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Patricia Himmels, Isidora Paredes, Heike Adler, Andromachi Karakatsani, Robert Luck, Hugo H Marti, Olga Ermakova, Eugen Rempel, Esther T Stoeckli, Carmen Ruiz de Almodóvar
Formation of a precise vascular network within the central nervous system is of critical importance to assure delivery of oxygen and nutrients and for accurate functionality of neuronal networks. Vascularization of the spinal cord is a highly stereotypical process. However, the guidance cues controlling blood vessel patterning in this organ remain largely unknown. Here we describe a new neuro-vascular communication mechanism that controls vessel guidance in the developing spinal cord. We show that motor neuron columns remain avascular during a developmental time window, despite expressing high levels of the pro-angiogenic vascular endothelial growth factor (VEGF)...
March 6, 2017: Nature Communications
Lakshmi Nayak, John de Groot, Jeffrey S Wefel, Timothy F Cloughesy, Frank Lieberman, Susan M Chang, Antonio Omuro, Jan Drappatz, Tracy T Batchelor, Lisa M DeAngelis, Mark R Gilbert, Kenneth D Aldape, Alfred W K Yung, Joy Fisher, Xiaobu Ye, Alice Chen, Stuart Grossman, Michael Prados, Patrick Y Wen
Anti-vascular endothelial growth factor (VEGF) therapy has shown promise in the treatment of high-grade gliomas (HGG). Aflibercept is a recombinant human fusion protein that acts as a soluble decoy receptor for VEGF-A, VEGF-B and placental growth factor, depleting circulating levels of these growth factors. The Adult Brain Tumor Consortium conducted a phase I trial of aflibercept and temozolomide (TMZ) in patients with newly diagnosed HGG with 2 dose levels and a 3+3 design. Three arms using aflibercept were examined; with radiation and concomitant temozolomide; with adjuvant temozolomide using the 5/28 regimen; and with adjuvant temozolomide using the 21/28 day regimen...
January 23, 2017: Journal of Neuro-oncology
João Rafael de Oliveira Dias, Gabriel Costa de Andrade, Eduardo Amorim Novais, Michel Eid Farah, Eduardo Büchele Rodrigues
In the last few years, monoclonal antibodies have revolutionized the treatment of retinal neovascular diseases. More recently, a different class of drugs, fusion proteins, has provided an alternative treatment strategy with pharmacological differences. In addition to commercially available aflibercept, two other drugs, ziv-aflibercept and conbercept, have been studied in antiangiogenic treatment of ocular diseases. In this scenario, a critical review of the currently available data regarding fusion proteins in ophthalmic diseases may be a timely and important contribution...
2016: International Journal of Retina and Vitreous
Wonseok Kang, Joon Seok Lim, Mi-Suk Park, Gou Young Koh, Honsoul Kim
PURPOSE: Hepatic malignancies can easily develop resistance to antiangiogenic therapy, but the underlying mechanism remains poorly understood. This study explores whether antiangiogenic therapy influences the tumor vascular network and/or the vessels feeding the hepatic tumor. METHODS: Mice implanted with Lewis lung carcinoma (LLC) cells were subcutaneously injected 3 times (once every other day starting 1 week after LLC implantation) with either an antiangiogenic agent [vascular endothelial growth factor (VEGF)-Trap] or control agent (bovine serum albumin) at a dose of 25 mg/kg before performing angiography...
2016: Journal of Vascular Research
Allison F O'Neill, Lei Qin, Patrick Y Wen, John F de Groot, Annick D Van den Abbeele, Jeffrey T Yap
Glioblastoma (GBM) is an incurable brain tumor characterized by the expression of pro-angiogenic cytokines. A recent phase II clinical trial studied VEGF Trap in adult patients with temozolomide-resistant GBM. We sought to explore changes in [(18)F]Fluorodeoxyglucose positron emission tomography (FDG-PET) or magnetic resonance imaging (MRI) in trial participants correlating these changes with disease response. FDG-PET and MRI images obtained before and after the first dose of VEGF Trap were spatially co-registered...
August 30, 2016: Journal of Neuro-oncology
Dong Li, Jiejun Shi, Yanhua Du, Kaiming Chen, Zhenping Liu, Bing Li, Jie Li, Fei Tao, Hua Gu, Cizhong Jiang, Jianmin Fang
Tumor cells become resistant after long-term use of anti-VEGF (vascular endothelial growth factor) agents. Our previous study shows that treatment with a VEGF inhibitor (VEGF-Trap) facilitates to develop tumor resistance through regulating angiogenesis-related genes. However, the underlying molecular mechanisms remain elusive. Histone modifications as a key epigenetic factor play a critical role in regulation of gene expression. Here, we explore the potential epigenetic gene regulatory functions of key histone modifications during tumor resistance in a mouse Lewis lung carcinoma (LLC) cell line...
2016: PloS One
Gilbert Deray, Nicolas Janus, Blandine Aloy, Vincent Launay-Vacher
During the last decade, inhibitors of the vascular endothelial growth factor (VEGF) were developed for the treatment of cancer. Many anti-VEGF are available but the issue is still the same: to inhibit the effect of the VEGF on their receptors. There are two main classes, depending on the mechanism of action by blocking the binding of the ligand on the receptor (VEGF trap or monoclonal antibody) or by affecting directly the receptor (tyrosine kinase inhibitor [TKI], monoclonal antibody directed against the VEGF receptor)...
July 2016: Bulletin du Cancer
Rosario Amato, Martina Biagioni, Maurizio Cammalleri, Massimo Dal Monte, Giovanni Casini
PURPOSE: Growing evidence indicates neuroprotection as a therapeutic target in diabetic retinopathy (DR). We tested the hypothesis that VEGF is released and acts as a survival factor in the retina in early DR. METHODS: Ex vivo mouse retinal explants were exposed to stressors similar to those characterizing DR, that is, high glucose (HG), oxidative stress (OS), or advanced glycation end-products (AGE). Neuroprotection was provided using octreotide (OCT), a somatostatin analog, and pituitary adenylate cyclase activating peptide (PACAP), two well-documented neuroprotectants...
June 1, 2016: Investigative Ophthalmology & Visual Science
Sang Jun Park, Yewon Choi, Young Mi Na, Hye Kyoung Hong, Ji Yeon Park, Kyu Hyung Park, Jae Yong Chung, Se Joon Woo
Purpose: We determined the intraocular pharmacokinetic properties of intravitreally injected aflibercept (Eylea) in a rabbit model. Methods: Aflibercept was injected intravitreally in 21 eyes from New Zealand White rabbits. The eyes were enucleated 1, 24, 48, 120, 216, 360, and 720 hours (1, 2, 5, 9, 15, and 30 days, respectively) after injection and immediately frozen at -80°C. The concentrations of aflibercept in the vitreous, aqueous humor, and retina/choroid were determined by performing an indirect enzyme-linked immunosorbent assay, and analyzed to understand the pharmacokinetic properties of the drug...
May 1, 2016: Investigative Ophthalmology & Visual Science
Maria Waizel, Annekatrin Rickmann, Björn R Blanke, Katharina Wolf, Sara Kazerounian, Peter Szurman
PURPOSE: To study the visual outcome and change in central macular thickness (CMT) in patients with neovascular age-related macular degeneration (AMD) who were previously treated with aflibercept (VEGF Trap-Eye, Eylea) and were subsequently switched to bevacizumab (Avastin). METHODS: In this observational analysis, 19 eyes initially treated with at least 3 injections of bevacizumab after initial treatment with at least 3 injections of aflibercept are reported. Outcome measures were Snellen visual acuity (best-corrected visual acuity (BCVA) and CMT measured by spectral-domain optical coherence tomography...
August 4, 2016: European Journal of Ophthalmology
James S Talks, Andrew J Lotery, Faruque Ghanchi, Sobha Sivaprasad, Robert L Johnston, Nishal Patel, Martin McKibbin, Clare Bailey, Sajjad Mahmood
PURPOSE: Aflibercept has the potential advantage of reducing capacity problems by allowing 2 monthly visits for patients with neovascular macular degeneration (nAMD) compared with monthly pro re nata regimens that are the most commonly used in the United Kingdom. This study aimed to report the visual outcomes achieved in routine clinical practice using the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) protocol at 1 year and compare with trials data and other real-world reports...
February 2016: Ophthalmology
Rastislav Bahleda, Jackie Baker, Christophe Massard, Sirish M Gadgeel, Jane E Rogers, Hassan Izzedine, Eric Deutsch, Jeana L Garris, Akbar Khan, Emmanuelle Boelle, Sylvie Assadourian, Jean-Charles Soria, Jaffer A Ajani
PURPOSE: This phase I study (EudraCT No. 2006-001177-25) investigated aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received 2, 4, or 6 mg/kg of intravenous aflibercept with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 5-fluorouracil 750 mg/m2 in 3-week cycles until disease progression or unacceptable toxicity...
2016: Oncology
Shiao-Pei Weathers, John de Groot
Glioblastoma is the most common malignant primary brain tumor that is universally lethal, despite optimized treatment including surgery, radiation, and chemotherapy. Targeting angiogenesis has been and continues to be an attractive therapeutic modality in both newly diagnosed and recurrent glioblastoma patients. Vascular endothelial growth factor (VEGF) is the most abundant and important mediator of angiogenesis in glioblastoma. Multiple strategies have been developed to target VEGF/VEGF receptor (VEGFR)-mediated angiogenesis, including VEGF blockade, VEGF Trap, and suppression of VEGFR signaling via receptor tyrosine kinase inhibitors (TKIs)...
October 2015: Oncology (Williston Park, NY)
Lukas J A C Hawinkels, Amaya Garcia de Vinuesa, Madelon Paauwe, Marianna Kruithof-de Julio, Eliza Wiercinska, Evangelia Pardali, Laura Mezzanotte, Stijn Keereweer, Tanya M Braumuller, Renier C Heijkants, Jos Jonkers, Clemens W Löwik, Marie-José Goumans, Timo L ten Hagen, Peter ten Dijke
PURPOSE: Antiangiogenic therapy, mostly targeting VEGF, has been applied in cancer patients for the last decade. However, resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new antiangiogenic strategies are needed. In the current study, we investigated the therapeutic effect of interfering with the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway by using an ALK1-Fc ligand trap. EXPERIMENTAL DESIGN: We analyzed the potential antiangiogenic and antitumor effects of ALK1-Fc protein as monotherapy and in combination with chemotherapy in vivo in mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas...
January 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jin Kyun Park, Andrea Fava, John Carrino, Filippo Del Grande, Antony Rosen, Francesco Boin
OBJECTIVE: Bone resorption of distal phalanges, or acroosteolysis (AO), can develop in patients with systemic sclerosis (SSc), causing pain and functional limitation. This study was undertaken to investigate whether AO may be associated with abnormal osteoclastogenesis in SSc patients and whether hypoxia may be involved in this process. METHODS: Peripheral blood mononuclear cells (PBMCs) obtained from 26 SSc patients (11 with AO and 15 without AO) and 14 healthy controls were cultured in the presence of RANKL and macrophage colony-stimulating factor for 9 days...
January 2016: Arthritis & Rheumatology
Kyu-Yeon Han, Jennifer Dugas-Ford, Hyun Lee, Jin-Hong Chang, Dimitri T Azar
PURPOSE: To determine the possible antiangiogenic effect of metalloproteinase (MMP) 14 cleavage of vascular endothelial growth factor receptor 1 (VEGFR1) in the cornea. METHODS: Recombinant mouse (rm) VEGFR1 was incubated with various concentrations of recombinant MMP14 to examine proteolysis in vitro. The reaction mixture was analyzed by SDS-PAGE and stained with Coomassie blue. The fragments resulting from rmVEGFR1 cleavage by MMP14 were subjected to Edman degradation, and the amino acid sequences were aligned with rmVEGFR1 sequences...
August 2015: Investigative Ophthalmology & Visual Science
Francesca Salamanna, Stefania Pagani, Melania Maglio, Veronica Borsari, Gianluca Giavaresi, Alberto M Martelli, Francesca Buontempo, Milena Fini
To reduce the burden of bone metastases, the pathophysiology of the metastatic niche should be elucidated and targeted. The aim of the present study was to assess the effect of tumor cells on osteoclast (OC) recruitment and activity in the presence of altered bone remodelling. Peripheral blood mononuclear cells (PBMC) were isolated from healthy and ovariectomized (OVX) rats and co-cultured with MRMT-1 rat breast carcinoma cells or with their conditioned medium for 1 and 2 weeks. Alamar Blue viability test, synthesis of cathepsin K, transforming growth factor-beta 1 (TGF-β1), tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), metalloproteinase (MMP)-7, MMP-9, FITC-conjugate phalloidin staining and tartrate-resistant acid phosphatase (TRAP) staining were evaluated...
January 2016: Histology and Histopathology
Da Ru Chi Moon, Dong Kyu Lee, Soon Hyun Kim, Yong Sung You, Oh Woong Kwon
PURPOSE: To report the results of switching treatment to vascular endothelial growth factor (VEGF) Trap-Eye (aflibercept) in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) refractory to anti-VEGF (ranibizumab and bevacizumab). METHODS: This is a retrospective study involving 32 eyes from 29 patients; 18 were cases of neovascular AMD and 14 were cases of PCV. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) of spectral-domain optical coherence tomography were evaluated...
August 2015: Korean Journal of Ophthalmology: KJO
Gabriel Coscas, Marco Lupidi, Florence Coscas, Catherine Français, Carlo Cagini, Eric H Souied
PURPOSE: To report the optical coherence tomography angiography (OCT-A) findings in an exudative age-related macular degeneration (AMD) patient presenting mixed type I and II choroidal neovascularization (CNV) during follow-up after intravitreal vascular endothelial growth factor (VEGF) trap treatment. METHODS: The clinical assessment included both traditional multimodal imaging, based on fluorescein angiography (FA), indocyanine green angiography (ICGA) and B-scan OCT, and OCT-A at baseline and follow-up...
2015: Ophthalmic Research
Zhengtuo Zhao, Mohammad Ali Al-Ameen, Kai Duan, Gargi Ghosh, Joe Fujiou Lo
Advances in medical diagnostics and personalized therapy require sensitive and rapid measurement of minute amounts of proteins from patients. Standard ELISA is difficult to prepare and involves lengthy protocols. Here we report a novel method using capture antibody immobilized porous poly (ethylene) glycol diacrylate (PEGDA) hydrogel microspheres to enable high sensitivity VEGF detection in arrayed microfluidics. Our technique incorporates antibody encapsulation, trapping, and flow perfusion on a single device...
December 15, 2015: Biosensors & Bioelectronics
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