesis and prognosis in PDAC. Paraffin-embedded specimens from 60 consecutive patients with PDAC were immunostained for VEGF, Id-1 and CD34 and staining quantification was assessed by Image analysis system. The correlations among the expression of individual angiogenic factors and microvessel density (MVD), clinicopathologic features and clinical prognosis were analyzed. Id-1 and VEGF Positive Activity Indices (PAIs) closely correlated with each other. MVD positively correlated with both Id-1 and VEGF expression. More advanced T and N status correlated with more intense expression of Id-1, VEGF and higher MVD. With regard to prognostic significance higher Id-1 PAI (adjusted HR = 1.69, 95%CI: 1.10-2.59, p = 0.017), higher VEGF PAI (adjusted HR = 2.66, 95%CI: 1.09-6.50, p = 0.032), and MVD (adjusted HR = 1.55, 95%CI: 1.27-1.88, p < 0.001) were associated with poorer survival. VEGF and Id-1 overexpression were found to be associated with high MVD and emerged as adverse prognostic factors in terms of patient survival in PDAC. The potential of selective anti-angiogenic targeting therapy for pancreatic malignancies should prompt further validation of the present findings in studies encompassing larger samples and more elaborate techniques. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Vascular endothelial growth factor (VEGF) expression in the lung in toxic septic shock.

    Science.gov (United States)

    Manoilescu, Irina; Teleman, S; Cojocaru, Elena; Mihăilă, Doina; Plămădeală, P

    2011-01-01

    The need for reasoning with medical evidence the different types of shock, especially when there are medical and legal implications, has determined the search of biological markers of the shock. In the case of toxic septic shock, the most important markers to be used are: the cytokines, the tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), procalcitonin, lactoferin and the vascular endothelial growth factor (VEGF). VEGF has an essential role in angiogenesis and vascular permeability. In our study group, we included 30 cases of different types of shock in which we studied the VEGF expression in the lungs. We added also 10 fragments of lung as control group. According to the etiology, the 30 cases of shock were: 15 with a toxic septic shock and 15 with a hemorrhagic shock. In all these cases we used the classical Hematoxylin and Eosin staining method and the immunohistochemical reactions for VEGF-A. Statistical analysis was performed using SPSS 13.0. The VEGF expression was decreased in all the cases of toxic septic shock, in the endothelium and also in the alveolar epithelium, compared to a high level of expression in other cases of shock and in the control lung. These data allow us to appreciate that VEGF has a different expression in different types of shock and in the normal lung. We observed a statistically significant difference between VEGF expression in toxic septic shock and hemorrhagic shock (p=0.000001). There is a similarity of VEGF expression between hemorrhagic shock and the control lungs (p=0.00001). An obviously low VEGF expression in the toxic septic shock represents a useful biological marker in the forensic medical cases.

  6. Attitudes Towards Catheter Ablation for Atrial Fibrillation

    DEFF Research Database (Denmark)

    Vadmann, Henrik; Pedersen, Susanne S; Nielsen, Jens Cosedis

    2015-01-01

    BACKGROUND: Catheter ablation for atrial fibrillation (AF) is an important but expensive procedure that is the subject of some debate. Physicians´ attitudes towards catheter ablation may influence promotion and patient acceptance. This is the first study to examine the attitudes of Danish...... cardiologists towards catheter ablation for AF, using a nationwide survey. METHODS AND RESULTS: We developed a purpose-designed questionnaire to evaluate attitudes towards catheter ablation for AF that was sent to all Danish cardiologists (n = 401; response n = 272 (67.8%)). There was no association between...... attitudes towards ablation and the experience or age of the cardiologist with respect to patients with recurrent AF episodes with a duration of 7 days and/or need for cardioversion. The majority (69%) expected a recurrence of AF after catheter ablation in more than 30% of the cases...

  7. Vascular endothelial growth factor (VEGF and monocyte chemoattractant protein (MCP-1 levels unaltered in symptomatic atherosclerotic carotid plaque patients from North India

    Directory of Open Access Journals (Sweden)

    Dheeraj eKhurana

    2013-04-01

    Full Text Available We aimed to identify the role of vascular endothelial growth factor(VEGF and monocyte chemoattractant protein(MCP-1 as a serum biomarker of symptomatic carotid atherosclerotic plaque in North Indian population. Individuals with symptomatic carotid atherosclerotic plaque have high risk of ischemic stroke. Previous studies from western countries have shown an association between VEGF and MCP-1 levels and the incidence of ischemic stroke. In this study, venous blood from 110 human subjects was collected, 57 blood samples of which were obtained from patients with carotid plaques, 38 neurological controls without carotid plaques and another 15 healthy controls who had no history of serious illness. Serum VEGF and MCP-1 levels were measured using commercially available enzyme-linked immunosorbent assay(ELISA. We also correlated the data clinically and carried out risk factor analysis based on the detailed questionnaire obtained from each patient. For risk factor analysis, a total of 70 symptomatic carotid plaque cases and equal number of age and sex matched healthy controls were analyzed. We found that serum VEGF levels in carotid plaque patients did not show any significant change when compared to either of the controls. Similarly, there was no significant upregulation of monocyte chemoattractant protein-1 in the serum of these patients. The risk factor analysis revealed that hypertension, diabetes, and physical inactivity were the main correlates of carotid atherosclerosis(p<0.05. Prevalence of patients was higher residing in urban areas as compared to rural region. We also found that patients coming from mountaineer region were relatively less vulnerable to cerebral atherosclerosis as compared to the ones residing at plain region. We conclude that the pathogenesis of carotid plaques may progress independent of these inflammatory molecules. In parallel, risk factor analysis indicates hypertension, diabetes and sedentary lifestyle as the most

  8. EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model.

    Science.gov (United States)

    Reynaud, Déborah; Sergent, Frédéric; Nahed, Roland Abi; 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.

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

    Science.gov (United States)

    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

  10. 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

    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 during knee extensor exercise. The dialysate was analyzed for content of VEGF protein and adenosine. The mechanism of VEGF secretion from muscle cells in culture was examined in resting and electro stimulated cells, and in response to the adenosine analogue NECA, and the adenosine A(2A) receptor specific...... infusion enhanced (Pmuscle cells, NECA...

  11. Encapsulated VEGF-secreting cells enhance proliferation of neuronal progenitors in the hippocampus of AβPP/Ps1 mice.

    Science.gov (United States)

    Antequera, Desiree; Portero, Aitziber; Bolos, Marta; Orive, Gorka; Hernández, Rosa M Rm A; Pedraz, José Luis; Carro, Eva

    2012-01-01

    Vascular endothelial growth factor (VEGF) promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the Alzheimer's disease (AD) brain is still unknown. We examined the proliferation of neuronal precursors with an ex vivo approach, using encapsulated VEGF secreting cells, in AβPP/PS1 mice, a mouse model of AD. Overexpression of VEGF and VEGF receptor flk-1 was observed in the cerebral cortex from VEGF microcapsules-treated AβPP/PS1 mice at 1, 3 and 6 months after VEGF-microcapsule implantation. Stereological counting of 5-bromodeoxyuridine positive cells revealed that encapsulated VEGF secreting cells significantly enhanced cellular proliferation in the hippocampal dentate gyrus (DG). The number of neuronal precursors in VEGF microcapsules-treated AβPP/PS1 mice was also greater, and this effect remains after 6 months. We also confirmed that encapsulated VEGF secreting cells also stimulated angiogenesis in the cerebral cortex and hippocampal dentate gyrus. In addition, we found that VEGF-microcapsule treatment was associated with a depressed expression and activity of acetylcholinesterase in the hippocampus of AβPP/PS1 mice, a similar pattern as first-line medications for the treatment of AD. We conclude that stereologically-implanted VEGF-microcapsules exert an acute and long-standing neurotrophic effects, and could be utilized to improve potential therapies to control the progression of AD.

  12. Moderne Technologien in der Ablation des Vorhofflimmerns

    OpenAIRE

    Haegeli, L; Duru, F.(The University of Iowa, Iowa City, USA); Lüscher, T.F.

    2010-01-01

    Catheter ablation for atrial fibrillation has become an accepted therapy. The arrhythmia affects around 6% of the population over the age of 65 years. Electrical isolation of the pulmonary veins from the left atrium is the central strategy in catheter ablation for paroxysmal atrial fibrillation. However, procedural outcomes and efficacy using sequential “point-by-point” radiofrequency lesion creation with a conventional ablation catheter are operator-dependent and time-consuming. Moreover, re...

  13. Vascular endothelial growth factor (VEGF) and the VEGF soluble receptor-1 (sFlt-1) in chorionic villus tissue from Chinese women with early recurrent spontaneous abortion.

    Science.gov (United States)

    Pang, L-H; Li, M-J; Li, M-Q; Yang, D-M; Shi, L

    2011-01-01

    This case-control study explored the relationship between early recurrent spontaneous abortion (RSA) and the expression of two genes: VEGFA, the gene encoding vascular endothelial growth factor (VEGF); and fms-related tyrosine kinase 1 (FLT1), the gene encoding the soluble VEGF receptor-1 (sFlt-1). Women experiencing RSA or undergoing induced abortions in the early stage of normal pregnancy were recruited to the study (n = 30 per group). There were no significant between-group differences in maternal age or duration of pregnancy. The levels of VEGF and sFlt-1 mRNA in chorionic villus tissue samples were examined by quanti tative reverse transcription-polymerase chain reaction. Levels of sFlt-1 and VEGF mRNA in the chorionic villus tissue of women with RSA were significantly higher than levels in the control group. This study demonstrated that there is a relationship between early RSA and VEGF and sFlt-1 levels, suggesting that over-expression of the FLT1 and VEGFA genes may be associated with the pathogenesis of RSA.

  14. Angiotensin II type 1 receptor (AT-1R) expression correlates with VEGF-A and VEGF-D expression in invasive ductal breast cancer.

    Science.gov (United States)

    Jethon, Aleksandra; Pula, Bartosz; Piotrowska, Aleksandra; Wojnar, Andrzej; Rys, Janusz; Dziegiel, Piotr; Podhorska-Okolow, Marzena

    2012-10-01

    Recent studies point to the involvement of angiotensin II (Ang II) receptor type 1 (AT-1R) on processes of metastasing, stimulation of invasiveness and angiogenesis in tumours. In this study, the correlation between intensity of AT-1R expression and expression of lymph- and angiogenesis markers in invasive ductal breast cancers (IDC) was examined. Immunohistochemical studies (IHC) were performed on archival material of 102 IDC cases. Only 28 (27.5%) cases manifested low AT-1R expression while 74 (72.5%) cases demonstrated a moderate or pronounced AT-1R expression. Expression intensity of AT-1R was found to correlate with expressions of VEGF-A (r = 0.26; p = 0.008) and VEGF-D (r = 0.24; p = 0.015). Out of the examined markers of angiogenesis and lymphangiogenesis only the pronounced expression of VEGF-C was found to correlate with patient poor clinical outcome (p = 0.009). The positive correlation between AT-1R and VEGF-A and VEGF-D could point to stimulatory action of Ang II on their expression what might result in augmented lymph- and angiogenesis in IDC.

  15. Ablative therapies for small renal tumors

    Science.gov (United States)

    Tworkiewicz, Jakub; Siekiera, Jerzy; Drewa, Tomasz

    2013-01-01

    Ablative therapies of renal tumors are steadily gaining popularity in clinical practice due to the many benefits they offer to patients. Moreover, ablative procedures hold promise in the field of uro-oncology for the best compromise between low invasiveness, high efficacy and advantages in terms of procedural costs. Reported outcomes with ablative therapies for small renal tumors are excellent and without significant differences for surgical procedures based on nephron-sparing surgery. Nevertheless, these methods for treatment of small renal tumors should still be confined to carefully selected patients. This review discusses the currently used ablative techniques in urology. PMID:23788957

  16. Aromatic Thermosetting Copolyesters for Ablative TPS Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Better performing ablative thermal protection systems than currently available are needed to satisfy requirements of the most severe crew exploration vehicles, such...

  17. Ablative therapies for small renal tumors.

    Science.gov (United States)

    Adamowicz, Jan; Tworkiewicz, Jakub; Siekiera, Jerzy; Drewa, Tomasz

    2013-01-01

    Ablative therapies of renal tumors are steadily gaining popularity in clinical practice due to the many benefits they offer to patients. Moreover, ablative procedures hold promise in the field of uro-oncology for the best compromise between low invasiveness, high efficacy and advantages in terms of procedural costs. Reported outcomes with ablative therapies for small renal tumors are excellent and without significant differences for surgical procedures based on nephron-sparing surgery. Nevertheless, these methods for treatment of small renal tumors should still be confined to carefully selected patients. This review discusses the currently used ablative techniques in urology.

  18. Cryoballoon Catheter Ablation in Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    Cevher Ozcan

    2011-01-01

    Full Text Available Pulmonary vein isolation with catheter ablation is an effective treatment in patients with symptomatic atrial fibrillation refractory or intolerant to antiarrhythmic medications. The cryoballoon catheter was recently approved for this procedure. In this paper, the basics of cryothermal energy ablation are reviewed including its ability of creating homogenous lesion formation, minimal destruction to surrounding vasculature, preserved tissue integrity, and lower risk of thrombus formation. Also summarized here are the publications describing the clinical experience with the cryoballoon catheter ablation in both paroxysmal and persistent atrial fibrillation, its safety and efficacy, and discussions on the technical aspect of the cryoballoon ablation procedure.

  19. The link in Linking

    Science.gov (United States)

    Caldwell, Jane C; Chiale, Pablo A; Gonzalez, Mario D; Baranchuk, Adrian

    2013-01-01

    We present 2 cases of the slow-fast form of AVNRT with initially narrow QRS complexes followed by sudden unexpected transition to persistently wide QRS complexes due to aberrant intraventricular conduction. Introduction of a properly timed extrastimulus in one case and critical oscillations in cycle length due to short-long coupling in the second case set the stage for the initial bundle branch block. However, persistence of the aberrancy pattern once the initial event abated was maintained by the "linking" phenomenon. Delayed, retrograde concealed activation from the contralateral bundle branch perpetuated the initial bundle branch block. PMID:23840106

  20. Vascular Endothelial Growth Factor (VEGF) Bioavailability Regulates Angiogenesis and Intestinal Stem and Progenitor Cell Proliferation during Postnatal Small Intestinal Development.

    Science.gov (United States)

    Schlieve, Christopher R; Mojica, Salvador Garcia; Holoyda, Kathleen A; Hou, Xiaogang; Fowler, Kathryn L; Grikscheit, Tracy C

    2016-01-01

    Vascular endothelial growth factor (VEGF) is a highly conserved, master regulatory molecule required for endothelial cell proliferation, organization, migration and branching morphogenesis. Podocoryne carnea and drosophila, which lack endothelial cells and a vascular system, express VEGF homologs, indicating potential roles beyond angiogenesis and vasculogenesis. The role of VEGF in the development and homeostasis of the postnatal small intestine is unknown. We hypothesized regulating VEGF bioavailability in the postnatal small intestine would exhibit effects beyond the vasculature and influence epithelial cell stem/progenitor populations. VEGF mutant mice were created that overexpressed VEGF in the brush border of epithelium via the villin promotor following doxycycline treatment. To decrease VEGF bioavailability, sFlt-1 mutant mice were generated that overexpressed the soluble VEGF receptor sFlt-1 upon doxycycline administration in the intestinal epithelium. Mice were analyzed after 21 days of doxycycline administration. Increased VEGF expression was confirmed by RT-qPCR and ELISA in the intestine of the VEGF mutants compared to littermates. The VEGF mutant duodenum demonstrated increased angiogenesis and vascular leak as compared to littermate controls. The VEGF mutant duodenum revealed taller villi and increased Ki-67-positive cells in the transit-amplifying zone with reduced Lgr5 expression. The duodenum of sFlt-1 mutants revealed shorter villi and longer crypts with reduced proliferation in the transit-amplifying zone, reduced expression of Dll1, Bmp4 and VE-cadherin, and increased expression of Sox9 and EphB2. Manipulating VEGF bioavailability leads to profound effects on not only the intestinal vasculature, but epithelial stem and progenitor cells in the intestinal crypt. Elucidation of the crosstalk between VEGF signaling in the vasculature, mesenchyme and epithelial stem/progenitor cell populations may direct future cell therapies for intestinal

  1. Ablation as targeted perturbation to rewire communication network of persistent atrial fibrillation.

    Science.gov (United States)

    Tao, Susumu; Way, Samuel F; Garland, Joshua; Chrispin, Jonathan; Ciuffo, Luisa A; Balouch, Muhammad A; Nazarian, Saman; Spragg, David D; Marine, Joseph E; Berger, Ronald D; Calkins, Hugh; Ashikaga, Hiroshi

    2017-01-01

    Persistent atrial fibrillation (AF) can be viewed as disintegrated patterns of information transmission by action potential across the communication network consisting of nodes linked by functional connectivity. To test the hypothesis that ablation of persistent AF is associated with improvement in both local and global connectivity within the communication networks, we analyzed multi-electrode basket catheter electrograms of 22 consecutive patients (63.5 ± 9.7 years, 78% male) during persistent AF before and after the focal impulse and rotor modulation-guided ablation. Eight patients (36%) developed recurrence within 6 months after ablation. We defined communication networks of AF by nodes (cardiac tissue adjacent to each electrode) and edges (mutual information between pairs of nodes). To evaluate patient-specific parameters of communication, thresholds of mutual information were applied to preserve 10% to 30% of the strongest edges. There was no significant difference in network parameters between both atria at baseline. Ablation effectively rewired the communication network of persistent AF to improve the overall connectivity. In addition, successful ablation improved local connectivity by increasing the average clustering coefficient, and also improved global connectivity by decreasing the characteristic path length. As a result, successful ablation improved the efficiency and robustness of the communication network by increasing the small-world index. These changes were not observed in patients with AF recurrence. Furthermore, a significant increase in the small-world index after ablation was associated with synchronization of the rhythm by acute AF termination. In conclusion, successful ablation rewires communication networks during persistent AF, making it more robust, efficient, and easier to synchronize. Quantitative analysis of communication networks provides not only a mechanistic insight that AF may be sustained by spatially localized sources and

  2. Two ligands signal through the Drosophila PDGF/VEGF receptor to ensure proper salivary gland positioning.

    Science.gov (United States)

    Harris, Katherine E; Schnittke, Nikolai; Beckendorf, Steven K

    2007-07-01

    The Drosophila embryonic salivary gland is a migrating tissue that undergoes a stereotypic pattern of migration into the embryo. We demonstrate that the migratory path of the salivary gland requires the PDGF/VEGF pathway. The PDGF/VEGF receptor, Pvr, is strongly expressed in the salivary glands, and Pvr mutations cause abnormal ventral curving of the glands, suggesting that Pvr is involved in gland migration. Although the Pvr ligands, Pvf1 and Pvf2, have distinct expression patterns in the Drosophila embryo, mutations for either one of the ligands result in salivary gland migration defects similar to those seen in embryos that lack Pvr. Rescue experiments indicate that the PDGF/VEGF pathway functions autonomously in the salivary gland. The results of this study demonstrate that the Drosophila PDGF/VEGF pathway is essential for proper positioning of the salivary glands.

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

    Science.gov (United States)

    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.

  4. Anti-VEGF agents in the treatment of diabetic macular edema

    Directory of Open Access Journals (Sweden)

    Vladimir Iosifovich Konenkov

    2013-12-01

    Full Text Available Diabetic macular edema (DME is a common complication associated with the loss of visual acuity in diabetic patients. Intravitreal injections of vascular endothelium growth factor (VEGF inhibitors (anti-VEGF therapy have been proposed recently as a new treatment option for patients with DME. In this review we summarized results of randomized clinical trials of VEGF inhibitors in DME patients. The results indicate that all studied inhibitors (ranibizumab, bevacizumab, pegaptanib and aflibersept reduce the retinal thickness and improve of visual acuity in DME when are used as a monotherapy or in combination with the laser treatment. Optimal course duration and effectiveness predictors of anti-VEGF therapy in DME should be elucidate in the future studies.

  5. EGF Regulation of VEGF: Role in Progression of ErbB2 Overexpressing Mammary Tumors

    National Research Council Canada - National Science Library

    Loureiro, Robyn

    2004-01-01

    .... ErbB2, an epidermal growth factor receptor family member whose overexpression in mammary tumors is correlated with poor patient prognosis, has been previously implicated as a positive modulator of VEGF expression...

  6. Perioral Rejuvenation With Ablative Erbium Resurfacing.

    Science.gov (United States)

    Cohen, Joel L

    2015-11-01

    Since the introduction of the scanning full-field erbium laser, misconceptions regarding ablative erbium resurfacing have resulted in its being largely overshadowed by ablative fractional resurfacing. This case report illustrates the appropriateness of full-field erbium ablation for perioral resurfacing. A patient with profoundly severe perioral photodamage etched-in lines underwent full-field ablative perioral resurfacing with an erbium laser (Contour TRL, Sciton Inc., Palo Alto, CA) that allows separate control of ablation and coagulation. The pre-procedure consultations included evaluation of the severity of etched-in lines, and discussion of patient goals, expectations, and appropriate treatment options, as well as a review of patient photos and post-treatment care required. The author generally avoids full-field erbium ablation in patients with Fitzpatrick type IV and above. For each of 2 treatment sessions (separated by approximately 4 months), the patient received (12 cc plain 2% lidodaine) sulcus blocks before undergoing 4 passes with the erbium laser at 150 μ ablation, no coagulation, and then some very focal 30 μ ablation to areas of residual lines still visualized through the pinpoint bleeding. Similarly, full-field ablative resurfacing can be very reliable for significant wrinkles and creping in the lower eyelid skin--where often a single treatment of 80 μ ablation, 50 μ coagulation can lead to a nice improvement. Standardized digital imaging revealed significant improvement in deeply etched rhytides without significant adverse events. For appropriately selected patients requiring perioral (or periorbital) rejuvenation, full-field ablative erbium resurfacing is safe, efficacious and merits consideration.

  7. Enhancement of musculocutaneous nerve reinnervation after vascular endothelial growth factor (VEGF gene therapy

    Directory of Open Access Journals (Sweden)

    Haninec Pavel

    2012-06-01

    Full Text Available Abstract Background Vascular endothelial growth factor (VEGF is not only a potent angiogenic factor but it also promotes axonal outgrowth and proliferation of Schwann cells. The aim of the present study was to quantitatively assess reinnervation of musculocutaneous nerve (MCN stumps using motor and primary sensory neurons after plasmid phVEGF transfection and end-to-end (ETE or end-to-side (ETS neurorrhaphy. The distal stump of rat transected MCN, was transfected with plasmid phVEGF, plasmid alone or treated with vehiculum and reinnervated following ETE or ETS neurorrhaphy for 2 months. The number of motor and dorsal root ganglia neurons reinnervating the MCN stump was estimated following their retrograde labeling with Fluoro-Ruby and Fluoro-Emerald. Reinnervation of the MCN stumps was assessed based on density, diameter and myelin sheath thickness of regenerated axons, grooming test and the wet weight index of the biceps brachii muscles. Results Immunohistochemical detection under the same conditions revealed increased VEGF in the Schwann cells of the MCN stumps transfected with the plasmid phVEGF, as opposed to control stumps transfected with only the plasmid or treated with vehiculum. The MCN stumps transfected with the plasmid phVEGF were reinnervated by moderately higher numbers of motor and sensory neurons after ETE neurorrhaphy compared with control stumps. However, morphometric quality of myelinated axons, grooming test and the wet weight index were significantly better in the MCN plasmid phVEGF transfected stumps. The ETS neurorrhaphy of the MCN plasmid phVEGF transfected stumps in comparison with control stumps resulted in significant elevation of motor and sensory neurons that reinnervated the MCN. Especially noteworthy was the increased numbers of neurons that sent out collateral sprouts into the MCN stumps. Similarly to ETE neurorrhaphy, phVEGF transfection resulted in significantly higher morphometric quality of myelinated axons

  8. What Next After Failed Septal Ventricular Tachycardia Ablation?

    Directory of Open Access Journals (Sweden)

    Laurent Roten, MD

    2012-07-01

    Full Text Available Ablation of ventricular tachycardia (VT by conventional radiofrequency ablation can be impossible if the ventricular wall at the targeted ablation site is very thick, as for example the ventricular septum. We present a case of a patient with incessant, non-sustained slow VT originating from the septal part of the lower outflow tracts. Radiofrequency catheter ablation from both ventricles as well as from the anterior cardiac vein were not successful. Both high power radiofrequency ablation and bipolar radiofrequency ablation neither were successfull. Finally, ethanol ablation of the first septal perforator successfully terminated arrhythmia. We discuss the possibilities to overcome failed conventional radiofrequency VT ablation of a septal focus.

  9. Therapeutic efficacy of percutaneous radiofrequency ablation versus microwave ablation for hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    Full Text Available The aim of this study was to investigate the therapeutic efficacy of percutaneous radiofrequency (RF ablation versus microwave (MW ablation for hepatocellular carcinoma (HCC measuring ≤ 5 cm in greatest diameter. From January 2006 to December 2006, 78 patients had undergone RF ablation whereas 77 had undergone MW ablation. Complete ablation (CA, local tumour progression (LTP and distant recurrence (DR were compared. The overall survival curves were calculated with the Kaplan-Meier technique and compared with the log-rank test. The CA rate was 83.4% (78/93 for RF ablation and 86.7%(91/105 for MW ablation. The LTP rate was 11.8% (11/93 for RF ablation and 10.5% (11/105 for MW ablation. DR was found in 51 (65.4% in the RF ablation and 62 (80.5% in the MW ablation. There was no significant difference in the 1-, 3-, and 5-year overall survival rates (P = 0.780 and the 1-, 3-, and 5-year disease-free survival rates (P = 0.123 between RF and MW ablation. At subgroup analyses, for patients with tumors ≤ 3.0 cm, there was no significant difference in the 1-, 3-, and 5-year overall survival rates (P = 0.067 and the corresponding disease-free survival rates(P = 0.849. For patients with tumor diameters of 3.1-5.0 cm, the 1-, 3-, and 5-year overall survival rates were 87.1%, 61.3%, and 40.1% for RF ablation and 85.4%, 36.6%, and 22% for MW ablation, with no significant difference (P = 0.068. The corresponding disease-free survival rates were 74.2%, 54.8%, and 45.2% for the RF ablation group and 53.3%, 26.8%, and 17.1% for the MW ablation group. The disease-free survival curve for the RF ablation group was significantly better than that for the MW ablation group (P = 0.018. RF ablation and MW ablation are both effective methods in treating hepatocellular carcinomas, with no significant differences in CA, LTP, DR, and overall survival.

  10. Deleterious effects of endogenous and exogenous testosterone on mesenchymal stem cell VEGF production.

    Science.gov (United States)

    Ray, Rinki; Herring, Christine M; Markel, Troy A; Crisostomo, Paul R; Wang, Meijing; Weil, Brent; Lahm, Tim; Meldrum, Daniel R

    2008-05-01

    Modulating the paracrine effects of bone marrow mesenchymal stem cells (BMSCs) may be important for the treatment of ischemic myocardial tissue. In this regard, endogenous estrogen may enhance BMSC vascular endothelial growth factor (VEGF) production. However, little information exists regarding the effect of testosterone on stem cell function. We hypothesized that 1) endogenous or exogenous estrogen will enhance stem cell production of VEGF and 2) endogenous or exogenous testosterone will inhibit BMSC VEGF production. BMSCs were collected from adult male, female, castrated male, and ovariectomized female rats. One hundred thousand cells were incubated with testosterone (1, 10, or 100 nM) or estrogen (0.15, 1.5, or 15 nM) for 48 h. Cell supernatants were collected, and VEGF was measured by ELISA. BMSCs harvested from castrated males, normal females, and ovariectomized females produced more VEGF compared with normal males. Castration was associated with the highest level (1,018 +/- 98.26 pg/ml) of VEGF production by BMSCs, which was significantly more than that produced by BMSCs harvested from normal male and normal female animals. Exogenous testosterone significantly reduced VEGF production in BMSCs harvested from ovariectomized females in a dose-dependent manner. Exogenous estrogen did not alter BMSC VEGF production. These findings suggest that testosterone may work on BMSCs to decrease protective growth factor production and that effective removal of testosterone's deleterious effects via castration may prove to be beneficial in terms of protective factor production. By manipulating the mechanisms that BMSCs use to produce growth factors, we may be able to engineer stem cells to produce maximum growth factors during therapeutic use.

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

    Science.gov (United States)

    Griffin, Helen R; Hall, Darroch H; Topf, Ana; Eden, James; Stuart, A Graham; Parsons, Jonathan; Peart, Ian; Deanfield, John E; O'Sullivan, John; Babu-Narayan, Sonya V; Gatzoulis, Michael A; Bu'lock, Frances A; Bhattacharya, Shoumo; Bentham, Jamie; Farrall, Martin; Granados Riveron, Javier; Brook, J David; Burn, John; Cordell, Heather J; Goodship, Judith A; Keavney, Bernard

    2009-01-01

    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.

  12. 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....

  13. Transcriptional profiling of mouse uterus at pre-implantation stage under VEGF repression.

    Directory of Open Access Journals (Sweden)

    Yan Ji

    Full Text Available Uterus development during pre-implantation stage affects implantation process and embryo growth. Aberrant uterus development is associated with many human reproductive diseases. Among the factors regulating uterus development, vascular remodeling promoters are critical for uterus function and fertility. Vascular endothelial growth factor (VEGF, as one of the major members, has been found to be important in endothelial cell growth and blood vessel development, as well as in non-endothelial cells. VEGF mediation in reproduction has been broadly studied, but VEGF-induced transcriptional machinery during implantation window has not been systematically studied. In this study, a genetically repressed VEGF mouse model was used to analyze uterus transcriptome at gestation 2.5 (G2.5 by Solexa/Illumina's digital gene expression (DGE system. A number of 831 uterus-specific and 2398 VEGF-regulated genes were identified. Gene ontology (GO analysis indicated that genes actively involved in uterus development were members of collagen biosynthesis, cell proliferation and cell apoptosis. Uterus-specific genes were enriched in activities of phosphatidyl inositol phosphate kinase, histone H3-K36 demethylation and protein acetylation. Among VEGF-regulated genes, up-regulated were associated with RNA polymerase III activity while down-regulated were strongly related with muscle development. Comparable numbers of antisense transcripts were identified. Expression levels of the antisense transcripts were found tightly correlated with their sense expression levels, an indication of possibly non-specific transcripts generated around the active promoters and enhancers. The antisense transcripts with exceptionally high or low expression levels and the antisense transcripts under VEGF regulation were also identified. These transcripts may be important candidates in regulation of uterus development. This study provides a global survey on genes and antisense transcripts

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

    Directory of Open Access Journals (Sweden)

    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.

  15. Platelet activation determines angiopoietin-1 and VEGF levels in malaria: implications for their use as biomarkers.

    Directory of Open Access Journals (Sweden)

    Judith Brouwers

    Full Text Available INTRODUCTION: The angiogenic proteins angiopoietin (Ang-1, Ang-2 and vascular endothelial growth factor (VEGF are regulators of endothelial inflammation and integrity. Since platelets store large amounts of Ang-1 and VEGF, measurement of circulation levels of these proteins is sensitive to platelet number, in vivo platelet activation and inadvertent platelet activation during blood processing. We studied plasma Ang-1, Ang-2 and VEGF levels in malaria patients, taking the necessary precautions to avoid ex vivo platelet activation, and related plasma levels to platelet count and the soluble platelet activation markers P-selectin and CXCL7. METHODS: Plasma levels of Ang-1, Ang-2, VEGF, P-selectin and CXCL7 were measured in CTAD plasma, minimizing ex vivo platelet activation, in 27 patients with febrile Plasmodium falciparum malaria at presentation and day 2 and 5 of treatment and in 25 healthy controls. RESULTS: Levels of Ang-1, Ang-2 and VEGF were higher at day 0 in malaria patients compared to healthy controls. Ang-2 levels, which is a marker of endothelial activation, decreased after start of antimalarial treatment. In contrast, Ang-1 and VEGF plasma levels increased and this corresponded with the increase in platelet number. Soluble P-selectin and CXCL7 levels followed the same trend as Ang-1 and VEGF levels. Plasma levels of these four proteins correlated strongly in malaria patients, but only moderately in controls. CONCLUSION: In contrast to previous studies, we found elevated plasma levels of Ang-1 and VEGF in patients with malaria resulting from in vivo platelet activation. Ang-1 release from platelets may be important to dampen the disturbing effects of Ang-2 on the endothelium. Evaluation of plasma levels of these angiogenic proteins requires close adherence to a stringent protocol to minimize ex vivo platelet activation.

  16. Moderation of calpain activity promotes neovascular integration and lumen formation during VEGF-induced pathological angiogenesis.

    Directory of Open Access Journals (Sweden)

    Mien V Hoang

    2010-10-01

    Full Text Available Successful neovascularization requires that sprouting endothelial cells (ECs integrate to form new vascular networks. However, architecturally defective, poorly integrated vessels with blind ends are typical of pathological angiogenesis induced by vascular endothelial growth factor-A (VEGF, thereby limiting the utility of VEGF for therapeutic angiogenesis and aggravating ischemia-related pathologies. Here we investigated the possibility that over-exuberant calpain activity is responsible for aberrant VEGF neovessel architecture and integration. Calpains are a family of intracellular calcium-dependent, non-lysosomal cysteine proteases that regulate cellular functions through proteolysis of numerous substrates.In a mouse skin model of VEGF-driven angiogenesis, retroviral transduction with dominant-negative (DN calpain-I promoted neovessel integration and lumen formation, reduced blind ends, and improved vascular perfusion. Moderate doses of calpain inhibitor-I improved VEGF-driven angiogenesis similarly to DN calpain-I. Conversely, retroviral transduction with wild-type (WT calpain-I abolished neovessel integration and lumen formation. In vitro, moderate suppression of calpain activity with DN calpain-I or calpain inhibitor-I increased the microtubule-stabilizing protein tau in endothelial cells (ECs, increased the average length of microtubules, increased actin cable length, and increased the interconnectivity of vascular cords. Conversely, WT calpain-I diminished tau, collapsed microtubules, disrupted actin cables, and inhibited integration of cord networks. Consistent with the critical importance of microtubules for vascular network integration, the microtubule-stabilizing agent taxol supported vascular cord integration whereas microtubule dissolution with nocodazole collapsed cord networks.These findings implicate VEGF-induction of calpain activity and impairment of cytoskeletal dynamics in the failure of VEGF-induced neovessels to form and

  17. VEGF-releasing suture material for enhancement of vascularization: development, in vitro and in vivo study.

    Science.gov (United States)

    Bigalke, Christian; Luderer, Frank; Wulf, Katharina; Storm, Thilo; Löbler, Marian; Arbeiter, Daniela; Rau, Bettina M; Nizze, Horst; Vollmar, Brigitte; Schmitz, Klaus-Peter; Klar, Ernst; Sternberg, Katrin

    2014-12-01

    As it has been demonstrated that bioactive substances can be delivered locally using coated surgical suture materials, the authors developed a vascular endothelial growth factor (VEGF)-releasing suture material that should promote vascularization and potentially wound healing. In this context, the study focused on the characterization of the developed suture material and the verification of its biological activity, as well as establishing a coating process that allows reproducible and stable coating of a commercially available polydioxanone suture material with poly(l-lactide) (PLLA) and 0.1μg and 1.0μg VEGF. The in vitro VEGF release kinetics was studied using a Sandwich ELISA. The biological activity of the released VEGF was investigated in vitro using human umbilical vein endothelial cells. The potential of the VEGF-releasing suture material was also studied in vivo 5days after implantation in the hind limb of Wistar rats, when the histological findings were analyzed. The essential results, enhanced cell viability in vitro as well as significantly increased vascularization in vivo, were achieved using PLLA/1.0μg VEGF-coated suture material. Furthermore, ELISA measurements revealed a high reproducibility of the VEGF release behavior. Based on the results achieved regarding the dose-effect relationship of VEGF, the stability during its processing and the release behavior, it can be predicted that a bioactive suture material would be successful in later in vivo studies. Therefore, this knowledge could be the basis for future studies, where bioactive substances with different modes of action are combined for targeted, overall enhancement of wound healing. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  18. Serum vascular endothelial growth factor (VEGF) is elevated in GH deficient adults.

    Science.gov (United States)

    Murray, Robert D; Randeva, Harpal S; Lewandowski, Krzysztof C; Komorowski, Jan; Lawrance, Jeremy A; Adams, Judith E; Shalet, Stephen M

    2011-04-01

    GHD adults exhibit a number of adverse surrogate markers of vascular risk culminating in excess vascular morbidity and mortality. Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of a number of vascular morbidities. Furthermore, serum levels decrease following GH replacement in GHD adults, though it remains unclear if levels are significantly elevated in untreated individuals. A cross-sectional case-control study. We measured fasting serum VEGF, MMP2, and MMP9 in 27 patients with GHD, 24 with partial GHD (GHI), and 25 sex- and age-matched controls. GHD (483±334 vs 326±180ng/l, P=0.04), but not GHI (354±192 vs 326±180ng/l, P=n/s) adults had significantly elevated VEGF levels compared with controls. Neither MMP2, nor MMP9 levels were elevated in the patient groups. Serum VEGF levels correlated positively with LDL-cholesterol (R=0.34, P=0.004) and serum MMP9 values (R=0.36, P=0.002), and negatively with IGF-I values, however, no correlation was observed with MMP2. Multiple regression analysis with VEGF levels as the dependent variable, and age, gender, % fat mass, LDL-C, insulin and IGF-I as independent variables revealed VEGF levels to be dependent on LDL-C alone (P=0.003, R=0.36). GHD adults have elevated VEGF levels, which correlate with MMP9 levels. Both VEGF and MMP9 are associated with vascular pathologies and may provide insight in to the pathophysiological mechanisms underlying the increased vascular morbidity and mortality observed in GHD adults. Copyright © 2011 Growth Hormone Research Society. Published by Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    Woliński, Kosma; Stangierski, Adam; Szczepanek-Parulska, Ewelina; Gurgul, Edyta; Budny, Bartłomiej; Wrotkowska, Elzbieta; Biczysko, Maciej; Ruchala, Marek

    2016-01-01

    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 (pthyroid nodules and should be interpreted carefully. Further studies on larger groups are indicated. However, measurement of VEGF-C on mRNA level can bring important information without exposing patient for additional risk and invasive procedures.

  20. Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PIGF-1/VEGF heterodimers

    DEFF Research Database (Denmark)

    Eriksson, A.; Cao, R.; Pawliuk, R.

    2002-01-01

    , the biological function of its related homolog, placenta growth factor (PlGF), is poorly understood. Here we demonstrate that PlGF-1, an alternatively spliced isoform of the PlGF gene, antagonizes VEGF-induced angiogenesis when both factors are coexpressed in murine fibrosarcoma cells. Overexpression of PlGF-1...... signaling pathways. Further, PlGF-1 inhibits the growth of a murine fibrosarcoma by approximately 90% when PlGF-1-expressing tumor cells are implanted in syngeneic mice. In contrast, overexpression of human VEGF in murine tumor cells causes accelerated and exponential growth of primary fibrosarcomas...

  1. Enhanced Vascularization in Hybrid PCL/Gelatin Fibrous Scaffolds with Sustained Release of VEGF

    Directory of Open Access Journals (Sweden)

    Kai Wang

    2015-01-01

    Full Text Available Creating a long-lasting and functional vasculature represents one of the most fundamental challenges in tissue engineering. VEGF has been widely accepted as a potent angiogenic factor involved in the early stages of blood vessel formation. In this study, fibrous scaffolds that consist of PCL and gelatin fibers were fabricated. The gelatin fibers were further functionalized by heparin immobilization, which provides binding sites for VEGF and thus enables the sustained release of VEGF. In vitro release test confirms the sustained releasing profile of VEGF, and stable release was observed over a time period of 25 days. In vitro cell assay indicates that VEGF release significantly promoted the proliferation of endothelial cells. More importantly, in vivo subcutaneous implantation reflects that vascularization has been effectively enhanced in the PCL/gelatin scaffolds compared with the PCL counterpart due to the sustained release of VEGF. Therefore, the heparinized PCL/gelatin scaffolds developed in this study may be a promising candidate for regeneration of complex tissues with sufficient vascularization.

  2. Local VEGF inhibition prevents ovarian alterations associated with ovarian hyperstimulation syndrome.

    Science.gov (United States)

    Scotti, Leopoldina; Abramovich, Dalhia; Pascuali, Natalia; Irusta, Griselda; Meresman, Gabriela; Tesone, Marta; Parborell, Fernanda

    2014-10-01

    The relationship between human chorionic gonadotropin and ovarian hyperstimulation syndrome (OHSS) is partially mediated by vascular endothelial growth factor A (VEGF). The aim of this study was to investigate the effects of VEGF inhibition on the development of corpora lutea (CL) and cystic structures, steroidogenesis, apoptosis, cell proliferation, endothelial cell area, VEGF receptors (KDR and Flt-1), claudin-5 and occludin levels in ovaries from an OHSS rat model. The VEGF inhibitor used (VEGF receptor-1 (FLT-1)/Fc chimera, TRAP) decreased the concentrations of progesterone and estradiol as well as the percentage of CL and cystic structures in OHSS rats, and increased apoptosis in CL. Endothelial cell area in CL and KDR expression and its phosphorylation were increased, whereas claudin-5 and occludin levels were decreased in the OHSS compared to the control TRAP reversed these parameters. Our findings indicate that VEGF inhibition prevents the early onset of OHSS and decreases its severity in rats. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

    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

  4. Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer.

    Science.gov (United States)

    Chatterjee, Sampurna; Heukamp, Lukas C; Siobal, Maike; Schöttle, Jakob; Wieczorek, Caroline; Peifer, Martin; Frasca, Davide; Koker, Mirjam; König, Katharina; Meder, Lydia; Rauh, Daniel; Buettner, Reinhard; Wolf, Jürgen; Brekken, Rolf A; Neumaier, Bernd; Christofori, Gerhard; Thomas, Roman K; Ullrich, Roland T

    2013-04-01

    The molecular mechanisms that control the balance between antiangiogenic and proangiogenic factors and initiate the angiogenic switch in tumors remain poorly defined. By combining chemical genetics with multimodal imaging, we have identified an autocrine feed-forward loop in tumor cells in which tumor-derived VEGF stimulates VEGF production via VEGFR2-dependent activation of mTOR, substantially amplifying the initial proangiogenic signal. Disruption of this feed-forward loop by chemical perturbation or knockdown of VEGFR2 in tumor cells dramatically inhibited production of VEGF in vitro and in vivo. This disruption was sufficient to prevent tumor growth in vivo. In patients with lung cancer, we found that this VEGF:VEGFR2 feed-forward loop was active, as the level of VEGF/VEGFR2 binding in tumor cells was highly correlated to tumor angiogenesis. We further demonstrated that inhibition of tumor cell VEGFR2 induces feedback activation of the IRS/MAPK signaling cascade. Most strikingly, combined pharmacological inhibition of VEGFR2 (ZD6474) and MEK (PD0325901) in tumor cells resulted in dramatic tumor shrinkage, whereas monotherapy only modestly slowed tumor growth. Thus, a tumor cell-autonomous VEGF:VEGFR2 feed-forward loop provides signal amplification required for the establishment of fully angiogenic tumors in lung cancer. Interrupting this feed-forward loop switches tumor cells from an angiogenic to a proliferative phenotype that sensitizes tumor cells to MAPK inhibition.

  5. A potential role for VEGF in the diagnostic approach of pleural effusions

    Science.gov (United States)

    Psatha, Aggeliki; Makris, Demosthenes; Daniil, Zoe; Kiropoulos, Theodoros; Gourgoulianis, Konstantinos

    2016-01-01

    Background Vascular endothelial growth factor (VEGF) may play a role in pleural fluid formation, as it represents a potent inducer of capillary permeability. We aimed to investigate the diagnostic utility of VEGF levels in pleural fluid and serum in patients with pleural effusions with initially negative diagnostic work up. Methods Seventy-one patients with exudative lymphocytic pleural effusions undiagnosed after initial diagnostic work up were enrolled in this prospective study and their clinical course was followed up to 24 months. VEGF levels were measured in serum and pleural fluid by using immunoenzymometric assay. Results During the follow up period, in 43 patients the pleural effusion was eventually attributed to malignancy while in the rest 28 patients it was due to non-malignant causes (benign and unknown origin). Patients with malignancy had significantly higher VEGF levels in pleural fluid compared to patients with non-malignant effusions (1,506 vs. 588 pg/dL, P=0.0001), while no statistically significant difference was found in the VEGF serum levels between the two groups. Conclusions Pleural VEGF levels may be helpful in identifying malignant pleural effusion (MPE) in patients with negative diagnostic work up at the initial assessment and help in selecting patients for more invasive procedures. PMID:27499957

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

    Directory of Open Access Journals (Sweden)

    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.

  7. Expression of VEGF-D in epithelial ovarian cancer and its relationship to lymphatic metastasis.

    Science.gov (United States)

    He, Lixia; He, Junyong; Zhao, Xia

    2016-03-01

    To investigate the contribution of vascular endothelial growth factor (VEGF)-D to tumor progression, tumor lymphangiogenesis and lymphatic metastasis in epithelial ovarian cancer. The expression profiles of VEGF-D in 18 benign, 14 borderline and 87 malignant epithelial ovarian cancers were examined using immunohistochemical (IHC) staining. Lymphatic vessels were identified using IHC staining on lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), which is a lymph-specific receptor for hyaluronan in identifying lymphatic vessels. The potential correlation among VEGF-D, lymphatic vessel density (LVD) and clinico-pathological factors of the epithelial ovarian cancer was also analyzed. Positive IHC staining of VEGF-D was observed in 17% of benign, 21% of borderline and 80% of malignant epithelial ovarian tumors specimens. In the epithelial ovarian cancer specimens, the LVD was 3.41 ± 2.37 in the VEGF-D negative (17 patients), 5.42 ± 3.49 in the weak (26 patients), 7.22 ± 2.36 in the moderate (27 patients) and 7.35 ± 4.06 in the strong (17 patients) groups, respectively. Additionally, the expression of VEGF-D was positively correlated with LVD (r = 0.415, P ovarian cancer than in lymph node-negative patients (P = 0.009, P ovarian cancer. © 2013 Wiley Publishing Asia Pty Ltd.

  8. Nitric Oxide Mediates Bleomycin-Induced Angiogenesis and Pulmonary Fibrosis via Regulation of VEGF

    Science.gov (United States)

    Iyer, Anand Krishnan V.; Ramesh, Vani; Castro, Carlos A.; Kaushik, Vivek; Kulkarni, Yogesh M.; Wright, Clayton A.; Venkatadri, Rajkumar; Rojanasakul, Yon; Azad, Neelam

    2015-01-01

    Pulmonary fibrosis is a progressive lung disease hallmarked by increased fibroblast proliferation, amplified levels of extracellular matrix deposition and increased angiogenesis. Although dysregulation of angiogenic mediators has been implicated in pulmonary fibrosis, the specific rate-limiting angiogenic markers involved and their role in the progression of pulmonary fibrosis remains unclear. We demonstrate that bleomycin treatment induces angiogenesis, and inhibition of the central angiogenic mediator VEGF using anti-VEGF antibody CBO-P11 significantly attenuates bleomycin-induced pulmonary fibrosis in vivo. Bleomycin-induced nitric oxide (NO) was observed to be the key upstream regulator of VEGF via the PI3k/Akt pathway. VEGF regulated other important angiogenic proteins including PAI-1 and IL-8 in response to bleomycin exposure. Inhibition of NO and VEGF activity significantly mitigated bleomycin-induced angiogenic and fibrogenic responses. NO and VEGF are key mediators of bleomycin-induced pulmonary fibrosis, and could serve as important targets against this debilitating disease. Overall, our data suggests an important role for angiogenic mediators in the pathogenesis of bleomycin-induced pulmonary fibrosis. PMID:25919965

  9. CD47 signaling regulates the immunosuppressive activity of VEGF in T cells*

    Science.gov (United States)

    Kaur, Sukhbir; Chang, Tiffany; Singh, Satya P.; Lim, Langston; Mannan, Poonam; Garfield, Susan H.; Pendrak, Michael L.; Pantoja, David R. Soto; Rosenberg, Avi Z.; Jin, Shelly; Roberts, David D.

    2014-01-01

    Thromobospondin-1 inhibits angiogenesis in part by interacting with the ubiquitous cell surface receptor CD47. In endothelial cells, CD47 interacts directly with vascular endothelial growth factor receptor-2 (VEGFR2), and thrombospondin-1 inhibits VEGFR2 phosphorylation and signaling by disrupting this association. We now show that CD47 similarly associates with and regulates VEGFR2 in T cells. Thrombospondin-1 inhibits phosphorylation of VEGFR2 and its downstream target Src in wild type but not in CD47-deficient human Jurkat and primary murine T cells. VEGFR2 signaling inhibits proliferation and TCR signaling in wild type T cells. However, ligation of CD47 by thrombospondin-1 or loss of CD47 expression reverses some inhibitory effects of VEGF on proliferation and T cell activation. We further found that VEGF and VEGFR2 expression are up-regulated in CD47-deficient murine CD4+ and human Jurkat T cells, and the resulting autocrine VEGFR2 signaling enhances proliferation and some TCR responses in the absence of CD47. Thus, CD47 signaling modulates the ability of VEGF to regulate proliferation and TCR signaling, and autocrine production of VEGF by T cells contributes to this regulation. This provides a mechanism to understand the context-dependent effects of thrombospondin-1 and VEGF on T cell activation and reveals an important role for CD47 signaling in regulating T cell production of the major angiogenic factor VEGF. PMID:25200950

  10. CD47 signaling regulates the immunosuppressive activity of VEGF in T cells.

    Science.gov (United States)

    Kaur, Sukhbir; Chang, Tiffany; Singh, Satya P; Lim, Langston; Mannan, Poonam; Garfield, Susan H; Pendrak, Michael L; Soto-Pantoja, David R; Rosenberg, Avi Z; Jin, Shelly; Roberts, David D

    2014-10-15

    Thrombospondin-1 (TSP1) inhibits angiogenesis, in part, by interacting with the ubiquitous cell-surface receptor CD47. In endothelial cells, CD47 interacts directly with vascular endothelial growth factor receptor (VEGFR)-2, and TSP1 inhibits VEGFR2 phosphorylation and signaling by disrupting this association. We show that CD47 similarly associates with and regulates VEGFR2 in T cells. TSP1 inhibits phosphorylation of VEGFR2 and its downstream target Src in wild type but not in CD47-deficient human Jurkat and primary murine T cells. VEGFR2 signaling inhibits proliferation and TCR signaling in wild type T cells. However, ligation of CD47 by TSP1 or loss of CD47 expression reverses some inhibitory effects of VEGF on proliferation and T cell activation. We further found that VEGF and VEGFR2 expression are upregulated in CD47-deficient murine CD4(+) and human Jurkat T cells, and the resulting autocrine VEGFR2 signaling enhances proliferation and some TCR responses in the absence of CD47. Thus, CD47 signaling modulates the ability of VEGF to regulate proliferation and TCR signaling, and autocrine production of VEGF by T cells contributes to this regulation. This provides a mechanism to understand the context-dependent effects of TSP1 and VEGF on T cell activation, and reveals an important role for CD47 signaling in regulating T cell production of the major angiogenic factor VEGF.

  11. Clinical significance of COX-2, GLUT-1 and VEGF expressions in endometrial cancer tissues.

    Science.gov (United States)

    Ma, Xiaoping; Hui, Yuzuo; Lin, Li; Wu, Yu; Zhang, Xian; Liu, Peishu

    2015-01-01

    To analyze the clinical significance of COX-2, GLUT-1 and VEGF expressions in endometrial cancer tissues. One hundred and eight tissue samples from the patients with endometrial cancer enrolled in our hospital from August 2011 to July 2014 were selected, including 60 normal tissue samples (normal group), 60 neoplastic tissue samples (neoplastic group) and 60 cancer tissue samples (cancer group). All the samples were subjected to immunohistochemical assay to detect the expressions of COX-2, GLUT-1 and VEGF. The clinical data were also investigated for correlation analysis. The positive rates of COX-2 in normal group, neoplastic group and cancer groups were 3.3%, 21.7% and 55.0% respectively. The positive rates of GLUT-1 in normal group, neoplastic group and cancer groups were 3.3%, 25.0% and 70.0% respectively. The positive rates of VEGF in normal group, neoplastic group and cancer groups were 1.7%, 23.3% and 63.3% respectively. With increasing stage of such cancer, decreasing degree of differentiation and lymphatic metastasis, the positive expression rates of COX-2, GLUT-1 and VEGF proteins were raised significantly (PGLUT-1 (r=0.207, PGLUT-1 and VEGF (r=0.758, PGLUT-1 and VEGF were highly prominent in endometrial cancer, especially in the patients with low degree of differentiation, late stage and metastasis. They functioned synergistically in the onset and progression of this cancer.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Use of Anti-VEGF Agents in Glaucoma Surgery

    Directory of Open Access Journals (Sweden)

    Mark Slabaugh

    2017-01-01

    Full Text Available A number of antivascular endothelial growth factor agents are currently used to treat ocular conditions. These agents have similar but distinct biologic qualities and have each been used in the management of neovascular glaucoma and in glaucoma surgery. Several different delivery methods are described, and because these medications are routinely given as intraocular injections, there are some benefits over traditional antifibrotic medications when used in glaucoma surgery. These agents effectively induce regression of anterior segment neovascularization and facilitate initial surgical management of neovascular glaucoma but the long-term outcome of this condition remains dependent on definitive management of the underlying process. Use in trabeculectomy or tube shunt procedures for other types of glaucoma has shown promise in affecting bleb morphology but has not yet been found to be as effective as traditional antifibrotic agents. There are reports of persistently raised intraocular pressure after repeated use of the anti-VEGF agents, possibly related to frequency of injection. These medications have wide application in the field of surgical glaucoma but a precise role has yet to be defined.

  14. Linked Partitions and Linked Cycles

    OpenAIRE

    Chen, William Y. C.; Wu, Susan Y. J.; Yan, Catherine H.

    2006-01-01

    The notion of noncrossing linked partition arose from the study of certain transforms in free probability theory. It is known that the number of noncrossing linked partitions of [n+1] is equal to the n-th large Schroder number $r_n$, which counts the number of Schroder paths. In this paper we give a bijective proof of this result. Then we introduce the structures of linked partitions and linked cycles. We present various combinatorial properties of noncrossing linked partitions, linked partit...

  15. Neutralizing Endogenous VEGF Following Traumatic Spinal Cord Injury Modulates Microvascular Plasticity but not Tissue Sparing or Functional Recovery

    Science.gov (United States)

    Benton, Richard L.; Maddie, Melissa A.; Gruenthal, Mark J.; Hagg, Theo; Whittemore, Scott R.

    2010-01-01

    Acute loss of spinal cord vascularity followed by an endogenous adaptive angiogenic response with concomitant microvascular dysfunction is a hallmark of traumatic spinal cord injury (SCI). Recently, the potent vasoactive factor vascular endothelial growth factor (VEGF) has received much attention as a putative therapeutic for the treatment of various neurodegenerative disorders, including SCI. Exogenous VEGF exerts both protective and destabilizing effects on microvascular elements and tissue following SCI but the role of endogenous VEGF is unclear. In the present study, we systemically applied a potent and well characterized soluble VEGF antagonist to adult C57Bl/6 mice post-SCI to elucidate the relative contribution of VEGF on the acute evolving microvascular response and its impact on functional recovery. While the VEGF Trap did not alter vascular density in the injury epicenter or penumbra, an overall increase in the number of Griffonia simplicifolia isolectin-B4 bound microvessels was observed, suggesting a VEGF-dependency to more subtle aspects of endothelial plasticity post-SCI. Neutralizing endogenous VEGF neither attenuated nor exacerbated chronic histopathology or functional recovery. These results support the idea that overall, endogenous VEGF is not neuroprotective or detrimental following traumatic SCI. Furthermore, they suggest that angiogenesis in traumatically injured spinal tissue is regulated by multiple effectors and is not limited by endogenous VEGF activation of affected spinal microvessels. PMID:19442162

  16. Applications of laser ablation to microengineering

    Science.gov (United States)

    Gower, Malcolm C.; Rizvi, Nadeem H.

    2000-08-01

    Applications of pulsed laser ablation to the manufacture of micro- electro-mechanical systems (MEMS) and micro-opto-electro-mechanical systems (MOEMS) devices are presented. Laser ablative processes used to manufacture a variety of microsystems technology (MST) components in the computer peripheral, sensing and biomedical industries are described together with a view of some future developments.

  17. Polyimide polymers provide improved ablative materials

    Science.gov (United States)

    Burns, E. A.; Jones, J. F.; Lubowitz, H. R.

    1970-01-01

    Principle heat absorption of silica-reinforced plastic ablative materials occurs from the in-depth reaction of silica with carbon to form silicon monoxide and carbon monoxide. The higher the degree of completion of this reaction, the higher the capacity of the ablative material to absorb heat.

  18. High Heat Flux Block Ablator-in-Honeycomb Heat Shield Using Ablator/Aerogel-Filled Foam Project

    Data.gov (United States)

    National Aeronautics and Space Administration — Ultramet and ARA Ablatives Laboratory previously developed and demonstrated advanced foam-reinforced carbon/phenolic ablators that offer substantially increased high...

  19. Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial proliferation, arterial relaxation, vascular permeability and angiogenesis by dobesilate.

    Science.gov (United States)

    Angulo, Javier; Peiró, Concepción; Romacho, Tania; Fernández, Argentina; Cuevas, Begoña; González-Corrochano, Rocío; Giménez-Gallego, Guillermo; de Tejada, Iñigo Sáenz; Sánchez-Ferrer, Carlos F; Cuevas, Pedro

    2011-09-30

    Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and vascular permeability which is associated with many pathological processes. 2,5-hydroxybenzene sulfonate (DHBS; dobesilate) is a small molecule with anti-angiogenic activity that has been described as an inhibitor of fibroblast growth factors (FGF). The aim of the present study was to evaluate the effects of DHBS on VEGF-induced actions. The effects of DHBS were evaluated on VEGF-induced proliferation in human umbilical vein endothelial cells (HUVEC) and rat aorta relaxation, as well as on in vivo VEGF-induced skin vascular permeability and neovascularization in rats. DHBS at 50 and 100 μM concentration significantly inhibited the proliferation of HUVEC induced by VEGF (10 ng/ml), without significantly affecting HUVEC proliferation in the absence of VEGF. Rapid VEGF-induced activation of Akt in HUVEC was also prevented by DHBS (100 μM). Additionally, DHBS (2 μM) specifically inhibited the relaxation of rat aorta induced by VEGF (0.1 to 30 ng/ml), but not endothelium-dependent relaxation to acetylcholine (1 nM to 10 μM). The in vivo enhancement of vascular permeability caused by VEGF injection (50 μl at 10 ng/ml) in rat skin was also inhibited by DHBS co-administration (200 μM) (74.8±3.8% inhibition of dye extravasation). Administration of DHBS (200 mg/kg/day; i.p.) also reduced VEGF-induced angiogenesis in vivo. DHBS inhibits main responses elicited in vitro and in vivo by VEGF. As a dual antagonist of VEGF and FGF activities, DHBS could be of therapeutic interest in the treatment of diseases related to VEGF/FGF overproduction and excessive angiogenesis. Copyright © 2011 Elsevier B.V. All rights reserved.

  20. The expression and underlying angiogenesis effect of DPC4 and VEGF on the progression of cervical carcinoma.

    Science.gov (United States)

    A, Yanni; Li, Ying; Zhao, Shuping

    2018-02-01

    The present study aimed to investigate the expression and roles of deleted in pancreatic carcinoma locus 4 (DPC4) and vascular endothelial growth factor (VEGF) in the development of cervical carcinoma. A total of 115 patients aged between 25 and 60 years were involved, including 19 cervical inflammation, 35 cervical intraepithelial neoplasia (CIN), and 61 cervical squamous-cell carcinoma (CSCC). The protein expression rates of DPC4 and VEGF in all samples were detected using immunohistochemistry. The protein levels of DPC4 and VEGF in CSCC samples were measured using ELISA. Microvessel density (MVD) of each CSCC sample was measured according to the Winder method. Association analysis between DPC4, VEGF and thrombospondin-1 (TSP-1) was conducted using Spearman's correlations. The negative expression rate of DPC4 [DPC4 (-)] and positive expression rate of VEGF [VEGF (+)] of the CSCC group were significantly higher compared with that in the cervical inflammation and CIN groups (P<0.05). In the CSCC group, the protein level of DPC4 decreased, while the VEGF level increased significantly compared with the healthy control group (P<0.05). The MVD in the DPC4 (-), VEGF (+) and TSP-1 (-) groups was significantly increased compared with that of the DPC4 (+), VEGF (-), and TSP-1 (+) groups (P<0.05). The expression of DPC4 was negatively associated with VEGF and TSP-1 (P<0.01). These results suggest that DPC4, VEGF and TSP-1 are involved in the carcinogenesis of cervical carcinoma by inducing angiogenesis. In addition, the loss of DPC4 induces angiogenesis through increasing VEGF. Thus, VEGF may be a target gene regulated by DPC4.

  1. Delineation of VEGF-regulated genes and functions in the cervix of pregnant rodents by DNA microarray analysis

    Directory of Open Access Journals (Sweden)

    Papka Raymond E

    2008-12-01

    Full Text Available Abstract Background VEGF-regulated genes in the cervices of pregnant and non-pregnant rodents (rats and mice were delineated by DNA microarray and Real Time PCR, after locally altering levels of or action of VEGF using VEGF agents, namely siRNA, VEGF receptor antagonist and mouse VEGF recombinant protein. Methods Tissues were analyzed by genome-wide DNA microarray analysis, Real-time and gel-based PCR, and SEM, to decipher VEGF function during cervical remodeling. Data were analyzed by EASE score (microarray and ANOVA (Real Time PCR followed by Scheffe's F-test for multiple comparisons. Results Of the 30,000 genes analyzed, about 4,200 genes were altered in expression by VEGF, i.e., expression of about 2,400 and 1,700 genes were down- and up-regulated, respectively. Based on EASE score, i.e., grouping of genes according to their biological process, cell component and molecular functions, a number of vascular- and non-vascular-related processes were found to be regulated by VEGF in the cervix, including immune response (including inflammatory, cell proliferation, protein kinase activity, and cell adhesion molecule activity. Of interest, mRNA levels of a select group of genes, known to or with potential to influence cervical remodeling were altered. For example, real time PCR analysis showed that levels of VCAM-1, a key molecule in leukocyte recruitment, endothelial adhesion, and subsequent trans-endothelial migration, were elevated about 10 folds by VEGF. Further, VEGF agents also altered mRNA levels of decorin, which is involved in cervical collagen fibrillogenesis, and expression of eNO, PLC and PKC mRNA, critical downstream mediators of VEGF. Of note, we show that VEGF may regulate cervical epithelial proliferation, as revealed by SEM. Conclusion These data are important in that they shed new insights in VEGF's possible roles and mechanisms in cervical events near-term, including cervical remodeling.

  2. Plume dynamics and shielding by the ablation plume during Er:YAG laser ablation.

    Science.gov (United States)

    Nahen, Kester; Vogel, Alfred

    2002-04-01

    Free-running Er:YAG lasers are used for precise tissue ablation in various clinical applications. The ablated material is ejected into the direction perpendicular to the tissue surface. We investigated the influence of shielding by the ablation plume on the energy deposition into an irradiated sample because it influences the ablation dynamics and the amount of material ablated. The investigations were performed using an Er:YAG laser with a pulse duration of 200 micros for the ablation of gelatin with different water contents, skin, and water. Laser flash photography combined with a dark field Schlieren technique was used to visualize gaseous and particulate ablation products, and to measure the distance traveled by the ablating laser beam through the ablation plume at various times after the beginning of the laser pulse. The temporal evolution of the transmission through the ablation plume was probed using a second free running Er:YAG laser beam directed parallel to the sample's surface. The ablation dynamics was found to consist of a vaporization phase followed by material ejection. The observation of droplet ejection during water ablation provided evidence that a phase explosion is the driving mechanism for material ejection. The laser light transmission was only slightly reduced by the vapor plume, but decreased by 25%-50% when the ejected material passed the probe beam. At radiant exposures approximately 10 times above the ablation threshold, the laser energy deposited into the sample amounted to only 61% of the incident energy for gelatin samples with 90% water content and to 86% for skin samples. For free-running Er:YAG laser pulses shielding must therefore be considered in modeling the ablation dynamics and determining the dosage for clinical applications.

  3. Laser systems for ablative fractional resurfacing

    DEFF Research Database (Denmark)

    Paasch, Uwe; Haedersdal, Merete

    2011-01-01

    Ablative fractional resurfacing (AFR) creates microscopic vertical ablated channels that are surrounded by a thin layer of coagulated tissue, constituting the microscopic treatment zones (MTZs). AFR induces epidermal and dermal remodeling, which raises new possibilities for the treatment of a var......Ablative fractional resurfacing (AFR) creates microscopic vertical ablated channels that are surrounded by a thin layer of coagulated tissue, constituting the microscopic treatment zones (MTZs). AFR induces epidermal and dermal remodeling, which raises new possibilities for the treatment...... ablative laser systems. Fractionated CO(2) (10,600-nm), erbium yttrium aluminum garnet, 2940-nm and yttrium scandium gallium garnet, 2790-nm lasers are available. In this article, we present an overview of AFR technology, devices and histopathology, and we summarize the current clinical possibilities...

  4. Catheter ablation of epicardial ventricular tachycardia

    Directory of Open Access Journals (Sweden)

    Takumi Yamada, MD, PhD

    2014-08-01

    Full Text Available Ventricular tachycardias (VTs can usually be treated by endocardial catheter ablation. However, some VTs can arise from the epicardial surface, and their substrate can be altered only by epicardial catheter ablation. There are two approaches to epicardial catheter ablation: transvenous and transthoracic. The transvenous approach through the coronary venous system (CVS has been commonly used because it is easily accessible. However, this approach may be limited by the distribution of the CVS and insufficient radiofrequency energy delivery. Transthoracic epicardial catheter ablation has been developed to overcome these limitations of the transvenous approach. It is a useful supplemental or even preferred strategy to eliminate epicardial VTs in the electrophysiology laboratory. This technique has been applied for scar-related VTs secondary to often non-ischemic cardiomyopathy and sometimes ischemic cardiomyopathy, and idiopathic VTs as the epicardial substrates of these VTs have become increasingly recognized. When endocardial ablation and epicardial ablation through the CVS are unsuccessful, transthoracic epicardial ablation should be the next option. Intrapericardial access is usually obtained through a subxiphoidal pericardial puncture. This approach might not be possible in patients with pericardial adhesions caused by prior cardiac surgery or pericarditis. In such cases, a hybrid procedure involving surgical access with a subxiphoid pericardial window and a limited anterior or lateral thoracotomy might be a feasible and safe method of performing an epicardial catheter ablation in the electrophysiology laboratory. Potential complications associated with this technique include bleeding and collateral damage to the coronary arteries and phrenic nerve. Although the risk of these complications is low, electrophysiologists who attempt epicardial catheter ablation should know the complications associated with this technique, how to minimize their

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

    Energy Technology Data Exchange (ETDEWEB)

    Dunst, J.; Becker, A.; Lautenschlaeger, C.; Markau, S.; Becker, H.; Fischer, K.; Haensgen, G. [Martin-Luther Univ. Halle-Wittenberg (Germany)

    2002-08-01

    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<0.001), and 89.9{+-}67.8 pg/ml in 23 patients with renal anemia (p=0.001). VEGF levels in cancer patients were significantly correlated with hemoglobin (hb) levels and platelet counts (each p=0.001), but not with type of tumor, stage, histology or age. Patients with cancers had higher plasma levels of VEGF than patients with non-malignant diseases in case of hb{>=}12 g/dl (33.1{+-}17.5 vs. 16.6{+-}13.0 pg/ml, p<0.001) and in case of hb between 11.0 and 11.9 g/dl (56.1{+-}26.4 vs 18.5{+-}14.5 pg/ml, p=0.038). In case of a hb<11 g/dl, plasma VEGF levels were significantly elevated in patients with and without cancers (67.0{+-}47.5 vs 88.9{+-}68.8 pg/ml, n.s.). In a multivariate model, a significant association between low hb levels and increased plasma levels of VEGF was confirmed. In 16 patients with renal anemia, changes in hb under erythropoietin treatment were inversely correlated with changes in plasma VEGF levels with decreasing VEGF after increase in hb (p=0.01). Conclusions: Anemic patients have elevated levels of VEGF. The data suggest that anemia might impact on the progression of

  6. Bacterial antigen induced release of soluble vascular endothelial growth factor (VEGF) and VEGFR1 before and after surgery

    DEFF Research Database (Denmark)

    Svendsen, Mads N; Lykke, J; Werther, Kim

    2005-01-01

    OBJECTIVE: The influence of surgery on release of soluble vascular endothelial growth factor (sVEGF) and the soluble inhibitory receptor (sVEGFR1) is unknown. The effect of major and minor surgery on variations in sVEGF and sVEGFR1 concentrations in vivo was studied, and on bacterial antigen...... concentrations in plasma changed during surgery. In vitro stimulation of blood samples with bacteria-derived antigens resulted in a significant increase in sVEGF (p Bacterial antigen-induced release of sVEGF correlated...... significantly with neutrophil cell counts (0.53 Bacterial antigen-induced sVEGFR1 release did not correlate with cell counts. CONCLUSIONS: Plasma sVEGF and sVEGFR1 concentrations did not change during surgery. In vitro bacterial stimulation led to increased release of sVEGF, which...

  7. A new impedimetric biosensor utilizing VEGF receptor-1 (Flt-1): early diagnosis of vascular endothelial growth factor in breast cancer.

    Science.gov (United States)

    Sezgintürk, Mustafa Kemal

    2011-06-15

    A new impedimetric biosensor, based on the use of vascular endothelial growth factor receptor-1 (VEGF-R1), was developed for the determination of vascular endothelial growth factor (VEGF). VEGF-R1 was immobilized through covalent coupling with 3-mercaptopropionic acid which formed a self-assembled monolayer on gold electrodes. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy techniques were employed to characterize the immobilization process and to detect VEGF. To successfully construct the biosensor current, experimental parameters were optimized. Kramers-Kronig Transform was performed on the experimental impedance data. The obtained results provided a linear response range from 10 to 70 pg/mL human VEGF. The applicability of the developed biosensor in the determination of VEGF in a spiked artificial human serum sample was experienced, yielding average recovery of 101%, in that order, with an average relative deviation value less than 5%. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Concentrations of VEGF and VEGFR1 in paired tumor arteries and veins in patients with rectal cancer

    DEFF Research Database (Denmark)

    Svendsen, Mads N; Lykke, Jakob; Werther, Kim

    2004-01-01

    a peripheral vein and intraoperative blood samples from a tumor artery, a tumor vein, and from a peripheral vein were drawn from 28 patients undergoing elective surgical resection of primary rectal cancer. Plasma concentrations of VEGF and VEGFR1 were determined by ELISA. Counts of white blood cells......Increased plasma concentrations of vascular endothelial growth factor (sVEGF) are associated with poor prognosis of colorectal cancer patients. The aim was to investigate the contribution of the tumor to plasma concentrations of VEGF and VEGF receptor 1 (VEGFR1). Preoperative blood samples from......VEGFR1 concentrations from preoperative to intraoperative samples was observed. There was a significant efflux of neutrophils to the tumor, but none of the observed changes in plasma VEGF or VEGFR1 levels correlated to changes in counts of white blood cells or platelets (sVEGF: 0.33

  9. A multimedia database system for thermal ablation therapy of brain tumors.

    Science.gov (United States)

    Dionisio, J D; Cárdenas, A F; Lufkin, R B; DeSalles, A; Black, K L; Taira, R K; Chu, W W

    1997-02-01

    A prototype multimedia medical database is described for supporting thermal ablation therapy of brain tumors. Its design is motivated by the major need to manage and access multimedia information on the progress and reaction of tumors to various therapy protocols. The database links images to patient data in a way that permits the use to view and query medical information using alphanumeric, temporal, and feature-based predicates. Visualization programs permit the user to view or annotate the query results in various ways. These results support the wide variety of data types and presentation methods required by neuroradiologists to manage thermal ablation therapy data. The database satisfactorily meets the requirements defined by thermal ablation therapy. A similar approach is being undertaken for supporting different therapies of other types of tumors, thus showing the generality of our approach.

  10. Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB

    Science.gov (United States)

    Banfi, Andrea; von Degenfeld, Georges; Gianni-Barrera, Roberto; Reginato, Silvia; Merchant, Milton J.; McDonald, Donald M.; Blau, Helen M.

    2012-01-01

    Therapeutic angiogenesis by delivery of vascular growth factors is an attractive strategy for treating debilitating occlusive vascular diseases, yet clinical trials have thus far failed to show efficacy. As a result, limb amputation remains a common outcome for muscle ischemia due to severe atherosclerotic disease, with an overall incidence of 100 per million people in the United States per year. A challenge has been that the angiogenic master regulator vascular endothelial growth factor (VEGF) induces dysfunctional vessels, if expressed outside of a narrow dosage window. We tested the hypothesis that codelivery of platelet-derived growth factor-BB (PDGF-BB), which recruits pericytes, could induce normal angiogenesis in skeletal muscle irrespective of VEGF levels. Coexpression of VEGF and PDGF-BB encoded by separate vectors in different cells or in the same cells only partially corrected aberrant angiogenesis. In marked contrast, coexpression of both factors in every cell at a fixed relative level via a single bicistronic vector led to robust, uniformly normal angiogenesis, even when VEGF expression was high and heterogeneous. Notably, in an ischemic hindlimb model, single-vector expression led to efficient growth of collateral arteries, revascularization, increased blood flow, and reduced tissue damage. Furthermore, these results were confirmed in a clinically applicable gene therapy approach by adenoviral-mediated delivery of the bicistronic vector. We conclude that coordinated expression of VEGF and PDGF-BB via a single vector constitutes a novel strategy for harnessing the potency of VEGF to induce safe and efficacious angiogenesis.—Banfi, A., von Degenfeld, G., Gianni-Barrera, R., Reginato, S., Merchant, M. J., McDonald, D. M., Blau, H. M. Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB. PMID:22391130

  11. Experimental Anterior Ischemic Optic Neuropathy in Diabetic Mice Exhibited Severe Retinal Swelling Associated With VEGF Elevation.

    Science.gov (United States)

    Sun, Ming-Hui; Shariati, Mohammad Ali; Liao, Yaping Joyce

    2017-04-01

    Diabetes mellitus (DM) is one of the most important risk factors for nonarteritic anterior ischemic optic neuropathy (AION). In this study, we investigated for the first time the impact of experimental AION in a DM model. We induced a photochemical thrombosis model of AION after streptozotocin-induced DM and performed serial optical coherence tomography (OCT), morphometric analyses, and VEGF levels in the retina and sera. Compared with non-DM animals, experimental AION in DM mice led to significantly greater retinal swelling on day 1 and worse thinning at week 3 on OCT measurements. Greater retinal swelling on OCT in DM-AION eyes was associated with significantly increased loss of brain-specific homeobox/POU domain protein 3A (Brn3A+) retinal ganglion cells at week 3. In acute AION, there was greater inflammation as seen by an increase in ionized calcium-binding adapter molecule 1 (Iba1+)-activated microglia. On day 1, there was increase in vascular endothelial growth factor (VEGF) level in nondiabetic AION retinae and sera, but the VEGF level was the highest in the diabetic AION group, which decreased to nondiabetic levels after insulin treatment. The decrease in retinal and serum VEGF levels after insulin treatment correlated with a reduction in retinal swelling. In the setting of hyperglycemia, AION led to greater acute, postischemic microglial activation and elevation of VEGF levels, which likely contributed to greater retinal swelling acutely and worse retinal thinning and loss of retinal ganglion cells chronically. Treatment of hyperglycemia with insulin reduced VEGF levels and retinal swelling, consistent with the idea that VEGF is an important factor in postischemic swelling and that good glycemic control following AION may lead to better visual outcome.

  12. Ultrastrong trapping of VEGF by graphene oxide: Anti-angiogenesis application.

    Science.gov (United States)

    Lai, Pei-Xin; Chen, Chung-Wein; Wei, Shih-Chun; Lin, Tzu-Yu; Jian, Hong-Jyuan; Lai, Irving Po-Jung; Mao, Ju-Yi; Hsu, Pang-Hung; Lin, Han-Jia; Tzou, Wen-Shyong; Chen, Shiow-Yi; Harroun, Scott G; Lai, Jui-Yang; Huang, Chih-Ching

    2016-12-01

    Angiogenesis is the process of formation of new blood vessels, which is essential to human biology, and also plays a crucial role in several pathologies such as tumor growth and metastasis, exudative age-related macular degeneration, and ischemia. Vascular endothelial growth factor (VEGF), in particular, VEGF-A165 is the most important pro-angiogenic factor for angiogenesis. Thus, blocking the interaction between VEGFs and their receptors is considered an effective anti-angiogenic strategy. We demonstrate for that first time that bovine serum albumin-capped graphene oxide (BSA-GO) exhibits high stability in physiological saline solution and possesses ultrastrong binding affinity towards VEGF-A165 [dissociation constant (Kd) ∼3 × 10-12 M], which is at least five orders of magnitude stronger than that of high-abundant plasma proteins such as human serum albumin, fibrinogen, transferrin, and immunoglobulin G. Due to the surprising binding specificity of BSA-GO for VEGF-A165 in complex plasma fluid, we have also studied the anti-angiogenic effects in vitro and in vivo. Results show that BSA-GO not only effectively inhibits the proliferation, migration and tube formation of human umbilical vein endothelial cells, but also strongly disturbs the physiological process of angiogenesis in chick chorioallantoic membrane and blocks VEGF-A165-induced blood vessel formation in rabbit corneal neovascularization. Our findings indicate that GO nanomaterials can potentially act as therapeutic anti-angiogenic agents via ultrastrong VEGF adsorption and its activity suppression. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. SERUM CONCENTRATIONS OF SOME ANGIOGENEIC FACTORS IN MULTIPLE MYELOMA: VEGF, bFGF IN MMP-9

    Directory of Open Access Journals (Sweden)

    Mojca Modic

    2004-12-01

    Full Text Available Background. Angiogenesis is a crucial process in progression of multiple myeloma. Vascular endothelial growth factor (VEGF, and basic fibroblast growth factor (bFGF are multifunctional cytokines that stimulate angiogenesis and myeloma growth. Matrix metalloproteinase 9 (MMP-9 plays a critical role in osteolytic bone destruction, angiogenesis and invasive growth of myeloma cells. We evaluated serum concentrations of these factors in patients with multiple myeloma.Methods. Levels of active and pro-matrix metalloproteinase 9 (total MMP-9, basic fibroblast growth factor (bFGF and vascular endothelial growth factor (VEGF were determined with a commercial quantitative enzyme immunoassay Quantikine  (R&D Systems, USA. All of these factors were measured in the serum obtained from pheripheral blood of 36 patients affected by multiple myeloma.This series included 12 patients with disease in plateau phase and without treatment, 14 patients on Thalidomide therapy and 10 patients at the beginning of chemotherapy because of active disease.Results. VEGF showed a strong correlation with MMP-9 while VEGF and bFGF did not correlate with each other. Blood platelets correlated with VEGF and MMP-9.The concentration of MMP-9 and VEGF were the highest in group of patients with active disease where the chemotherapy started. The level of bFGF was the lowest in the group devoid of treatment (plateau phase of disease.Conclusions. Production of the angiogenic factors such as VEGF, bFGF and MMP-9 are increased in multiple myeloma patients. The levels of these factors correlate with the activity of disease.

  14. Binding of VEGF-A to canine cancer cells with preferential expression of VEGFR1

    Directory of Open Access Journals (Sweden)

    Antonella Borgatti,

    2014-01-01

    Full Text Available Aim: Despite encouraging results in syngeneic and xenografts cancer models with various inhibitors of vascular endothelial growth factor (VEGF or its receptors (VEGFRs, beneficial effects have not been consistently translated to the clinic, underscoring the need to develop strategies that go beyond the inhibition of these targets. The purpose of this study was to generate data to support the hypothesis that VEGF may be used as “bait” to selectively deliver therapeutics to VEGFR-expressing cancer cells. Materials and Methods: VEGFR1 and VEGFR2 expression was characterized using real time quantitative reverse transcriptase polymerase chain reaction (RT-qPCR in canine hemangiosarcoma (Grace-HSA, Emma-HSA, melanoma (TLM-1, and thyroid adenocarcinoma (CTAC cell lines. TLM-1 and Grace-HSA were identified as representative cell lines that selectively expressed high levels of VEGFR1. Flow cytometry was performed to examine binding of a single VEGF molecule (biotinylated VEGFA and avidin conjugated to fluorescein isothiocyanate (FITC by these chemoresistant cell lines. Results: RT-qPCR showed that canine tumor cells can preferentially express VEGFR1 over VEGFR2. Both TLM-1 and Grace-HSA cell lines, which represent VEGFR1-expressing tumors, showed specific binding to VEGF-A and this binding was competitively inhibited by anti-VEGF antibody. Conclusions: Cells preferentially expressing VEGFR1 can be targeted with a single VEGF molecule and these ligand-receptor pairs are well suited for targeting cytotoxic molecules in various canine tumor cells. Further studies are needed to develop strategies to selectively deliver therapeutics through VEGF-VEGFRs binding into VEGFR-expressing tumors.

  15. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells.

    Science.gov (United States)

    Greenberger, Shoshana; Boscolo, Elisa; Adini, Irit; Mulliken, John B; Bischoff, Joyce

    2010-03-18

    Corticosteroids are commonly used to treat infantile hemangioma, but the mechanism of action of this therapy is unknown. We investigated the effect of corticosteroids in a previously described in vivo model of infantile hemangioma and in cultured hemangioma-derived cells. We tested hemangioma-derived stem cells for vasculogenic activity in vivo after implantation into immune-deficient (nude) mice. We studied dexamethasone treatment of both the cells before implantation and the mice after implantation. We also tested hemangioma-derived stem cells for expression of vascular endothelial growth factor A (VEGF-A) in vitro and studied the inhibition of VEGF-A expression, using short hairpin RNA (shRNA) in vivo and in vitro. Systemic treatment with dexamethasone led to dose-dependent inhibition of tumor vasculogenesis in the murine model. Pretreatment of hemangioma-derived stem cells in vitro before implantation also inhibited vasculogenesis. Dexamethasone suppressed VEGF-A production by hemangioma-derived stem cells in vitro but not by hemangioma-derived endothelial cells or human umbilical-vein endothelial cells. Silencing VEGF-A in hemangioma-derived stem cells reduced vasculogenesis in vivo. VEGF-A was detected in hemangioma specimens in the proliferating phase but not in the involuting phase and was shown by immunostaining to reside outside of vessels. Corticosteroid treatment suppressed other proangiogenic factors in hemangioma-derived stem cells, including urokinase plasminogen activator receptor, interleukin-6, monocyte chemoattractant protein 1, and matrix metalloproteinase 1. In a murine model, dexamethasone inhibited the vasculogenic potential of stem cells derived from human infantile hemangioma. The corticosteroid also inhibited the expression of VEGF-A by hemangioma-derived stem cells, and silencing of VEGF-A expression in these cells inhibited vasculogenesis in vivo. 2010 Massachusetts Medical Society

  16. Depth-profile investigations of triterpenoid varnishes by KrF excimer laser ablation and laser-induced breakdown spectroscopy

    Science.gov (United States)

    Theodorakopoulos, C.; Zafiropulos, V.

    2009-07-01

    The ablation properties of aged triterpenoid dammar and mastic films were investigated using a Krypton Fluoride excimer laser (248 nm, 25 ns). Ablation rate variations between surface and bulk layers indicated changes of the ablation mechanisms across the depth profiles of the films. In particular, after removal of the uppermost surface varnish layers there was a reduction of the ablation step in the bulk that was in line with a significant reduction of carbon dimer emission beneath the surface layers as detected by laser-induced breakdown spectroscopy. The results are explicable by the generation of condensation, cross-linking and oxidative gradients across the depth profile of triterpenoid varnish films during the aging degradation process, which were recently quantified and established on the molecular level.

  17. Local Electrical Dyssynchrony during Atrial Fibrillation: Theoretical Considerations and Initial Catheter Ablation Results.

    Directory of Open Access Journals (Sweden)

    Pawel Kuklik

    Full Text Available Electrogram-based identification of the regions maintaining persistent Atrial Fibrillation (AF is a subject of ongoing debate. Here, we explore the concept of local electrical dyssynchrony to identify AF drivers.Local electrical dyssynchrony was calculated using mean phase coherence. High-density epicardial mapping along with mathematical model were used to explore the link between local dyssynchrony and properties of wave conduction. High-density mapping showed a positive correlation between the dyssynchrony and number of fibrillatory waves (R2 = 0.68, p<0.001. In the mathematical model, virtual ablation at high dyssynchrony regions resulted in conduction regularization. The clinical study consisted of eighteen patients undergoing catheter ablation of persistent AF. High-density maps of left atrial (LA were constructed using a circular mapping catheter. After pulmonary vein isolation, regions with the top 10% of the highest dyssynchrony in LA were targeted during ablation and followed with ablation of complex atrial electrograms. Catheter ablation resulted in termination during ablation at high dyssynchrony regions in 7 (41% patients. In another 4 (24% patients, transient organization was observed. In 6 (35% there was no clear effect. Long-term follow-up showed 65% AF freedom at 1 year and 22% at 2 years.Local electrical dyssynchrony provides a reasonable estimator of regional AF complexity defined as the number of fibrillatory waves. Additionally, it points to regions of dynamical instability related with action potential alternans. However, despite those characteristics, its utility in guiding catheter ablation of AF is limited suggesting other factors are responsible for AF persistence.

  18. An increase in vascular endothelial growth factor (VEGF and VEGF soluble receptor-1 (sFlt-1 are associated with early recurrent spontaneous abortion.

    Directory of Open Access Journals (Sweden)

    Lihong Pang

    Full Text Available Recurrent spontaneous abortion (RSA is a health problem that affects approximately 1% to 5% reproductive age woman. Yet, in around half of these patients, the mechanism for RSA is unexplained. Recent studies have indicated that placental ischemia/hypoxia and endothelial dysfunction are important factors in miscarriage. Other studies have indicated that the level and expression of soluble FMS-like tyrosine kinase-1 (sFlt1 is increased under a hypoxic environment. However, decreased sFlt-1 in the maternal circulation during the first trimester has recently been proposed as a potential marker for identifying risk of pregnancy loss. In this prospective study clinical samples were obtained within a short time after the fetal death, protein expression and maternal serum levels of sFlt1 were assessed and compared to samples taken from those with normal pregnancies. Our results indicate that levels of VEGF and sFlt-1 are both increased in women during early pregnancy compared women that are not pregnant (p<0.05 indicating that VEGF and sFlt-1 are both associated with pregnancy. More importantly, we detected a significant (p<0.05 increase in sFlt1 and VEGF levels and expression in the RSA patients who suffered subsequent miscarriages compare to controls. These results demonstrate that there is likely a relationship between VEGF, sFlt-1 and RSA suggesting that the high levels and over expression of sFlt-1 and VEGF might be associated with the pathogenesis of RSA.

  19. Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164

    OpenAIRE

    Sacchi, Veronica; Mittermayr, Rainer; Hartinger, Joachim; Martino, Mikaël M.; Lorentz, Kristen M.; Wolbank, Susanne; Hofmann, Anna; Largo, Remo A.; Marschall, Jeffrey S.; Groppa, Elena; Gianni-Barrera, Roberto; Ehrbar, Martin; Hubbell, Jeffrey A.; Redl, Heinz; Banfi, Andrea

    2014-01-01

    Inducing the growth of new blood vessels by specific factors is an attractive strategy to restore blood flow in ischemic tissues. Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis, yet clinical trials of VEGF gene delivery failed. Major challenges include the need to control the tissue distribution of factor dose and the duration of expression. Here, we developed a highly tunable fibrin-based platform to precisely control the dose and duration of VEGF protein d...

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  3. Temperature-controlled irrigated tip radiofrequency catheter ablation

    DEFF Research Database (Denmark)

    Petersen, H H; Chen, X; Pietersen, Adrian

    1998-01-01

    INTRODUCTION: In patients with ventricular tachycardias due to structural heart disease, catheter ablation cures ... AND RESULTS: In vivo anesthetized pigs were ablated in the left ventricle. In vitro strips of porcine left ventricular myocardium were ablated in a tissue bath. Lesion volume was significantly larger after irrigated tip ablation both in vivo (544 +/- 218 vs 325 +/- 194 mm3, P

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. SLT-VEGF Reduces Lung Metastases, Decreases Tumor Recurrence, and Improves Survival in an Orthotopic Melanoma Model

    Directory of Open Access Journals (Sweden)

    Sini Skariah

    2010-08-01

    Full Text Available SLT-VEGF is a recombinant cytotoxin comprised of Shiga-like toxin (SLT subunit A fused to human vascular endothelial growth factor (VEGF. It is highly cytotoxic to tumor endothelial cells overexpressing VEGF receptor-2 (VEGFR-2/KDR/Flk1 and inhibits the growth of primary tumors in subcutaneous models of breast and prostate cancer and inhibits metastatic dissemination in orthotopic models of pancreatic cancer. We examined the efficacy of SLT-VEGF in limiting tumor growth and metastasis in an orthotopic melanoma model, using NCR athymic nude mice inoculated with highly metastatic Line IV Cl 1 cultured human melanoma cells. Twice weekly injections of SLT-VEGF were started when tumors became palpable at one week after intradermal injection of 1 × 106 cells/mouse. Despite selective depletion of VEGFR-2 overexpressing endothelial cells from the tumor vasculature, SLT-VEGF treatment did not affect tumor growth. However, after primary tumors were removed, continued SLT-VEGF treatment led to fewer tumor recurrences (p = 0.007, reduced the incidence of lung metastasis (p = 0.038, and improved survival (p = 0.002. These results suggest that SLT-VEGF is effective at the very early stages of tumor development, when selective killing of VEGFR-2 overexpressing endothelial cells can still prevent further progression. We hypothesize that SLT-VEGF could be a promising adjuvant therapy to inhibit or prevent outgrowth of metastatic foci after excision of aggressive primary melanoma lesions.

  7. MicroRNA-100 shuttled by mesenchymal stem cell-derived exosomes suppresses in vitro angiogenesis through modulating the mTOR/HIF-1α/VEGF signaling axis in breast cancer cells.

    Science.gov (United States)

    Pakravan, Katayoon; Babashah, Sadegh; Sadeghizadeh, Majid; Mowla, Seyed Javad; Mossahebi-Mohammadi, Majid; Ataei, Farangis; Dana, Nasim; Javan, Mohammad

    2017-10-01

    Human mesenchymal stem cells (MSCs) have been shown to be involved in the formation and modulation of tumor stroma and in interacting with tumor cells, partly through their secretome. Exosomes are nano-sized intraluminal multi-vesicular bodies secreted by most types of cells and have been found to mediate intercellular communication through the transfer of genetic information via coding and non-coding RNAs to recipient cells. Since exosomes are considered as protective and enriched sources of shuttle microRNAs (miRNAs), we hypothesized that exosomal transfer of miRNAs from MSCs may affect tumor cell behavior, particularly angiogenesis. Exosomes derived from MSCs were isolated and characterized by scanning electron microscopy analyses, dynamic light scattering measurements, and Western blotting. Fold changes in miR-100 expression levels were calculated in exosomes and their corresponding donor cells by qRT-PCR. The effects of exosomal transfer of miR-100 from MSCs were assessed by qRT-PCR and Western blotting of the mTOR/HIF-1α/VEGF signaling axis in breast cancer cells. The quantification of secreted VEGF protein was determined by enzyme-linked immunosorbent assay. The putative paracrine effects of MSC-derived exosomes on tumor angiogenesis were explored by in vitro angiogenesis assays including endothelial cell proliferation, migration and tube formation assays. We found that MSC-derived exosomes induce a significant and dose-dependent decrease in the expression and secretion of vascular endothelial growth factor (VEGF) through modulating the mTOR/HIF-1α signaling axis in breast cancer-derived cells. We also found that miR-100 is enriched in MSC-derived exosomes and that its transfer to breast cancer-derived cells is associated with the down-regulation of VEGF in a time-dependent manner. The putative role of exosomal miR-100 transfer in regulating VEGF expression was substantiated by the ability of anti-miR-100 to rescue the inhibitory effects of MSC

  8. Thermal protection system ablation sensor

    Science.gov (United States)

    Gorbunov, Sergey (Inventor); Martinez, Edward R. (Inventor); Scott, James B. (Inventor); Oishi, Tomomi (Inventor); Fu, Johnny (Inventor); Mach, Joseph G. (Inventor); Santos, Jose B. (Inventor)

    2011-01-01

    An isotherm sensor tracks space vehicle temperatures by a thermal protection system (TPS) material during vehicle re-entry as a function of time, and surface recession through calibration, calculation, analysis and exposed surface modeling. Sensor design includes: two resistive conductors, wound around a tube, with a first end of each conductor connected to a constant current source, and second ends electrically insulated from each other by a selected material that becomes an electrically conductive char at higher temperatures to thereby complete an electrical circuit. The sensor conductors become shorter as ablation proceeds and reduced resistance in the completed electrical circuit (proportional to conductor length) is continually monitored, using measured end-to-end voltage change or current in the circuit. Thermocouple and/or piezoelectric measurements provide consistency checks on local temperatures.

  9. Scandinavian links

    DEFF Research Database (Denmark)

    Matthiessen, Christian Wichmann; Knowles, Richard D.

    2014-01-01

    The European Round Table of Industrialists identified in the 1980ies 14 missing links in the transportation network of the continent. Three of them were found around the Danish island of Zealand. One link is within the nation, the other two are between nations. One link connects heavy economic....... They concentrate traffic flows and create strong transport corridors. They are the basis of new regional development regimes. “Ferries connect systems, fixed links unite systems”....

  10. IR laser ablation of dental enamel

    Science.gov (United States)

    Fried, Daniel

    2000-03-01

    An overview of the basic mechanisms of IR laser ablation of dental enamel is presented. Enamel is a highly structured tissue consisting of an heterogeneous distribution of water, mineral, protein and lipid. Absorption bands of water and carbonated hydroxyapatite can be selectively targeted from 2.7 to 11-micrometer via several laser wavelengths. Mechanistic differences in the nature of ablation and the varying surface morphology produced can be explained by the microstructure of the tissue. Suggested criteria for the choice of the optimum laser parameters for clinical use, the influence of plasma shielding and the role of exogenous water on the mechanism of ablation are discussed.

  11. Diamond Ablators for Inertial Confinement Fusion

    Energy Technology Data Exchange (ETDEWEB)

    Biener, J; Mirkarimi, P B; Tringe, J W; Baker, S L; Wang, Y M; Kucheyev, S O; Teslich, N E; Wu, K J; Hamza, A V; Wild, C; Woerner, E; Koidl, P; Bruehne, K; Fecht, H

    2005-06-21

    Diamond has a unique combination of physical properties for the inertial confinement fusion ablator application, such as appropriate optical properties, high atomic density, high yield strength, and high thermal conductivity. Here, we present a feasible concept to fabricate diamond ablator shells. The fabrication of diamond capsules is a multi-step process, which involves diamond chemical vapor deposition on silicon mandrels followed by polishing, microfabrication of holes, and removing of the silicon mandrel by an etch process. We also discuss the pros and cons of coarse-grained optical quality and nanocrystalline chemical vapor deposition diamond films for the ablator application.

  12. Anti-VEGF therapy in symptomatic peripheral exudative hemorrhagic chorioretinopathy (PEHCR) involving the macula.

    Science.gov (United States)

    Seibel, Ira; Hager, Annette; Duncker, Tobias; Riechardt, Aline I; Nürnberg, Daniela; Klein, Julian P; Rehak, Matus; Joussen, Antonia M

    2016-04-01

    The purpose of this study was to describe the anatomical and functional outcome of vascular endothelial growth factor inhibitor (anti-VEGF) treatment in symptomatic peripheral exudative hemorrhagic chorioretinopathy (PEHCR) involving the macula. Clinical records from patients seen between 2012 and 2013 at a single academic center were reviewed to identify PEHCR patients receiving anti-VEGF therapy due to disease-associated changes involving the macula. Affected eyes were either treated with consecutive intravitreal injections of anti-VEGF or vitrectomy combined with anti-VEGF followed by pro re nata injections. The mean age of the patients was 76 years (range 70-89 years). In all nine eyes, visual acuity was reduced due to central subretinal fluid. On average, three anti-VEGF injections (range 2-5 injections) were required initially to achieve complete resolution of macular subretinal fluid. In three eyes, subretinal fluid reappeared after an average of 10 months (range 5-16 months), and an average of 2.5 anti-VEGF injections (range 2-3 injections) were necessary to attain complete resolution of macular subretinal fluid a second time. Median visual acuity at the visit before the first injection was 1.0 logMAR (range 2.1-0.4 logMAR) and increased to 0.8 logMAR (range 2-0.1 logMAR) at the last visit. Results of this study show that for cases in which PEHCR becomes symptomatic due to macular involvement, anti-VEGF treatment may have drying potential. Although vision was improved in some patients, it remained limited in cases with long-term macular involvement, precluding any definitive functional conclusion. However, we believe that the use of anti-VEGF agents should be recommended in PEHCR that threatens the macula. Due to its often self-limiting course, peripheral lesions should be closely observed. Larger studies are needed in order to provide clear evidence of the efficacy of anti-VEGF therapy in PEHCR.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  14. Effects of Shuangdanmingmu capsule on retinal vascular morphology and VEGF expression in rats with diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    Yu-Hui Qin

    2015-01-01

    Full Text Available AIM: To observe the effects of Shuangdanmingmu capsule on VEGF expression and retinal vascular morphology in rats with diabetic retinopathy(DR. METHODS: DR rats were fed with Shuangdanmingmu capsule. By comparing with the normal group, the model control group, and positive control group, the effect of Shuangdanmingmu capsule on retinal tissue of DR rats was observed under electron microscopy. After HE staining, retinal structure was observed under the light microscope. Immunohitochemical staining was used to detect the VEGF expression in retina.RESULTS:Two months after treatment, the layers tissue of retina presented mild edema, capillary pericytes performed edema, mitochondria showed mild swelling and less clear structure, some endothelial cells showed slight proliferation in Shuangdanmingmu group. Compared with the normal group, the expression level of VEGF in retina increased in the other groups, especially in model control group. A significant differential in expression of VEGF was found between Shuangdanmingmu group, positive control group and model control group(PCONCLUSION: Shuangdanmingmu capsule can effectively improve the retinal microvascular, reduce edema and necrosis of each layer of retina, improve the ultrastructure of retina's tissue and inhibit VEGF expression in DR rats.

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

    Science.gov (United States)

    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.

  16. TNF-α-Induced VEGF and MMP-9 Expression Promotes Hemorrhagic Transformation in Pituitary Adenomas

    Directory of Open Access Journals (Sweden)

    Qin Liu

    2011-06-01

    Full Text Available Pituitary apoplexy is a clinical syndrome with unknown pathogenesis. Therefore, identifying the underlying mechanisms is of high clinical relevance. Tumor necrosis factor alpha (TNF-α is a critical cytokine mediating various hemorrhagic events, but little is known about its involvement in pituitary apoplexy. Here we show that TNF-α may be an important regulator of hemorrhagic transformation in pituitary adenomas. In this study, sixty surgical specimens of hemorrhagic and non-hemorrhagic human pituitary adenomas were examined. Hemorrhagic pituitary adenomas displayed higher protein and mRNA levels of TNF-α, vascular endothelial growth factor (VEGF and matrix metalloproteinase-9 (MMP-9 compared with those of non-hemorrhagic tumors. Exposure of MMQ pituitary adenoma cells to TNF-α induced VEGF and MMP-9 expression in vitro. Additionally, TNF-α administration caused hemorrhagic transformation and enhanced VEGF and MMP-9 expression in MMQ pituitary adenoma cell xenografts in mice. Blockers of VEGF or MMP-9, either alone or in combination, attenuated but not abrogated TNF-α mediated hemorrhagic transformation in xenografts. This study suggests that TNF-α may play a role in the development of intratumoral hemorrhage in pituitary adenomas via up-regulation of VEGF and MMP-9.

  17. Prediction of Anti-VEGF Response in Diabetic Macular Edema After 1 Injection.

    Science.gov (United States)

    Shah, Ankoor R; Yonekawa, Yoshihiro; Todorich, Bozho; Van Laere, Lily; Hussain, Rehan; Woodward, Maria A; Abbey, Ashkan M; Wolfe, Jeremy D

    2017-05-01

    With multiple anti-vascular endothelial growth factor and steroid therapies available for diabetic macular edema (DME), there is a need for early determination of the best treatment for a particular patient to prevent irreversible vision loss from chronic DME. In this study, we classify patients as responders or non-responders to anti-vascular endothelial growth factor (VEGF) monotherapy in the treatment of DME after a single anti-VEGF injection. The study was designed as a single center, retrospective, interventional case series. We included patients who received 3 consecutive monthly injections with the same anti-VEGF agent. We excluded patients who were treated for DME in the preceding 3 months with any form of anti-VEGF therapy. Visual acuity and central retinal thickness (CRT) data were followed for one year. Receiver operating characteristic (ROC) curve analysis was performed in order to identify cutoff values for identifying responders. 107 eyes were reviewed, with 40 eyes of 34 patients meeting all inclusion criteria. Based on ROC curve analysis, a reduction in CRT by > 15% at 1-month, identified eyes that responded to treatment and had a >25% reduction in CRT at 3-months (sensitivity 0.75, specificity 0.92). DME eyes that have early response to anti-VEGF treatment by reduction in CRT will have significant response to treatment by 3 months.

  18. Effects of finasteride on microvascular density and VEGF expression in glomeruli of diabetic mice

    Directory of Open Access Journals (Sweden)

    He-lin TIAN

    2013-01-01

    Full Text Available Objective  To investigate the effects of finasteride on microvascular density and vascular endothelial growth factor (VEGF expression in glomeruli of streptozotocin-induced diabetic mice. Methods  Diabetes was induced in mice with a single intraperitoneal injection of streptozotocin in a dose of 150mg/kg, and they were randomly divided into 4 groups (7 each: diabetic model group and 3 treatment groups (treated with 0.1, 1, 10mg/kg of finasteride, respectively. Seven normal mice served as control group. Animals in finasteride treatment groups were intragastrically administered with finasteride 0.1, 1 and 10mg/kg once daily for 4 weeks, respectively, and those in control and diabetic model group were given the same volume of normal saline at the same time. The kidney sections from all mice were stained with hematoxylin and eosin (HE for the pathological study, and immunohistochemistry methods were performed to detect the microvascular density, and VEGF expression in glomeruli. Results  Compared with control group, the glomerular area and volume, microvascular density and VEGF index were significantly increased in diabetic model and finasteride treated groups (P<0.05. However, the glomerular area and volume, microvessel density and VEGF index were significantly decreased in 10mg/kg finasteride treated group compared with that in diabetic model group (P<0.05. Conclusion  Finasteride can inhibit the VEGF expression and decrease the glomerular microvascular density in diabetic mice.

  19. Expression of VEGF and semaphorin genes define subgroups of triple negative breast cancer.

    Directory of Open Access Journals (Sweden)

    R Joseph Bender

    Full Text Available Triple negative breast cancers (TNBC are difficult to treat due to a lack of targets and heterogeneity. Inhibition of angiogenesis is a promising therapeutic strategy, but has had limited effectiveness so far in breast cancer. To quantify heterogeneity in angiogenesis-related gene expression in breast cancer, we focused on two families--VEGFs and semaphorins--that compete for neuropilin co-receptors on endothelial cells. We compiled microarray data for over 2,600 patient tumor samples and analyzed the expression of VEGF- and semaphorin-related ligands and receptors. We used principal component analysis to identify patterns of gene expression, and clustering to group samples according to these patterns. We used available survival data to determine whether these clusters had prognostic as well as therapeutic relevance. TNBC was highly associated with dysregulation of VEGF- and semaphorin-related genes; in particular, it appeared that expression of both VEGF and semaphorin genes were altered in a pro-angiogenesis direction. A pattern of high VEGFA expression with low expression of secreted semaphorins was associated with 60% of triple-negative breast tumors. While all TNBC groups demonstrated poor prognosis, this signature also correlated with lower 5-year survival rates in non-TNBC samples. A second TNBC pattern, including high VEGFC expression, was also identified. These pro-angiogenesis signatures may identify cancers that are more susceptible to VEGF inhibition.

  20. Calotropis procera root extracts block VEGF-induced angiogenesis: quantitative analysis.

    Science.gov (United States)

    Mathur, Rajani; Gupta, Suresh Kumar; Mathur, Sandeep Rajinder; Velpandian, Thirumurthy

    2011-01-01

    Angiogenesis is controlled by number of growth factors, including vascular endothelial growth factor (VEGF). Plant derived anti-angiogenic molecules acting via VEGF are being investigated for curtailing angiogenesis dependent diseases. In this study, methanolic (CM), n-hexane (CH), ethylacetate (CE) and water (CW) extracts of the roots of Calotropis procera were tested for anti-angiogenic activity. In the chicken egg chorioallantoic membrane (CAM) assay, CM, CH and CE but not CW inhibited VEGF-induced neovascularization in a dose-dependent manner. Of all the tested extracts, CM at the dose of 10, 5 and 2.5 ng most effectively inhibited over 83, 71 and 64%, of neovascularization induced by 10ng of VEGF, respectively. Sponge implantation assay in mice further showed that at the dose of 100ng CM, CH and CE but not CW significantly inhibited neovascularization induced by VEGF (100 ng). Taken together, this study indicates that the root extracts of C. procera may possess anti-angiogenic activity.

  1. DC electric stimulation upregulates angiogenic factors in endothelial cells through activation of VEGF receptors.

    Science.gov (United States)

    Bai, Huai; Forrester, John V; Zhao, Min

    2011-07-01

    Small direct current (DC) electric fields direct some important angiogenic responses of vascular endothelial cells. Those responses indicate promising use of electric fields to modulate angiogenesis. We sought to determine the regulation of electric fields on transcription and expression of a serial of import angiogenic factors by endothelial cells themselves. Using semi-quantitative PCR and ELISA we found that electric stimulation upregulates the levels of mRNAs and proteins of a number of angiogenic proteins, most importantly VEGF165, VEGF121 and IL-8 in human endothelial cells. The up-regulation of mRNA levels might be specific, as the mRNA encoding bFGF, TGF-beta and eNOS are not affected by DC electric stimulation at 24h time-point. Inhibition of VEGF receptor (VEGFR1 or VEGFR2) signaling significantly decreased VEGF production and completely abolished IL-8 production. DC electric stimulation selectively regulates production of some growth factors and cytokines important for angiogenesis through a feed-back loop mediated by VEGF receptors. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. PEDF and VEGF-A output from human retinal pigment epithelial cells grown on novel microcarriers.

    Science.gov (United States)

    Falk, Torsten; Congrove, Nicole R; Zhang, Shiling; McCourt, Alexander D; Sherman, Scott J; McKay, Brian S

    2012-01-01

    Human retinal pigment epithelial (hRPE) cells have been tested as a cell-based therapy for Parkinson's disease but will require additional study before further clinical trials can be planned. We now show that the long-term survival and neurotrophic potential of hRPE cells can be enhanced by the use of FDA-approved plastic-based microcarriers compared to a gelatin-based microcarrier as used in failed clinical trials. The hRPE cells grown on these plastic-based microcarriers display several important characteristics of hRPE found in vivo: (1) characteristic morphological features, (2) accumulation of melanin pigment, and (3) high levels of production of the neurotrophic factors pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor-A (VEGF-A). Growth of hRPE cells on plastic-based microcarriers led to sustained levels (>1 ng/ml) of PEDF and VEGF-A in conditioned media for two months. We also show that the expression of VEGF-A and PEDF is reciprocally regulated by activation of the GPR143 pathway. GPR143 is activated by L-DOPA (1 μM) which decreased VEGF-A secretion as opposed to the previously reported increase in PEDF secretion. The hRPE microcarriers are therefore novel candidate delivery systems for achieving long-term delivery of the neuroprotective factors PEDF and VEGF-A, which could have a value in neurodegenerative conditions such as Parkinson's disease.

  3. Low Molecular Weight Fucoidan Inhibits Tumor Angiogenesis through Downregulation of HIF-1/VEGF Signaling under Hypoxia

    Directory of Open Access Journals (Sweden)

    Meng-Chuan Chen

    2015-07-01

    Full Text Available Activation of hypoxia-induced hypoxia-inducible factors-1 (HIF-1 plays a critical role in promoting tumor angiogenesis, growth and metastasis. Low molecular weight fucoidan (LMWF is prepared from brown algae, and exhibits anticancer activity. However, whether LMWF attenuates hypoxia-induced angiogenesis in bladder cancer cells and the molecular mechanisms involved remain unclear. This is the first study to demonstrate that LMWF can inhibit hypoxia-stimulated H2O2 formation, HIF-1 accumulation and transcriptional activity vascular endothelial growth factor (VEGF secretion, and the migration and invasion in hypoxic human bladder cancer cells (T24 cells. LMWF also downregulated hypoxia-activated phosphorylation of PI3K/AKT/mTOR/p70S6K/4EBP-1 signaling in T24 cells. Blocking PI3K/AKT or mTOR activity strongly diminished hypoxia-induced HIF-1α expression and VEGF secretion in T24 cells, supporting the involvement of PI3K/AKT/mTOR in the induction of HIF-1α and VEGF. Additionally, LMWF significantly attenuated angiogenesis in vitro and in vivo evidenced by reduction of tube formation of hypoxic human umbilical vascular endothelial cells and blood capillary generation in the tumor. Similarly, administration of LMWF also inhibited the HIF-1α and VEGF expression in vivo, accompanied by a reduction of tumor growth. In summary, under hypoxia conditions, the antiangiogenic activity of LMWF in bladder cancer may be associated with suppressing HIF-1/VEGF-regulated signaling pathway.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Expression of VEGF and semaphorin genes define subgroups of triple negative breast cancer.

    Science.gov (United States)

    Bender, R Joseph; Mac Gabhann, Feilim

    2013-01-01

    Triple negative breast cancers (TNBC) are difficult to treat due to a lack of targets and heterogeneity. Inhibition of angiogenesis is a promising therapeutic strategy, but has had limited effectiveness so far in breast cancer. To quantify heterogeneity in angiogenesis-related gene expression in breast cancer, we focused on two families--VEGFs and semaphorins--that compete for neuropilin co-receptors on endothelial cells. We compiled microarray data for over 2,600 patient tumor samples and analyzed the expression of VEGF- and semaphorin-related ligands and receptors. We used principal component analysis to identify patterns of gene expression, and clustering to group samples according to these patterns. We used available survival data to determine whether these clusters had prognostic as well as therapeutic relevance. TNBC was highly associated with dysregulation of VEGF- and semaphorin-related genes; in particular, it appeared that expression of both VEGF and semaphorin genes were altered in a pro-angiogenesis direction. A pattern of high VEGFA expression with low expression of secreted semaphorins was associated with 60% of triple-negative breast tumors. While all TNBC groups demonstrated poor prognosis, this signature also correlated with lower 5-year survival rates in non-TNBC samples. A second TNBC pattern, including high VEGFC expression, was also identified. These pro-angiogenesis signatures may identify cancers that are more susceptible to VEGF inhibition.

  6. Femtosecond laser ablation of dentin and enamel: relationship between laser fluence and ablation efficiency.

    Science.gov (United States)

    Chen, Hu; Liu, Jing; Li, Hong; Ge, Wenqi; Sun, Yuchun; Wang, Yong; Lü, Peijun

    2015-02-01

    The objective was to study the relationship between laser fluence and ablation efficiency of a femtosecond laser with a Gaussian-shaped pulse used to ablate dentin and enamel for prosthodontic tooth preparation. A diode-pumped thin-disk femtosecond laser with wavelength of 1025 nm and pulse width of 400 fs was used for the ablation of dentin and enamel. The laser spot was guided in a line on the dentin and enamel surfaces to form a groove-shaped ablation zone under a series of laser pulse energies. The width and volume of the ablated line were measured under a three-dimensional confocal microscope to calculate the ablation efficiency. Ablation efficiency for dentin reached a maximum value of 0.020 mm3∕J when the laser fluence was set at 6.51 J∕cm2. For enamel, the maximum ablation efficiency was 0.009 mm3∕J at a fluence of 7.59 J∕cm2.Ablation efficiency of the femtosecond laser on dentin and enamel is closely related to the laser fluence and may reach a maximum when the laser fluence is set to an appropriate value. © 2015 Society of Photo-Optical Instrumentation Engineers (SPIE)

  7. Laser ablation in analytical chemistry - A review

    Energy Technology Data Exchange (ETDEWEB)

    Russo, Richard E.; Mao, Xianglei; Liu, Haichen; Gonzalez, Jhanis; Mao, Samuel S.

    2001-10-10

    Laser ablation is becoming a dominant technology for direct solid sampling in analytical chemistry. Laser ablation refers to the process in which an intense burst of energy delivered by a short laser pulse is used to sample (remove a portion of) a material. The advantages of laser ablation chemical analysis include direct characterization of solids, no chemical procedures for dissolution, reduced risk of contamination or sample loss, analysis of very small samples not separable for solution analysis, and determination of spatial distributions of elemental composition. This review describes recent research to understand and utilize laser ablation for direct solid sampling, with emphasis on sample introduction to an inductively coupled plasma (ICP). Current research related to contemporary experimental systems, calibration and optimization, and fractionation is discussed, with a summary of applications in several areas.

  8. Ablative Ceramic Foam Based TPS Project

    Data.gov (United States)

    National Aeronautics and Space Administration — A novel composite material ablative TPS for planetary vehicles that can survive a dual heating exposure is proposed. NextGen's TPS concept is a bi-layer functional...

  9. Thoracoscopic sympathectomy ganglia ablation in the management ...

    African Journals Online (AJOL)

    Thoracoscopic sympathectomy ganglia ablation in the management of palmer hyperhidrosis: A decade experience in a single institution. D Kravarusic, E Freud. Abstract. Background: Hyperhidrosis can cause significant professional and social handicaps. Surgery is the preferred treatment modality for hyperhidrosis.

  10. Pulmonary oligometastases : Metastasectomy or stereotactic ablative radiotherapy?

    NARCIS (Netherlands)

    Widder, Joachim; Klinkenberg, Theo J.; Ubbels, Jan F.; Wiegman, Erwin M.; Groen, Harry J. M.; Langendijk, Johannes A.

    Background and purpose: Stereotactic ablative radiotherapy (SABR; or stereotactic body radiotherapy, SBRT) emerges as treatment option for pulmonary oligometastatic disease (OMD), but there are no studies comparing SABR with pulmonary metastasectomy (PME). We analysed consecutive patients referred

  11. Thermal Ablation Modeling for Silicate Materials

    Science.gov (United States)

    Chen, Yih-Kanq

    2016-01-01

    A general thermal ablation model for silicates is proposed. The model includes the mass losses through the balance between evaporation and condensation, and through the moving molten layer driven by surface shear force and pressure gradient. This model can be applied in the ablation simulation of the meteoroid and the glassy ablator for spacecraft Thermal Protection Systems. Time-dependent axisymmetric computations are performed by coupling the fluid dynamics code, Data-Parallel Line Relaxation program, with the material response code, Two-dimensional Implicit Thermal Ablation simulation program, to predict the mass lost rates and shape change. The predicted mass loss rates will be compared with available data for model validation, and parametric studies will also be performed for meteoroid earth entry conditions.

  12. Lightweight Ablating Insulation for Ramjet Combustion

    National Research Council Canada - National Science Library

    Carter, Roy

    2002-01-01

    Parmax(trade name), a self reinforcing ultra-high performance polymer, was investigated as an ablative material in ramjet combustor applications, Phase I effort has demonstrated that Parmax(trade name...

  13. Simple spherical ablative-implosion model

    Energy Technology Data Exchange (ETDEWEB)

    Mayer, F.J.; Steele, J.T.; Larsen, J.T.

    1980-06-23

    A simple model of the ablative implosion of a high-aspect-ratio (shell radius to shell thickness ratio) spherical shell is described. The model is similar in spirit to Rosenbluth's snowplow model. The scaling of the implosion time was determined in terms of the ablation pressure and the shell parameters such as diameter, wall thickness, and shell density, and compared these to complete hydrodynamic code calculations. The energy transfer efficiency from ablation pressure to shell implosion kinetic energy was examined and found to be very efficient. It may be possible to attach a simple heat-transport calculation to our implosion model to describe the laser-driven ablation-implosion process. The model may be useful for determining other energy driven (e.g., ion beam) implosion scaling.

  14. Prognostic significance of cellular vascular endothelial growth factor (VEGF expression in the course of chronic myeloid leukaemia

    Directory of Open Access Journals (Sweden)

    Vidović Ana

    2009-01-01

    Full Text Available Introduction. Increased angiogenesis in bone marrow is one of the characteristics of chronic myeloid leukaemia (CML, a clonal myeloproliferative disorder that expresses a chimeric bcr/abl protein. Vascular endothelial growth factor (VEGF is one of the most potent and a specific regulator of angiogenesis which principally targets endothelial cells and regulates several of their functions, including mitogenesis, permeability and migration. The impact of elevated VEGF expression on the course of chronic myeloid leukaemia is unknown. Objective. The aim of this study was the follow-up of VEGF expression during the course of CML. Methods. We studied VEGF expression of 85 CML patients (median age 50 years, range 16-75 years. At the commencement of the study, 29 patients were in chronic phase (CP, 25 in an accelerated phase (AP, and 31 in the blast crisis (BC. The temporal expression (percentage positivity per 1000 analysed cells VEGF proteins over the course of CML were studied using the immunohistochemical technique utilizing relevant monoclonal antibodies. It was correlated with the laboratory (Hb, WBC and platelet counts, and the percentage of blasts and clinical parameters (organomegaly, duration of CP, AP, and BC of disease progression. Results. The expression of VEGF protein was most pronounced in AP (ANOVA, p=0.033. The level of VEGF expression correlated inversely with the degree of splenomegaly (Pearson, r=-0.400, p=0.011. High expression of VEGF correlated with a shorter overall survival (log rank, p=0.042. Conclusion. Immunohistochemically confirmed significance of the expression of VEGF in dependence of the CML stage could be of clinical importance in deciding on the timing therapy. These data suggest that VEGF plays a role in the biology of CML and that VEGF inhibitors should be investigated in CML.

  15. Diagnostics of laser ablated plasma plumes

    DEFF Research Database (Denmark)

    Amoruso, S.; Toftmann, B.; Schou, Jørgen

    2004-01-01

    The effect of an ambient gas on the expansion dynamics of laser ablated plasmas has been studied for two systems by exploiting different diagnostic techniques. First, the dynamics of a MgB2 laser produced plasma plume in an Ar atmosphere has been investigated by space-and time-resolved optical...... of the laser ablated plasma plume propagation in a background gas. (C) 2003 Elsevier B.V All rights reserved....

  16. ROLE OF RADIOFREQUENCY ABLATION IN ADENOMA SEBACEUM

    Directory of Open Access Journals (Sweden)

    Ch. Madh

    2016-03-01

    Full Text Available Adenoma sebaceum, pathognomonic of tuberous sclerosis, are tiny angiofibromas which commonly occur over central part of face. Recurrence after treatment is common and hence a need for inexpensive, safe and efficient treatment is required. Radiofrequency ablation is a safe and an economical procedure and has been known to cause less scarring with good aesthetic results compared to other ablative methods such as electrocautery.

  17. Fructose diet and VEGF-induced plasma extravasation in hamster cheek pouch.

    Science.gov (United States)

    Félétou, Michel; Boulanger, Michelle; Staczek, Joanna; Broux, Olivier; Duhault, Jacques

    2003-03-01

    To determine in the hamster cheek pouch whether or not the changes in plasma extravasation induced by vascular endothelial growth factor (VEGF) could be affected by fructose diet. Hamsters were subjected to control drinking water or to water containing fructose (10 %) for 18 weeks. The fructose diet induced a small but significant increase in glycemia (0.80+/-0.11 and 1.09+/-0.15, n=8 and 9 for control and fructose- treated animals, respectively, Pdiet while the effects of VEGF were markedly increased (maximal number of leakage sites: 76+/-20 and 126+/-55, n = 8 and 9 for control and fructose-treated animals, respectively, P<0.01). Even moderate changes in glycemic levels can produce profound alteration in the VEGF response.

  18. Increased serum levels of sortilin are associated with depression and correlated with BDNF and VEGF

    DEFF Research Database (Denmark)

    Buttenschøn, Henriette Nørmølle; Demontis, Ditte; Ollendorff, Mathias Kaas

    2015-01-01

    measured by immunoassay, and potential determinants of the serum sortilin level were assessed by generalized linear models. Serum levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were measured in previous studies. We identified a significant increase of serum...... sortilin levels in depressed individuals compared with controls (P = 0.0002) and significant positive correlation between serum sortilin levels and the corresponding levels of BDNF and VEGF. None of the genotyped SNPs were associated with depression. Additional analyses showed that the serum sortilin level...... was influenced by several other factors. Alcohol intake and body mass index, as well as depression, serum BDNF and serum VEGF were identified as predictors of serum sortilin levels in our final multivariate model. In conclusion, the results suggest a role of circulating sortilin in depression which may relate...

  19. 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

    . Material and methods: We immunostained whole tumor sections for VEGF-A, -B, and VEGFR-1 of invasive ductal carcinomas of the breast and scored the tumors manually by staining intensity as the only parameter and by a combination of qualitative and quantitative staining information. We also introduced...... 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...

  20. 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

    whole tumor sections for VEGF-A, -B, and VEGFR-1 of invasive ductal carcinomas of the breast and scored the tumors manually with staining intensity as the only parameter and by a combination of qualitative and quantitative information. We also introduce 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. We found that the AI scores were correlated to the manual scoring of VEGF intensity, but reproducibility of manual IHC scores was rather poor. The AI scores were reproducible and the restricted analysis of 25% of the tumor area at 5x magnifications was the most efficient...

  1. Water extract of Cinnamomum cassia suppresses angiogenesis through inhibition of VEGF receptor 2 phosphorylation.

    Science.gov (United States)

    Kim, Eok-Cheon; Kim, Hye Jin; Kim, Tack-Joong

    2015-01-01

    Angiogenesis, the process of new blood vessel formation, has been a major target for cancer therapy. Antiangiogenic herbal medicines are useful in the treatment of cancer. In this study, we found that a water extract of Cinnamomum cassia (CCWE) was a potent inhibitor of angiogenesis. In cultured human umbilical vein endothelial cells, CCWE suppressed vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, tube formation, and intracellular signaling events such as phosphorylation of ERK, p38 and VEGFR2, and activation of matrix metalloproteinase. Furthermore, CCWE inhibited VEGF-induced vessel sprouting of rat aorta ex vivo. These findings might be of particular interest for drug development because VEGF signaling is a potential target for treatment of angiogenesis-associated diseases.

  2. A positive circuit of VEGF increases Glut-1 expression by increasing HIF-1α gene expression in human retinal endothelial cells.

    Science.gov (United States)

    Choi, Yoon Kyung

    2017-12-01

    Treatment of human retinal microvascular endothelial cells (HRMECs) with vascular endothelial growth factor 165 (VEGF 165 ) increased hypoxia-inducible factor 1α (HIF-1α), VEGF, and glucose transporter 1 (Glut-1) mRNA expression and Glut-1 protein localization to the membrane. In contrast, treatment of human retinal pigment epithelium cells with VEGF 165 did not induce HIF-1α, VEGF, and Glut-1 gene expression. Microvascular endothelial cells are surrounded by astrocytic end feet in the retina. Astrocyte-derived A-kinase anchor protein 12 overexpression during hypoxia downregulated VEGF secretion, and this conditioned medium reduced VEGF and Glut-1 expression in HRMECs, suggesting that communications between astrocytes and endothelial cells may be the determinants of the blood vessel network. In HRMECs, HIF-1α small interfering RNA transfection blocked the VEGF 165 -mediated increase in VEGF and Glut-1 gene expression. Inhibition of protein kinase C (PKC) with inhibitor GF109203X or with a small interfering RNA targeting PKCζ attenuated the VEGF 165 -induced Glut-1 protein expression and VEGF and Glut-1 mRNA expression. In addition, results of an immunoprecipitation assay imply an interaction between VEGF receptor 2 (VEGFR2) and PKCζ in HRMECs. Therefore, VEGF secretion by hypoxic astrocytes may upregulate HIF-1α gene expression, inducing VEGF and Glut-1 expression via the VEGFR2-PKCζ axis in HRMECs.

  3. Laser Ablation for Small Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Claudio Maurizio Pacella

    2011-01-01

    Full Text Available Hepatocellular carcinoma (HCC is one of the most common malignancies worldwide and is increasingly detected at small size (<5 cm owing to surveillance programmes in high-risk patients. For these cases, curative therapies such as resection, liver transplantation, or percutaneous ablation have been proposed. When surgical options are precluded, image-guided tumor ablation is recommended as the most appropriate therapeutic choice in terms of tumor local control, safety, and improvement in survival. Laser ablation (LA represents one of currently available loco-ablative techniques: light is delivered via flexible quartz fibers of diameter from 300 to 600 μm inserted into tumor lesion through either fine needles (21g Chiba needles or large-bore catheters. The thermal destruction of tissue is achieved through conversion of absorbed light (usually infrared into heat. A range of different imaging modalities have been used to guide percutaneous laser ablation, but ultrasound and magnetic resonance imaging are most widely employed, according to local experience and resource availability. Available clinical data suggest that LA is highly effective in terms of tumoricidal capability with an excellent safety profile; the best results in terms of long-term survival are obtained in early HCC so that LA can be proposed not only in unresectable cases but, not differently from radiofrequency ablation, also as the first-line treatment.

  4. Femtosecond Laser Ablation: Fundamentals and Applications

    Science.gov (United States)

    Harilal, Sivanandan S.; Freeman, Justin R.; Diwakar, Prasoon K.; Hassanein, Ahmed

    Traditionally nanosecond laser pulses have been used for Laser-induced Breakdown Spectroscopy (LIBS) for quantitative and qualitative analysis of the samples. Laser produced plasmas using nanosecond laser pulses have been studied extensively since 1960s. With the advent of short and ultrashort laser pulses, there has been a growing interest in the applications of femtosecond and picosecond lasers for analysis of materials using LIBS and LA-ICP-MS. The fundamentals of laser ablation process using ultrashort laser pulses are not still fully understood. Pulse duration of femtosecond laser pulse is shorter than electron-to-ion energy transfer time and heat conduction time in the sample lattice. This results in different laser ablation and heat dissipation mechanisms as compared to nanosecond laser ablation. In this chapter, the focus will be on understanding the basics of femtosecond laser ablation processes including laser target interaction, ablation efficiency, ablation threshold, laser plasma interactions, and plume hydrodynamics. Analytical figures of merit will be discussed in contrast to nanosecond LIBS.

  5. Shielding by the ablation plume during Er:YAG laser ablation

    Science.gov (United States)

    Nahen, Kester; Vogel, Alfred

    2001-07-01

    Free running Er:YAG lasers are used for a precise tissue ablation in various clinical application as, for example, laser skin resurfacing. The ablated material is ejected from the tissue surface in the direction of the incident laser beam. We investigated the influence of the shielding by the ablation plume on the energy deposition into the irradiated sample because it influences the ablation dynamics and the amount of ablated material. The shielding was investigated for gelatin with different water content, skin and water. Laser flash photography combined with a dark field Schlieren technique was used to visualize the gaseous and liquid ablation products. The distance traveled by the ablating laser beam through the ablation plume was evaluated from the photographs for various times after the beginning of the laser pulse. The temporal evolution of the transmission through the ablation plume was probed using a second free running Er:YAG laser beam directed parallel to the sample surface. The ablation dynamics shows two phases: Vaporization and material ejection. The photographic observations give evidence for a phase explosion to be the driving mechanism for the material ejection. The photographic observations give evidence for a phase explosion to be the driving mechanism for the material ejection. The transmission is only slightly reduced by the vapor plume, but it decreases by 25-50% when the ejected material passes the probe beam. The laser energy deposited into the sample amounts to only 61% of the incident energy for gelatin samples with 90% water content and 86% for skin samples. The shielding must therefore be considered in modeling the ablation dynamics and determining the dosage for clinical applications.

  6. The response of VEGF-stimulated endothelial cells to angiostatic molecules is substrate-dependent

    Directory of Open Access Journals (Sweden)

    Polverini Peter J

    2005-10-01

    Full Text Available Abstract Background The microenvironment surrounding cells can exert multiple effects on their biological responses. In particular the extracellular matrix surrounding cells can profoundly influence their behavior. It has been shown that the extracellular matrix composition in tumors is vastly different than that found in normal tissue with increased amounts of certain matrices such as collagen I. It has been previously demonstrated that VEGF stimulation of endothelial cells growing on type I collagen results in the induction of bcl-2 expression and enhanced endothelial cell survival. We sought to investigate whether this increased endothelial cell survival resulted in the failure of angiostatic molecules to inhibit angiogenesis. Results We now demonstrate that VEGF-induced survival on collagen I impairs the ability of three known angiostatic molecules, TSP-1, IP-10 and endostatin to inhibit endothelial cell proliferation. Apoptosis of endothelial cells, growing on collagen I, induced by TSP-1 and IP-10 was also inhibited following VEGF stimulation. In contrast, endostatin induced apoptosis in these same cells. Further analysis determined that endostatin did not decrease the expression of bcl-2 nor did it increase activation of caspase-3 in the presence of VEGF. Alternatively, it appeared that in the presence of VEGF, endostatin induced the activation of caspase-8 in endothelial cells grown on collagen I. Furthermore, only endostatin had the ability to inhibit VEGF-induced sprout formation in collagen I gels. Conclusion These data suggest that TSP-1, IP-10 and endostatin inhibit endothelial cells via different mechanisms and that only endostatin is effective in inhibiting angiogenic activities in the presence of collagen I. Our results suggest that the efficacy of angiostatic treatments may be impaired depending on the context of the extracellular matrix within the tumor environment and thus could impede the efficacy of angiostatic therapies.

  7. PDGF-BB/KLF4/VEGF Signaling Axis in Pulmonary Artery Endothelial Cell Angiogenesis.

    Science.gov (United States)

    Liang, Songhe; Yu, Hao; Chen, Xinxin; Shen, Tingting; Cui, Zhongqi; Si, Genle; Zhang, JunTing; Cheng, Yue; Jia, Shiwei; Song, Shasha; Zhang, Xiang; Yu, Xiufeng

    2017-01-01

    Accumulating evidence suggests that platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor(VEGF) play a role in the progression of pulmonary arterial hypertension (PAH).Since chronic hypoxia is responsible for intimal hyperplasia and disordered angiogenesis of pulmonary arteries, which are histological hallmarks of PAH, we explored the role of the PDGF-BB/KLF4/VEGF signaling axis in the angiogenesis of pulmonary artery endothelial cells (PAECs). Adult male Wistar rats were used to study hypoxia-induced or monocrotaline (MCT)-induced right ventricular (RV) remodeling as well as systolic function and hemodynamics using echocardiography and a pressure-volume admittance catheter. Morphometric analyses of lung vasculature and RV vessels were performed. The results revealed that both the PDGF receptor-tyrosine kinase inhibitor imatinib and the multi-targeted VEGF and PDGF receptor inhibit or sunitinib malate reversed hypoxia-induced increases in right ventricular systolic pressure (RVSP), right ventricular function and thickening of the medial walls. Mechanistically VEGF/VEGFR and PDGF/PDGFR formed a biological complex. We also showed that PDGF-BBincreasedKLF4 promoter activity transcriptionally activating VEGF expression, which regulates PAEC proliferation; migration; and the cell-cycle transition from G0/G1phase to S phase and G2/M-phase and eventually leads to PAEC angiogenesis Conclusion: Our study indicates that hypoxia-induced angiogenesis of PAECs is associated with increased levels of PDGF-BB/KLF4/VEGF, which contribute to pulmonary vascular remodeling. Overall, our study contributes to a better understanding of PAH pathogenesis. © 2017 The Author(s). Published by S. Karger AG, Basel.

  8. Angiogenetic axis angiopoietins/Tie2 and VEGF in familial breast cancer.

    Science.gov (United States)

    Danza, K; Pilato, B; Lacalamita, R; Addati, T; Giotta, F; Bruno, A; Paradiso, A; Tommasi, S

    2013-08-01

    Angiogenesis leads to the formation of blood vessels from pre-existing ones, allowing tumor growth. Vascular endothelial growth factor (VEGF) and Angiopoietins (Ang-1, Ang-2) have a pivotal role in tumor angiogenesis but few data regarding their role in hereditary breast cancer are available. The aim of the present study was to analyze Ang-1, Ang-2, tyrosine-protein kinase receptor Tie2 and VEGF expression and their correlation in a cohort of familial and sporadic breast cancers in order to verify whether the presence of germline mutations in BRCA may have a role in tumor microenvironment regulation. Tumor samples from a cohort of 41 patients with a first diagnosis and a family history of breast cancer and 19 patients with sporadic breast cancers were enrolled. The expression of Tie2, Ang-1, Ang-2 and VEGF were analyzed by quantitative real-time PCR. Patients harboring BRCA mutations had higher levels of Ang-1 (P=0.05), Ang-2 (P=0.02) and VEGF (P=0.04) mRNA compared with those without BRCA mutations (BRCAX). The same was observed in triple-negative breast cancer (TNBC). Moreover, a positive correlation between Ang-2 and VEGF was found in both the familial breast cancer group (BRCA carriers: r=0.83; P<0.0001 and BRCAX: r=0.58; P=0.008) and in TNBC (r=0.62; P=0.007). The higher levels of Ang-1, Ang-2 and VEGF mRNA found in BRCA carriers and TNBCs suggest that they could be attractive angiogenic therapeutic targets in these breast cancers.

  9. Outer retinal tubulation in diabetic macular edema following anti-VEGF treatment.

    Science.gov (United States)

    Al-Halafi, Ali M

    2015-01-01

    To address the presence and features of outer retinal tubulation (ORT) found in diabetic macular edema (DME) treated with anti-vascular endothelial growth factor (anti-VEGF) and to differentiate between ORT and cystoid DME, which have different plans of management. This was a retrospective review of a total of 514 patients investigated with spectral domain optical coherence tomography (OCT) in patients with diabetic macular edema treated with anti-VEGF. ORT was seen in 12 eyes of 11 patients. The morphologic characteristics of ORT and its progress over time were examined using OCT data. The retinal images were obtained by horizontal and vertical scans to analyze the possible presence of ORT and to explore their morphologic features and location in the retinal layers. ORT was seen in DME treated with anti-VEGF. ORT was shown as round or ovoid hyporeflective spaces with hyperreflective borders on the B-scans, measuring 30 to 120 μm high and 30 to 1775 μm wide. The tubules generally remained stable over time. In a retinal practice specializing in advanced diabetic retinopathy clinic, this ORT was seen in 12 eyes of 11 patients during a 12-month period. ORT presented either after receiving 0.05 mL open-label intravitreal injections of 0.5 mg ranibizumab or 1.25 mg bevacizumab. ORT is found in DME treated with anti-VEGF that may show damage to the outer retina secondary to the severity and chronicity of the DME. ORT may be a result of underlying chronic and severe diabetic macular edema that may occur later possibly secondary to retinal layers rearrangement after several anti-VEGF injections. It is important to differentiate between ORT and cystoids DME. The presence of the ORT entity alone without the presence of DME does not require further anti-VEGF re-injections.

  10. Association of mast cell-derived VEGF and proteases in Dengue shock syndrome.

    Directory of Open Access Journals (Sweden)

    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.

  11. 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.

  12. P70S6K 1 regulation of angiogenesis through VEGF and HIF-1{alpha} expression

    Energy Technology Data Exchange (ETDEWEB)

    Bian, Chuan-Xiu; Shi, Zhumei [Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing 210029 (China); Meng, Qiao; Jiang, Yue; Liu, Ling-Zhi [Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107 (United States); Jiang, Bing-Hua, E-mail: binghjiang@yahoo.com [Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing 210029 (China); Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107 (United States)

    2010-07-30

    Research highlights: {yields} P70S6K1 regulates VEGF expression; {yields} P70S6K1 induces transcriptional activation through HIF-1{alpha} binding site; {yields} P70S6K1 regulates HIF-1{alpha}, but not HIF-1{beta} protein expression; {yields} P70S6K1 mediates tumor growth and angiogenesis through HIF-1{alpha} and VEGF expression. -- Abstract: The 70 kDa ribosomal S6 kinase 1 (p70S6K1), a downstream target of phosphoinositide 3-kinase (PI3K) and ERK mitogen-activated protein kinase (MAPK), is an important regulator of cell cycle progression, and cell proliferation. Recent studies indicated an important role of p70S6K1 in PTEN-negative and AKT-overexpressing tumors. However, the mechanism of p70S6K1 in tumor angiogenesis remains to be elucidated. In this study, we specifically inhibited p70S6K1 activity in ovarian cancer cells using vector-based small interfering RNA (siRNA) against p70S6K1. We found that knockdown of p70S6K1 significantly decreased VEGF protein expression and VEGF transcriptional activation through the HIF-1{alpha} binding site at its enhancer region. The expression of p70S6K1 siRNA specifically inhibited HIF-1{alpha}, but not HIF-1{beta} protein expression. We also found that p70S6K1 down-regulation inhibited ovarian tumor growth and angiogenesis, and decreased cell proliferation and levels of VEGF and HIF-1{alpha} expression in tumor tissues. Our results suggest that p70S6K1 is required for tumor growth and angiogenesis through HIF-1{alpha} and VEGF expression, providing a molecular mechanism of human ovarian cancer mediated by p70S6K1 signaling.

  13. Expressions and clinical significance of COX-2, VEGF-C, and EFGR in endometrial carcinoma.

    Science.gov (United States)

    Cai, Shengnan; Zhang, Yue-Xiang; Han, Ke; Ding, Yi-Qian

    2017-07-01

    The article is to study the expressions of COX-2, VEGF-C, and EGFR in endometrial carcinoma as well as its clinical significances. Clinical data of 183 patients with endometrial carcinoma who received surgery as initial treatment in the Nanjing Drum Tower Hospital Affiliated to the Nanjing University Medical School and the Nantong Maternal and Child Health Hospital Affiliated to the Nantong University from January 2005 to December 2010 were retrospectively investigated; 152 out of the 183 patients were closely followed up. Expressions of COX-2, VEGF-C, and EGFR proteins in 152 endometrial carcinoma samples were detected by immunohistochemical S-P assay. A 5-year survival rate of 152 patients was 81.56% (124/152). Positive COX-2 expression rate was 67.76% (103/152), and its positive expression was related to FIGO stage, differentiation degree, and myometrial invasion depth of patients (P  0.05). Positive expression rates of VEGF-C and EGFR were 64.47% (98/152) and 82.24% (125/152), respectively, and their positive expression was associated with FIGO stage, differentiation degree, myometrial invasion depth, and lymphatic metastasis (P  0). Patient prognosis was associated with the FIGO stage, differentiation degree, and myometrial invasion depth of tumors, as well as the presence or absence of lymph node metastasis (P  0.05). COX-2, VEGF-C, and EGFR are of significance for determining the FIGO stage, differentiation degree, and myometrial invasion depth of endometrial carcinoma, of which VEGF-C and EGFR are important in determining whether tumors metastasize to lymph nodes. Combined detection of COX-2, EGFR, and VEGF-C can be used as the indices for early diagnosis, recurrence prediction, and outcome evaluation for patients with endometrial carcinoma.

  14. The association between vascular endothelial growth factor (VEGF) +405G>C genetic polymorphism and endometriosis.

    Science.gov (United States)

    Fang, Fang; Gong, Lili; Wang, Xiaojuan; Zhang, Ling

    2015-09-01

    The vascular endothelial growth factor (VEGF) is one of the most important candidate genes for the development of endometriosis, and VEGF genetic polymorphisms might be potentially associated with endometriosis risk. However, the results still remain controversial. The objective of this study aimed to perform a comprehensive meta-analysis to explore a better understanding of the effects of VEGF +405G>C genetic polymorphism on the risk of endometriosis. A total of eleven eligible studies were eventually identified in this meta-analysis, including 2829 endometriosis cases and 2947 controls. In the overall analysis, no significant association between the VEGF +405G>C genetic polymorphism and the risk of endometriosis was detected in all genetic models (for homozygote comparison [CC versus vs. GG]: OR = 1.21, 95% CI 0.67-2.19, P = 0.537; for heterozygote comparison [CG vs. GG]: OR = 1.16, 95% CI 0.86-1.56, P = 0.348; for dominant comparison CC/CG vs. GG: OR = 1.10, 95% CI 0.93-1.30, P = 0.263; for recessive comparison [CC vs. CG/GG]: OR = 1.03, 95% CI 0.73-1.47, P = 0.857; allele comparison [C vs. G]: OR = 0.99, 95% CI 0.70-1.40, P = 0.962). In the subgroup analysis by ethnicities, there was no significant association between VEGF +405G>C genetic polymorphism and endometriosis risk in Asians and/or Caucasians under all genetic models (all P-values >0.05). No publication bias was observed in this study. This meta-analysis supports that the VEGF +405G>C genetic polymorphism is not significant associated with the risk of endometriosis. © 2015 by the Society for Experimental Biology and Medicine.

  15. Upregulation of CREM/ICER suppresses wound endothelial CRE-HIF-1α-VEGF-dependent signaling and impairs angiogenesis in type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Milad S. Bitar

    2015-01-01

    Full Text Available Impaired angiogenesis and endothelial dysfunction in type 2 diabetes constitute dominant risk factors for non-healing wounds and most forms of cardiovascular disease. We propose that diabetes shifts the ‘angiogenic balance’ in favor of an excessive anti-angiogenic phenotype. Herein, we report that diabetes impairs in vivo sponge angiogenic capacity by decreasing VEGF expression and fibrovascular invasion, and reciprocally enhances the formation of angiostatic molecules, such as thrombospondins, NFκB and FasL. Defective in vivo angiogenesis prompted cellular studies in cultured endothelial cells derived from subcutaneous sponge implants (SIECs of control and Goto-Kakizaki rats. Ensuing data from diabetic SIECs demonstrated a marked upregulation in cAMP-PKA-CREB signaling, possibly stemming from increased expression of adenylyl cyclase isoforms 3 and 8, and decreased expression of PDE3. Mechanistically, we found that oxidative stress and PKA activation in diabetes enhanced CREM/ICER expression. This reduces IRS2 cellular content by inhibiting cAMP response element (CRE transcriptional activity. Consequently, a decrease in the activity of Akt-mTOR ensued with a concomitant reduction in the total and nuclear protein levels of HIF-1α. Limiting HIF-1α availability for the specific hypoxia response elements in diabetic SIECs elicited a marked reduction in VEGF expression, both at the mRNA and protein levels. These molecular abnormalities were illustrated functionally by a defect in various pro-angiogenic properties, including cell proliferation, migration and tube formation. A genetic-based strategy in diabetic SIECs using siRNAs against CREM/ICER significantly augmented the PKA-dependent VEGF expression. To this end, the current data identify the importance of CREM/ICER as a negative regulator of endothelial function and establish a link between CREM/ICER overexpression and impaired angiogenesis during the course of diabetes. Moreover, it could

  16. Thermal Ablation of Colorectal Lung Metastases: Retrospective Comparison Among Laser-Induced Thermotherapy, Radiofrequency Ablation, and Microwave Ablation.

    Science.gov (United States)

    Vogl, Thomas J; Eckert, Romina; Naguib, Nagy N N; Beeres, Martin; Gruber-Rouh, Tatjana; Nour-Eldin, Nour-Eldin A

    2016-12-01

    The purpose of this study is to retrospectively evaluate local tumor control, time to tumor progression, and survival rates among patients with lung metastatic colorectal cancer who have undergone ablation therapy performed using laser-induced thermotherapy (LITT), radiofrequency ablation (RFA), or microwave ablation (MWA). Data for this retrospective study were collected from 231 CT-guided ablation sessions performed for 109 patients (71 men and 38 women; mean [± SD] age, 68.6 ± 11.2 years; range, 34-94 years) from May 2000 to May 2014. Twenty-one patients underwent LITT (31 ablations), 41 patients underwent RFA (75 ablations), and 47 patients underwent MWA (125 ablations). CT scans were acquired 24 hours after each therapy session and at follow-up visits occurring at 3, 6, 12, 18, and 24 months after ablation. Survival rates were calculated from the time of the first ablation session, with the use of Kaplan-Meier and log-rank tests. Changes in the volume of the ablated lesions were measured using the Kruskal-Wallis method. Local tumor control was achieved in 17 of 25 lesions (68.0%) treated with LITT, 45 of 65 lesions (69.2%) treated with RFA, and 91 of 103 lesions (88.3%) treated with MWA. Statistically significant differences were noted when MWA was compared with LITT at 18 months after ablation (p = 0.01) and when MWA was compared with RFA at 6 months (p = 0.004) and 18 months (p = 0.01) after ablation. The overall median time to local tumor progression was 7.6 months. The median time to local tumor progression was 10.4 months for lesions treated with LITT, 7.2 months for lesions treated with RFA, and 7.5 months for lesions treated with MWA, with no statistically significant difference noted. New pulmonary metastases developed in 47.6% of patients treated with LITT, in 51.2% of patients treated with RFA, and in 53.2% of patients treated with MWA. According to the Kaplan-Meier test, median survival was 22.1 months for patients who underwent LITT, 24.2 months

  17. The Safety and Efficacy of an Alcohol-Free Pancreatic Cyst Ablation Protocol.

    Science.gov (United States)

    Moyer, Matthew T; Sharzehi, Setareh; Mathew, Abraham; Levenick, John M; Headlee, Brandy D; Blandford, Jonathan T; Heisey, Heather D; Birkholz, James H; Ancrile, Brooke B; Maranki, Jennifer L; Gusani, Niraj J; McGarrity, Thomas J; Dye, Charles E

    2017-11-01

    Endoscopic ultrasound (EUS)-guided chemoablation with ethanol lavage followed by infusion of paclitaxel is effective for the treatment of mucinous pancreatic cysts. However, complications arise in 3%-10% of patients, presumably linked to the inflammatory effects of ethanol. We aimed to determine whether alcohol is required for effective pancreatic cyst ablation, if removing alcohol from the ablation process would improve complication rates, and whether a multi-agent chemotherapeutic cocktail could increase the rate of complete cyst resolution compared with findings reported from previous trials using alcohol followed by paclitaxel alone. Between November 2011 and December 2016, we conducted a single-center, prospective, double-blind trial of 39 patients with mucinous-type pancreatic cysts. Patients were randomly assigned to 1 of 2 groups that underwent EUS-guided pancreatic cyst lavage with either 80% ethanol (control) or normal saline (alcohol-free group). Cysts in both groups were then infused with an admixture of paclitaxel and gemcitabine. Primary outcomes were the rates of complete ablation 12 months after the procedure, and rates of serious and minor adverse events within 30 days of the procedure. At 12 months, 67% of patients who underwent alcohol-free EUS-guided cyst chemoablation had complete ablation of cysts compared with 61% of patients in the control group. Serious adverse events occurred in 6% of patients in the control group vs none of the patients in the alcohol-free group. Minor adverse events occurred in 22% of patients in the control group and none of the patients in the alcohol-free group. The overall rate of complete ablation was 64%. In this prospective, randomized, controlled trial, we found that alcohol is not required for effective EUS-guided pancreatic cyst ablation, and when alcohol is removed from the ablation process, there is a significant reduction in associated adverse events. A multi-agent chemotherapeutic ablation admixture did

  18. Dual delivery of VEGF and ANG-1 in ischemic hearts using an injectable hydrogel.

    Science.gov (United States)

    Rufaihah, Abdul Jalil; Johari, Nurul Azizah; Vaibavi, Srirangam Ramanujam; Plotkin, Marian; Di Thien, Do Thi; Kofidis, Theodoros; Seliktar, Dror

    2017-01-15

    Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. While growth factor therapy is promising, the retention in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Here, we demonstrated the use of polyethylene glycol-fibrinogen (PF) hydrogels for sustained dual delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) to enhance myocardial repair and function. VEGF and ANG-1 were incorporated in PF hydrogels and their in vitro characteristics were studied. Acute MI was generated in a rodent model with rats randomly assigned to 4 groups; sham, saline, PF and PF-VEGF-ANG1 (n=10 each group). Saline or hydrogel was injected in infarct and peri-infarct areas of the myocardium. After 4weeks, myocardial function was assessed using echocardiography. Tissue samples were harvested for Hematoxylin and Eosin, Masson Trichrome and capillary staining to assess the extent of fibrotic scar and arteriogenesis. Both VEGF and ANG-1 were released in a sustained and controlled manner over 30days. PF-VEGF-ANG1 treated animals showed the best improvement in cardiac function, highest degree of cardiac muscle preservation, and arteriogenesis. This study demonstrates that PF hydrogels can simultaneously provide mechanical support to attenuate adverse myocardial remodelling, and a pro-angiogenic benefit from the sustained VEGF and ANG1 delivery that culminates in a restorative effect following MI. The utility of this synergistic, biomaterial-based growth factor delivery may have clinical implications in the prevention of post-MI cardiac dysfunction. Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. Here, we demonstrated the use of polyethylene glycol-fibrinogen (PF) hydrogels for sustained dual delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) to enhance myocardial repair

  19. Operative Links

    DEFF Research Database (Denmark)

    Wistoft, Karen; Højlund, Holger

    2012-01-01

    educational goals, learning content, or value clarification. Health pedagogy is often a matter of retrospective rationalization rather than the starting point of planning. Health and risk behaviour approaches override health educational approaches. Conclusions: Operational links between health education......, health professionalism, and management strategies pose the foremost challenge. Operational links indicates cooperative levels that facilitate a creative and innovative effort across traditional professional boundaries. It is proposed that such links are supported by network structures, shared semantics...

  20. Application of local ablative therapies for hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    ZHU Xiaoli

    2016-01-01

    Full Text Available Hepatocellular carcinoma (HCC is a common malignant tumor in the world, and surgical resection and liver transplantation are two radical treatment modalities, but only 10%-20% of all patients can receive such treatments. In recent years, local therapies including radiofrequency ablation, microwave ablation, cryoablation, and the irreversible electroporation ablation which appeared recently have gradually become the alternative therapies for the patients who are unable to undergo surgery. In addition to local tumor growth control and improvement in survival outcomes, the ablation technology also helps to downgrade tumor for secondary resection. This article focuses on the research progress in radiofrequency ablation alone and in combination with other therapies in the treatment of HCC, compares radiofrequency ablation with other local ablative therapies, and briefly introduces the application of intelligent navigation technology in adjuvant ablation. With the development of medical imaging and progress in related fields, the ablation technology will be widely applied in clinical practice in the future.

  1. Potentiated Osteoinductivity via Cotransfection with BMP-2 and VEGF Genes in Microencapsulated C2C12 Cells

    Directory of Open Access Journals (Sweden)

    Yang Shen

    2015-01-01

    Full Text Available Microcapsules with entrapped cells hold great promise for repairing bone defects. Unfortunately, the osteoinductivity of microcapsules has been restricted by many factors, among which the deficiency of functional proteins is a significant priority. We potentiated the osteoinductivity of microencapsulated cells via cotransfection with BMP-2 and VEGF genes. Various tissue-derived mesenchymal stem cells and cell lines were compared for BMP-2 and VEGF cotransfection. Ethidium bromide (EB/Calcein AM staining revealed that all of the cell categories could survive for 4 weeks after microencapsulation. An ELISA assay indicated that all microencapsulated BMP-2 or VEGF transfected cells could secrete gene products constitutively for 1 month. Particularly, the recombinant microencapsulated C2C12 cells released the most desirable level of BMP-2 and VEGF. Further experiments demonstrated that microencapsulated BMP-2 and VEGF cotransfected C2C12 cells generated both BMP-2 and VEGF for 4 weeks. Additionally, the cotransfection of BMP-2 and VEGF in microencapsulated C2C12 cells showed a stronger osteogenic induction against BMSCs than individual BMP-2-transfected microencapsulated C2C12 cells. These results demonstrated that the cotransfection of BMP-2 and VEGF into microencapsulated C2C12 cells is of potent utility for the potentiation of bone regeneration, which would provide a promising clinical strategy for cellular therapy in bone defects.

  2. Penduliflaworosin, a Diterpenoid from Croton crassifolius, Exerts Anti-Angiogenic Effect via VEGF Receptor-2 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Yeyin Liang

    2017-01-01

    Full Text Available Anti-angiogenesis targeting vascular endothelial growth factor receptor-2 (VEGFR-2 has been considered as an important strategy for cancer therapy. Penduliflaworosin is a diterpenoid isolated from the plant Croton crassifolius. Our previous study showed that this diterpenoid possesses strong anti-angiogenic activity by inhibiting vessel formation in zebrafish. This study was conducted to further investigate the anti-angiogenic activity and mechanism of penduliflaworosin. Results revealed that penduliflaworosin significantly inhibited VEGF-induced angiogenesis processes including proliferation, invasion, migration, and tube formation of human umbilical vein endothelial cells (HUVECs. Moreover, it notably inhibited VEGF-induced sprout formation of aortic rings and blocked VEGF-induced vessel formation in mice. Western blotting studies showed that penduliflaworosin inhibited phosphorylation of the VEGF receptor-2 and its downstream signaling mediators in HUVECs, suggesting that the anti-angiogenic activity was due to an interference with the VEGF/VEGF receptor-2 pathway. In addition, molecular docking simulation indicated that penduliflaworosin could form hydrogen bonds within the ATP-binding region of the VEGF receptor-2 kinase unit. Finally, cytotoxicity assay showed that penduliflaworosin possessed little toxicity toward both cancer and normal cells. Taken together, our findings demonstrate that penduliflaworosin exerts its anti-angiogenic effect via the VEGF receptor-2 signaling pathway. The anti-angiogenic property and low cytotoxicity of penduliflaworosin suggest that it may be useful in cancer treatments.

  3. Percutaneous Microwave Ablation of Renal Angiomyolipomas

    Energy Technology Data Exchange (ETDEWEB)

    Cristescu, Mircea, E-mail: mcristescu@uwhealth.org [University of Wisconsin, Department of Radiology (United States); Abel, E. Jason, E-mail: abel@urology.wisc.edu [University of Wisconsin, Department of Urology (United States); Wells, Shane, E-mail: swells@uwhealth.org; Ziemlewicz, Timothy J., E-mail: tziemlewicz@uwhealth.org [University of Wisconsin, Department of Radiology (United States); Hedican, Sean P., E-mail: hedican@surgery.wisc.edu [University of Wisconsin, Department of Urology (United States); Lubner, Megan G., E-mail: mlubner@uwhealth.org; Hinshaw, J. Louis, E-mail: jhinshaw@uwhealth.org; Brace, Christopher L., E-mail: cbrace@uwhealth.org; Lee, Fred T., E-mail: flee@uwhealth.org [University of Wisconsin, Department of Radiology (United States)

    2016-03-15

    PurposeTo evaluate the safety and efficacy of US-guided percutaneous microwave (MW) ablation in the treatment of renal angiomyolipoma (AML).Materials and MethodsFrom January 2011 to April 2014, seven patients (5 females and 2 males; mean age 51.4) with 11 renal AMLs (9 sporadic type and 2 tuberous sclerosis associated) with a mean size of 3.4 ± 0.7 cm (range 2.4–4.9 cm) were treated with high-powered, gas-cooled percutaneous MW ablation under US guidance. Tumoral diameter, volume, and CT/MR enhancement were measured on pre-treatment, immediate post-ablation, and delayed post-ablation imaging. Clinical symptoms and creatinine were assessed on follow-up visits.ResultsAll ablations were technically successful and no major complications were encountered. Mean ablation parameters were ablation power of 65 W (range 60–70 W), using 456 mL of hydrodissection fluid per patient, over 4.7 min (range 3–8 min). Immediate post-ablation imaging demonstrated mean tumor diameter and volume decreases of 1.8 % (3.4–3.3 cm) and 1.7 % (27.5–26.3 cm{sup 3}), respectively. Delayed imaging follow-up obtained at a mean interval of 23.1 months (median 17.6; range 9–47) demonstrated mean tumor diameter and volume decreases of 29 % (3.4–2.4 cm) and 47 % (27.5–12.1 cm{sup 3}), respectively. Tumoral enhancement decreased on immediate post-procedure and delayed imaging by CT/MR parameters, indicating decreased tumor vascularity. No patients required additional intervention and no patients experienced spontaneous bleeding post-ablation.ConclusionOur early experience with high-powered, gas-cooled percutaneous MW ablation demonstrates it to be a safe and effective modality to devascularize and decrease the size of renal AMLs.

  4. Remote magnetic catheter navigation versus conventional ablation in atrial fibrillation ablation: Fluoroscopy reduction

    Directory of Open Access Journals (Sweden)

    Paul Chun Yih Lim

    2017-06-01

    Conclusions: In radiofrequency ablation of atrial fibrillation, RMN appears to significantly reduce fluoroscopy time compared with conventional MAN ablation, though at a cost of increased total procedural time, with comparable acute success rates and safety profile. A reduction in procedure and fluoroscopy times is possible with gaining experience.

  5. Quantification and controllability study of minimally invasive exothermic chemo-ablation therapy for tumor ablation.

    Science.gov (United States)

    Liu, Ran; Huang, Yu; Liu, Jing

    2009-01-01

    The recently proposed exothermic chemical reaction based tumor hyperthermia method presented a new way of realizing truly minimally invasive treatment for tumor. This method utilizes heat generated from the reaction between acid and alkali solutions to allow for tumor ablation. Successful clinical implementation of this method requires a clearer understanding and quantification of the ablation area such that a more controllable operation can be made. A number of in-vitro and in-vivo experiments are designed to examine the features of thermal chemo-ablation therapy which include micro and macro characteristics of ablated tissue and temperature change during the ablation process. A Quantitative study on the relationship between velocity and ablation volume as well as a Graphical User Interface in Matlab for computerized ablation area analysis are also presented in this article. We present in here two instrument designs for thermal chemo-ablation and have completed the prototype design for the injection pump which has been tested and successfully applied in ex-vivo and vivo experiments.

  6. An Increase in Vascular Endothelial Growth Factor (VEGF) and VEGF Soluble Receptor-1 (sFlt-1) Are Associated with Early Recurrent Spontaneous Abortion

    Science.gov (United States)

    Pang, Lihong; Wei, Zhouling; Li, Ouyang; Huang, Rudian; Qin, Junzhen; Chen, Hongyan; Fan, Xiaojing; Chen, Zi-Jiang

    2013-01-01

    Recurrent spontaneous abortion (RSA) is a health problem that affects approximately 1% to 5% reproductive age woman. Yet, in around half of these patients, the mechanism for RSA is unexplained. Recent studies have indicated that placental ischemia/hypoxia and endothelial dysfunction are important factors in miscarriage. Other studies have indicated that the level and expression of soluble FMS-like tyrosine kinase-1 (sFlt1) is increased under a hypoxic environment. However, decreased sFlt-1 in the maternal circulation during the first trimester has recently been proposed as a potential marker for identifying risk of pregnancy loss. In this prospective study clinical samples were obtained within a short time after the fetal death, protein expression and maternal serum levels of sFlt1 were assessed and compared to samples taken from those with normal pregnancies. Our results indicate that levels of VEGF and sFlt-1 are both increased in women during early pregnancy compared women that are not pregnant (pmiscarriages compare to controls. These results demonstrate that there is likely a relationship between VEGF, sFlt-1 and RSA suggesting that the high levels and over expression of sFlt-1 and VEGF might be associated with the pathogenesis of RSA. PMID:24098721

  7. Radiofrequency thermal ablation of malignant hepatic tumors: post-ablation syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jung Bin; Rhim, Hyunchul; Kim, Yongsoo; Koh, Byung Hee; Cho, On Koo; Seo, Heung Suk; Lee, Seung Ro [College of Medicine, Hanyang University, Seoul (Korea, Republic of)

    2000-07-01

    To evaluate post-ablation syndrome after radiofrequency thermal ablation of malignant hepatic tumors. Forty-two patients with primary (n=3D29) or secondary (n=3D13) hepatic tumors underwent radiofrequency thermal ablation. A total of 65 nodules ranging in size from 1.1 to 5.0 (mean, 3.1) cm were treated percutaneously using a 50W RF generator with 15G expandable needle electrodes. We retrospectively evaluated the spectrum of post-ablation syndrome including pain, fever ({>=}3D 38 deg C), nausea, vomiting, right shoulder pain, and chest discomfort according to frequency, intensity and duration, and the findings were correlated with tumor location and number of ablations. We also evaluated changes in pre-/post-ablation serum aminotransferase (ALT/AST) and prothrombin time, and correlated these findings with the number of ablations. Post-ablation syndrome was noted in 29 of 42 patients (69.0%), and most symptoms improved with conservative treatment. The most important of these were abdominal plan (n=3D20, 47.6%), fever (n=3D8, 19.0%), and nausea (n=3D7, 16.7%), and four of 42 (9.5%) patients complained of severe pain. The abdominal pain lasted from 3 hours to 5.5 days (mean; 20.4 hours), the fever from 6 hours to 5 days (mean; 63.0 hours). And the nausea from 1 hours to 4 days (mean; 21.0 hours). Other symptoms were right shoulder pain (n=3D6, 14.3%), chest discomfort (n=3D3, 7.1%), and headache (n=3D3, 7.1%). Seventeen of 20 patients (85%) with abdominal pain had subcapsular tumor of the liver. There was significant correlation between pain, location of the tumor, and a number of ablations. After ablation, ALT/AST was elevated more than two-fold in 52.6%/73.7% of patients, respectively but there was no significant correlation with the number of ablation. Post-ablation syndrome is a frequent and tolerable post-procedural process after radiofrequency thermal ablation. The spectrum of this syndrome provides a useful guideline for the post-ablation management. (author)

  8. Loss of autocrine endothelial-derived VEGF significantly reduces hemangiosarcoma development in conditional p53-deficient mice.

    Science.gov (United States)

    Farhang Ghahremani, Morvarid; Radaelli, Enrico; Haigh, Katharina; Bartunkova, Sonia; Haenebalcke, Lieven; Marine, Jean-Christophe; Goossens, Steven; Haigh, Jody J

    2014-01-01

    Malignant transformation of the endothelium is rare, and hemangiosarcomas comprise only 1% of all sarcomas. For this reason and due to the lack of appropriate mouse models, the genetic mechanisms of malignant endothelial transformation are poorly understood. Here, we describe a hemangiosarcoma mouse model generated by deleting p53 specifically in the endothelial and hematopoietic lineages. This strategy led to a high incidence of hemangiosarcoma, with an average latency of 25 weeks. To study the in vivo roles of autocrine or endothelial cell autonomous VEGF signaling in the initiation and/or progression of hemangiosarcomas, we genetically deleted autocrine endothelial sources of VEGF in this mouse model. We found that loss of even a single conditional VEGF allele results in substantial rescue from endothelial cell transformation. These findings highlight the important role of threshold levels of autocrine VEGF signaling in endothelial malignancies and suggest a new approach for hemangiosarcoma treatment using targeted autocrine VEGF inhibition.

  9. Femtosecond ultraviolet laser ablation of silver and comparison with nanosecond ablation

    DEFF Research Database (Denmark)

    Christensen, Bo Toftmann; Doggett, B.; Budtz-Jørgensen, C.

    2013-01-01

    ablation are similar; both show a singly peaked time-of-flight distribution. The angular distribution of ion emission and the deposition are well described by the adiabatic and isentropic model of plume expansion, though distributions for femtosecond ablation are significantly narrower. In this laser......The ablation plume dynamics arising from ablation of silver with a 500 fs, 248 nm laser at ~2 J cm-2 has been studied using angle-resolved Langmuir ion probe and thin film deposition techniques. For the same laser fluence, the time-of-flight ion signals from femtosecond and nanosecond laser...... fluence regime, the energy efficiency of mass ablation is higher for femtosecond pulses than for nanosecond pulses, but the ion production efficiency is lower....

  10. Tissue temperatures and lesion size during irrigated tip catheter radiofrequency ablation: an in vitro comparison of temperature-controlled irrigated tip ablation, power-controlled irrigated tip ablation, and standard temperature-controlled ablation

    DEFF Research Database (Denmark)

    Petersen, H H; Chen, X; Pietersen, A

    2000-01-01

    The limited success rate of radiofrequency catheter ablation in patients with ventricular tachycardias related to structural heart disease may be increased by enlarging the lesion size. Irrigated tip catheter ablation is a new method for enlarging the size of the lesion. It was introduced...... temperature-controlled ablation and power-controlled irrigated tip ablation. In vitro strips of porcine left ventricular myocardium were ablated. Temperature-controlled irrigated tip ablation at target temperatures 60 degrees C, 70 degrees C, and 80 degrees C with infusion of 1 mL saline/min were compared...

  11. Global microwave endometrial ablation for menorrhagia treatment

    Science.gov (United States)

    Fallahi, Hojjatollah; Å ebek, Jan; Frattura, Eric; Schenck, Jessica; Prakash, Punit

    2017-02-01

    Thermal ablation is a dominant therapeutic option for minimally invasive treatment of menorrhagia. Compared to other energy modalities for ablation, microwaves offer the advantages of conformal energy delivery to tissue within short times. The objective of endometrial ablation is to destroy the endometrial lining of the uterine cavity, with the clinical goal of achieving reduction in bleeding. Previous efforts have demonstrated clinical use of microwaves for endometrial ablation. A considerable shortcoming of most systems is that they achieve ablation of the target by translating the applicator in a point-to-point fashion. Consequently, treatment outcome may be highly dependent on physician skill. Global endometrial ablation (GEA) not only eliminates this operator dependence and simplifies the procedure but also facilitates shorter and more reliable treatments. The objective of our study was to investigate antenna structures and microwave energy delivery parameters to achieve GEA. Another objective was to investigate a method for automatic and reliable determination of treatment end-point. A 3D-coupled FEM electromagnetic and heat transfer model with temperature and frequency dependent material properties was implemented to characterize microwave GEA. The unique triangular geometry of the uterus where lateral narrow walls extend from the cervix to the fundus forming a wide base and access afforded through an endocervical approach limit the overall diameter of the final device. We investigated microwave antenna designs in a deployed state inside the uterus. The impact of ablation duration on treatment outcome was investigated. Prototype applicators were fabricated and experimentally evaluated in ex vivo tissue to verify the simulation results and demonstrate proof-of-concept.

  12. Photoacoustic characterization of radiofrequency ablation lesions

    Science.gov (United States)

    Bouchard, Richard; Dana, Nicholas; Di Biase, Luigi; Natale, Andrea; Emelianov, Stanislav

    2012-02-01

    Radiofrequency ablation (RFA) procedures are used to destroy abnormal electrical pathways in the heart that can cause cardiac arrhythmias. Current methods relying on fluoroscopy, echocardiography and electrical conduction mapping are unable to accurately assess ablation lesion size. In an effort to better visualize RFA lesions, photoacoustic (PA) and ultrasonic (US) imaging were utilized to obtain co-registered images of ablated porcine cardiac tissue. The left ventricular free wall of fresh (i.e., never frozen) porcine hearts was harvested within 24 hours of the animals' sacrifice. A THERMOCOOLR Ablation System (Biosense Webster, Inc.) operating at 40 W for 30-60 s was used to induce lesions through the endocardial and epicardial walls of the cardiac samples. Following lesion creation, the ablated tissue samples were placed in 25 °C saline to allow for multi-wavelength PA imaging. Samples were imaged with a VevoR 2100 ultrasound system (VisualSonics, Inc.) using a modified 20-MHz array that could provide laser irradiation to the sample from a pulsed tunable laser (Newport Corp.) to allow for co-registered photoacoustic-ultrasound (PAUS) imaging. PA imaging was conducted from 750-1064 nm, with a surface fluence of approximately 15 mJ/cm2 maintained during imaging. In this preliminary study with PA imaging, the ablated region could be well visualized on the surface of the sample, with contrasts of 6-10 dB achieved at 750 nm. Although imaging penetration depth is a concern, PA imaging shows promise in being able to reliably visualize RF ablation lesions.

  13. [Epi-Bowman Keratectomy: Clinical Evaluation of a New Method of Surface Ablation].

    Science.gov (United States)

    Taneri, S; Kießler, S; Rost, A; Schultz, T; Elling, M; Dick, B

    2017-02-10

    Purpose A new device for epithelial abrasion before excimer laser surface ablation or corneal cross-linking (CXL) has recently been introduced (Epi-Clear™, Orca Surgical, Kiryat-Shmona, Israel). We have reviewed the literature on the clinical results, potential benefits and drawbacks of this instrument, compared to other methods of epithelial removal. Method Literature search for "Epi-Bowman Keratectomy", "Epi-clear", and "Epikeratome" yielded 1 peer-review publication, 1 non-peer-review publication, 18 posters and presentations at international conferences (European Society of Cataract and Refractive Surgeons [ESCRS] and American Society of Cataract and Refractive Surgery [ASCRS]) on the use of the Epi-Clear™ device before surface ablation, 2 posters on the use of Epi-Clear before corneal crosslinking and 1 presentation on the experimental use of Epi-Clear for removal of a pterygium. Results Comparison of laser ablation after epithelial removal with the Epi-Clear device (Epi-Bowman Keratectomy™, EBK™) to other established methods of surface ablation, i.e. alcohol-assisted PRK or PRK with a metallic scraper, EBK, suggests that the results are generally similar. Pain perception, haze formation, and epithelial healing are reported to be better than with conventional surface ablation methods. Studies evaluating the use of the Epi-Clear device before CXL report that the healing time is significantly reduced and that less pain is perceived. Conclusion The Epi-Clear device seems to be a promising new option for epithelial removal before refractive laser ablation, although a convincing explanation for its potential superiority is still missing. In contrast, when the Epi-Clear device is used before CXL, then the Bowman's layer remains intact; this may provide an adequate explanation for the reported benefits of this application. However, currently available studies are of low level of evidence, so that more prospective randomised trials are needed for a robust

  14. Elevated Vascular Endothelial Growth Factor (VEGF) levels in the blood serum of dogs with malignant neoplasms of the oral cavity.

    Science.gov (United States)

    Sobczyńska-Rak, Aleksandra; Polkowska, Izabela; Silmanowicz, Piotr

    2014-09-01

    Angiogenesis plays an essential role in the development of a neoplastic tumour by conditioning both its growth and the formation of metastases. The induction of blood vessel growth occurs under the influence of proangiogenic factors, among which Vascular Endothelial Growth Factor (VEGF) seems to be the most important. The aim of this research was to study the level of VEGF measured by ELISA in the serum of dogs with neoplasms of the oral cavity. The study material comprised samples of neoplastic tissue from 17 operated dogs and the serum of the examined animals as well as of dogs from the control group. The tissue samples were taken from dogs of different breeds, aged 6-14 years. The tumour type was determined in accordance with the applicable WHO classification. Blood samples taken from sick dogs and from animals of the control group were centrifuged, and immunoenzymatic labelling of VEGF was performed in the obtained serum using ELISA and R&D system reagents (Quantikine Canine VEGF). All stages of VEGF labelling were performed according to the recommendation of the test manufacturer. The median of VEGF in the serum of the dogs with neoplasms of the oral cavity was 40.64 pg/mL. The lowest value of 14.26 pg/mL was observed in the case of fibrosarcoma, and the highest value of 99.19 pg/mL in the case of squamous cell carcinoma. The VEGF median in the control group amounted to 11.14 pg/mL whereas the VEGF value in the groups of animals diagnosed with benign tumours ranged between 2.30 and 19.74 pg/mL. Elevated VEGF in the blood serum, in comparison with the benign tumour group and the control group, was observed in all examined neoplasms of the oral cavity. It was suggested that overexpression of VEGF can have a prognostic value and is useful in the early detection of neoplasms.

  15. Receiver operating characteristic curve to predict anti-VEGF resistance in retinal vein occlusions and efficacy of Ozurdex.

    Science.gov (United States)

    Wolfe, Jeremy D; Shah, Ankoor R; Yonekawa, Yoshihiro; Al Faran, Abdulrahman; Franklin, Michael S; Abbey, Ashkan M; Capone, Antonio

    2016-01-01

    Current treatment paradigms for macular edema associated with retinal vein occlusions (RVO) often involve initial treatment with anti-vascular endothelial growth factor (VEGF) agents, then switching to intravitreal dexamethasone implant (IDI; Ozurdex, Allergan, Parsippany, NJ) for poor responders. However, many patients undergo multiple injections prior to being declared a nonresponder. We devised a method for prediction of poor anti-VEGF response after one injection, and show that these patients subsequently respond well to IDI. This study is a retrospective consecutive interventional case series of patients with RVO receiving anti-VEGF agents that were switched to IDI. Patients were categorized as nonresponders to anti-VEGF agents (edema did not improve) or responders (edema improved, but switched to IDI for longer treatment duration). Receiver operating characteristics (ROC) curve analysis was used to determine cutoffs of reduction in central retinal thickness (CRT) to predict poor response to anti-VEGF treatment. Twenty-three patients met inclusion criteria. There were 14 nonresponders and 9 responders. The ROC curve analysis found that the maximal sensitivity and specificity in correctly identifying responders to anti-VEGF therapy was those with >25% reduction in CRT 1 month after 1 anti-VEGF treatment (sensitivity 0.89, specificity 0.79, area under the curve 0.93). After IDI placement, anti-VEGF nonresponders showed significant improvement in visual acuity (VA) (p = 0.02) and CRT (p = 0.01). In patients with macular edema secondary to RVOs, a reduction in CRT by ≤25%, 1 month after 1 anti-VEGF injection, is predictive of poor response to anti-VEGF treatment. These patients may benefit from earlier conversion to IDI treatment, which in our study, resulted in improved VA and CRT.

  16. Berberine Suppresses TPA-Induced Fibronectin Expression through the Inhibition of VEGF Secretion in Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Sangmin Kim

    2013-11-01

    Full Text Available Background/Aims: Berberine (BBR is an isoquinoline alkaloid and is beneficial for the anticancer effect on a variety of human tumor cells. However, BBR's anti-angiogenesis property and its clinical potential as an inhibitor of tumor angiogenesis in breast cancer cells have not been fully elucidated. Here, we investigated the effect of BBR on TPA-induced VEGF and fibronectin (FN as well as VEGF-induced FN in breast cancer cells. Methods: The secretion of VEGF protein was detected by ELISA. Fibronectin mRNA and protein expression was analyzed by Real-Time PCR and western blotting, respectively. The overexpressions of CA-MEK, and CA-Akt were examined by adenovirus system. Results: Our results showed that TPA, a tumor promoter, significantly increased the level of VEGF and FN expression in both MCF7 and T47D breast cancer cells. On the other hand, TPA-induced VEGF and FN expression was suppressed by LY294002, a PI-3K inhibitor. In contrast, the level of FN expression also significantly increased by constitutively active (CA-AKT overexpression. We also found that TPA-induced VEGF and FN expression was decreased by BBR treatment. Finally, our results showed that VEGF augmented the expression of FN whereas VEGF-induced FN expression was decreased by BBR treatment. Conclusion: Taken together, we suggest that BBR may suppress TPA-induced VEGF and FN as well as VEGF-induced FN through the inhibition of the PI-3K/AKT pathway in breast cancer cells. Therefore, we suggest that BBR may be used as a candidate drug for the inhibition of angiogenesis of human breast cancer.

  17. Candesartan, an angiotensin II type 1 receptor antagonist, inhibits pathological retinal neovascularization by downregulating VEGF receptor-2 expression.

    Science.gov (United States)

    Nakamura, Shinsuke; Tsuruma, Kazuhiro; Shimazawa, Masamitsu; Hara, Hideaki

    2012-06-15

    Several studies have examined the anti-angiogenic effects of angiotensin II type 1 (AT(1)) receptor antagonists; however, the mechanisms underlying these effects are currently unclear. In the present study, we examined the efficacy and the mechanism of candesartan, an AT(1) receptor antagonist, in suppressing pathological retinal neovascularization. We used an in vivo murine oxygen-induced retinopathy (OIR) model and also studied the in vitro proliferation and migration of human retinal microvascular endothelial cells (HRMECs) induced by vascular endothelial growth factor (VEGF)-A. The regulation of angiogenesis-associated genes such as hypoxia-inducible factor (HIF-1α), VEGF-A, VEGF receptor-1, and VEGF receptor-2 was evaluated with real-time RT-PCR in the OIR model. In the OIR model, candesartan suppressed the pathological neovascularization in a dose-dependent manner, but did not prevent the physiological angiogenesis. However, candesartan did not inhibit VEGF-A-induced proliferation or migration in HRMECs in the in vitro study. When administered interperitoneally in the OIR model, candesartan reduced the upregulation of VEGF receptor-2 in the retina, but had no effects in the other angiogenesis-related genes, such as HIF-1α, VEGF-A, and VEGF receptor-1. These findings indicate that candesartan inhibited the retinal pathological neovascularization, at least in part, by suppressing the expression of VEGF receptor-2, independent of VEGF signaling cascade. Therefore, candesartan may be a useful therapeutic target for the inhibition of retinal neovascularization that has a low risk of serious side effects. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Predictors of recurrence following catheter ablation of atrial fibrillation using an irrigated-tip ablation catheter.

    Science.gov (United States)

    Vasamreddy, Chandrasekhar R; Lickfett, Lars; Jayam, Vinod K; Nasir, Khurram; Bradley, David J; Eldadah, Zayd; Dickfeld, Timm; Berger, Ronald; Calkins, Hugh

    2004-06-01

    The aims of this study were to identify predictors of recurrence after catheter ablation of atrial fibrillation (AF) and to report the safety and efficacy of catheter ablation of AF using an irrigated-tip ablation catheter. Seventy-five consecutive patients (51 men [68%]; age 54 +/- 13 years) with symptomatic drug-refractory paroxysmal (42 patients), persistent (21 patients), or permanent (12 patients) AF underwent catheter ablation of AF using an irrigated-tip ablation catheter and a standard ablation strategy, which involved electrical isolation of all pulmonary veins (PVs) and creation of a cavotricuspid linear lesion. At 10.5 +/- 7.5 months of follow-up following a single (n = 75) or redo ablation procedure (n = 11), 39 (52%) of the 75 patients were free of AF, 10 were improved (13%), and 26 had experienced no benefit from the ablation procedure (35%). Seventy-six percent of patients with paroxysmal AF were free from recurrent AF. The most significant complications were two episodes of pericardial tamponade, mitral valve injury in one patient, two strokes, and complete but asymptomatic PV stenosis in one patient. Cox proportional hazards multivariate regression analysis identified the presence of persistent AF, permanent AF, and age >50 years prior to the ablation are the only independent predictors of AF recurrence after the first PV isolation procedure. Catheter ablation of AF using a strategy involving isolation of all PVs and creation of a linear lesion in the cavotricuspid isthmus using cooled radiofrequency energy is associated with moderate efficacy and an important risk for complications. The best results of this procedure are achieved in the subset of patients who are younger than 50 years and have only paroxysmal AF.

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

    Science.gov (United States)

    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).

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  1. Comparison of the efficacy of anti-VEGF monotherapy versus PDT and intravitreal anti-VEGF combination treatment in AMD: a Meta-analysis and systematic review.

    Science.gov (United States)

    Tong, Yao; Zhao, Ke-Ke; Feng, Dong; Biswal, Manas; Zhao, Pei-Quan; Wang, Zhao-Yang; Zhang, Yun

    2016-01-01

    To compare the effect of anti-vascular endothelial growth factor (VEGF) monotherapy versus photodynamic therapy (PDT) and anti-VEGF combination treatment in age-related macular degeneration (AMD). A computerized online search was performed using PubMed, Web of Science and the Cochrane Library. Studies that compared anti-VEGF monotherapy with PDT and anti-VEGF combination treatment of AMD and were designed as randomized controlled trials were included. The means and standard deviations of the best-corrected visual acuity (BCVA), central retinal thickness (CRT), number of treatments and proportions of patients who gained BCVA ≥15, 10, 5, or 0 letters at 12(th) month were extracted. A systematic review and Meta-analysis of the comparison of the two approaches was conducted using Review Manager 5.2. Subgroup. A sensitivity analysis was also performed. Eight studies were included. When the subgroup and sensitivity analysis was conducted, the results indicated that in the findings that included the monotherapy group and PDT (standard fluence, SF) group of Kaiser's study, the patients in the monotherapy group had a better BCVA compared with the combination group at 12(th) month in the PDT (SF) subgroup [weighted mean difference (WMD): 3.54; 95%CI: 0.36 to 6.73; P=0.03], and there were more patients who gained ≥15 letters of BCVA in the monotherapy group compared with the combination group in the total result [odds ratio (OR): 1.41; 95%CI: 1.02 to 1.95; P=0.04]. The same conclusion was obtained in the total result that included the monotherapy group and PDT (reduced fluence, RF) group of Kaiser's study (OR: 1.56; 95%CI: 1.13 to 2.15; P=0.007). However, there were no significant differences in the other indexes between the two therapies. We found that anti-VEGF monotherapy is more effective on the recovery of visual acuity than combination therapy and more researches with lager sample size should be performed to study on the effect of the two therapy approaches on CRT

  2. The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer

    NARCIS (Netherlands)

    X.B. Trinh; W.A.A. Tjalma; P.B. Vermeulen; G. van den Eynden; I. van der Auwera; S.J. van Laere (Steven); J. Helleman (Jozien); P.M.J.J. Berns (Els); L.Y. Dirix (Luc); P.A. van Dam

    2009-01-01

    textabstractVascular endothelial growth factor (VEGF)-A inhibitors exhibit unseen high responses and toxicity in recurrent epithelial ovarian cancer suggesting an important role for the VEGF/VEGFR pathway. We studied the correlation of VEGF signalling and AKT/mTOR signalling. Using a tissue

  3. Association of pre-ablation level of potential blood markers with atrial fibrillation recurrence after catheter ablation: a meta-analysis.

    Science.gov (United States)

    Jiang, Hui; Wang, Weizong; Wang, Cong; Xie, Xinxing; Hou, Yinglong

    2017-03-01

    The meta-analysis was aimed to search for candidate blood markers whose pre-ablation level was associated with atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA). A systematic literature search of PubMed, EMBASE, Springer Link, Web of Science, Wiley-Cochrane library, and supplemented with Google scholar search engine was performed. Thirty-six studies covering 11 blood markers were qualified for this meta-analysis. Compared with the nonrecurrence group, the recurrence group had increased pre-ablation level of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-pro-BNP), interleukin-6 (IL-6), C-reactive protein, low density lipoprotein (LDL), and tissue inhibitor of metal loproteinase-2 (TIMP-2) [standardized mean difference (95% confidence interval): 0.37 (0.13-0.61), 0.77 (0.40-1.14), 1.25 (0.64-1.87), 0.37 (0.21-0.52), 0.35 (0.10-0.60), 0.24 (0.07-0.42), 0.17 (0.00-0.34), respectively], while no statistical difference of pre-ablation level of white blood cell, total cholesterol, triglyceride, and transforming growth factor-β1 was found. Subgroup analysis demonstrated that ANP was associated with AF recurrence in participants who had no concomitant structural heart diseases (SHD); however, not in participants who had SHD, C-reactive protein was associated with AF recurrence in Asian studies, whereas not in European studies. Increased pre-ablation level of ANP, BNP, NT-pro-BNP, IL-6, C-reactive protein, LDL, and TIMP-2 was associated with greater risk of AF recurrence after RFCA.

  4. Comparison of the Three NIF Ablators

    Energy Technology Data Exchange (ETDEWEB)

    Kritcher, A. L. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Clark, D. S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Haan, S. W. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Yi, S. A. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Zylstra, A. B. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Ralph, J. E. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Weber, C. R. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2017-11-01

    Indirect drive implosion experiments on NIF have now been performed using three different ablator materials: glow discharge polymer (GDP) or CH, high density carbon (HDC, which we also refer to as diamond), and sputtered beryllium (Be). It has been appreciated for some time that each of these materials has specific advantages and disadvantages as an ICF ablator.[1-4] In light of experiments conducted on NIF in the last few years, how do these ablators compare? Given current understanding, is any ablator more or less likely to reach ignition on NIF? Has the understanding of their respective strengths and weaknesses changed since NIF experiments began? How are those strengths and weaknesses highlighted by implosion designs currently being tested or planned for testing soon? This document aims to address these questions by combining modern simulation results with a survey of the current experimental data base. More particularly, this document is meant to fulfill an L2 Milestone for FY17 to “Document our understanding of the relative advantages and disadvantages of CH, HDC, and Be designs.” Note that this document does not aim to recommend a down-selection of the current three ablator choices. It is intended only to gather and document the current understanding of the differences between these ablators and thereby inform the choices made in planning future implosion experiments. This document has two themes: (i) We report on a reanalysis project in which post-shot simulations were done on a common basis for layered shots using each ablator. This included data from keyholes, 2D ConA, and so forth, from each campaign, leading up to the layered shots. (“Keyholes” are shots dedicated to measuring the shock timing in a NIF target, as described in Ref. 5. “2DConAs” are backlit implosions in which the symmetry of the implosion is measured between about half and full convergence, as described in Ref. 6.) This set of common-basis postshot simulations is compared to

  5. Comparison of the Three NIF Ablators

    Energy Technology Data Exchange (ETDEWEB)

    Kritcher, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States; Clark, D. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States; Haan, S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States; Yi, S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States; Kritcher, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States; Clark, D. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States; Haan, S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States; Yi, S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States; Zylstra, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States; Ralph, J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States; Weber, C. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States

    2017-09-27

    Indirect drive implosion experiments on NIF have now been performed using three different ablator materials: glow discharge polymer (GDP) or CH, high density carbon (HDC, which we also refer to as diamond), and sputtered beryllium (Be). It has been appreciated for some time that each of these materials has specific advantages and disadvantages as an ICF ablator.[1-4] In light of experiments conducted on NIF in the last few years, how do these ablators compare? Given current understanding, is any ablator more or less likely to reach ignition on NIF? Has the understanding of their respective strengths and weaknesses changed since NIF experiments began? How are those strengths and weaknesses highlighted by implosion designs currently being tested or planned for testing soon? This document aims to address these questions by combining modern simulation results with a survey of the current experimental data base. More particularly, this document is meant to fulfill an L2 Milestone for FY17 to “Document our understanding of the relative advantages and disadvantages of CH, HDC, and Be designs.” Note that this document does not aim to recommend a down-selection of the current three ablator choices. It is intended only to gather and document the current understanding of the differences between these ablators and thereby inform the choices made in planning future implosion experiments. This document has two themes: (i) We report on a reanalysis project in which post-shot simulations were done on a common basis for layered shots using each ablator. This included data from keyholes, 2D ConA, and so forth, from each campaign, leading up to the layered shots. This set of common-basis postshot simulations is compared to the respective shots. Each was then scaled to a “full NIF” experiment that could be done using the respective ablators at full NIF power and/or energy, and these scaled-up designs were simulated in detail. (ii) The report also contains a general survey of

  6. Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage.

    Science.gov (United States)

    Kim, Kyoung-Han; Kim, Yun Hye; Son, Joe Eun; Lee, Ju Hee; Kim, Sarah; Choe, Min Seon; Moon, Joon Ho; Zhong, Jian; Fu, Kiya; Lenglin, Florine; Yoo, Jeong-Ah; Bilan, Philip J; Klip, Amira; Nagy, Andras; Kim, Jae-Ryong; Park, Jin Gyoon; Hussein, Samer Mi; Doh, Kyung-Oh; Hui, Chi-Chung; Sung, Hoon-Ki

    2017-11-01

    Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.

  7. [Human umbilic mesenchymal stromal cells repairs diabetic foot in rats associated with VEGF expressional change].

    Science.gov (United States)

    Wang, Ying; Dan, Qi-Qin; Wang, Qing-Ping; Zhou, Ning; Jin, Xing-Fang; Hou, Zong-Liua; Peng, Bao-Kun; Wang, Ting-Hua

    2014-01-01

    OBJECTITVE: To explore the mechanism of human umbilic mesenchymal cells (HUMSCs) implantation for the treatment of diabetic foot in rats associate with vascular endothelia growth factor (VEGF) expression changes. After diabetic foot model in rats were established by administration of streptozotozin (STZ) in intraperitoneal injection (2 weeks), ulceration in foot was induced by incision injury combined with swearing staphylococcus aureas. Then, HUMSCs were smeared on the ulceration of foot in diabetic rats. Ten days later, the densities of blood vessel and the level of VEGF expression were determined by using immunohistochemistry, RT-PCR and Western blot. HUMSC grafts reduced significantly the volume of ulceration in diabetic foot rats (P < 0.05). RT-PCR and Western blot showed that VEGF and its mRNA were significantly upregulated (P < 0.05). VEGF immunstaining was found in blood vessels and the densities of blood vessels in HUMSC group were increased significantly (P < 0.05). HUMSC implantation showed a positive role in promoting the recovery of the ulceration in foot with diabetic rats.

  8. The role of VEGF-C staining in predicting regional metastasis in melanoma.

    NARCIS (Netherlands)

    Boone, B.; Blokx, W.; Bacquer, D. de; Lambert, J.; Ruiter, D.; Brochez, L.

    2008-01-01

    Sentinel lymph node status is the most important prognostic factor in primary melanoma. The number of melanoma-associated lymphatic vessels has been associated with sentinel lymph node status and survival. Vascular endothelial growth factor-C (VEGF-C) is found to promote tumour-associated lymphatic

  9. Polymorphisms in VEGF and KDR genes in the development of endometriosis: a systematic review

    Directory of Open Access Journals (Sweden)

    Jessica Vilarinho Cardoso

    Full Text Available Abstract Objectives: to review studies that used case-control design to verify the association of polymorphisms in VEGF and KDR genes in the development of endometriosis. Methods: the systematic review selected articles published until September 1, 2015 from PubMed, MEDLINE, BVS, SciELO databases, considering the following key words: endometriosis and ("polymorphism" or "SNP" or "genetic polymorphism" and ("VEGF" OR "Vascular endothelial growth factor" or "VEGFR-2" or "Vascular endothelial growth factor-2" or "KDR" or "Kinase Insert Domain Receptor". Results: 106 articles were identified, only 11 were eligible. Discrepant results were observed regarding polymorphisms in VEGF gene in the development of endometriosis, which can be explained by methodological differences, sample size, eligible control type, using the unadjusted risk estimates and the heterogeneity of the studied population. Only one study investigated polymorphisms in KDR gene in the development of endometriosis, however it was ineligible for this review. Conclusions: to avoid discrepancy in the results, we suggest that the ideal control group should be formed by fertile women and free of gynecological diseases. Multicentric studies with adequate design, involving different population besides the combined analysis on polymorphisms in VEGF and KDR genes are still necessary to contribute in the understanding of this disease, which are social, clinical and economical problems.

  10. Evaluation of VEGF in placental bed biopsies from preeclamptic women by immunohistochemistry.

    Science.gov (United States)

    Cirpan, T; Akercan, F; Terek, M C; Kazandi, M; Ozcakir, H T; Giray, G; Sagol, S

    2007-01-01

    The aim of the study was to determine VEGF protein with immunohistochemical staining in placental bed biopsies of preeclamptic pregnancies in comparison to normal controls. Prospective cohort study. The placental bed biopsies were obtained from 12 patients with preeclapmsia and ten patients for a control group at the time of cesarean delivery. Tissue samples of the placental bed were examined for VEGF protein distribution with avidin-biotin-peroxidase immunohistochemistry. Two blinded histopathologists were asked to score each sample for the intensity of staining and the number of cells stained in a randomly selected HPF of each sample. The resulting "H-score" was computed as a product of intensity and percent of cells stained. VEGF expression was significantly lower in both the myometrium and stroma of the preeclamptic group compared to the control group (77.2 +/- 25.4 vs 134 +/- 44.3, p = 0.007; 194.1 +/- 20.7 vs 170.2 +/- 17, p = 0.017, respectively). VEGF expression is significantly lower in placental bed biopsies of preeclamptic pregnancies.

  11. Retinal reperfusion in diabetic retinopathy following treatment with anti-VEGF intravitreal injections.

    Science.gov (United States)

    Levin, Ariana M; Rusu, Irene; Orlin, Anton; Gupta, Mrinali P; Coombs, Peter; D'Amico, Donald J; Kiss, Szilárd

    2017-01-01

    The aim of this study is to report peripheral reperfusion of ischemic areas of the retina on ultra-widefield fluorescein angiography (UWFA) following anti-vascular endothelial growth factor (VEGF) intravitreal injections in patients treated for diabetic retinopathy. This study is a retrospective review of 16 eyes of 15 patients with diabetic retinopathy, who received anti-VEGF intravitreal injections and underwent pre- and postinjection UWFA. The main outcome measured was the presence of reperfusion in postinjection UWFA images in areas of the retina that demonstrated nonperfusion in preinjection images. Images were analyzed for reperfusion qualitatively and quantitatively by two graders. Twelve of 16 eyes (75%) or 11 of 15 patients (73.3%) demonstrated reperfusion following anti-VEGF injection. On UWFA, reperfusion was detected both within the field of 7-standard field (7SF) fluorescein angiography and in the periphery outside the 7SF. Four of 16 eyes or 4 of 15 patients did not demonstrate reperfusion, one of which had extensive scarring from prior panretinal photocoagulation. In patients with diabetic retinopathy, treatment with anti-VEGF agents can be associated with reperfusion of areas of nonperfusion, as demonstrated by UWFA.

  12. Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract.

    Science.gov (United States)

    Baluk, Peter; Yao, Li-Chin; Flores, Julio C; Choi, Dongwon; Hong, Young-Kwon; McDonald, Donald M

    2017-08-17

    Lymphatic malformations are serious but poorly understood conditions that present therapeutic challenges. The goal of this study was to compare strategies for inducing regression of abnormal lymphatics and explore underlying mechanisms. CCSP-rtTA/tetO-VEGF-C mice, in which doxycycline regulates VEGF-C expression in the airway epithelium, were used as a model of pulmonary lymphangiectasia. After doxycycline was stopped, VEGF-C expression returned to normal, but lymphangiectasia persisted for at least 9 months. Inhibition of VEGFR-2/VEGFR-3 signaling, Notch, β-adrenergic receptors, or autophagy and antiinflammatory steroids had no noticeable effect on the amount or severity of lymphangiectasia. However, rapamycin inhibition of mTOR reduced lymphangiectasia by 76% within 7 days without affecting normal lymphatics. Efficacy of rapamycin was not increased by coadministration with the other agents. In prevention trials, rapamycin suppressed VEGF-C-driven mTOR phosphorylation and lymphatic endothelial cell sprouting and proliferation. However, in reversal trials, no lymphatic endothelial cell proliferation was present to block in established lymphangiectasia, and rapamycin did not increase caspase-dependent apoptosis. However, rapamycin potently suppressed Prox1 and VEGFR-3. These experiments revealed that lymphangiectasia is remarkably resistant to regression but is responsive to rapamycin, which rapidly reduces and normalizes the abnormal lymphatics without affecting normal lymphatics.

  13. Development of Anti-VEGF Therapies for Intraocular Use: A Guide for Clinicians

    Directory of Open Access Journals (Sweden)

    Pearse A. Keane

    2012-01-01

    Full Text Available Angiogenesis is the process by which new blood vessels form from existing vessel networks. In the past three decades, significant progress has been made in our understanding of angiogenesis; progress driven in large part by the increasing realization that blood vessel growth can promote or facilitate disease. By the early 1990s, it had become clear that the recently discovered “vascular endothelial growth factor” (VEGF was a powerful mediator of angiogenesis. As a result, several groups targeted this molecule as a potential mediator of retinal ischemia-induced neovascularization in disorders such as diabetic retinopathy and retinal vein occlusion. Around this time, it also became clear that increased intraocular VEGF production was not limited to ischemic retinal diseases but was also a feature of choroidal vascular diseases such as neovascular age-related macular degeneration (AMD. Thus, a new therapeutic era emerged, utilizing VEGF blockade for the management of chorioretinal diseases characterized by vascular hyperpermeability and/or neovascularization. In this review, we provide a guide for clinicians on the development of anti-VEGF therapies for intraocular use.

  14. Immunolocalization of FGF-2 and VEGF in rat periodontal ligament during experimental tooth movement

    Directory of Open Access Journals (Sweden)

    Milene Freitas Lima Salomão

    2014-06-01

    Full Text Available OBJECTIVE: This article aimed at identifying the expression of fibroblast growth factor-2 (FGF-2 and vascular endothelial growth factor (VEGF in the tension and pressure areas of rat periodontal ligament, in different periods of experimental orthodontic tooth movement. METHODS: An orthodontic force of 0.5 N was applied to the upper right first molar of 18 male Wistar rats for periods of 3 (group I, 7 (group II and 14 days (group III. The counter-side first molar was used as a control. The animals were euthanized at the aforementioned time periods, and their maxillary bone was removed and fixed. After demineralization, the specimens were histologically processed and embedded in paraffin. FGF-2 and VEGF expressions were studied through immunohistochemistry and morphological analysis. RESULTS: The experimental side showed a higher expression of both FGF-2 and VEGF in all groups, when compared with the control side (P < 0.05. Statistically significant differences were also found between the tension and pressure areas in the experimental side. CONCLUSION: Both FGF-2 and VEGF are expressed in rat periodontal tissue. Additionally, these growth factors are upregulated when orthodontic forces are applied, thereby suggesting that they play an important role in changes that occur in periodontal tissue during orthodontic movement.

  15. Analysis on the relation of pterygium with VEGF,SDF-1,Ki-67,PCNA and Survivin

    Directory of Open Access Journals (Sweden)

    Ying Song

    2015-12-01

    Full Text Available AIM:To analyze and study the relation of pterygium with vascular endothelial growth factor(VEGF,stroma cell-derived factor 1(SDF-1,tumor proliferating antigen(Ki-67,proliferating cell nuclear antigen(PCNAand survivin. METHODS:Seventy-nine patients(106 eyeswith pterygium from January 2013 to May 2015 in our hospital were selected as observation group. Seventy-nine persons with normal conjunctiva during the same period were selected as control group. Then the number of positive cells and staining intensity classification of the two groups for VEGF,SDF-1,Ki-67,PCNA and survivin were compared,and the detection results of patients with different gender,stages and types were compared too. Then the relation between pterygium and those indexes were analyzed by the Logistic analysis. RESULTS:The number of positive cells and staining intensity classification of observation group for VEGF,SDF-1,Ki-67,PCNA and survivin were all higher than those of control group,and the detection results of patients with different stages and types had certain differences too(all PP>0.05. All those indexes had close relation to pterygium by the Logistic analysis. CONCLUSION:The expression of VEGF,SDF-1,Ki-67,PCNA and survivin in tissue of patients with pterygium all show abnormal state,and those indexes all have close relation to pterygium.

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

    African Journals Online (AJOL)

    Yomi

    2012-01-16

    Jan 16, 2012 ... pMDV plasmid was digested by Hind III and Xba I (TaKaRa, Japan) and inserted into the pCAG vector (Wang et al., 2009) digested with the corresponding enzymes, replacing the CAT gene with VEGF165 gene, to generate the resultant plasmid pCGV. The constructs were shown schematically in Figure 2A.

  17. VEGF expression and microvascular density in relation to high-risk ...

    African Journals Online (AJOL)

    Bassma M. El Sabaa

    2012-01-13

    Jan 13, 2012 ... employed; VEGF antibody (Ab-7 Cat. #MS-1467-R7), human papillomavirus antibody (Ab-3, Clone K1H8, Cat. #MS-1826-. R7) and CD34 antibody (Ab-1, Clone QBEnd/10, Cat. #MS-. 363-R7). All three primary ..... survival in carcinoma of the cervix treated with radiotherapy. Int. J Radiat Oncol Biol Phys ...

  18. Exogenous VEGF introduced by bioceramic composite materials promotes the restoration of bone defect in rabbits.

    Science.gov (United States)

    Yu, Hedong; Zeng, Xiantao; Deng, Cai; Shi, Congyu; Ai, Jun; Leng, Weidong

    2017-12-20

    This study aimed to investigate the effect of exogenous vascular endothelial growth factor (VEGF) introduced by bioceramic composite materials on jawbone defect. Rabbits were randomly divided into four groups: control, sham, model, and stent. In the model group, holes of jawbone defect were created through surgery. In the stent group, rabbits with jawbone defect were treated with polyether ketone (PEK)/biphasic bioceramic ((PEK-BBC)) composite materials encapsulating VEGF. At 4, 8, and 16 weeks post-operation, HE and Van Gieson staining of jawbones were performed to characterize the repair status of the bone defect. For all time intervals, we found intact bone structures in the control and sham groups and there was no improvement in the bone defect position in the model group. However, in the stent group, we excitingly observed the growth of many osteocytes in the margin of stents at 8 and 16 weeks. RT-PCR, western blot, and immunofluorescence analysis were conducted to investigate the VEGF expression at 4, 8, and 16 weeks post-operation. At 8 weeks, the level of VEGF in the model group was sharply downregulated as compared with the control group (P composite materials promoted the restoration of bone defect in rabbits. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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

  20. p38 MAP kinase inhibition promotes primary tumour growth via VEGF independent mechanism.

    Science.gov (United States)

    O'Sullivan, Adrian W; Wang, Jiang H; Redmond, Henry P

    2009-11-15

    The surgical insult induces an inflammatory response that activates P38 MAP kinases and solid tumours can also release cytokines. Therfore inhibition of these pathways may reduce tumour growth We set out to examine the effects of P38-MAPK inhibition on apoptosis, proliferation, VEGF release and cell cycle effects in-vitro and on primary tumour growth in-vivo. 4T-1 cells (2 x 105 cells/well) were incubated, in 24 well plates with control, 25, 50 or 100 ng/ml of SB-202190 for 24 hours. Cells were subsequently asessed for apoptosis, proliferation, VEGF release and cell cycle analysis. Balb-c mice each received 1 x 106 4T 1 cells subcutaneously in the flank and were then randomised to receive control or SB202190 (2.5 microM/kg) by intraperitoneal injection daily. Tumour size was measured alternate days and at day 24 animals were sacrificed and serum VEGF assessed. P38-MAPK inhibition in-vitro resulted in a significant reduction in proliferation (75.2 +/- 8.4% vs. 100 +/- 4.3%, p etag/ml compared to 158.6 +/- 27.1 etag/ml) These findings demonstrate that P38-MAPK inhibition in-vitro reduces proliferation and G1 cell cycle phase as well as promoting primary tumour growth in-vivo. These effects would appear to be independent of VEGF.

  1. Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A.

    Science.gov (United States)

    Markovic-Mueller, Sandra; Stuttfeld, Edward; Asthana, Mayanka; Weinert, Tobias; Bliven, Spencer; Goldie, Kenneth N; Kisko, Kaisa; Capitani, Guido; Ballmer-Hofer, Kurt

    2017-02-07

    Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases: VEGFR-1, -2, and -3. Partial structures of VEGFR/VEGF complexes based on single-particle electron microscopy, small-angle X-ray scattering, and X-ray crystallography revealed the location of VEGF binding and domain arrangement of individual receptor subdomains. Here, we describe the structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A at 4 Å resolution. We combined X-ray crystallography, single-particle electron microscopy, and molecular modeling for structure determination and validation. The structure reveals the molecular details of ligand-induced receptor dimerization, in particular of homotypic receptor interactions in immunoglobulin homology domains 4, 5, and 7. Functional analyses of ligand binding and receptor activation confirm the relevance of these homotypic contacts and identify them as potential therapeutic sites to allosterically inhibit VEGFR-1 activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Prognostic Relevance of the Expression of CA IX, GLUT-1, and VEGF in Ovarian Epithelial Cancers.

    Science.gov (United States)

    Kim, Kyungbin; Park, Won Young; Kim, Jee Yeon; Sol, Mee Young; Shin, Dong Hun; Park, Do Youn; Lee, Chang Hun; Lee, Jeong Hee; Choi, Kyung Un

    2012-12-01

    Tumor hypoxia is associated with malignant progression and treatment resistance. Hypoxia-related factors, such as carbonic anhydrase IX (CA IX), glucose transporter-1 (GLUT-1), and vascular endothelial growth factor (VEGF) permit tumor cell adaptation to hypoxia. We attempted to elucidate the correlation of these markers with variable clinicopathological factors and overall prognosis. Immunohistochemistry for CA IX, GLUT-1, and VEGF was performed on formalin-fixed, paraffin-embedded tissues from 125 cases of ovarian epithelial cancer (OEC). CA IX expression was significantly associated with an endometrioid and mucinous histology, nuclear grade, tumor necrosis, and mitosis. GLUT-1 expression was associated with tumor necrosis and mitosis. VEGF expression was correlated only with disease recurrence. Expression of each marker was not significant in terms of overall survival in OECs; however, there was a significant correlation between poor overall survival rate and high coexpression of these markers. The present study suggests that it is questionable whether CA IX, GLUT-1, or VEGF can be used alone as independent prognostic factors in OECs. Using at least two markers helps to predict patient outcomes in total OECs. Moreover, the inhibition of two target gene combinations might prove to be a novel anticancer therapy.

  3. The Increased Expression of Connexin and VEGF in Mouse Ovarian Tissue Vitrification by Follicle Stimulating Hormone

    Directory of Open Access Journals (Sweden)

    Yanzhou Yang

    2015-01-01

    Full Text Available Ovarian follicular damages were caused by cryoinjury during the process of ovarian vitrification and ischemia/reperfusion during the process of ovarian transplantation. And appropriate FSH plays an important role in antiapoptosis during ovarian follicle development. Therefore, in this study, 0.3 IU/mL FSH was administered into medium during mouse ovarian cryopreservation by vitrification to ascertain the function of FSH on ovarian vitrification and avascular transplantation. The results suggested that the expressions of Cx37, Cx43, apoptotic molecular caspase-3, and angiogenesis molecular VEGF were confirmed using immunohistochemistry, western blotting, and real-time PCR, and the results suggested that the treatment with FSH remarkably increased the number of morphologically normal follicles in vitrified/warmed ovaries by upregulating the expression of Cx37, Cx43, VEGF, and VEGF receptor 2, but downregulating the expression of caspase-3. In addition, the vitrified/warmed ovaries were transplanted, and the related fertility was analyzed, and the results suggested that the fertility, neoangiogenesis, and follicle reserve were remarkably increased in the FSH administrated group. Taken together, administration of 0.3 IU/mL FSH during ovarian cryopreservation by vitrification can maintain ovarian survival during ovarian vitrification and increases the blood supply with avascular transplantation via upregulation of Cx43, Cx37, and VEGF/VEGFR2, as well as through its antiapoptotic effects.

  4. Luteolin suppresses angiogenesis and vasculogenic mimicry formation through inhibiting Notch1-VEGF signaling in gastric cancer.

    Science.gov (United States)

    Zang, Mingde; Hu, Lei; Zhang, Baogui; Zhu, Zhenglun; Li, Jianfang; Zhu, Zhenggang; Yan, Min; Liu, Bingya

    2017-08-26

    Gastric cancer is a great threat to the health of the people worldwide and lacks effective therapeutic regimens. Luteolin is one of Chinese herbs and presents in many fruits and green plants. In our previous study, we observed that luteolin inhibited cell migration and promoted cell apoptosis in gastric cancer. In the present study, luteolin significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) through decreasing cell migration and proliferation of HUVECs in a dose-dependent manner. Vasculogenic mimicry (VM) tubes formed by gastric cancer cells were also inhibited with luteolin treatment. To explore how luteolin inhibited tubes formation, ELISA assay for VEGF was performed. Both of the VEGF secretion from Hs-746T cells and HUVECs were significantly decreased subsequent to luteolin treatment. In addition, cell migration was increased with the interaction between gastric cancer cells and HUVECs in co-culture assays. However, the promoting effects were abolished subsequent to luteolin treatment. Furthermore, luteolin inhibited VEGF secretion through suppressing Notch1 expression in gastric cancer. Overexpression of Notch1 in gastric cancer cells partially rescued the effects on cell migration, proliferation, HUVECs tube formation, and VM formation induced by luteolin treatment. In conclusion, luteolin inhibits angiogenesis and VM formation in gastric cancer through suppressing VEGF secretion dependent on Notch1 expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Diagnostic value of urinary CK-20 RNA and VEGF in bladder cancer ...

    African Journals Online (AJOL)

    The present study was carried out to evaluate the diagnostic value of urinary cytokeratin 20 (CK-20) RNA and vascular endothelial growth factor (VEGF) in comparison with urine cytology in the detection of bladder cancer. This study included 80 patients with bladder cancer, 20 patients with bilharzial bladder lesions and 20 ...

  6. Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery

    NARCIS (Netherlands)

    Christensen, Lane V.; Christensen, L.; Chang, Chien-Wen; Yockman, James W.; Conners, Rafe; Jackson, Heidi; Zhong, Zhiyuan; Feijen, Jan; Bull, David A.; Kim, Sung Wan

    2007-01-01

    Delivery of the hypoxia-inducible vascular endothelial growth factor (RTP-VEGF) plasmid using a novel reducible disulfide poly(amido ethylenediamine) (SS-PAED) polymer carrier was studied in vitro and in vivo. In vitro transfection of primary rat cardiomyoblasts (H9C2) showed SS-PAED at a weighted

  7. Lymphatic Regeneration within Porous VEGF-C Hydrogels for Secondary Lymphedema

    Science.gov (United States)

    2006-01-01

    Figure 6: Ang-2 & VEGF-C Alginate gels Transplantation Animal Model. All procedures were performed in accordance with the Animal Care Act and...PS. The psycological morbidity of breast cancer related arm swelling. Cancer 1993;72:3248-52. 19) Veikkola Tanja and Alitalo Kari. Dual

  8. Fracture in Phenolic Impregnated Carbon Ablator

    Science.gov (United States)

    Agrawal, Parul; Chavez-Garcia, Jose; Pham, John

    2013-01-01

    This paper describes the development of a novel technique to understand the failure mechanisms inside thermal protection materials. The focus of this research is on the class of materials known as phenolic impregnated carbon ablators. It has successfully flown on the Stardust spacecraft and is the thermal protection system material chosen for the Mars Science Laboratory and SpaceX Dragon spacecraft. Although it has good thermal properties, structurally, it is a weak material. To understand failure mechanisms in carbon ablators, fracture tests were performed on FiberForm(Registered TradeMark) (precursor), virgin, and charred ablator materials. Several samples of these materials were tested to investigate failure mechanisms at a microstructural scale. Stress-strain data were obtained simultaneously to estimate the tensile strength and toughness. It was observed that cracks initiated and grew in the FiberForm when a critical stress limit was reached such that the carbon fibers separated from the binder. However, both for virgin and charred carbon ablators, crack initiation and growth occurred in the matrix (phenolic) phase. Both virgin and charred carbon ablators showed greater strength values compared with FiberForm samples, confirming that the presence of the porous matrix helps in absorbing the fracture energy.

  9. Percutaneous tumor ablation in medical radiology

    Energy Technology Data Exchange (ETDEWEB)

    Vogl, T.J.; Mack, M.G. [University Hospital Frankfurt Univ. (Germany). Inst. for Diagnostic and Interventional Radiology; Helmberger, T.K. [Klinikum Bogenhausen, Academic Teaching Hospital of the Technical Univ. Munich (Germany). Dept. for Diagnostic and Interventional Radiology and Nuclear Medicine; Reiser, M.F. (eds.) [University Hospitals - Grosshadern and Innenstadt Munich Univ. (Germany). Dept. of Clinical Radiology

    2008-07-01

    Thermal ablation has become an integral part of oncology, especially in the field of interventional oncology. This very comprehensive book encompasses the different technologies employed in thermal ablation, its indications and the results achieved in various clinical conditions. The first part of the book clearly explains the basics of thermal ablative techniques such as laser-induced thermotherapy, radiofrequency ablation, microwave ablation, cryotherapy, and localized tumor therapy. The latest developments in the application of minimally invasive therapies in localized neoplastic disease are demonstrated. In the main part of the book, techniques of guiding the applicators to the target structures by use of different imaging tools such as ultrasound, computed tomography and magnetic resonance imaging are discussed. The results are presented for a variety of clinical indications, including liver and lung tumors and metastases and some rather rare conditions involving the kidney, the head and neck, the prostate, and soft tissue structures. A large number of acknowledged experts have contributed to the book, which benefits from a lucid structure and excellent images. (orig.)

  10. Fundamental studies of pulsed laser ablation

    CERN Document Server

    Claeyssens, F

    2001-01-01

    dopant) have resulted in a coherent view of the resulting plume, which exhibits a multi-component structure correlated with different regimes of ablation, which are attributed to ejection from ZnO and ablation from a Zn melt. OES measurements show that the emitting Zn component within the plume accelerates during expansion in vacuum - an observation attributable to the presence of hot, fast electrons in the plume. The same acceleration behaviour is observed in the case of Al atomic emissions resulting from ablation of an Al target in vacuum. Deposition conditions, substrate temperature and background gas pressure were all varied in a quest for optimally aligned, high quality ZnO thin films. Initial ab initio calculations were performed also, to aid in understanding the stability of these c-axis aligned films. The pulsed ultraviolet (lambda = 193, 248 nm) laser ablation of graphite, polycrystalline diamond and ZnO targets has been investigated. Characteristics of the resulting plumes of ablated material have b...

  11. Imaging in percutaneous ablation for atrial fibrillation

    Energy Technology Data Exchange (ETDEWEB)

    Maksimovic, Ruzica [Erasmus Medical Center, Department of Radiology, GD Rotterdam (Netherlands); Institute for Cardiovascular Diseases of the University Medical Center, Belgrade (Czechoslovakia); Dill, Thorsten [Kerckhoff-Heart Center, Department of Cardiology, Bad Nauheim (Germany); Ristic, Arsen D.; Seferovic, Petar M. [Institute for Cardiovascular Diseases of the University Medical Center, Belgrade (Czechoslovakia)

    2006-11-15

    Percutaneous ablation for electrical disconnection of the arrhythmogenic foci using various forms of energy has become a well-established technique for treating atrial fibrillation (AF). Success rate in preventing recurrence of AF episodes is high although associated with a significant incidence of pulmonary vein (PV) stenosis and other rare complications. Clinical workup of AF patients includes imaging before and after ablative treatment using different noninvasive and invasive techniques such as conventional angiography, transoesophageal and intracardiac echocardiography, computed tomography (CT) and magnetic resonance imaging (MRI), which offer different information with variable diagnostic accuracy. Evaluation before percutaneous ablation involves assessment of PVs (PV pattern, branching pattern, orientation and ostial size) to facilitate position and size of catheters and reduce procedure time as well as examining the left atrium (presence of thrombi, dimensions and volumes). Imaging after the percutaneous ablation is important for assessment of overall success of the procedure and revealing potential complications. Therefore, imaging methods enable depiction of PVs and the anatomy of surrounding structures essential for preprocedural management and early detection of PV stenosis and other ablation-related procedures, as well as long-term follow-up of these patients. (orig.)

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

    Directory of Open Access Journals (Sweden)

    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

  13. [Roles of VEGF-C and its receptor Flt-4 in proliferation and metastasis of primary breast cancer].

    Science.gov (United States)

    Liu, Fang; Zhang, Ya-Jie

    2003-10-01

    Vascular endothelial growth factor-C(VEGF-C) is a member of VEGF family and the only factor that can combine receptor VEGFR-3 (fms-like tyrosine kinase, Flt-4) located at endothelium of lymphatic vessel and modulates the physiological function of lymphatic vessel. Previous study showed that VEGF-C/Flt-4 system play a modulating role in metastasis of many kinds of tumors, but there were few reports about its function for primary breast cancer at home and abroad. The objective of this study was to identify the function of VEGF-C/Flt-4 system in proliferation and metastasis of primary breast cancer and its significance. A series of 101 primary breast cancer specimens were detected for the expression of VEGF-C, Flt-4,and PCNA by Immunohistochemical methods. Among 101 cases of breast cancer, the positive rate of VEGF-C was 93.1% (94/101), the positive rate of flt-4 was 86.1% (87/101). With the increase of the expression of VEGF-C, the positive index of flt-4 increased (r=0.816,P< 0.001). The positive rate of PCNA was 88.8% (89/101). With the increase of the expression of VEGF-C, the proliferation activity of PCNA was stronger (r=0.673,P< 0.001). The positive index of VEGF-C in lymph node metastases group (61.89+/-17.79) was significantly higher than that of no lymph node metastasis group (44.28+/-17.87)(P< 0.05). With the increase of VEGF-C protein level, the number of flt-4 positive vessels increased and significant differences among these groups were observed (P< 0.001). The number of flt-4 positive vessels in lymph node metastases group (15.55+/-3.63)was significantly higher than that of no lymph node metastasis group (10.71+/-2.90 ) (P< 0.05). VEGF-C and Flt-4 are overexpressed in primary breast cancer and related to lymph node metastasis. VEGF-C can promote proliferation of breast cancer cell. VEGF-C/flt-4 system can promote vasculogenesis in stroma of breast cancer. The number of Flt-4 positive vessels is closely related to lymph node metastasis.

  14. Promotion of adhesion and proliferation of endothelial progenitor cells on decellularized valves by covalent incorporation of RGD peptide and VEGF.

    Science.gov (United States)

    Zhou, Jianliang; Ding, Jingli; Nie, Bin'en; Hu, Shidong; Zhu, Zhigang; Chen, Jia; Xu, Jianjun; Shi, Jiawei; Dong, Nianguo

    2016-09-01

    Tissue engineered heart valve is a promising alternative to current heart valve surgery, for its capability of growth, repair, and remodeling. However, extensive development is needed to ensure tissue compatibility, durability and antithrombotic potential. This study aims to investigate the biological effects of multi-signal composite material of polyethyl glycol-cross-linked decellularized valve on adhesion and proliferation of endothelial progenitor cells. Group A to E was decellularized valve leaflets, composite material of polyethyl glycol-cross-linked decellularized valves leaflets, vascular endothelial growth factor-composite materials, Arg-Gly-Asp peptide-composite materials and multi-signal modified materials of polyethyl glycol-cross-linked decellularized valve leaflets, respectively. The endothelial progenitor cells were seeded for each group, cell adhesion and proliferation were detected and neo-endothelium antithrombotic function of the multi-signal composite materials was evaluated. At 2, 4, and 8 h after the seeding, the cell numbers and 3H-TdR incorporation in group D were the highest. At 2, 4, and 8 days after the seeding, the cell numbers and 3H-TdR incorporation were significantly higher in groups C, D, and E compared with groups A and B (P cell numbers and the expression of t-PA and eons in the neo-endothelium were quite similar to those in the human umbilical vein endothelial cells at 2, 4, and 8 days after the seeding. The Arg-Gly-Asp- peptides (a sequential peptide composed of arginine (Arg), glycine (Gly) and aspartic acid (Asp)) and VEGF-conjugated onto the composite material of PEG-crosslinked decellularized valve leaflets synergistically promoted the adhesion and proliferation of endothelial progenitor cells on the composite material, which may help in tissue engineering of heart valves.

  15. Diffusion of anti-VEGF injections in the Portuguese National Health System.

    Science.gov (United States)

    Marques, Ana Patrícia; Macedo, António Filipe; Perelman, Julian; Aguiar, Pedro; Rocha-Sousa, Amândio; Santana, Rui

    2015-11-23

    To analyse the temporal and geographical diffusion of antivascular endothelial growth factor (anti-VEGF) interventions, and its determinants in a National Health System (NHS). NHS Portuguese hospitals. All inpatient and day cases related to eye diseases at all Portuguese public hospitals for the period 2002-2012 were selected on the basis of four International Classification of Diseases 9th revision, Clinical Modification (ICD-9-CM) codes for procedures: 1474, 1475, 1479 and 149. We measured anti-VEGF treatment rates by year and county. The determinants of the geographical diffusion were investigated using generalised linear modelling. We analysed all hospital discharges from all NHS hospitals in Portugal (98,408 hospital discharges corresponding to 57,984 patients). National rates of hospitals episodes for the codes for procedures used were low before anti-VEGF approval in 2007 (less than 12% of hospital discharges). Between 2007 and 2012, the rates of hospital episodes related to the introduction of anti-VEGF injections increased by 27% per year. Patients from areas without ophthalmology departments received fewer treatments than those from areas with ophthalmology departments. The availability of an ophthalmology department in the county increased the rates of hospital episodes by 243%, and a 100-persons greater density per km(2) raised the rates by 11%. Our study shows a large but unequal diffusion of anti-VEGF treatments despite the universal coverage and very low copayments. The technological innovation in ophthalmology may thus produce unexpected inequalities related to financial constraints unless the implementation of innovative techniques is planned and regulated. 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/

  16. Effect of saffron extract on VEGF-A expression in MCF7 cell line

    Directory of Open Access Journals (Sweden)

    Marzieh Mousavi

    2014-03-01

    Full Text Available Background: Various studies have focused on the anticancer effects of saffron. Angiogenesis or new blood vessel formation, which is required for embryonic development and many physiological events, plays a crucial role in many pathological conditions such as tumor growth. One of the main genes which is involved in the process of angiogenesis is VEGF-A. In this in vitro study, the effects of saffron extract on VEGF-A expression were examined. Methods: In this experimental study, the saffron extract was obtained by Soxhlet extractor and then the powder was frozen and dried in vacuum (lyophilisation using a freeze dryer. MCF7 cells were grown in RPMI 1640 medium supplemented with 10% Fetal Bovine Serum (FBS and incubated at 37˚C with 5% CO2. After 24 h of cell culture, their adhesion to the bottom flasks was investigated, then, they were treated by the aqueous extract of saffron at concentrations of 100, 200, 400 and 800 µg/ml. 48 hours after treatment, total RNA was extracted and cDNA was synthesized using the sequence of target gene. Finally, the synthesized products were analysed by Real Time PCR to determine the expression level of VEGF-A. Results: The results of data analysis showed the inhibitory effect of saffron extract in concentrations of 100, 200, 400 and 800 µg/ml on VEGF-A expression in MCF7 cells in comparison with control group, indicating the highest reduction of gen expression for the highest concentration of saffron extract (800 µg/ml. Conclusion: Results indicated a decrease in the expression of VEGF-A, specific biomarker of angiogenesis, in the treated samples compared to the control group.

  17. Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway.

    Directory of Open Access Journals (Sweden)

    Zhiyu Wang

    Full Text Available Angiogenesis is crucial for cancer initiation, development and metastasis. Identifying natural botanicals targeting angiogenesis has been paid much attention for drug discovery in recent years, with the advantage of increased safety. Isoliquiritigenin (ISL is a dietary chalcone-type flavonoid with various anti-cancer activities. However, little is known about the anti-angiogenic activity of isoliquiritigenin and its underlying mechanisms. Herein, we found that ISL significantly inhibited the VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs at non-toxic concentration. A series of angiogenesis processes including tube formation, invasion and migration abilities of HUVECs were also interrupted by ISL in vitro. Furthermore, ISL suppressed sprout formation from VEGF-treated aortic rings in an ex-vivo model. Molecular mechanisms study demonstrated that ISL could significantly inhibit VEGF expression in breast cancer cells via promoting HIF-1α (Hypoxia inducible factor-1α proteasome degradation and directly interacted with VEGFR-2 to block its kinase activity. In vivo studies further showed that ISL administration could inhibit breast cancer growth and neoangiogenesis accompanying with suppressed VEGF/VEGFR-2 signaling, elevated apoptosis ratio and little toxicity effects. Molecular docking simulation indicated that ISL could stably form hydrogen bonds and aromatic interactions within the ATP-binding region of VEGFR-2. Taken together, our study shed light on the potential application of ISL as a novel natural inhibitor for cancer angiogenesis via the VEGF/VEGFR-2 pathway. Future studies of ISL for chemoprevention or chemosensitization against breast cancer are thus warranted.

  18. Endostatin inhibits VEGF-A induced osteoclastic bone resorption in vitro

    Directory of Open Access Journals (Sweden)

    Ilvesaro Joanna

    2006-07-01

    Full Text Available Abstract Background Endostatin is a C-terminal fragment of collagen XVIII which is a component of basement membranes with the structural properties of both collagens and proteoglycans. Endostatin has a major role in angiogenesis which is intimately associated with bone development and remodeling. Signaling between the endothelial cells and the bone cells, for example, may have a role in recruitment of osteoclastic precursor cells. Our study aims at exploring a possibility that endostatin, either as a part of basement membrane or as a soluble molecule, may control osteoclastogenesis and osteoclastic bone resorption in vitro. Methods Rat pit formation assay was employed in order to examine the effect of endostatin alone or in combination with vascular endothelial growth factor-A (VEGF-A on bone resorption in vitro. Effect of these agents on osteoclast differentiation in vitro was also tested. Osteoclastogenesis and the number of osteoclasts were followed by tartrate resistant acid phosphatase (TRACP staining and resorption was evaluated by measuring the area of excavated pits. Results Endostatin inhibited the VEGF-A stimulated osteoclastic bone resorption, whereas endostatin alone had no effect on the basal resorption level in the absence of VEGF-A. In addition, endostatin could inhibit osteoclast differentiation in vitro independent of VEGF-A. Conclusion Our in vitro data indicate that collagen XVIII/endostatin can suppress VEGF-A induced osteoclastic bone resorption to the basal level. Osteoclastogenesis is also inhibited by endostatin. The regulatory effect of endostatin, however, is not critical since endostatin alone does not modify the basal bone resorption.

  19. Anti-VEGF antibodies mitigate the development of radiation necrosis in mouse brain

    Science.gov (United States)

    Jiang, Xiaoyu; Engelbach, John A; Yuan, Liya; Cates, Jeremy; Gao, Feng; Drzymala, Robert E; Hallahan, Dennis E; Rich, Keith M; Schmidt, Robert E; Ackerman, Joseph JH; Garbow, Joel R

    2014-01-01

    Purpose To quantify the effectiveness of anti-VEGF antibodies (bevacizumab and B20-4.1.1) as mitigators of radiation-induced, CNS (brain) necrosis in a mouse model. Experimental Design Cohorts of mice were irradiated with single-fraction 50- or 60-Gy doses of radiation targeted to the left hemisphere (brain) using the Leksell Perfexion Gamma Knife. The onset and progression of radiation necrosis were monitored longitudinally by in vivo, small-animal MRI, beginning four weeks post-irradiation. MRI-derived necrotic volumes for antibody (Ab)-treated and untreated mice were compared. MRI results were supported by correlative histology. Results Hematoxylin and eosin stained sections of brains from irradiated, non-Ab-treated mice confirmed profound tissue damage, including regions of fibrinoid vascular necrosis, vascular telangiectasia, hemorrhage, loss of neurons, and edema. Treatment with the murine anti-VEGF antibody B20-4.1.1 mitigated radiation-induced changes in an extraordinary, highly statistically-significant manner. The development of radiation necrosis in mice under treatment with bevacizumab (a humanized anti-VEGF antibody) was intermediate between that for B20-4.1.1-treated and non-Ab-treated animals. MRI findings were validated by histologic assessment, which confirmed that anti-VEGF-antibody treatment dramatically reduced late-onset necrosis in irradiated brain. Conclusions The single-hemispheric-irradiation mouse model, with longitudinal MRI monitoring, provides a powerful platform for studying the onset and progression of radiation necrosis and for developing and testing new therapies. The observation that anti-VEGF antibodies are effective mitigants of necrosis in our mouse model will enable a wide variety of studies aimed at dose optimization and timing and mechanism of action with direct relevance to ongoing clinical trials of bevacizumab as a treatment for radiation necrosis. PMID:24647570

  20. Anti-VEGF treatment for myopic choroid neovascularization: from molecular characterization to update on clinical application

    Directory of Open Access Journals (Sweden)

    Zhang Y

    2015-07-01

    Full Text Available Yan Zhang,1 Qian Han,2 Yusha Ru,1 Qiyu Bo,1 Rui Hua Wei1 1Tianjin Medical University Eye Hospital, Tianjin Medical University Eye Institute, College of Optometry and Ophthalmology, Tianjin Medical University, Tianjin, 2Tangshan Eye Hospital, Tangshan, Hebei Province, People’s Republic of China Abstract: Choroidal neovascularization (CNV secondary to pathologic myopia has a very high incidence in global, especially in Asian, populations. It is a common cause of irreversible central vision loss, and severely affects the quality of life in the patients with pathologic myopia. The traditional therapeutic modalities for CNV secondary to pathologic myopia include thermal laser photocoagulation, surgical management, transpupillary thermotherapy, and photodynamic therapy with verteporfin. However, the long-term outcomes of these modalities are disappointing. Recently, intravitreal administration of anti-VEGF biological agents, including bevacizumab, ranibizumab, pegaptanib, aflibercept, and conbercept, has demonstrated promising outcomes for this ocular disease. The anti-VEGF regimens are more effective on improving visual acuity, reducing central fundus thickness and central retina thickness than the traditional modalities. These anti-VEGF agents thus hold the potential to become the first-line medicine for treatment of CNV secondary to pathologic myopia. This review follows the trend of “from bench to bedside”, initially discussing the pathogenesis of myopic CNV, delineating the molecular structures and mechanisms of action of the currently available anti-VEGF drugs, and then systematically comparing the up to date clinical applications as well as the efficacy and safety of the anti-VEGF drugs to the CNV secondary to pathologic myopia. Keywords: formation of new vessels, choroid membrane, pathologic myopia, vascular endothelial growth factor, molecular mechanisms, clinical trials

  1. Neuroprotection of VEGF-expression neural stem cells in neonatal cerebral palsy rats.

    Science.gov (United States)

    Zheng, Xiang-Rong; Zhang, Shan-Shan; Yin, Fei; Tang, Jie-Lu; Yang, Yu-Jia; Wang, Xia; Zhong, Le

    2012-04-21

    Cerebral palsy (CP) is a very common neural system development disorder that can cause physical disability in human. Here, we studied the neuroprotective effect of vascular endothelial growth factor (VEGF)-transfected neural stem cells (NSCs) in newborn rats with cerebral palsy (CP). Seven-day-old Sprague-Dawley rats were randomly divided into four groups: sham operation (control group), PBS transplantation (PBS group), VEGF+NSCs transplantation (transgene NSCs group) and NSCs transplantation groups (NSCs group). PBS, Transgene NSCs and NSCs groups respectively received stereotactic injections of PBS, lentiviral vector (pGC-FU-VEGF) infected NSCs or a NSCs suspension in the left sensory-motor cortex 3 days after CP model was established. The NSCs activity, their impacts on neural cell growth and apoptosis, brain development and animal behaviors were examined on the animals up to age 35-days. As expected, unilateral carotid artery occlusion plus hypoxia (cerebral palsy model) resulted in severe neural developmental disorders, including slowed growth, increased in cortical neuron apoptosis, decreased cerebral cortex micro-vessel density and retarded behavior developments. Transplantation of NSCs not only resulted in increases in VEGF protein expression in rat brains, but also largely prevented the behavioral defects and brain tissue pathology that resulted from cerebral palsy procedure, with animals received VEGF transfected NSCs always being marginally better than these received un-transfected cells. In conclusion, NSCs transplantation can partially prevent/slow down the brain damages that are associated with CP in the newborn rats, suggesting a new possible strategy for CP treatment. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. The Role of VEGF and KDR Polymorphisms in Moyamoya Disease and Collateral Revascularization

    Science.gov (United States)

    Park, Young Seok; Jeon, Young Joo; Kim, Hyun Seok; Chae, Kyu Young; Oh, Seung-Hun; Han, In Bo; Kim, Hyun Sook; Kim, Won-Chan; Kim, Ok-Joon; Kim, Tae Gon; Choi, Joong-Uhn; Kim, Dong-Seok; Kim, Nam Keun

    2012-01-01

    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. PMID:23077562

  3. Linked data

    NARCIS (Netherlands)

    Koster, L.

    2011-01-01

    Semantisch web, linked data, web 3.0… Het zijn allemaal termen die vaak door elkaar worden gebruikt. Onterecht vindt Lukas Koster van de Universiteit van Amsterdam. Wat houden die begrippen nu eigenlijk in?

  4. Management of the Temporomandibular Joint after Ablative Surgery

    OpenAIRE

    Bredell, Marius; Grätz, Klaus; Obwegeser, Joachim; Gujer, Astrid Kruse

    2014-01-01

    Management of the temporomandibular joint in ablative head and neck surgery is controversial with no standardized approach. The aim of the study was to establish risk-based guidelines for the management of the temporomandibular joint after ablative surgery.

  5. Alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy

    DEFF Research Database (Denmark)

    Jensen, Morten K; Prinz, Christian; Horstkotte, Dieter

    2013-01-01

    The infarction induced by alcohol septal ablation (ASA) may predispose to arrhythmia and sudden cardiac death (SCD).......The infarction induced by alcohol septal ablation (ASA) may predispose to arrhythmia and sudden cardiac death (SCD)....

  6. Effective treatment of chronic radiation proctitis using radiofrequency ablation

    National Research Council Canada - National Science Library

    Chao Zhou; Adler, Desmond C; Becker, Laren; Yu Chen; Tsai, Tsung-Han; Figueiredo, Marisa; Schmitt, Joseph M; Fujimoto, James G; Mashimo, Hiroshi

    2009-01-01

    .... Radiofrequency ablation (RFA) has been successful for mucosal ablation in the esophagus. Here we report the efficacy of RFA with the BarRx Halo90 system in three patients with bleeding from chronic radiation proctitis...

  7. Bilateral cornual abscess after endometrial ablation following Essure sterilization.

    NARCIS (Netherlands)

    Jansen, N.E.; Vleugels, M.P.; Kluivers, K.B.; Vierhout, M.E.

    2007-01-01

    Endometrial ablation is used extensively to treat dysfunctional bleeding. Since the introduction of Essure tubal sterilization, this permanent contraception method has been widely used. Both endometrial ablation and Essure sterilization are procedures reported to have only a few complications. We

  8. Link Analysis

    Science.gov (United States)

    Donoho, Steve

    Link analysis is a collection of techniques that operate on data that can be represented as nodes and links. This chapter surveys a variety of techniques including subgraph matching, finding cliques and K-plexes, maximizing spread of influence, visualization, finding hubs and authorities, and combining with traditional techniques (classification, clustering, etc). It also surveys applications including social network analysis, viral marketing, Internet search, fraud detection, and crime prevention.

  9. Kinetic depletion model for pellet ablation

    Energy Technology Data Exchange (ETDEWEB)

    Kuteev, Boris V. [State Technical Univ., St. Petersburg (Russian Federation)

    2001-11-01

    A kinetic model for depletion effect, which determines pellet ablation when the pellet passes a rational magnetic surface, is formulated. The model predicts a moderate decrease of the ablation rate compared with the earlier considered monoenergy versions [1, 2]. For typical T-10 conditions the ablation rate reduces by a reactor of 2.5 when the 1-mm pellet penetrates through the plasma center. A substantial deceleration of pellets -about 15% per centimeter of low shire rational q region; is predicted. Penetration for Low Field Side and High Field Side injections is considered taking into account modification of the electron distribution function by toroidal magnetic field. It is shown that Shafranov shift and toroidal effects yield the penetration length for HFS injection higher by a factor of 1.5. This fact should be taken into account when plasma-shielding effects on penetration are considered. (author)

  10. Advances in Imaging for Atrial Fibrillation Ablation

    Directory of Open Access Journals (Sweden)

    Andrew D'Silva

    2011-01-01

    Full Text Available Over the last fifteen years, our understanding of the pathophysiology of atrial fibrillation (AF has paved the way for ablation to be utilized as an effective treatment option. With the aim of gaining more detailed anatomical representation, advances have been made using various imaging modalities, both before and during the ablation procedure, in planning and execution. Options have flourished from procedural fluoroscopy, electroanatomic mapping systems, preprocedural computed tomography (CT, magnetic resonance imaging (MRI, ultrasound, and combinations of these technologies. Exciting work is underway in an effort to allow the electrophysiologist to assess scar formation in real time. One advantage would be to lessen the learning curve for what are very complex procedures. The hope of these developments is to improve the likelihood of a successful ablation procedure and to allow more patients access to this treatment.

  11. Image-Guided Spinal Ablation: A Review

    Energy Technology Data Exchange (ETDEWEB)

    Tsoumakidou, Georgia, E-mail: gtsoumakidou@yahoo.com; Koch, Guillaume, E-mail: guillaume.koch@chru-strasbourg.fr; Caudrelier, Jean, E-mail: jean.caudrelier@chru-strasbourg.fr; Garnon, Julien, E-mail: julien.garnon@chru-strasbourg.fr; Cazzato, Roberto Luigi, E-mail: roberto-luigi.cazzato@chru-strasbourg.fr; Edalat, Faramarz, E-mail: faramarz.edalat@gmail.com; Gangi, Afshin, E-mail: gangi@unistra.fr [Strasbourg University Hospital (France)

    2016-09-15

    The image-guided thermal ablation procedures can be used to treat a variety of benign and malignant spinal tumours. Small size osteoid osteoma can be treated with laser or radiofrequency. Larger tumours (osteoblastoma, aneurysmal bone cyst and metastasis) can be addressed with radiofrequency or cryoablation. Results on the literature of spinal microwave ablation are scarce, and thus it should be used with caution. A distinct advantage of cryoablation is the ability to monitor the ice-ball by intermittent CT or MRI. The different thermal insulation, temperature and electrophysiological monitoring techniques should be applied. Cautious pre-procedural planning and intermittent intra-procedural monitoring of the ablation zone can help reduce neural complications. Tumour histology, patient clinical-functional status and life-expectancy should define the most efficient and least disabling treatment option.

  12. Deep Dive Topic: Choosing between ablators

    Energy Technology Data Exchange (ETDEWEB)

    Hurricane, O. A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Thomas, C. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Olson, R. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-07-14

    Recent data on implosions using identical hohlraums and very similar laser drives underscores the conundrum of making a clear choice of one ablator over another. Table I shows a comparison of Be and CH in a nominal length, gold, 575 μm-diameter, 1.6 mg/cc He gas-fill hohlraum while Table II shows a comparison of undoped HDC and CH in a +700 length, gold, 575 μm diameter, 1.6 mg/cc He gas fill hohlraum. As can be seen in the tables, the net integrated fusion performance of these ablators is the same to within error bars. In the case of the undoped HDC and CH ablators, the hot spot shapes of the implosions were nearly indistinguishable for the experiments listed in Table II.

  13. Numerical Modeling of Ablation Heat Transfer

    Science.gov (United States)

    Ewing, Mark E.; Laker, Travis S.; Walker, David T.

    2013-01-01

    A unique numerical method has been developed for solving one-dimensional ablation heat transfer problems. This paper provides a comprehensive description of the method, along with detailed derivations of the governing equations. This methodology supports solutions for traditional ablation modeling including such effects as heat transfer, material decomposition, pyrolysis gas permeation and heat exchange, and thermochemical surface erosion. The numerical scheme utilizes a control-volume approach with a variable grid to account for surface movement. This method directly supports implementation of nontraditional models such as material swelling and mechanical erosion, extending capabilities for modeling complex ablation phenomena. Verifications of the numerical implementation are provided using analytical solutions, code comparisons, and the method of manufactured solutions. These verifications are used to demonstrate solution accuracy and proper error convergence rates. A simple demonstration of a mechanical erosion (spallation) model is also provided to illustrate the unique capabilities of the method.

  14. Catheter Ablation of Fascicular Ventricular Tachycardia

    Directory of Open Access Journals (Sweden)

    Hygriv B. Rao

    2008-08-01

    Full Text Available Fascicular ventricular tachycardia (VT is an idiopathic VT with right bundle branch block morphology and left-axis deviation occuring predominantly in young males. Fascicular tachycardia has been classified into three subtypes namely, left posterior fascicular VT, left anterior fascicular VT and upper septal fascicular VT. The mechanism of this tachycardia is believed to be localized reentry close to the fascicle of the left bundle branch. The reentrant circuit is composed of a verapamil sensitive zone, activated antegradely during tachycardia and the fast conduction Purkinje fibers activated retrogradely during tachycardia recorded as the pre Purkinje and the Purkinje potentials respectively. Catheter ablation is the preferred choice of therapy in patients with fascicular VT. Ablation is carried out during tachycardia, using conventional mapping techniques in majority of the patients, while three dimensional mapping and sinus rhythm ablation is reserved for patients with nonmappable tachycardia.

  15. Assessment of ablative margin by unenhanced magnetic resonance imaging after radiofrequency ablation for hepatocellular carcinoma.

    Science.gov (United States)

    Koda, Masahiko; Tokunaga, Shiho; Miyoshi, Kennichi; Kishina, Manabu; Fujise, Yuki; Kato, Jun; Matono, Tomomitsu; Okamoto, Kinya; Murawaki, Yoshikazu; Kakite, Suguru

    2012-10-01

    The aim of this study was to evaluate the feasibility of magnetic resonance imaging (MRI) without a contrast agent to visualize the ablative margin after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC), compared with enhanced CT. Twenty-five HCCs in 19 patients were treated by RFA. T1-weighted MRI was performed before and after RFA, and the signal intensities of the tumors and surrounding liver tissues were measured. Treatment efficacy was assessed based on three grades: margin (+), a continuous high-intensity rim around the index tumor; margin zero, a partially discontinuous high-intensity rim; margin (-), the tumor extends beyond the high-intensity rim. Twelve (86%) of fourteen low-intensity tumors on the pre-MRI were visualized as low-intensity tumors on post-MRI, and the ablative margins were visualized as high-intensity rims. Two (67%) of three high-intensity tumors on pre-MRI were visualized as higher-intensity tumors in the high-intensity ablative margin. Because the signal intensities of tumors and surrounding tissues in 14 tumors that were low- or high-intensity tumors on pre-MRI increased to the same extent, the tumors and ablative margin could be distinguished on post images. In 6 (75%) of the 8 iso-intensity tumors on pre-MRI, the ablative margin and tumor could also not be discriminated on post-MRI. The overall agreement between MRI and CT for the ablative margin was good (κ coefficient=0.716, p=0.00002). In 82% of low- or high-intensity tumors on pre-MRI, post-MRI without a contrast agent enabled visualization of the ablative margin as a high-intensity rim, and it was possible to evaluate the ablative margin earlier and easier than with enhanced CT. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  16. Subcellular analysis by laser ablation electrospray ionization mass spectrometry

    Science.gov (United States)

    Vertes, Akos; Stolee, Jessica A; Shrestha, Bindesh

    2014-12-02

    In various embodiments, a method of laser ablation electrospray ionization mass spectrometry (LAESI-MS) may generally comprise micro-dissecting a cell comprising at least one of a cell wall and a cell membrane to expose at least one subcellular component therein, ablating the at least one subcellular component by an infrared laser pulse to form an ablation plume, intercepting the ablation plume by an electrospray plume to form ions, and detecting the ions by mass spectrometry.

  17. Catheter Ablation of Tachyarrhythmias in Small Children

    Directory of Open Access Journals (Sweden)

    Andrew D. Blaufox

    2005-01-01

    Full Text Available An estimated 80,000-100,000 radiofrequency ablation (RFA procedures are performed in the United States each year.1 Approximately 1% of these are performed on pediatric patients at centers that contribute data to the Pediatric Radiofrequency Registry.2 Previous reports from this registry have demonstrated that RFA can safely and effectively be performed in pediatric patients.3,4 However, patients weighing less than 15 kg have been identified as being at greater risk for complications.3,4 Consequently, there has been great reluctance to perform RFA in small children such that children weighing less than 15 kg only represent approximately 6% of the pediatric RFA experience2 despite the fact that this age group carries the highest incidence of tachycardia, particularly supraventricular tachycardia (SVT.5 Factors other than the risk of complications contribute to the lower incidence of RFA in this group, including the natural history of the most common tachycardias (SVT, technical issues with RFA in small hearts, and the potential unknown long-term effects of RF applications in the maturing myocardium. Conversely, there are several reasons why ablation may be desirable in small children, including greater difficulties with medical management,6,7,8 the higher risk for hemodynamic compromise during tachycardia in infants with congenital heart disease (CHD, and the inability of these small children to effectively communicate their symptoms thereby making it more likely that their symptoms may go unnoticed until the children become more seriously ill. Before ultimately deciding that catheter ablation is indicated in small children, one must consider which tachycardias are likely to be ablated, the clinical presentation of these tachycardias, alternatives to ablation, the relative potential for success or complications, and modifications of the procedure that might reduce the risk of ablation in this group.

  18. Percutaneous epicardial ablation in ventricular arrhythmias.

    Science.gov (United States)

    Galvão Santos, Pedro; Cavaco, Diogo; Adragão, Pedro; Scanavacca, Mauricio; Reis Santos, Katya; Belo Morgado, Francisco; Carmo, Pedro; Costa, Francisco; Bernardo, Ricardo; Nunes, Manuela; Abecasis, Miguel; Neves, José; Mendes, Miguel

    2014-05-01

    Reentrant circuits of ventricular tachycardia may involve not only the endocardium but also the epicardium. Epicardial ablation can be useful in these situations. The aim of this study was to assess efficacy, safety and complications in a series of consecutive patients who underwent ablation of ventricular tachycardia with epicardial mapping. The study included all patients undergoing ventricular tachycardia ablation with epicardial mapping from 2004 to 2012. Of a total of 95 ablations, an epicardial approach was attempted in nine patients, eight male, mean age 58±12 years. Endocardial mapping was performed in all patients previously or simultaneously. The etiology of the arrhythmia was non-ischemic in eight patients and ischemic in one. We compared the number of events in the six months prior to the epicardial procedure and six months after. Percutaneous epicardial access was achieved in eight patients. In one case it was not possible due to the presence of adhesions. In none of the patients was the procedure repeated and there were no major complications during hospitalization. In a mean follow-up of 3.5±1.2 years, one patient suffered stroke; there were no other medium-to-long-term complications and the number of ventricular tachycardia episodes was reduced in all patients after ablation. Epicardial radiofrequency ablation of ventricular tachycardia was effective in reducing morbidity in eight patients, with a low risk of complications in the short and medium-to-long term. Copyright © 2012 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  19. Ablative Rocket Deflector Testing and Computational Modeling

    Science.gov (United States)

    Allgood, Daniel C.; Lott, Jeffrey W.; Raines, Nickey

    2010-01-01

    A deflector risk mitigation program was recently conducted at the NASA Stennis Space Center. The primary objective was to develop a database that characterizes the behavior of industry-grade refractory materials subjected to rocket plume impingement conditions commonly experienced on static test stands. The program consisted of short and long duration engine tests where the supersonic exhaust flow from the engine impinged on an ablative panel. Quasi time-dependent erosion depths and patterns generated by the plume impingement were recorded for a variety of different ablative materials. The erosion behavior was found to be highly dependent on the material s composition and corresponding thermal properties. For example, in the case of the HP CAST 93Z ablative material, the erosion rate actually decreased under continued thermal heating conditions due to the formation of a low thermal conductivity "crystallization" layer. The "crystallization" layer produced near the surface of the material provided an effective insulation from the hot rocket exhaust plume. To gain further insight into the complex interaction of the plume with the ablative deflector, computational fluid dynamic modeling was performed in parallel to the ablative panel testing. The results from the current study demonstrated that locally high heating occurred due to shock reflections. These localized regions of shock-induced heat flux resulted in non-uniform erosion of the ablative panels. In turn, it was observed that the non-uniform erosion exacerbated the localized shock heating causing eventual plume separation and reversed flow for long duration tests under certain conditions. Overall, the flow simulations compared very well with the available experimental data obtained during this project.

  20. Vascular endothelial growth factor (VEGF-C - a potent risk factor in children diagnosed with stadium 4 neuroblastoma.

    Directory of Open Access Journals (Sweden)

    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.

  1. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer.

    Directory of Open Access Journals (Sweden)

    Christina L Roland

    2009-11-01

    Full Text Available The effect of blocking VEGF activity in solid tumors extends beyond inhibition of angiogenesis. However, no studies have compared the effectiveness of mechanistically different anti-VEGF inhibitors with respect to changes in tumor growth and alterations in the tumor microenvironment. In this study we use three distinct breast cancer models, a MDA-MB-231 xenograft model, a 4T1 syngenic model, and a transgenic model using MMTV-PyMT mice, to explore the effects of various anti-VEGF therapies on tumor vasculature, immune cell infiltration, and cytokine levels. Tumor vasculature and immune cell infiltration were evaluated using immunohistochemistry. Cytokine levels were evaluated using ELISA and electrochemiluminescence. We found that blocking the activation of VEGF receptor resulted in changes in intra-tumoral cytokine levels, specifically IL-1beta, IL-6 and CXCL1. Modulation of the level these cytokines is important for controlling immune cell infiltration and ultimately tumor growth. Furthermore, we demonstrate that selective inhibition of VEGF binding to VEGFR2 with r84 is more effective at controlling tumor growth and inhibiting the infiltration of suppressive immune cells (MDSC, Treg, macrophages while increasing the mature dendritic cell fraction than other anti-VEGF strategies. In addition, we found that changes in serum IL-1beta and IL-6 levels correlated with response to therapy, identifying two possible biomarkers for assessing the effectiveness of anti-VEGF therapy in breast cancer patients.

  2. VEGF and eNOS Expression in Umbilical Cord from Pregnancy Complicated by Hypertensive Disorder with Different Severity

    Directory of Open Access Journals (Sweden)

    K. Bhavina

    2014-01-01

    Full Text Available Background. Reduced blood flow in hypertensive pregnancy may influence the production vasoconstrictors; subsequently the vessel remains in highly contracted state. NO is a vasodilator; VEGF influences its synthesis by regulating eNOS production. Aim of our study was to evaluate the expression of VEGF and eNOS in different severity of hypertensive pregnancy. Methods. Study was conducted in 4 groups with 40 members: group 1—control, group 2—gestational hypertension, group 3—mild preeclampsia, and group 4—severe preeclampsia. Fetal end of umbilical cord was taken and follows IHC staining protocol for VEGF and eNOS antibody. Staining intensity were measured by semiquantitative scoring method. Mann Whitney U test was used to compare each group. Results. Decreased expression of both VEGF and eNOS was found in hypertensive condition than in normal condition. Among hypertensive group, severe preeclamptic group showed more intensity in staining than gestational hypertension and mild preeclampsia. Conclusion. Reduction of VEGF and eNOS in gestational hypertension may lead to hypoperfusion and subsequent hypoxia of fetus in hypertensive pregnancy. The developed hypoxic state may upregulate the synthesis of VEGF and thereby eNOS. Increased expression of VEGF and eNOS in severe group may be a compensatory mechanism to dilate the blood vessels and to improve blood flow of fetus.

  3. Expression of VEGF in Periodontal Tissues of Type II Diabetes Mellitus Patients with Chronic Periodontitis -an Immunohistochemical Study.

    Science.gov (United States)

    Ramya; Kumar, Senthil

    2014-08-01

    Vascular endothelial growth factor (VEGF) induces proliferation of endothelial cells, stimulates angiogenesis, and increases vascular permeability, but information about its role in periodontal diseases is limited. The aim of this study is to determine the association between VEGF expression in healthy and periodontally diseased tissues of healthy and diabetic patients. Seventeen systemically healthy and 17 Type 2 diabetic patients (DM), all diagnosed with periodontitis were enrolled into the study. Gingival samples were collected from both periodontal and healthy sites in all patients. Each patient served as his/her own control samples were subjected to immunohistochemical analysis. The diseased sites of diabetic subjects expressed higher level of VEGF when compared to diseased sites of non diabetic subjects with chronic periodontitis, VEGF was observed in healthy periodontal tissues of both diabetic and systemically healthy people with periodontitis and VEGF was intensely present in monocytes and macrophages. The increased expression of VEGF in diseased sites of diabetic patients suggests that diabetes mellitus might have direct influence over VEGF expression.

  4. 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.

  5. Ranibizumab interacts with the VEGF-A/VEGFR-2 signaling pathway in human RPE cells at different levels.

    Science.gov (United States)

    Ranjbar, Mahdy; Brinkmann, Max Philipp; Tura, Aysegül; Rudolf, Martin; Miura, Yoko; Grisanti, Salvatore

    2016-07-01

    Vascular endothelial growth factor (VEGF) secreted by the retinal pigment epithelium (RPE) plays an important role in ocular homeostasis, but also in diseases, most notably age-related macular degeneration (AMD). To date, anti-VEGF drugs like ranibizumab have been shown to be most effective in treating these pathologic conditions. However, clinical trials suggest that the RPE could degenerate and perish through anti-VEGF treatment. Herein, we evaluated possible pathways and outcomes of the interaction between ranibizumab and human RPE cells (ARPE-19). Results indicate that ranibizumab affects the VEGF-A metabolism in RPE cells from an extra- as well as intracellular site. The drug is taken up into the cells, with the VEGF receptor 2 (VEGFR-2) being involved, and decreases VEGF-A protein levels within the cells as well as extracellularly. Oxidative stress plays a key role in various inflammatory disorders of the eye. Our results suggest that oxidative stress inhibits RPE cell proliferation. This anti-proliferative effect on RPE cells is significantly enhanced through ranibizumab, which does not inhibit RPE cell proliferation substantially in absence of relevant oxidative stress. Therefore, we emphasize that anti-VEGF treatment should be selected carefully in AMD patients with preexistent extensive RPE atrophy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Biliary Infection May Exacerbate Biliary Cystogenesis Through the Induction of VEGF in Cholangiocytes of the Polycystic Kidney (PCK) Rat

    Science.gov (United States)

    Ren, Xiang Shan; Sato, Yasunori; Harada, Kenichi; Sasaki, Motoko; Yoneda, Norihide; Lin, Zhen Hua; Nakanuma, Yasuni

    2011-01-01

    Cholangitis arising from biliary infection dominates the prognosis in Caroli's disease. To clarify the influences of bacterial infection on the biliary cystogenesis, in vivo and in vitro studies were performed using the polycystic kidney (PCK) rat as an animal model of Caroli's disease. Cholangitis became a frequent histological finding in aged PCK rats, and neovascularization around the bile ducts also increased in aged PCK rats. Immunohistochemistry revealed that expression of vascular endothelial growth factor (VEGF) was increased in PCK rat biliary epithelium. In vitro, PCK cholangiocytes overexpressed VEGF, and the supernatant of cultured PCK cholangiocytes significantly increased the proliferative activity, migration, and tube formation of cultured rat vascular endothelial cells. Stimulation with lipopolysaccharide (LPS) further induced VEGF expression in PCK cholangiocytes, which might be mediated by signaling pathways involving phosphatidylinositol 3-kinase (PI3K)-Akt and c-Jun N-terminal kinase (JNK). Both LPS and VEGF increased cell proliferative activity in PCK cholangiocytes, and siRNA against VEGF significantly reduced LPS-induced cell proliferation. Thus, LPS-induced overexpression of VEGF in the biliary epithelium may lead to hypervascularity around the bile ducts; concurrently, LPS and VEGF act as cell proliferation factors for cholangiocytes. Biliary infection may thus exacerbate biliary cystogenesis in PCK rats. PMID:22015458

  7. High throughput solar cell ablation system

    Science.gov (United States)

    Harley, Gabriel; Pass, Thomas; Cousins, Peter John; Viatella, John

    2012-09-11

    A solar cell is formed using a solar cell ablation system. The ablation system includes a single laser source and several laser scanners. The laser scanners include a master laser scanner, with the rest of the laser scanners being slaved to the master laser scanner. A laser beam from the laser source is split into several laser beams, with the laser beams being scanned onto corresponding wafers using the laser scanners in accordance with one or more patterns. The laser beams may be scanned on the wafers using the same or different power levels of the laser source.

  8. The Atrial Fibrillation Ablation Pilot Study

    DEFF Research Database (Denmark)

    Arbelo, Elena; Brugada, Josep; Hindricks, Gerhard

    2014-01-01

    . A web-based case report form captured information on pre-procedural, procedural, and 1-year follow-up data. Between October 2010 and May 2011, 1410 patients were included and 1391 underwent an AFib ablation (98.7%). A total of 1300 patients (93.5%) completed a follow-up control 367 ± 42 days after...... the procedure. Arrhythmia documentation was done by an electrocardiogram in 76%, Holter-monitoring in 52%, transtelephonic monitoring in 8%, and/or implanted systems in 4.5%. Over 50% became asymptomatic. Twenty-one per cent were re-admitted due to post-ablation arrhythmias. Success without antiarrhythmic drugs...

  9. General Model for Multicomponent Ablation Thermochemistry

    Science.gov (United States)

    Milos, Frank S.; Marschall, Jochen; Rasky, Daniel J. (Technical Monitor)

    1994-01-01

    A previous paper (AIAA 94-2042) presented equations and numerical procedures for modeling the thermochemical ablation and pyrolysis of thermal protection materials which contain multiple surface species. This work describes modifications and enhancements to the Multicomponent Ablation Thermochemistry (MAT) theory and code for application to the general case which includes surface area constraints, rate limited surface reactions, and non-thermochemical mass loss (failure). Detailed results and comparisons with data are presented for the Shuttle Orbiter reinforced carbon-carbon oxidation protection system which contains a mixture of sodium silicate (Na2SiO3), silica (SiO2), silicon carbide (SiC), and carbon (C).

  10. Testing of Advanced Conformal Ablative TPS

    Science.gov (United States)

    Gasch, Matthew; Agrawal, Parul; Beck, Robin

    2013-01-01

    In support of the CA250 project, this paper details the results of a test campaign that was conducted at the Ames Arcjet Facility, wherein several novel low density thermal protection (TPS) materials were evaluated in an entry like environment. The motivation for these tests was to investigate whether novel conformal ablative TPS materials can perform under high heat flux and shear environment as a viable alternative to rigid ablators like PICA or Avcoat for missions like MSL and beyond. A conformable TPS over a rigid aeroshell has the potential to solve a number of challenges faced by traditional rigid TPS materials (such as tiled Phenolic Impregnated Carbon Ablator (PICA) system on MSL, and honeycomb-based Avcoat on the Orion Multi Purpose Crew Vehicle (MPCV)). The compliant (high strain to failure) nature of the conformable ablative materials will allow better integration of the TPS with the underlying aeroshell structure and enable monolithic-like configuration and larger segments to be used in fabrication.A novel SPRITE1 architecture, developed by the researchers at NASA Ames was used for arcjet testing. This small probe like configuration with 450 spherecone, enabled us to test the materials in a combination of high heat flux, pressure and shear environment. The heat flux near the nose were in the range of 500-1000 W/sq cm whereas in the flank section of the test article the magnitudes were about 50 of the nose, 250-500W/sq cm range. There were two candidate conformable materials under consideration for this test series. Both test materials are low density (0.28 g/cu cm) similar to Phenolic Impregnated Carbon Ablator (PICA) or Silicone Impregnated Refractory Ceramic Ablator (SIRCA) and are comprised of: A flexible carbon substrate (Carbon felt) infiltrated with an ablative resin system: phenolic (Conformal-PICA) or silicone (Conformal-SICA). The test demonstrated a successful performance of both the conformable ablators for heat flux conditions between 50

  11. Radiofrequency Ablation Complicated by Skin Burn

    Science.gov (United States)

    Huffman, S.D.; Huffman, N.P.; Lewandowski, Robert J.; Brown, Daniel B.

    2011-01-01

    Radiofrequency (RF) ablation has been increasingly utilized as a minimally invasive treatment for primary and metastatic liver tumors, as well as tumors in the kidneys, bones, and adrenal glands. The development of high-current RF ablation has subsequently led to an increased risk of thermal skin injuries at the grounding pad site. The incidence of skin burns in recent studies ranges from 0.1–3.2% for severe skin burns (second-/third-degree), and from 5–33% for first-degree burns.1–3 PMID:22654258

  12. Targeted VEGF-triggered release of an anti-cancer drug from aptamer-functionalized metal-organic framework nanoparticles.

    Science.gov (United States)

    Chen, Wei-Hai; Yang Sung, Sohn; Fadeev, Michael; Cecconello, Alessandro; Nechushtai, Rachel; Willner, Itamar

    2018-02-21

    Amino-triphenyl dicarboxylate-bridged Zr 4+ metal-organic framework nanoparticles (NMOFs), 100-130 nm, are modified with a nucleic acid complementary to the VEGF aptamer. The nucleic acid-functionalized NMOFs were loaded with the anti-cancer drug doxorubicin (or Rhodamine 6G as a drug model), and the loaded NMOFs were capped by hybridization with the VEGF aptamer that yielded VEGF-responsive duplex nucleic acid gates. In the presence of VEGF, a biomarker over-expressed in cancer cells, selective unlocking of the gates proceeds through the formation of VEGF/aptamer complexes, resulting in the release of the loads. In addition, the VEGF aptamer locking units were conjugated to the AS1411 aptamer sequence that binds to nucleolin receptors associated with cancer cells, resulting in the construction of cancer-cell targeted VEGF-responsive doxorubicin-loaded NMOFs. The different drug-loaded stimuli-responsive NMOFs reveal selective permeation into MDA-MB-231 breast cancer cells, compared to their incorporation into normal MCF-10A breast cells, with a two-fold enhanced incorporation into the MDA-MB-231 cells of the AS1411 aptamer-functionalized NMOFs. Cytotoxicity experiments revealed impressive selective apoptosis of the doxorubicin-loaded NMOFs towards the MDA-MB-231 cancer cells compared to the normal MCF-10A breast cells. A 55% and 70% MDA-MB-231 cell apoptosis was observed upon subjecting the cells to the VEGF aptamer and the VEGF aptamer/AS1411 aptamer conjugate-caged NMOFs, respectively, for a time-interval of three days, where only <10% apoptosis of the MCF-10A cells was observed under similar conditions.

  13. The mRNA expression of hTERT in human breast carcinomas correlates with VEGF expression

    Directory of Open Access Journals (Sweden)

    Kirkpatrick Katharine L

    2004-01-01

    Full Text Available Abstract Background Telomerase is a ribonucleoprotein enzyme that synthesises telomeres after cell division and maintains chromosomal stability leading to cellular immortalisation. hTERT (human telomerase reverse transcriptase is the rate-limiting determinant of telomerase reactivation. Telomerase has been associated with negative prognostic indicators in some studies. The present study aims to detect any correlation between hTERT and the negative prognostic indicators VEGF and PCNA by quantitatively measuring the mRNA expression of these genes in human breast cancer and in adjacent non-cancerous tissue (ANCT. Materials and methods RNA was extracted from 38 breast carcinomas and 40 ANCT. hTERT and VEGF165, VEGF189 and PCNA mRNA expressions were estimated by reverse transcriptase-PCR (RT-PCR and Taqman methodology. Results The level of expression of VEGF-165 and PCNA was significantly higher in carcinoma tissue than ANCT (p = 0.02. The ratio of VEGF165/189 expression was significantly higher in breast carcinoma than ANCT (p = 0.025. hTERT mRNA expression correlated with VEGF-189 mRNA (p = 0.008 and VEGF165 (p = 0.07. Conclusions hTERT mRNA expression is associated with the expression of the VEGF189 and 165 isoforms. This could explain the poorer prognosis reported in breast tumours expressing high levels of hTERT. The relative expression of the VEGF isoforms is significantly different in breast tumour to ANCT, and this may be important in breast carcinogenesis.

  14. VEGF serum concentrations in patients with long bone fractures: a comparison between impaired and normal fracture healing.

    Science.gov (United States)

    Sarahrudi, Kambiz; Thomas, Anita; Braunsteiner, Tomas; Wolf, Harald; Vécsei, Vilmos; Aharinejad, Seyedhossein

    2009-10-01

    Vascular endothelial growth factor (VEGF) plays an important role in the bone repair process as a potent mediator of angiogenesis and it influences directly osteoblast differentiation. Inhibiting VEGF suppresses angiogenesis and callus mineralization in animals. However, no data exist so far on systemic expression of VEGF with regard to delayed or failed fracture healing in humans. One hundred fourteen patients with long bone fractures were included in the study. Serum samples were collected over a period of 6 months following a standardized time schedule. VEGF serum concentrations were measured. Patients were assigned to one of two groups according to their course of fracture healing. The first group contained 103 patients with physiological fracture healing. Eleven patients with delayed or nonunions formed the second group of the study. In addition, 33 healthy volunteers served as controls. An increase of VEGF serum concentration within the first 2 weeks after fracture in both groups with a following decrease within 6 months after trauma was observed. Serum VEGF concentrations in patients with impaired fracture healing were higher compared to the patients with physiological healing during the entire observation period. However, statistically significant differences were not observed at any time point between both groups. VEGF concentrations in both groups were significantly higher than those in controls. The present results show significantly elevated serum concentrations of VEGF in patients after fracture of long bones especially at the initial healing phase, indicating the importance of VEGF in the process of fracture healing in humans. (c) 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  15. Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart.

    Science.gov (United States)

    Tao, Zhengxian; Chen, Bo; Tan, Xiao; Zhao, Yingming; Wang, Liansheng; Zhu, Tiebing; Cao, Kejiang; Yang, Zhijian; Kan, Yuet Wai; Su, Hua

    2011-02-01

    VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac-specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis.

  16. Pulsed laser ablation of LaSrCoO

    NARCIS (Netherlands)

    Span, E.A.F.; Roesthuis, Frank J.G.; Blank, David H.A.; Rogalla, Horst

    1999-01-01

    The ablation process of La0.5Sr0.5CoO3 by a spatial uniform 248 nm excimer laser beam has been characterized. Ablation rates, changes in the target surface morphology and composition have been studied as a function of the laser fluence. The dependence of the ablation rate on the laser fluence has

  17. Sensors measure surface ablation rate of reentry vehicle heat shield

    Science.gov (United States)

    Russel, J. M., III

    1966-01-01

    Sensors measure surface erosion rate of ablating material in reentry vehicle heat shield. Each sensor, which is placed at precise depths in the heat shield is activated when the ablator surface erodes to the location of a sensing point. Sensor depth and activation time determine ablator surface erosion rate.

  18. Indications for Ablative Surgery in Extremity Musculoskeletal Tumours

    African Journals Online (AJOL)

    Background: Surgical options for treatment of extremity musculoskeletal tumours include excision [limb sparing] surgery or amputation [limb ablation]. Ablative surgery is for advanced extremity musculoskeletal tumours when limb salvage surgery is not feasible. Objective: To determine the indications for ablative surgery in ...

  19. VEGF receptor antagonist Cyclo-VEGI reduces inflammatory reactivity and vascular leakiness and is neuroprotective against acute excitotoxic striatal insult

    Directory of Open Access Journals (Sweden)

    McLarnon James G

    2008-05-01

    Full Text Available Abstract Background Excitotoxic brain insult is associated with extensive neuronal damage but could also cause inflammatory reactivity and vascular remodeling. The effects of the vascular endothelial growth factor (VEGF inhibitor, Cyclo-VEGI on expression of VEGF, microgliosis and astrogliosis, blood-brain barrier (BBB integrity and neuronal viability have been studied following intra-striatal injection of the excitotoxin, quinolinic acid (QUIN. The purpose of this study was to examine VEGF-dependent inflammatory responses in excitotoxin-injected brain and their dependence on pharmacological antagonism of VEGF receptors. Methods Single and double immunofluorescence staining of cellular (microglia, astrocyte, neuron responses and dye and protein infiltration of blood-brain barrier have been applied in the absence, and presence, of pharmacological modulation using a VEGF receptor antagonist, Cyclo-VEGI. Dunn-Bonferroni statistical analysis was used to measure for significance between animal groups. Results Detailed analysis, at a single time point of 1 d post-QUIN injection, showed excitotoxin-injected striatum to exhibit marked increases in microgliosis (ED1 marker, astrogliosis (GFAP marker and VEGF expression, compared with PBS injection. Single and double immunostaining demonstrated significant effects of Cyclo-VEGI treatment of QUIN-injected striatum to inhibit microgliosis (by 38%, ED1/VEGF (by 42% and VEGF striatal immunoreactivity (by 43%; astrogliosis and GFAP/VEGF were not significantly altered with Cyclo-VEGI treatment. Leakiness of BBB was indicated by infiltration of Evans blue dye and plasma protein fibrinogen into QUIN-injected striatum with barrier permeability restored by 62% (Evans blue permeability and 49% (fibrinogen permeability with Cyclo-VEGI application. QUIN-induced toxicity was demonstrated with loss of striatal neurons (NeuN marker and increased neuronal damage (Fluoro-Jade marker with significant neuroprotection

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

    Energy Technology Data Exchange (ETDEWEB)

    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

  1. Concentrations of VEGF and VEGFR1 in paired tumor arteries and veins in patients with rectal cancer

    DEFF Research Database (Denmark)

    Svendsen, Mads N; Lykke, Jakob; Werther, Kim

    2004-01-01

    a peripheral vein and intraoperative blood samples from a tumor artery, a tumor vein, and from a peripheral vein were drawn from 28 patients undergoing elective surgical resection of primary rectal cancer. Plasma concentrations of VEGF and VEGFR1 were determined by ELISA. Counts of white blood cells......VEGFR1 concentrations from preoperative to intraoperative samples was observed. There was a significant efflux of neutrophils to the tumor, but none of the observed changes in plasma VEGF or VEGFR1 levels correlated to changes in counts of white blood cells or platelets (sVEGF: 0.33 ... in counts of white blood cells or platelets....

  2. Is It Complete Left Bundle Branch Block? Just Ablate the Right Bundle.

    Science.gov (United States)

    Ali, Hussam; Lupo, Pierpaolo; Foresti, Sara; De Ambroggi, Guido; Epicoco, Gianluca; Fundaliotis, Angelica; Cappato, Riccardo

    2017-03-01

    Complete left bundle branch block (LBBB) is established according to standard electrocardiographic criteria. However, functional LBBB may be rate-dependent or can perpetuate during tachycardia due to repetitive concealed retrograde penetration of impulses through the contralateral bundle "linking phenomenon." In this brief article, we present two patients with basal complete LBBB in whom ablating the right bundle unmasked the actual antegrade conduction capabilities of the left bundle. These cases highlight intriguing overlap between electrophysiological concepts of complete block, linking, extremely slow, and concealed conduction. © 2016 Wiley Periodicals, Inc.

  3. Cryospray ablation using pressurized CO2 for ablation of Barrett's esophagus with early neoplasia: early termination of a prospective series

    NARCIS (Netherlands)

    Verbeek, R.E.; Vleggaar, F.P.; Kate, F.J. ten; Baal, J.W. van; Siersema, P.D.

    2015-01-01

    BACKGROUND: Cryotherapy is a relatively novel ablation modality for the endoscopic ablation of Barrett's esophagus (BE). Data on the use of pressurized carbon dioxide (CO2) gas for cryoablation are scarce. STUDY AIM: To determine the efficacy and safety of cryospray ablation using pressurized CO2

  4. A review of the safety aspects of radio frequency ablation

    Directory of Open Access Journals (Sweden)

    Abhishek Bhaskaran

    2015-09-01

    Full Text Available In light of recent reports showing high incidence of silent cerebral infarcts and organized atrial arrhythmias following radiofrequency (RF atrial fibrillation (AF ablation, a review of its safety aspects is timely. Serious complications do occur during supraventricular tachycardia (SVT ablations and knowledge of their incidence is important when deciding whether to proceed with ablation. Evidence is emerging for the probable role of prophylactic ischemic scar ablation to prevent VT. This might increase the number of procedures performed. Here we look at the various complications of RF ablation and also the methods to minimize them. Electronic database was searched for relevant articles from 1990 to 2015. With better awareness and technological advancements in RF ablation the incidence of complications has improved considerably. In AF ablation it has decreased from 6% to less than 4% comprising of vascular complications, cardiac tamponade, stroke, phrenic nerve injury, pulmonary vein stenosis, atrio-esophageal fistula (AEF and death. Safety of SVT ablation has also improved with less than 1% incidence of AV node injury in AVNRT ablation. In VT ablation the incidence of major complications was 5–11%, up to 3.4%, up to 1.8% and 4.1–8.8% in patients with structural heart disease, without structural heart disease, prophylactic ablations and epicardial ablations respectively. Vascular and pericardial complications dominated endocardial and epicardial VT ablations respectively. Up to 3% mortality and similar rates of tamponade were reported in endocardial VT ablation. Recent reports about the high incidence of asymptomatic cerebral embolism during AF ablation are concerning, warranting more research into its etiology and prevention.

  5. Lymphatic vessel density and VEGF-C expression as independent predictors of melanoma metastases.

    Science.gov (United States)

    Špirić, Zorica; Eri, Živka; Erić, Mirela

    2017-11-01

    In many patients, the clinical behaviour of cutaneous melanoma is very difficult to predict by traditional histologic and clinical parameters. This study aimed to examine the role of quantitative parameters of tumour lymphangiogenesis and vascular endothelial growth factor (VEGF)-C in predicting metastatic risk in patients with cutaneous melanoma. One hundred melanoma specimens were stained with lymphatic-specific antibody D2-40 and with anti-VEGF-C antibody. Quantitative parameters of lymphangiogenesis-lymphatic vessel density (LVD) and lymphatic vessel area (LVA)-were determined by computer-assisted morphometric analysis. Moderate or strong staining was assessed as a positive expression of VEGF-C in tumour cells. Univariate analysis revealed that intratumoural LVD, peritumoural LVD, VEGF-C expression in tumour cells, melanoma thickness, Clark level, ulceration, gender and histologic type were significant predictors of lymph node metastasis (p = 0.000, p = 0.000, p = 0.000, p = 0.000, p = 0.005, p = 0.005, p = 0.011 and p = 0.027, respectively). No significant association of intratumoural and peritumoural LVA with metastases was found. In multivariate analysis, independent predictors of metastatic risks were melanoma thickness [odds ratio OR = 1.655, 95% confidence interval (CI) 1.102-2.484, p = 0.015], intratumoural LVD (OR = 1.086, 95% CI 1.027-1.148, p = 0.004), peritumoural LVD (OR = 1.050, 95% CI 1.008-1.094, p = 0.020) and a positive VEGF-C expression in tumour cells (OR = 20.337, 95% CI 2.579-160.350, p = 0.004). This study identified intratumoural and peritumoural LVD and the VEGF-C expression in tumour cells as more significant predictors of metastatic risk than melanoma thickness, ulceration and other clinical-pathological parameters. Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  6. Insight into 144 patients with ocular vascular events during VEGF antagonist injections

    Directory of Open Access Journals (Sweden)

    Shami M

    2012-03-01

    Full Text Available Ahmad M Mansour1, Maha Shahin2, Peter K Kofoed3, Maurizio B Parodi4, Michel Shami5, Stephen G Schwartz6, Collaborative Anti-VEGF Ocular Vascular Complications GroupDepartment of Ophthalmology, 1American University of Beirut, Beirut, Lebanon, Rafic Hariri University Hospital, Beirut, Lebanon; 2Mansoura University, Mansoura City, Egypt; 3Glostrup Hospital, University of Copenhagen, Denmark, National Eye Clinic, Kennedy Center, Glostrup, Denmark; 4University Vita-Salute, Scientific Institute San Raffaele, Milan, Italy; 5Texas Tech University Health Sciences Center, Lubbock, TX, USA; 6Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Naples and Miami, FL, USAAim: To record ocular vascular events following injections of vascular endothelium growth factor (VEGF antagonists.Methods: Collaborative multicenter case series (48 cases, literature reviews (32 cases, and reports to the FDA (64 cases of patients that had vascular occlusions during anti-VEGF therapy were collected and analyzed.Results: A total of 144 cases of ocular vascular events were identified, with these diagnosed a median of 15 days after anti-VEGF injection. The majority of patients had pre-existing risk factors for cardiovascular events and nine patients had a prior history of glaucoma. Mean visual acuity dropped by 6.4 lines with severe visual loss after injection to NLP (five eyes, LP (six eyes, and HM (two eyes. The overall risk of ocular vascular events following a VEGF antagonist injection was 0.108% in the general population and 2.61% in the diabetic population. Mean retinal arterial constriction after intravitreal bevacizumab in 13 eyes was 21% (standard deviation = 27%, and mean retinal venous constriction was 8% (standard deviation = 30%.Conclusion: Ocular vascular events are rare during anti-VEGF therapy, but can lead to severe visual loss and may be caused by a number of factors including the vasoconstrictor effect of the drug, a post-injection rise

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

    Directory of Open Access Journals (Sweden)

    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