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Sánchez-Martínez C, Grueso E, Calvo-López T, Martinez-Ortega J, Ruiz A, Almendral JM. VEGF-Virus Interactions: Pathogenic Mechanisms and Therapeutic Applications. Cells 2024; 13:1815. [PMID: 39513922 PMCID: PMC11545703 DOI: 10.3390/cells13211815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Many types of viruses directly or indirectly target the vascular endothelial growth factor (VEGF) system, which is a central regulator of vasculogenesis and angiogenesis in physiological homeostasis, causing diverse pathologies. Other viruses have been developed into effective therapeutic tools for VEGF modulation in conditions such as cancer and eye diseases. Some viruses may alter the levels of VEGF in the pathogenesis of respiratory syndromes, or they may encode VEGF-like factors, promoting vascular disruption and angiogenesis to enable viruses' systemic spread. Oncogenic viruses may express interactive factors that perturb VEGF's functional levels or downstream signaling, which increases the neovascularization and metastasis of tumors. Furthermore, many viruses are being developed as therapeutic vectors for vascular pathologies in clinical trials. Major examples are those viral vectors that inhibit the role of VEGF in the neovascularization required for cancer progression; this is achieved through the induction of immune responses, by exposing specific peptides that block signaling or by expressing anti-VEGF and anti-VEGF receptor-neutralizing antibodies. Other viruses have been engineered into effective pro- or anti-angiogenesis multitarget vectors for neovascular eye diseases, paving the way for therapies with improved safety and minimal side effects. This article critically reviews the large body of literature on these issues, highlighting those contributions that describe the molecular mechanisms, thus expanding our understanding of the VEGF-virus interactions in disease and therapy. This could facilitate the clinical use of therapeutic virus vectors in precision medicine for the VEGF system.
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Affiliation(s)
- Cristina Sánchez-Martínez
- Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain; (C.S.-M.); (E.G.)
| | - Esther Grueso
- Biosciences Research Institute, School of Experimental Sciences, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain; (C.S.-M.); (E.G.)
| | - Tania Calvo-López
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
- Department of Biomedicine, Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
| | - Jorge Martinez-Ortega
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
| | - Ana Ruiz
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
| | - José M. Almendral
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain or (T.C.-L.); (J.M.-O.); (A.R.)
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
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Yang Y, Wen W, Chen FL, Zhang YJ, Liu XC, Yang XY, Hu SS, Jiang Y, Yuan J. Expression and significance of pigment epithelium-derived factor and vascular endothelial growth factor in colorectal adenoma and cancer. World J Gastrointest Oncol 2024; 16:670-686. [PMID: 38577437 PMCID: PMC10989378 DOI: 10.4251/wjgo.v16.i3.670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/16/2024] [Accepted: 02/04/2024] [Indexed: 03/12/2024] Open
Abstract
BACKGROUND The incidence and mortality of colorectal cancer (CRC) are among the highest in the world, and its occurrence and development are closely related to tumor neovascularization. When the balance between pigment epithelium-derived factors (PEDF) that inhibit angiogenesis and vascular endothelial growth factors (VEGF) that stimulate angiogenesis is broken, angiogenesis is out of control, resulting in tumor development. Therefore, it is very necessary to find more therapeutic targets for CRC for early intervention and later treatment. AIM To investigate the expression and significance of PEDF, VEGF, and CD31-stained microvessel density values (CD31-MVD) in normal colorectal mucosa, adenoma, and CRC. METHODS In this case-control study, we collected archived wax blocks of specimens from the Digestive Endoscopy Center and the General Surgery Department of Chengdu Second People's Hospital from April 2022 to October 2022. Fifty cases of specimen wax blocks were selected as normal intestinal mucosa confirmed by electronic colonoscopy and concurrent biopsy (normal control group), 50 cases of specimen wax blocks were selected as colorectal adenoma confirmed by electronic colonoscopy and pathological biopsy (adenoma group), and 50 cases of specimen wax blocks were selected as CRC confirmed by postoperative pathological biopsy after inpatient operation of general surgery (CRC group). An immunohistochemical staining experiment was carried out to detect PEDF and VEGF expression in three groups of specimens, analyze their differences, study the relationship between the two and clinicopathological factors in CRC group, record CD31-MVD in the three groups, and analyze the correlation of PEDF, VEGF, and CD31-MVD in the colorectal adenoma group and the CRC group. The F test or adjusted F test is used to analyze measurement data statistically. Kruskal-Wallis rank sum test was used between groups for ranked data. The chi-square test, adjusted chi-square test, or Fisher's exact test were used to compare the rates between groups. All differences between groups were compared using the Bonferroni method for multiple comparisons. Spearman correlation analysis was used to test the correlation of the data. The test level (α) was 0.05, and a two-sided P< 0.05 was considered statistically significant. RESULTS The positive expression rate and expression intensity of PEDF were gradually decreased in the normal control group, adenoma group, and CRC group (100% vs 78% vs 50%, χ2 = 34.430, P < 0.001; ++~++ vs +~++ vs -~+, H = 94.059, P < 0.001), while VEGF increased gradually (0% vs 68% vs 96%, χ2 = 98.35, P < 0.001; - vs -~+ vs ++~+++, H = 107.734, P < 0.001). In the CRC group, the positive expression rate of PEDF decreased with the increase of differentiation degree, invasion depth, lymph node metastasis, distant metastasis, and TNM stage (χ2 = 20.513, 4.160, 5.128, 6.349, 5.128, P < 0.05); the high expression rate of VEGF was the opposite (χ2 = 10.317, 13.134, 17.643, 21.844, 17.643, P < 0.05). In the colorectal adenoma group, the expression intensity of PEDF correlated negatively with CD31-MVD (r = -0.601, P < 0.001), whereas VEGF was not significantly different (r = 0.258, P = 0.07). In the CRC group, the expression intensity of PEDF correlated negatively with the expression intensity of CD31-MVD and VEGF (r = -0.297, P < 0.05; r = -0.548, P < 0.05), while VEGF expression intensity was positively related to CD31-MVD (r = 0.421, P = 0.002). CONCLUSION It is possible that PEDF can be used as a new treatment and prevention target for CRC by upregulating the expression of PEDF while inhibiting the expression of VEGF.
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Affiliation(s)
- Ye Yang
- Digestive Diseases, Chengdu Qingbaijiang District People's Hospital, Chengdu 610300, Sichuan Province, China
| | - Wu Wen
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Feng-Lin Chen
- Graduate School, Chengdu Medical College, Chengdu 610000, Sichuan Province, China
| | - Ying-Jie Zhang
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Xiao-Cong Liu
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Xiao-Yan Yang
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Shan-Shan Hu
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Ye Jiang
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
| | - Jing Yuan
- Digestive Diseases, Chengdu Second People’s Hospital, Chengdu 610000, Sichuan Province, China
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Franco AFDV, Malinverni ACM, Waitzberg AFL. Immunoexpression of HER2 pathway related markers in HER2 invasive breast carcinomas treated with trastuzumab. Pathol Res Pract 2023; 252:154917. [PMID: 37977031 DOI: 10.1016/j.prp.2023.154917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/19/2023]
Abstract
PURPOSE We evaluated the immunoexpression of potential markers involved in the HER2 pathway in invasive breast carcinoma with HER2 amplification treated with trastuzumab. METHODS Samples of ninety patients diagnosed and treated at two public Brazilian hospitals with overexpressed invasive carcinoma between 2009 and 2018 were included. Several markers (Bcl-2, CDK4, cyclin D1, EGFR, IGF1, IGF-1R, MDM2, MUC4, p16, p21, p27, p53, PTEN, RA, TNFα, and VEGF) were immune analyzed in the tumor by immunohistochemistry and then correlated with clinicopathological variables. RESULTS Tumor sample expression results determined potential markers of good prognosis with statistically significant values: cyclin D1 with a nuclear grade, and recurrence; IGF-1 with tumor size, and death; p16 with a response after treatment; PTEN with a response after treatment, and death. Markers of poor prognosis: p53 with histological, and nuclear grade; IGF-1R with a compromised lymph node. The treatment resistance rate after trastuzumab was 40%; the overall survival was 4.13 years (95% CI 5.1-12.5) and the disease-free survival was 3.6 years (95% CI 5.1-13.1). CONCLUSIONS The tumor samples profile demonstrated that cyclin D1, IGF-1, p16, and PTEN presented the potential for a good prognosis and p53 and IGF-1R for worse.
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Affiliation(s)
- Andreia Fabiana do Vale Franco
- Pathology Department, Universidade Federal de São Paulo, Escola Paulista, de Medicina, Botucatu Street, 740, 1st Floor Vila Clementino, São Paulo, SP, Brazil; Laboratory of Molecular and Experimental Pathology, Universidade Federal, de São Paulo, Escola Paulista de Medicina, Pedro de Toledo Street, 781, 5th Floor - Vila Clementino, São Paulo, SP, Brazil.
| | - Andrea Cristina Moraes Malinverni
- Pathology Department, Universidade Federal de São Paulo, Escola Paulista, de Medicina, Botucatu Street, 740, 1st Floor Vila Clementino, São Paulo, SP, Brazil; Laboratory of Molecular and Experimental Pathology, Universidade Federal, de São Paulo, Escola Paulista de Medicina, Pedro de Toledo Street, 781, 5th Floor - Vila Clementino, São Paulo, SP, Brazil
| | - Angela Flavia Logullo Waitzberg
- Pathology Department, Universidade Federal de São Paulo, Escola Paulista, de Medicina, Botucatu Street, 740, 1st Floor Vila Clementino, São Paulo, SP, Brazil; Laboratory of Molecular and Experimental Pathology, Universidade Federal, de São Paulo, Escola Paulista de Medicina, Pedro de Toledo Street, 781, 5th Floor - Vila Clementino, São Paulo, SP, Brazil
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Guzzeloni V, Veschini L, Pedica F, Ferrero E, Ferrarini M. 3D Models as a Tool to Assess the Anti-Tumor Efficacy of Therapeutic Antibodies: Advantages and Limitations. Antibodies (Basel) 2022; 11:antib11030046. [PMID: 35892706 PMCID: PMC9326665 DOI: 10.3390/antib11030046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/30/2022] [Accepted: 07/06/2022] [Indexed: 02/07/2023] Open
Abstract
Therapeutic monoclonal antibodies (mAbs) are an emerging and very active frontier in clinical oncology, with hundred molecules currently in use or being tested. These treatments have already revolutionized clinical outcomes in both solid and hematological malignancies. However, identifying patients who are most likely to benefit from mAbs treatment is currently challenging and limiting the impact of such therapies. To overcome this issue, and to fulfill the expectations of mAbs therapies, it is urgently required to develop proper culture models capable of faithfully reproducing the interactions between tumor and its surrounding native microenvironment (TME). Three-dimensional (3D) models which allow the assessment of the impact of drugs on tumors within its TME in a patient-specific context are promising avenues to progressively fill the gap between conventional 2D cultures and animal models, substantially contributing to the achievement of personalized medicine. This review aims to give a brief overview of the currently available 3D models, together with their specific exploitation for therapeutic mAbs testing, underlying advantages and current limitations to a broader use in preclinical oncology.
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Affiliation(s)
- Virginia Guzzeloni
- B-Cell Neoplasia Unit, Division of Experimental Oncology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (V.G.); (E.F.)
| | - Lorenzo Veschini
- Academic Centre of Reconstructive Science, Faculty of Dentistry Oral & Craniofacial Sciences, King’s College London, Guy’s Hospital, London SE1 9RT, UK;
| | - Federica Pedica
- Pathology Unit, IRCCS Ospedale San Raffaele, 20132 Milan, Italy;
| | - Elisabetta Ferrero
- B-Cell Neoplasia Unit, Division of Experimental Oncology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (V.G.); (E.F.)
| | - Marina Ferrarini
- B-Cell Neoplasia Unit, Division of Experimental Oncology, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (V.G.); (E.F.)
- Correspondence:
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Real-life study of the use of anti-VEGF therapy versus dexamethasone implant for treatment of macular edema in retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2021; 259:2653-2660. [PMID: 33738625 PMCID: PMC8380569 DOI: 10.1007/s00417-021-05146-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 02/24/2021] [Accepted: 03/02/2021] [Indexed: 01/31/2023] Open
Abstract
Purpose To investigate the long-time outcome of patients with branch vein occlusion (BRVO) and central vein occlusion (CRVO) treated with anti-VEGF injections compared to the dexamethasone (DEX) implant. Methods This retrospective real-life study included all 492 patients presenting with retinal vein occlusion (RVO) during 2012–2013 at St. Erik Eye Hospital. Maximum follow-up was 5 years. Results The mean time of follow-up for patients treated for macular edema was 33.2±17.7 and 34.3±18.1 months in the BRVO and CRVO groups, respectively. At the end of follow-up, the best-corrected visual acuity improved +9.8±20.4 Early Treatment Diabetic Retinopathy Study letters in BRVO patients receiving anti-VEGF therapy while patients treated with the DEX implant lost −2.1±23.4 letters (p<0.05). CRVO patients treated with anti-VEGF therapy improved +0.2±27.6 letters while patients receiving a DEX implant lost −9.7±32.6 letters (p=0.11). Overall, in RVO patients treated with anti-VEGF injections, the central retinal thickness decreased to 322±174μm compared to 398±174 μm in patients treated with the DEX implant (p<0.05). Conclusions In a clinical setting, a substantial part of patients is still in follow-up a long time after presentation. The visual and anatomical outcomes were better in patients treated with anti-VEGF agents compared to subjects receiving a DEX implant.![]()
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Yozgat Z, Doğan M, Sabaner MC, Gobeka HH, Yazgan Akpolat S. Impacts of intravitreal anti-VEGF therapy on retinal anatomy and neurophysiology in diabetic macular edema. Int Ophthalmol 2021; 41:1783-1798. [PMID: 33606153 DOI: 10.1007/s10792-021-01737-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 02/01/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE To evaluate anatomical and neuroretinal functional aspects in patients with diabetic macular edema (DME) after intravitreal anti-vascular endothelial growth factor (VEGF) therapy, in particular aflibercept. MATERIALS AND METHODS This prospective single-centered interventional study was performed at Afyonkarahisar Health Science University Faculty of Medicine, Department of Ophthalmology, where 32 eyes of 32 patients with DME were investigated. All patients received five intravitreal aflibercept injections on a monthly basis and were followed up for ≥ 6 months. After a comprehensive ophthalmological examination, including the measurements of visual acuity and intraocular pressure, and an antero-posterior segment slit-lamp biomicroscopy before and after full pupil dilation, fundus fluorescein angiography and optical coherence tomography were performed at baseline and during the third and sixth months post-therapy. Microperimetry and multifocal electroretinography were also performed at baseline and during the sixth months. RESULTS Mean visual acuity increased from 0.73 to 0.57 and 0.33 logarithm of the minimum angle of resolution (logMAR) during the third and sixth months, respectively (p < 0.001). Changes in intraocular pressure were not statistically significant (p = 0.472). There was statistically significantly decreased mean central macular thickness from 390.2 μm to 242.6 and 289.7 μm during the third and sixth months, respectively (p < 0.001). Significantly improved fixation patterns during the sixth month, along with significantly increased macular sensitivity from 8.2 to 14.2 dB (p < 0.001) and significantly decreased local deficit from - 10.3 to 5.5 dB (p < 0.001) were observed. Further, there was a significantly increased N1 amplitude in the first ring and significantly increased P1 amplitude in all rings (p for each parameter < 0.05). There was also significantly decreased N1 wave implicit time in all rings and significantly decreased P1 wave in the second, third, fourth and fifth rings (p for each parameter < 0.05). CONCLUSIONS Patients with DME showed profound improvement in the retinal neurophysiological function, which was also accompanied by anatomical and ultrastructural integrity recovery after intravitreal aflibercept therapy. In the pathogenesis of DME, the influence of neurodegeneration has been increasingly gaining significant attention. Consequently, the need to assess neurophysiological effects of anti-VEGF therapy using a variety of diagnostic measures like electrophysiological studies and multimodal imaging technologies is undeniably growing.
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Affiliation(s)
- Zübeyir Yozgat
- Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey
| | - Mustafa Doğan
- Afyonkarahisar Health Sciences University, Afyonkarahisar, Turkey.
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Jin J, Chen L, Liu GQ, Lu PR. Proteomic analysis of anti-angiogenic effects by conbercept in the mice with oxygen induced retinopathy. Int J Ophthalmol 2020; 13:1844-1853. [PMID: 33344181 PMCID: PMC7708359 DOI: 10.18240/ijo.2020.12.02] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 08/14/2020] [Indexed: 12/27/2022] Open
Abstract
AIM To analyze the retinal proteomes with and without conbercept treatments in mice with oxygen-induced retinopathy (OIR) and identify proteins involved in the molecular mechanisms mediated by conbercept. METHODS OIR was induced in fifty-six C57BL/6J mouse pups and randomly divided into four groups. Group 1: Normal17 (n=7), mice without OIR and treated with normal air. Group 2: OIR12/EXP1 (n=14), mice received 75% oxygen from postnatal day (P) 7 to 12. Group 3: OIR17/Control (n=14), mice received 75% oxygen from P7 to P12 and then normal air to P17. Group 4: Lang17/EXP2 (n=21), mice received 75% oxygen from P7 to P12 with intravitreal injection of 1 µL conbercept at the concentration of 10 mg/mL at P12, and then normal air from P12 to P17. Liquid Chromatography-Mass Spectrometry (LC-MS)/MS data were reviewed to find proteins that were up-regulated after the conbercept treatment. Gene ontology (GO) analysis was performed of conbercept-mediated changes in proteins involved in single-organism processes, biological regulation, cellular processes, immune responses, metabolic processes, locomotion and multiple-organism processes. RESULTS Conbercept induced a reversal of hypoxia-inducible factor 1 signaling pathway as revealed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and also induced down-regulation of proteins involved in blood coagulation and fibrin clot formation as demonstrated by the Database for Annotation, Visualization and Integrated Discovery (DAVID) and the stimulation of interferon genes studies. These appear to be risk factors of retinal fibrosis. Additional conbercept-specific fibrosis risk factors were also identified and may serve as therapeutic targets for fibrosis. CONCLUSION Our studies reveal that many novel proteins are differentially regulated by conbercept. The new insights may warrant a valuable resource for conbercept treatment.
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Affiliation(s)
- Ji Jin
- Department of Ophthalmology, the First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
- Department of Ophthalmology, the Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu Province, China
| | - Lei Chen
- Department of Ophthalmology, Children's Hospital of Soochow University, Suzhou 215025, Jiangsu Province, China
| | - Gao-Qin Liu
- Department of Ophthalmology, the First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
| | - Pei-Rong Lu
- Department of Ophthalmology, the First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
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Ben-Yehuda Greenwald M, Tacconi C, Jukic M, Joshi N, Hiebert P, Brinckmann J, Tenor H, Naef R, Werner S. A Dual-Acting Nitric Oxide Donor and Phosphodiesterase 5 Inhibitor Promotes Wound Healing in Normal Mice and Mice with Diabetes. J Invest Dermatol 2020; 141:415-426. [PMID: 32598925 DOI: 10.1016/j.jid.2020.05.111] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 04/12/2020] [Accepted: 05/18/2020] [Indexed: 12/14/2022]
Abstract
Chronic wounds affect a large percentage of the population worldwide and cause significant morbidity. Unfortunately, efficient compounds for the treatment of chronic wounds are yet not available. Endothelial dysfunction, which is at least in part a result of compromised nitric oxide production and concomitant reduction in cGMP levels, is a major pathologic feature of chronic wounds. Therefore, we designed and synthesized a compound with a unique dual-acting activity (TOP-N53), acting as a nitric oxide donor and phosphodiesterase 5 inhibitor, and applied it locally to full-thickness skin wounds in healthy and healing-impaired mice with diabetes. TOP-N53 promoted keratinocyte proliferation, angiogenesis, and collagen maturation in healthy mice without accelerating the wound inflammatory response or scar formation. Most importantly, it partially rescued the healing impairment of mice with genetically determined type II diabetes (db/db) by stimulating re-epithelialization and granulation tissue formation, including angiogenesis. In vitro studies with human and murine primary cells showed a positive effect of TOP-N53 on keratinocyte and fibroblast migration, keratinocyte proliferation, and endothelial cell migration and tube formation. These results demonstrate a remarkable healing-promoting activity of TOP-N53 by targeting the major resident cells in the wound tissue.
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Affiliation(s)
| | - Carlotta Tacconi
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland
| | - Marko Jukic
- Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Natasha Joshi
- Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Paul Hiebert
- Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland
| | - Jürgen Brinckmann
- Department of Dermatology, University of Lübeck, Lübeck, Germany; Institute of Virology and Cell Biology, University of Lubeck, Lübeck, Germany
| | | | - Reto Naef
- Topadur Pharma AG, Schlieren, Switzerland
| | - Sabine Werner
- Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
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Rehfuss JP, DeSart KM, Rozowsky JM, O'Malley KA, Moldawer LL, Baker HV, Wang Y, Wu R, Nelson PR, Berceli SA. Hyperacute Monocyte Gene Response Patterns Are Associated With Lower Extremity Vein Bypass Graft Failure. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2019. [PMID: 29530886 DOI: 10.1161/circgen.117.001970] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Despite being the definitive treatment for lower extremity peripheral arterial disease, vein bypass grafts fail in half of all cases. Early repair mechanisms after implantation, governed largely by the immune environment, contribute significantly to long-term outcomes. The current study investigates the early response patterns of circulating monocytes as a determinant of graft outcome. METHODS In 48 patients undergoing infrainguinal vein bypass grafting, the transcriptomes of circulating monocytes were analyzed preoperatively and at 1, 7, and 28 days post-operation. RESULTS Dynamic clustering algorithms identified 50 independent gene response patterns. Three clusters (64 genes) were differentially expressed, with a hyperacute response pattern defining those patients with failed versus patent grafts 12 months post-operation. A second independent data set, comprised of 96 patients subjected to major trauma, confirmed the value of these 64 genes in predicting an uncomplicated versus complicated recovery. Causal network analysis identified 8 upstream elements that regulate these mediator genes, and Bayesian analysis with a priori knowledge of the biological interactions was integrated to create a functional network describing the relationships among the regulatory elements and downstream mediator genes. Linear models predicted the removal of either STAT3 (signal transducer and activator of transcription 3) or MYD88 (myeloid differentiation primary response 88) to shift mediator gene expression levels toward those seen in successful grafts. CONCLUSIONS A novel combination of dynamic gene clustering, linear models, and Bayesian network analysis has identified a core set of regulatory genes whose manipulations could migrate vein grafts toward a more favorable remodeling phenotype.
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Affiliation(s)
- Jonathan P Rehfuss
- From the Malcom Randall Veterans Affairs Medical Center, Gainesville, FL (J.P.R., K.M.D., J.M.R., K.A.O., S.A.B.); Department of Surgery (J.P.R., K.M.D., J.M.R., K.A.O., L.L.M., S.A.B.) and Department of Molecular Genetics and Microbiology (H.V.B.), University of Florida, Gainesville; Department of Biostatistics, Rutgers University, New Brunswick, NJ (Y.W.); Center for Statistical Genetics, Pennsylvania State University, Hershey (R.W.); and Department of Surgery, University of South Florida, Tampa (P.R.N.)
| | - Kenneth M DeSart
- From the Malcom Randall Veterans Affairs Medical Center, Gainesville, FL (J.P.R., K.M.D., J.M.R., K.A.O., S.A.B.); Department of Surgery (J.P.R., K.M.D., J.M.R., K.A.O., L.L.M., S.A.B.) and Department of Molecular Genetics and Microbiology (H.V.B.), University of Florida, Gainesville; Department of Biostatistics, Rutgers University, New Brunswick, NJ (Y.W.); Center for Statistical Genetics, Pennsylvania State University, Hershey (R.W.); and Department of Surgery, University of South Florida, Tampa (P.R.N.)
| | - Jared M Rozowsky
- From the Malcom Randall Veterans Affairs Medical Center, Gainesville, FL (J.P.R., K.M.D., J.M.R., K.A.O., S.A.B.); Department of Surgery (J.P.R., K.M.D., J.M.R., K.A.O., L.L.M., S.A.B.) and Department of Molecular Genetics and Microbiology (H.V.B.), University of Florida, Gainesville; Department of Biostatistics, Rutgers University, New Brunswick, NJ (Y.W.); Center for Statistical Genetics, Pennsylvania State University, Hershey (R.W.); and Department of Surgery, University of South Florida, Tampa (P.R.N.)
| | - Kerri A O'Malley
- From the Malcom Randall Veterans Affairs Medical Center, Gainesville, FL (J.P.R., K.M.D., J.M.R., K.A.O., S.A.B.); Department of Surgery (J.P.R., K.M.D., J.M.R., K.A.O., L.L.M., S.A.B.) and Department of Molecular Genetics and Microbiology (H.V.B.), University of Florida, Gainesville; Department of Biostatistics, Rutgers University, New Brunswick, NJ (Y.W.); Center for Statistical Genetics, Pennsylvania State University, Hershey (R.W.); and Department of Surgery, University of South Florida, Tampa (P.R.N.)
| | - Lyle L Moldawer
- From the Malcom Randall Veterans Affairs Medical Center, Gainesville, FL (J.P.R., K.M.D., J.M.R., K.A.O., S.A.B.); Department of Surgery (J.P.R., K.M.D., J.M.R., K.A.O., L.L.M., S.A.B.) and Department of Molecular Genetics and Microbiology (H.V.B.), University of Florida, Gainesville; Department of Biostatistics, Rutgers University, New Brunswick, NJ (Y.W.); Center for Statistical Genetics, Pennsylvania State University, Hershey (R.W.); and Department of Surgery, University of South Florida, Tampa (P.R.N.)
| | - Henry V Baker
- From the Malcom Randall Veterans Affairs Medical Center, Gainesville, FL (J.P.R., K.M.D., J.M.R., K.A.O., S.A.B.); Department of Surgery (J.P.R., K.M.D., J.M.R., K.A.O., L.L.M., S.A.B.) and Department of Molecular Genetics and Microbiology (H.V.B.), University of Florida, Gainesville; Department of Biostatistics, Rutgers University, New Brunswick, NJ (Y.W.); Center for Statistical Genetics, Pennsylvania State University, Hershey (R.W.); and Department of Surgery, University of South Florida, Tampa (P.R.N.)
| | - Yaqun Wang
- From the Malcom Randall Veterans Affairs Medical Center, Gainesville, FL (J.P.R., K.M.D., J.M.R., K.A.O., S.A.B.); Department of Surgery (J.P.R., K.M.D., J.M.R., K.A.O., L.L.M., S.A.B.) and Department of Molecular Genetics and Microbiology (H.V.B.), University of Florida, Gainesville; Department of Biostatistics, Rutgers University, New Brunswick, NJ (Y.W.); Center for Statistical Genetics, Pennsylvania State University, Hershey (R.W.); and Department of Surgery, University of South Florida, Tampa (P.R.N.)
| | - Rongling Wu
- From the Malcom Randall Veterans Affairs Medical Center, Gainesville, FL (J.P.R., K.M.D., J.M.R., K.A.O., S.A.B.); Department of Surgery (J.P.R., K.M.D., J.M.R., K.A.O., L.L.M., S.A.B.) and Department of Molecular Genetics and Microbiology (H.V.B.), University of Florida, Gainesville; Department of Biostatistics, Rutgers University, New Brunswick, NJ (Y.W.); Center for Statistical Genetics, Pennsylvania State University, Hershey (R.W.); and Department of Surgery, University of South Florida, Tampa (P.R.N.)
| | - Peter R Nelson
- From the Malcom Randall Veterans Affairs Medical Center, Gainesville, FL (J.P.R., K.M.D., J.M.R., K.A.O., S.A.B.); Department of Surgery (J.P.R., K.M.D., J.M.R., K.A.O., L.L.M., S.A.B.) and Department of Molecular Genetics and Microbiology (H.V.B.), University of Florida, Gainesville; Department of Biostatistics, Rutgers University, New Brunswick, NJ (Y.W.); Center for Statistical Genetics, Pennsylvania State University, Hershey (R.W.); and Department of Surgery, University of South Florida, Tampa (P.R.N.)
| | - Scott A Berceli
- From the Malcom Randall Veterans Affairs Medical Center, Gainesville, FL (J.P.R., K.M.D., J.M.R., K.A.O., S.A.B.); Department of Surgery (J.P.R., K.M.D., J.M.R., K.A.O., L.L.M., S.A.B.) and Department of Molecular Genetics and Microbiology (H.V.B.), University of Florida, Gainesville; Department of Biostatistics, Rutgers University, New Brunswick, NJ (Y.W.); Center for Statistical Genetics, Pennsylvania State University, Hershey (R.W.); and Department of Surgery, University of South Florida, Tampa (P.R.N.).
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10
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Devesa J, Caicedo D. The Role of Growth Hormone on Ovarian Functioning and Ovarian Angiogenesis. Front Endocrinol (Lausanne) 2019; 10:450. [PMID: 31379735 PMCID: PMC6646585 DOI: 10.3389/fendo.2019.00450] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 06/21/2019] [Indexed: 12/21/2022] Open
Abstract
Although not yet well-understood, today it is clear that Growth Hormone (GH) exerts a relevant role in the regulation of ovulation and fertility; in fact, fertility is lower in women with GH deficiency (GHD), and GH receptors (GHR) and GH mRNA have been found in the ovary since the onset of follicular development in humans. However, despite the strong evidence of GH in the regulation of fertility, many aspects of GH actions at this level are still not well-established, and it is likely that some controversial data depend on the species analyzed, the dose of the hormone and the duration of use of GH. Folliculogenesis, ovulation, and corpus luteum formation and maintenance are processes that are critically dependent on angiogenesis. In the ovary, new blood vessel formation facilitates oxygen, nutrients, and hormone substrate delivery, and also secures transfer of different hormones to targeted cells. Some growth factors and hormones overlap their actions in order to control the angiogenic process for fertility. However, we still know very little about the factors that play a critical role in the vascular changes that occur during folliculogenesis or luteal regression. To promote and maintain the production of VEGF-A in granulosa cells, the effects of local factors such as IGF-I and steroids are needed; that VEGF-A-inducing effect cannot be induced by luteinizing hormone (LH) or chorionic gonadotropin (CG) alone. As a result of the influences that GH exerts on the hypothalamic-pituitary-gonadal axis, facilitating the release of gonadotropins, and given the relationship between GH and local ovarian factors such as VEGF-A, FGF-2, IGF-1, or production of sex steroids, we assume that GH has to be a necessary factor in ovarian angiogenesis, as it happens in other vascular beds. In this review we will discuss the actions of GH in the ovary, most of them likely due to the local production of the hormone and its mediators.
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Affiliation(s)
- Jesús Devesa
- Scientific Direction, Medical Center Foltra, Foundation Foltra, Teo, Spain
- *Correspondence: Jesús Devesa ;
| | - Diego Caicedo
- Department of Vascular Surgery, Health Research Institute of Santiago de Compostela (IDIS), University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
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11
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Lin-Wang HT, Cipullo R, Dias França JI, Finger MA, Rossi Neto JM, Correia EDB, Dinkhuysen JJ, Hirata MH. Intragraft vasculitis and gene expression analysis: Association with acute rejection and prediction of mortality in long-term heart transplantation. Clin Transplant 2018; 32:e13373. [PMID: 30080295 DOI: 10.1111/ctr.13373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/31/2018] [Accepted: 08/01/2018] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Vasculitis entails heterogeneous origins; it starts with an inflammatory process that leads to small vessels' necrosis, hemorrhage, and ischemic lesion, and may further result in occlusion of the vascular lumen. Vasculitis' contribution to allograft rejection is still unclear. This study aims to investigate the incidence of vasculitis in the early stages of heart transplantation as well as to assess the intragraft genes' expression associated with vascular function and subsequently to verify the way in which it affects the outcome of the allograft. METHODS In this retrospective study, 300 archive paraffin-embedded endomyocardial biopsies from 63 heart allograft recipients were assessed. Cellular rejection and vasculitis were diagnosed through histological analysis, and antibody-mediated rejection was performed with immunohistochemical C4d staining. The transcripts of ICAM, VCAM, VEGF, CCL2, IFNG, TGFB, TNF, ADIPOR1, and ADIPOR2 genes were examined through quantitative polymerase chain reaction using B2M for normalization. RESULTS We observed a higher prevalence of severe vasculitis in the early period of post-transplant, and recovery was observed to take place around 1 year post-transplant. Additionally, vasculitis was found to be directly associated with acute cellular rejection and antibody-mediated rejection. The intense C4d capillary positivity predicts higher long-term cardiovascular disease mortality. In comparison with the vasculitis-free group, the group with severe vasculitis displayed reduced left ventricular ejection fraction and an upregulation of VCAM and IFNG associated with the downregulation of VEGF, ADIPOR1, and ADIPOR2. CONCLUSION The vasculitis associated with the presence of C4d and the change in intragraft gene expression profile may contribute to poor allograft outcomes.
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Affiliation(s)
- Hui Tzu Lin-Wang
- Laboratory of Molecular Investigation in Cardiology, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
| | - Reginaldo Cipullo
- Department of Heart Transplantation, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
| | - João Italo Dias França
- Statistic and Epidemiology Laboratory, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
| | - Marco Aurelio Finger
- Department of Heart Transplantation, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
| | - Joao Manoel Rossi Neto
- Department of Heart Transplantation, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil
| | | | | | - Mário Hiroyuki Hirata
- Laboratory of Molecular Investigation in Cardiology, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil.,School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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12
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Hussein Z, Mizuo H, Hayato S, Namiki M, Shumaker R. Clinical Pharmacokinetic and Pharmacodynamic Profile of Lenvatinib, an Orally Active, Small-Molecule, Multitargeted Tyrosine Kinase Inhibitor. Eur J Drug Metab Pharmacokinet 2018; 42:903-914. [PMID: 28236116 DOI: 10.1007/s13318-017-0403-4] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Lenvatinib is a multikinase inhibitor that targets vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor-alpha, and RET and KIT proto-oncogenes. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer in the United States (US), European Union (EU), Canada, Japan, and Switzerland. It is also approved in combination with everolimus for the treatment of advanced renal cell carcinoma following ≥1 VEGF-targeted treatment in the US and EU. In addition, lenvatinib is under investigation for the treatment of hepatocellular carcinoma. As lenvatinib becomes more widely available, a better understanding of its pharmacokinetic profile has become increasingly important. Following oral administration, lenvatinib is absorbed rapidly and is metabolized extensively prior to excretion. This metabolism is mediated by multiple pathways, and several metabolites of lenvatinib have been identified. The effect of food intake on lenvatinib exposure has also been studied and was found to not significantly influence overall exposure to the drug. Exposure to lenvatinib is increased in patients with severe hepatic impairment, indicating that dose reduction must be considered for those patients. The findings summarized here indicate that the clinical pharmacokinetic and pharmacodynamic profile for lenvatinib are predictable, with a dose-independent absorption and elimination profile that supports once-daily administration, and has minimal effects due to mild or moderate renal or hepatic impairment or drug interactions.
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Affiliation(s)
| | | | | | | | - Robert Shumaker
- Clinical Pharmacology and Translational Medicine, Oncology, Eisai Inc., 155 Tice Boulevard, Woodcliff Lake, NJ, 07677, USA.
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13
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Association between three VEGF polymorphisms and renal cell carcinoma susceptibility: a meta-analysis. Oncotarget 2018; 8:50061-50070. [PMID: 28562357 PMCID: PMC5564828 DOI: 10.18632/oncotarget.17833] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 04/11/2017] [Indexed: 12/14/2022] Open
Abstract
Several studies have reported an association between vascular endothelial growth factor (VEGF) gene polymorphisms rs2010963, rs3025039 and rs699947 and renal cell carcinoma (RCC). However, the results remain inconclusive and controversial. We therefore conducted a meta-analysis to evaluate this association. Electronic databases were searched for relevant case-control studies up to November 2016. RevMan 5.2 software and STATA version 12.0 were used for statistical analysis in our meta-analysis. Heterogeneity was assessed using the I2 value. Nine eligible studies were retrieved for detailed evaluation. The pooled estimates indicated that the GG genotype of VEGF rs2010963 polymorphism significantly decreased RCC risk [GG vs. GC+CC; GG vs. GC]. There was also a significant association between VEGF rs3025039 polymorphism and RCC susceptibility [CC+CT vs. TT; CC vs. TT]. Furthermore, a significant association between VEGF rs699947 polymorphism and RCC susceptibility was detected [A vs. C; AA+AC vs. CC; AA vs. AC+CC; AA vs. CC; AA vs. AC; AC vs. CC]. Subgroup analysis revealed that these associations held true especially for Asians. Our meta-analysis suggested that there may be a relationship between the VEGF rs2010963, rs3025039 and rs699947 polymorphisms and RCC susceptibility.
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14
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Bačić I, Karlo R, Zadro AŠ, Zadro Z, Skitarelić N, Antabak A. Tumor angiogenesis as an important prognostic factor in advanced non-small cell lung cancer (Stage IIIA). Oncol Lett 2017; 15:2335-2339. [PMID: 29434942 PMCID: PMC5777107 DOI: 10.3892/ol.2017.7576] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 11/07/2017] [Indexed: 12/03/2022] Open
Abstract
The aim of the present study was to evaluate angiogenesis by determining the micro vascular density (MVD) and the expression of vascular endothelial growth factor (VEGF-A) in advanced non-small cell lung cancer (NSCLC) tumor samples, and to analyze their associations with clinical parameters and survival. Tumor tissue specimens of fifty patients (41 males and 9 females), who underwent radical surgical treatment for NSCLC in stage IIIA (T1-3N2) were collected for immunohistochemical analysis. MVD evaluation was performed using an anti-CD31 monoclonal antibody and VEGF-A expression using a polyclonal anti-VEGF-A antibody. The results were associated with two-year survival. Statistical analysis revealed significant associations in the level of angiogenesis (high MVD) and shorter survival of patients with NSCLC (P=0.0007). VEGF-A expression showed no association with micro vascular density (P=0.51) or survival (P=0.68). There was no significant association between MVD and VEGF-A. The measurable, clinical MVD parameters could be used as a reliable prognostic factor for the survival of patients with advanced NSCLC.
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Affiliation(s)
- Ivan Bačić
- Department of Surgery, Zadar General Hospital, Zadar 23000, Croatia.,Department of Health Studies, University of Zadar, Zadar 23000, Croatia
| | - Robert Karlo
- Department of Surgery, Zadar General Hospital, Zadar 23000, Croatia.,Department of Health Studies, University of Zadar, Zadar 23000, Croatia
| | - Ana Šoštarić Zadro
- Department of Radiology, University Hospital for Infectious Diseases, Zagreb 10000, Croatia
| | - Zvonko Zadro
- Department of Surgery, University Hospital, Sveti Duh, University of Zagreb, Zagreb 10000, Croatia
| | - Neven Skitarelić
- Department of Health Studies, University of Zadar, Zadar 23000, Croatia.,Department of Otorhinolaryngology, Zadar General Hospital, Zadar 23000, Croatia
| | - Anko Antabak
- Surgery Clinic, University Hospital Centre Zagreb, Zagreb 10000, Croatia
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15
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Fiebai B, Odogu V. Intravitreal Anti Vascular Endothelial Growth Factor Agents in The Management of Retinal Diseases: An Audit. Open Ophthalmol J 2017; 11:315-321. [PMID: 29299078 PMCID: PMC5725526 DOI: 10.2174/1874364101711010315] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 09/26/2017] [Accepted: 10/23/2017] [Indexed: 11/22/2022] Open
Abstract
Purpose The study aimed to describe our initial experience with the use of anti vascular endothelial growth factors (anti-VEGFs) in the treatment of retinal diseases. Methods The case records of all patients who had received at least 3 doses of intravitreal anti- VEGF injections between January 2012 to December 2016 were reviewed. Information culled from the data was age, sex, indications for treatment, type of injection, presenting visual acuity, post injection visual acuity, systemic and ocular co morbidities. Results were analyzed using Statistical Package for Social Sciences (SPSS) 20.0 for Windows statistical software. Results A total of 190 injections were given during the study period, to 58 eyes of 50 patients. Twenty-eight females (56.00%) and twenty-two males (44.00%) were seen with a mean age of 59.6± 11.66. Bevacizumab was the most frequently administered anti- VEGF, 142 (74.74%) while only 48(25.26%) injections of Ranibizumab were given. Three eyes had both bevacizumab and ranibizumab (1.58%). Retinal vein occlusion 61(32.11%) was the commonest indication for the injections followed by diabetic macular edema 43(22.63%) and proliferative diabetic retinopathy 42(22.11%). Others were neovascular age related macular degeneration, neovascular glaucoma, vitreous hemorrhage, myopic choroidal neovascularization and cystoid macular edema. There was an association between age and disease, (p = 0.001). There was an improvement in visual acuity after intervention in cases with retinal vein occlusion and diabetic macular edema, and this was statistically significant. Hypertension was the commonest systemic disorder in this series 81(42.36%) and the supero-temporal quadrant 131(68.95%) was the most preferred position to administer the injection. Floaters was the commonest complication seen. Conclusion Anti VEGFs have become an invaluable tool in the management of a number of retinal diseases in our center. However, the cost implications are a hindrance to an increased uptake of this form of treatment. Cheaper alternative preparations should be made available to encourage the uptake. Government in developing countries should be encouraged to bear the health burden of the old aged pensioner (OAP).
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Affiliation(s)
- Bassey Fiebai
- Department of Ophthalmology, University of Port Harcourt Teaching Hospital, , Nigeria
| | - Victor Odogu
- Department of Ophthalmology, Niger Delta University Hospital, Yenagoa, Nigeria
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16
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Lin-Wang HT, Cipullo R, Dinkhuysen JJ, Finger MA, Rossi JM, Correia EB, Hirata MH. Down regulation of protective genes is associated with cellular and antibody-mediated rejection. Clin Transplant 2017; 31. [DOI: 10.1111/ctr.13060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/20/2017] [Indexed: 11/28/2022]
Affiliation(s)
- Hui Tzu Lin-Wang
- Laboratory of Molecular Investigation in Cardiology; Dante Pazzanese Institute of Cardiology; São Paulo Brazil
| | - Reginaldo Cipullo
- Department of Heart Transplantation; Dante Pazzanese Institute of Cardiology; São Paulo Brazil
| | - Jarbas J. Dinkhuysen
- Department of Heart Transplantation; Dante Pazzanese Institute of Cardiology; São Paulo Brazil
| | - Marco A. Finger
- Department of Heart Transplantation; Dante Pazzanese Institute of Cardiology; São Paulo Brazil
| | - João M. Rossi
- Department of Heart Transplantation; Dante Pazzanese Institute of Cardiology; São Paulo Brazil
| | - Edileide B. Correia
- Department of Heart Transplantation; Dante Pazzanese Institute of Cardiology; São Paulo Brazil
| | - Mário H. Hirata
- Laboratory of Molecular Investigation in Cardiology; Dante Pazzanese Institute of Cardiology; São Paulo Brazil
- School of Pharmaceutical Sciences; University of São Paulo; São Paulo Brazil
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17
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Al-Dissi AN, Haines DM, Singh B, Kidney BA. Immunohistochemical Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor Associated with Tumor Cell Proliferation in Canine Cutaneous Squamous Cell Carcinomas and Trichoepitheliomas. Vet Pathol 2016; 44:823-30. [DOI: 10.1354/vp.44-6-823] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The expression of 5 markers associated with angiogenesis was studied in canine squamous cell carcinomas (SCCs) ( n = 19) and canine trichoepitheliomas (TCPs) ( n = 24). SCCs were assigned histologic grades, and tissue sections from both tumor types were immunohistochemially stained for the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2 (VEGFR-2), as well as intratumoral microvessel density (iMVD), tumor proliferation index (PI), and tumor apoptotic index (AI), using antibodies against VEGF, VEGFR-2, von Willebrand's factor, Ki-67 antigen, and the terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate endlabeling method (TUNEL), respectively. VEGF and VEGFR-2 were detected in 17/19 (89.4%) and 19/19 (100%) SCCs and in 17/24 (70.8%) and 20/24 (83.3%) TCPs, respectively. In SCCs, there was substantial correlation between histologic grade and PI ( r = 0.51); and moderate correlation between VEGF and histologic grade ( r = 0.43), VEGFR-2 and histologic grade ( r = 0.47), VEGF and PI ( r = 0.47), and VEGFR-2 and PI ( r = 0.47) (Spearman rank correlation coefficient). In TCPs, there was substantial correlation between VEGF and PI ( r = 0.51) and a moderate correlation between VEGFR-2 and iMVD ( r = 0.36). The median iMVD of SCCs (15.5) was significantly higher than the median iMVD of TCPs (9.05) ( P value < .05). It was concluded that VEGF and VEGFR-2 may promote tumor cell proliferation in TCPs and SCCs. An autocrine pathway for VEGF probably operates in canine SCCs and TCPs, as VEGF and VEGFR-2 expression was found in most tumors and was associated with evidence for tumor cell proliferation.
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Affiliation(s)
- A. N. Al-Dissi
- Departments of Veterinary Pathology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - D. M. Haines
- Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - B. Singh
- Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - B. A. Kidney
- Departments of Veterinary Pathology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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18
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Rodler D. Localization of Vascular Endothelial Growth Factor and Fibroblast Growth Factor 2 in the Ovary of the Ostrich (Struthio camelus). Anat Histol Embryol 2015; 45:428-436. [PMID: 26497821 DOI: 10.1111/ahe.12211] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 09/15/2015] [Indexed: 11/28/2022]
Abstract
Vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) play a paramount role in the regulation of normal and pathologic angiogenesis in the ovary of mammals. Very little is known on the expression of these two growth factors in the avian ovary. The aim of this study was to determine for the first time the localization of VEGF and FGF-2 in the ovary of the ostrich using immunohistochemical techniques to investigate the vascularization of the rapidly growing huge ostrich oocyte. At the oocyte periphery, distinct VEGF-positive granules are visible. In our opinion, the expression of VEGF in the growing oocytes, which does not occur in mammals such as bovines, does not significantly contribute to angiogenesis in the theca interna and externa, where all the original and developing vessels are located, but may contribute to the mitoses and survival of granulosa cells during folliculogenesis. A different immunostaining can be demonstrated for FGF-2: from late pre-vitellogenic follicles, FGF-2 immunopositivity can be observed at the inner perivitelline layer area. In the stroma, the smooth muscle cells of small arteries and the endothelial cells of venules and veins are positively stained for FGF-2. Another interesting finding of this study is the occurrence of a significant number of VEGF- and FGF-2 positive heterophilic granulocytes within the ovarian stroma, which migrate from the periphery of the ovary towards the growing follicles. We assume that the growth factors of the heterophilic granulocytes contribute significantly to the angiogenesis seen in both theca layers.
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Affiliation(s)
- D Rodler
- Institute of Anatomy, Histology and Embryology, Department of Veterinary Sciences, Ludwig-Maximilians-University Munich, Veterinaerstrasse 13, 80539 Munich, Germany.
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Finkenzeller G, Stark GB, Strassburg S. Growth differentiation factor 11 supports migration and sprouting of endothelial progenitor cells. J Surg Res 2015; 198:50-6. [PMID: 26026854 DOI: 10.1016/j.jss.2015.05.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 04/22/2015] [Accepted: 05/01/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Neovascularization plays an important role in tissue engineering applications. In animal models, it was demonstrated that implantation of endothelial progenitor cells (EPCs) from cord blood led to the formation of a complex functional neovasculature, whereas EPCs isolated from peripheral blood (pbEPCs) showed a limited vasculogenic potential, which may be attributed to age-related dysfunction. Growth differentiation factor 11 (GDF11) was recently identified as a rejuvenation factor, which was able to reverse age-related dysfunction of stem cells. Therefore, we hypothesized that GDF11 may improve the vasculogenesis-related phenotype of pbEPCs. MATERIALS AND METHODS pbEPCs were isolated from adult peripheral blood. Transforming growth factor (TGF)-β type-I receptor expression was analyzed by immunostaining. pbEPCs were treated with recombinant GDF11 for various time periods. Thereafter, phosphorylation of Smad2/Smad3, adhesion, proliferation, cell survival, migration, and in vitro sprout formation was investigated. RESULTS pbEPCs express the TGF-β type-I receptors ALK4 and ALK5, but not ALK7. Treatment of pbEPCs with recombinant GDF11 resulted in activation of the Smad2/Smad3 pathway and in increased migration, which was inhibited by the TGF-β1 superfamily type-I activin receptor-like kinase inhibitor SB431542, demonstrating that the TGF-β receptor-Smad2/Smad3 pathway is involved in GDF11 induced migration. Moreover, in vitro sprout formation was increased as well by GDF11 treatment. However, other parameters such as adherence, proliferation, and apoptosis were not affected by GDF11. CONCLUSIONS This study provides evidence that GDF11 improves vasculogenesis-related growth parameters in pbEPCs and may represent a therapeutic option to ameliorate the angiogenic and vasculogenic properties of pbEPCs.
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Affiliation(s)
- Günter Finkenzeller
- Department of Plastic and Hand Surgery, University of Freiburg Medical Center, Freiburg, Germany.
| | - Gerhard Björn Stark
- Department of Plastic and Hand Surgery, University of Freiburg Medical Center, Freiburg, Germany
| | - Sandra Strassburg
- Department of Plastic and Hand Surgery, University of Freiburg Medical Center, Freiburg, Germany
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20
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Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 2015; 16:499-508. [PMID: 25877855 DOI: 10.1016/s1470-2045(15)70127-0] [Citation(s) in RCA: 657] [Impact Index Per Article: 65.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. METHODS Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01183780.ld FINDINGS We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4-14·5) for patients in the ramucirumab group versus 11·7 months (10·8-12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730-0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 [38%] of 529 patients in the ramucirumab group vs 123 [23%] of 528 in the placebo group, with febrile neutropenia incidence of 18 [3%] vs 13 [2%]), hypertension (59 [11%] vs 15 [3%]), diarrhoea (57 [11%] vs 51 [10%]), and fatigue (61 [12%] vs 41 [8%]). INTERPRETATION Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable. FUNDING Eli Lilly.
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Affiliation(s)
- Josep Tabernero
- Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.
| | - Takayuki Yoshino
- Department of Gastroenterology, National Cancer Centre Hospital East, Chiba, Japan
| | - Allen Lee Cohn
- Rocky Mountain Cancer Center/US Oncology, Denver, CO, USA
| | - Radka Obermannova
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Gyorgy Bodoky
- Department of Oncology, Szent László Hospital, Budapest, Hungary
| | - Rocio Garcia-Carbonero
- Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla, RTICC, Instituto Carlos III, Spanish Ministry of Science and Innovation, Seville, Spain
| | - Tudor-Eliade Ciuleanu
- Prof Dr Ion Chiricuta Institute of Oncology and UMF Iuliu Hatieganu, Cluj-Napoca, Romania
| | | | | | - Axel Grothey
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | | | | | | | | | - Sara Lonardi
- Medical Oncology 1, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy
| | - Tae Won Kim
- Department of Oncology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea
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Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P, Yamazaki K, Clingan PR, Lonardi S, Kim TW, Simms L, Chang SC, Nasroulah F. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 2015. [DOI: 10.1016/s1470-2045%2815%2970127-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Kwong TQ, Mohamed M. Anti-vascular endothelial growth factor therapies in ophthalmology: current use, controversies and the future. Br J Clin Pharmacol 2014; 78:699-706. [PMID: 24602183 PMCID: PMC4239964 DOI: 10.1111/bcp.12371] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 02/26/2014] [Indexed: 12/14/2022] Open
Abstract
Use of anti-vascular endothelial growth factor (VEGF) therapies was introduced for the treatment of ocular disorders in 2005. In the UK, the current licensed and NICE approved indications are for the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO), macular oedema secondary to a retinal vein occlusion (RVO) and choroidal neovascularization in pathological myopia. These diagnoses alone account for two-thirds of the main causes of legally registrable visual impairment and blindness. Ranibizumab (Lucentis®; Genentech/Novartis), a drug specifically designed for intraocular use, is the primary licensed medication. Controversially however, clinicians have been using an unlicensed cheaper drug, bevacizumab (Avastin®; Genentech/Roche), originally designed for systemic administration, with a similar mode of action and shown to have a similar efficacy. However, there are fears of greater side effects with bevacizumab though studies have not been sufficiently powered to show statistical difference. In the current global economic climate, anti-VEGF treatment places huge financial and logistical pressure on already strained health care systems. Bevacizumab is considerably more cost effective than ranibizumab, and thus using bevacizumab would widen access to treatment particularly in developing countries. This licensing issue also places clinicians in a difficult medico-legal position especially in Europe, where doctors are duty bound to use a licensed drug for a particular indication if this is available. As the indications of anti-VEGF therapies expand and the cost of health care provision becomes more expensive, the controversies surrounding their use will inevitably become more important.
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Affiliation(s)
- Tsong Qiang Kwong
- Department of Ophthalmology, Eastbourne District General Hospital, Eastbourne, East Sussex, BN21 2UD, UK
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A systems-pharmacology analysis of herbal medicines used in health improvement treatment: predicting potential new drugs and targets. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:938764. [PMID: 24369484 PMCID: PMC3863530 DOI: 10.1155/2013/938764] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 09/23/2013] [Accepted: 10/04/2013] [Indexed: 11/24/2022]
Abstract
For thousands of years, tonic herbs have been successfully used all around the world to improve health, energy, and vitality. However, their underlying mechanisms of action in molecular/systems levels are still a mystery. In this work, two sets of tonic herbs, so called Qi-enriching herbs (QEH) and Blood-tonifying herbs (BTH) in TCM, were selected to elucidate why they can restore proper balance and harmony inside body, organ and energy system. Firstly, a pattern recognition model based on artificial neural network and discriminant analysis for assessing the molecular difference between QEH and BTH was developed. It is indicated that QEH compounds have high lipophilicity while BTH compounds possess high chemical reactivity. Secondly, a systematic investigation integrating ADME (absorption, distribution, metabolism, and excretion) prediction, target fishing and network analysis was performed and validated on these herbs to obtain the compound-target associations for reconstructing the biologically-meaningful networks. The results suggest QEH enhance physical strength, immune system and normal well-being, acting as adjuvant therapy for chronic disorders while BTH stimulate hematopoiesis function in body. As an emerging approach, the systems pharmacology model might facilitate to understand the mechanisms of action of the tonic herbs, which brings about new development for complementary and alternative medicine.
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Senthilkumar K, Venkatesan J, Manivasagan P, Kim SK. Antiangiogenic effects of marine sponge derived compounds on cancer. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2013; 36:1097-1108. [PMID: 24148290 DOI: 10.1016/j.etap.2013.09.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Revised: 09/17/2013] [Accepted: 09/20/2013] [Indexed: 06/02/2023]
Abstract
The term "angiogenic switch" refers to a time-restricted event during tumor progression where the balance between pro- and anti-angiogenic factors, resulting in the transition from dormant avascularized hyperplasia to outgrowing vascularized tumor and eventually to malignant tumor progression. Targeting angiogenesis and its mechanistic pathways are critical target for cancer therapy. Recently, marine derived compounds, plays major role in cancer research. Several sponge derived compounds such as alkaloids, terpenes, macrocylic lactone and polyketide are leading drugs in the treatment of different types of diseases including cancer. Those marine sponge compounds inhibit cancer cell proliferation and tumor angiogenesis. Hence, this review sheds light on angiogenic regulators and marine sponge derived antiangiogenic compounds for cancer.
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Affiliation(s)
- Kalimuthu Senthilkumar
- Marine Bioprocess Research Center, Department of Chemistry, Pukyong National University, Busan, 608-737, Republic of Korea
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Regulation of vascular function on posttranscriptional level. THROMBOSIS 2013; 2013:948765. [PMID: 24288605 PMCID: PMC3833109 DOI: 10.1155/2013/948765] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 09/17/2013] [Indexed: 11/17/2022]
Abstract
Posttranscriptional control of gene expression is crucial for regulating plurality of proteins and functional plasticity of the proteome under (patho)physiologic conditions. Alternative splicing as well as micro (mi)RNA-mediated mechanisms play an important role for the regulation of protein expression on posttranscriptional level. Both alternative splicing and miRNAs were shown to influence cardiovascular functions, such as endothelial thrombogenicity and the vascular tone, by regulating the expression of several vascular proteins and their isoforms, such as Tissue Factor (TF) or the endothelial nitric oxide synthase (eNOS). This review will summarize and discuss the latest findings on the (patho)physiologic role of alternative splicing processes as well as of miRNAs on modulation of vascular functions, such as coagulation, thrombosis, and regulation of the vascular tone.
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Experimental assessment of the neo-vascularisation of acellular dermal matrix in the wound bed pretreated with mesenchymal stem cell under subatmospheric pressure. J Plast Reconstr Aesthet Surg 2013; 67:107-14. [PMID: 24055332 DOI: 10.1016/j.bjps.2013.08.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 06/21/2013] [Accepted: 08/04/2013] [Indexed: 01/09/2023]
Abstract
Neo-vascularisation of the acellular dermal matrix (ADM) is an essential procedure if a full-thickness wound is closed with ADM and skin is grafted over the ADM. In this study, we aimed to improve the neo-vascularisation of ADM by combining the effects of negative pressure wound therapy (NPWT) and mesenchymal stem cells (MSCs) on angiogenesis. In this study, 28 female Sprague-Dawley rats were used and divided into four groups. Full-thickness dorsal skin defects were created in 2 × 2 cm dimensions. The wounds were treated with only the ADM in group 1, the ADM and NPWT in group 2, the ADM and MSCs in group 3 and the ADM, NPWT and MSCs in group 4. By the ninth day of surgery, the excisional biopsy samples were histologically examined to identify the rates of ADM adherence to the recipient bed; the newly formed blood vessels which penetrate the ADM vertically and vascularisation were evaluated by immunohistochemical staining. The graft adherence rates were higher in group 4 than in the other groups statistically, p = 0.003. The numbers of cluster of differentiation 31 (CD31)-stained newly formed microvessels were higher in group 4 than in the other groups statistically, p < 0.05. All subjects in group 4 had the vertical vessels in normal calibration with open lumen vessels which penetrate the ADM. These findings suggest that MSC transplantation induces angiogenesis more efficiently than NPWT. The combination of the NPWT with MSC in this study has shown a synergistic effect on angiogenesis and has affected the neo-vascularisation of the ADM significantly.
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Zhang Y, Li S, Xiao HQ, Hu ZX, Xu YC, Huang Q. Vascular endothelial growth factor gene polymorphisms and renal cell carcinoma: A systematic review and meta-analysis. Oncol Lett 2013; 6:1068-1078. [PMID: 24137466 PMCID: PMC3796421 DOI: 10.3892/ol.2013.1499] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2013] [Accepted: 07/01/2013] [Indexed: 12/11/2022] Open
Abstract
Renal cell carcinoma (RCC) accounts for 3% of all cancer-related mortalities in adults. The risk factors for the development of RCC remain under investigation. Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis and is crucial for the development and metastasis of tumors, including RCC. VEGF gene polymorphisms may alter VEGF protein concentrations, affect the process of angiogenesis and may be involved in inter-individual variation in carcinogenesis. In the present study, a systematic review and meta-analysis were performed based on published case-control studies in order to estimate the association between VEGF gene polymorphisms and the susceptibility to RCC. A total of five studies that involved eight polymorphisms and were published between January 2000 and December 2012 were identified from PubMed. The results of this systematic review and meta-analysis indicate that the VEGF 936C/T, 1612G/A, −1154G/A, −2549I/D, −460T/C and 405G/C gene polymorphisms are not associated with the risk of RCC. There was no polymorphism in 702C/T and RCC and the −2578C/A gene polymorphism may be associated with an increased risk of RCC. However, due to the limitations of the present study, further high quality case-control studies are warranted to confirm these findings.
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Affiliation(s)
- Yong Zhang
- Department of Endocrinology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China ; Department of Nephropathy, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
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Prospective study of peripheral panretinal photocoagulation of areas of nonperfusion in central retinal vein occlusion. Retina 2013; 33:56-62. [PMID: 23269405 DOI: 10.1097/iae.0b013e3182641875] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
PURPOSE To investigate the effect that panretinal photocoagulation to peripheral areas of retinal vascular nonperfusion has on the visual acuity and injection frequency of ranibizumab in eyes with previous central retinal vein occlusion. METHODS Patients enrolled in a prospective study of ranibizumab for central retinal vein occlusion were imaged with wide-field angiography using the Optos P200 system. Laser photocoagulation was carried out and the extent of laser photocoagulation was evaluated with repeat wide-field angiography. Injection of ranibizumab was based on an as needed strategy throughout the study. The injection frequency in the 6 months before laser was compared with a 6-month period starting 2 months after the laser photocoagulation. The visual acuity was measured by Early Treatment Diabetic Retinopathy Study protocol refraction at both the end of the 6-month follow-up period and at the time of laser photocoagulation. RESULTS There were 10 patients treated in this study with a mean number of 1,757 spots of laser photocoagulation in the peripheral retina. The injection frequency in the 6-month lead-in period was 3.4 and in the 6-month follow-up period was 3.1, a difference that was not significant (P = 0.26). The visual acuity at the time of laser photocoagulation was 54.2 letters (approximate Snellen equivalent of 20/80) and at the end of the observation period was 51.4 letters, a difference that was not significant (P = 0.33). CONCLUSION In this small study, laser photocoagulation to peripheral areas of nonperfusion as visualized by wide-field angiography did not result in either decreased injection frequency or improved visual acuity in eyes with central retinal vein occlusion treated with ranibizumab.
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Use of fast conformational sampling to improve the characterization of VEGF A–peptide interactions. J Theor Biol 2013; 317:293-300. [DOI: 10.1016/j.jtbi.2012.10.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2012] [Revised: 10/12/2012] [Accepted: 10/15/2012] [Indexed: 01/25/2023]
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Liu F, Wang J, Chang AK, Liu B, Yang L, Li Q, Wang P, Zou X. Fucoidan extract derived from Undaria pinnatifida inhibits angiogenesis by human umbilical vein endothelial cells. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2012; 19:797-803. [PMID: 22510492 DOI: 10.1016/j.phymed.2012.03.015] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 02/24/2012] [Accepted: 03/10/2012] [Indexed: 05/06/2023]
Abstract
In recent years, anti-angiogenic therapy has become an effective strategy for inhibiting tumor growth. Fucoidan is a class of fucose-enriched sulfated polysaccharides found in brown algae, and it is known to have strong anti-tumor property. Using a human umbilical vein endothelial cells (HUVEC)-based cell culture model, the present study investigated the anti-angiogenic activity of fucoidan extracted from the brown seaweed Undaria pinnatifida. Treatment of HUVECs with various concentrations of fucoidan resulted in significant inhibition of cell proliferation, cell migration, tube formation and vascular network formation. However, significant inhibition of cell proliferation only occurred with longer treatment time (48 h instead of 24h or less). About 40% of cell proliferation and cell migration and 61% of tube formation by HUVECs were inhibited by 400 μg/ml fucoidan, the maximum concentration tested. These results appeared to suggest that modulation of angiogenesis by fucoidan might not occur through growth inhibition and apoptosis. Ex vivo angiogenesis assay demonstrated that at 100 μg/ml, fucoidan caused significant reduction in microvessel outgrowth. Western blot and RT-PCR analyses indicated that at 400 μg/ml, fucoidan significantly reduced the expression of the angiogenesis factor VEGF-A in the suppression of angiogenesis activity. Our results showed that fucoidan isolated from U. pinnatifida may have a new therapeutic potential in the prevention angiogenesis-related diseases.
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Affiliation(s)
- Fang Liu
- Department of Biotechnology, Dalian Medical University, Dalian, 116044 Liaoning Province, China
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Xiang F, Tanaka J, Takahashi J, Fukuda T. Expression of vascular endothelial growth factor (VEGF) and its two receptors in diffusely infiltrating astrocytomas and relationship to proliferative activity of tumor cells. Brain Tumor Pathol 2012; 18:67-71. [PMID: 11908876 DOI: 10.1007/bf02479418] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We studied the relationships among vascular endothelial growth factor (VEGF), its receptors (Flt1 and Flk1), and MIB-1. Their expression in 47 diffusely infiltrating astrocytomas obtained at surgery or autopsy was investigated by the ABC method and analyzed quantitatively. The positive rate of VEGF in tumor cells was higher than that in endothelial cells, and Flk1 was lower in tumor cells (P < 0.01, 0.01), whereas Flt1 in both tumor cells and endothelial cells was found at similar levels (P > 0.05). In tumor cells, VEGF became high with increased histological grades (P < 0.01). whereas both Flt1 and Flk1 were higher in grade 4 than in grades 2 and 3 (P < 0.01, 0.05). VEGF, Flt1, and Flk1 in endothelial cells were also highly expressed in grade 4 (P < 0.01). The distribution of MIB-1-positive nuclei in grade 4 was similar to VEGF, and the percent of positivity from grade 2 to grade 4 also increased (P < 0.01). There was a linear positive correlation between VEGF and both Flt1 and Flk1 in both tumor cells and endothelial cells (P < 0.01). So was the percent of positivity with VEGF, Flt1, and Flk1 in tumor cells and endothelial cells (P < 0.01). The experiment suggests that VEGF may act as a growth factor for both endothelial cells and tumor cells. VEGF, Flt1, and Flk1 can be considered as indicators of the malignancy potential of diffusely infiltrating astrocytomas. The expression of VEGF and the two receptors may be affected by the proliferative activity of tumor cells.
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Affiliation(s)
- F Xiang
- Department of Pathology, Medical College of Qingdao University, China
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Ye J, Li Y, Teruya K, Katakura Y, Ichikawa A, Eto H, Hosoi M, Hosoi M, Nishimoto S, Shirahata S. Enzyme-digested Fucoidan Extracts Derived from Seaweed Mozuku of Cladosiphon novae-caledoniae kylin Inhibit Invasion and Angiogenesis of Tumor Cells. Cytotechnology 2011; 47:117-26. [PMID: 19003051 DOI: 10.1007/s10616-005-3761-8] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2005] [Accepted: 03/04/2005] [Indexed: 10/25/2022] Open
Abstract
Fucoidan is a uniquely-structured sulfated polysaccharide found in the cell walls of several types of brown seaweed that has recently, especially as enzyme-digested fucoidan extract, attracted a lot attention due to its anti-tumor potential. In this study, we evaluated the effects of enzyme-digested fucoidan extracts prepared from seaweed Mozuku of Cladosiphon novae-caledoniae kylin on in vitro invasion and angiogenesis abilities of human tumor cells. First, we evaluated the effect of the fucoidan extracts on oxidative stress of tumor cells, and demonstrated that intracellular H(2)O(2) level and released H(2)O(2) from tumor cells were both greatly repressed upon the treatment with the fucoidan extracts, suggesting that fucoidan extracts ameliorate oxidative stress of tumor cells. Next, we tested for the effects of fucoidan extracts on invasion ability of human fibrosarcoma HT1080 cells, showing that fucoidan extracts significantly inhibit their invasion, possibly via suppressing matrix metalloproteinases (MMPs) MMP-2/9 activities. Further, we investigated the effects of the fucoidan extracts on angiogenesis of human uterine carcinoma HeLa cells, and found that fucoidan extracts suppressed expression and secretion of an angiogenesis factor vascular endothelial growth factor (VEGF), resulting in suppressed vascular tubules formation of tumor cells. The results taken together clarified that enzyme-digested fucoidan extracts from Cladosiphon novae-caledoniae kylin possess inhibitory effects on invasion and angiogenesis of tumor cells. These effects might, at least partially, be elicited by the antioxidative potential of enzyme digested fucoidan extracts.
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Affiliation(s)
- Jun Ye
- Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, 812-8581, Fukuoka, Japan
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Cho KS, Lee DG, Shin DH, Park YD, Chon KM. The importance of vascular endothelial growth factor in the healing of acute tympanic membrane perforation. Am J Otolaryngol 2010; 31:309-14. [PMID: 20015768 DOI: 10.1016/j.amjoto.2009.03.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2008] [Accepted: 03/02/2009] [Indexed: 10/20/2022]
Abstract
PURPOSE The purpose of this study was to determine the more important growth factor expression between basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the healing of acute tympanic membrane (TM) perforation. MATERIALS AND METHODS Bilateral perforations of the TM were created in 12 rats. The TM perforations in the right ears were treated with dexamethasone, and left ears were designated as the control group. The TM was examined for the growth factor expression immunohistochemically in the epithelial and fibrous layers according to the rate of TM perforation healing. RESULTS The mean spontaneous healing time of the TM perforations was 11.0 +/- 2.0 days. However, dexamethasone-treated group showed no evidence of closure. The bFGF and VEGF expression were significantly correlated with the rate of healing of acute TM perforations. The VEGF expression was decreased both in the epithelial and fibrous layers, but bFGF expression was decreased only in the epithelial layer in the dexamethasone-treated group. The VEGF was expressed to a lesser degree than bFGF in the dexamethasone-treated group. CONCLUSION Vascular endothelial growth factor is the more specific and important growth factor than bFGF in the healing of acute TM perforation.
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Al-Dissi AN, Haines DM, Singh B, Kidney BA. Immunohistochemical expression of vascular endothelial growth factor and vascular endothelial growth factor receptor in canine cutaneous fibrosarcomas. J Comp Pathol 2009; 141:229-36. [PMID: 19560781 DOI: 10.1016/j.jcpa.2009.05.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2008] [Revised: 04/28/2009] [Accepted: 05/12/2009] [Indexed: 11/27/2022]
Abstract
The expression of five markers associated with tumour angiogenesis, proliferation and apoptosis was studied in 24 canine cutaneous fibrosarcomas. Tumours were assigned histological grades and were immunohistochemically evaluated for the expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor-2 (VEGFR-2). Additionally, intra-tumour microvessel density (iMVD) was assessed by immunohistochemical labelling for expression of von Willebrand factor (vWf) and tumour proliferation index (PI) was measured following labelling of Ki-67 antigen. Finally, tumour apoptotic index (AI) was determined by application of the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP end-labelling method (TUNEL). VEGF and VEGFR-2 expression were detected in 22/24 (92%) and 24/24 (100%) of fibrosarcomas, respectively. There was correlation between VEGF and VEGFR-2 expression (r = 0.51) and between histological grade and PI (r = 0.82). A significant difference in PI between tumours of different histological grade was found (P < 0.05). The median PI in grade 2 and 3 tumours (30.6 and 54.7, respectively) was significantly higher than in grade 1 tumours (6.4). Therefore, only PI correlates significantly with the histological grade of canine cutaneous fibrosarcomas. The potential for autocrine activity for VEGF exists in canine cutaneous fibrosarcomas, as VEGF and VEGFR-2 expression was found in most tumours.
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Affiliation(s)
- A N Al-Dissi
- Department of Veterinary Pathology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
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Díaz R, Peña C, Silva J, Lorenzo Y, García V, García JM, Sánchez A, Espinosa P, Yuste R, Bonilla F, Domínguez G. p73 isoforms affect VEGF, VEGF165b and PEDF expression in human colorectal tumors: VEGF165b downregulation as a marker of poor prognosis. Int J Cancer 2008; 123:1060-7. [DOI: 10.1002/ijc.23619] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Kirk Field A, Goodchild J. Section Review: Biologicals & Immunologicals: Antisense oligonucleotides: Rational drug design for genetic pharmacology. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.4.9.799] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Ye J, Li Y, Hamasaki T, Nakamichi N, Komatsu T, Kashiwagi T, Teruya K, Nishikawa R, Kawahara T, Osada K, Toh K, Abe M, Tian H, Kabayama S, Otsubo K, Morisawa S, Katakura Y, Shirahata S. Inhibitory effect of electrolyzed reduced water on tumor angiogenesis. Biol Pharm Bull 2008; 31:19-26. [PMID: 18175936 DOI: 10.1248/bpb.31.19] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis. Tumor cells are exposed to higher oxidative stress compared to normal cells. Numerous reports have demonstrated that the intracellular redox (oxidation/reduction) state is closely associated with the pattern of VEGF expression. Electrolyzed reduced water (ERW) produced near the cathode during the electrolysis of water scavenged intracellular H(2)O(2) and decreased the release of H(2)O(2) from a human lung adenocarcinoma cell line, A549, and down-regulated both VEGF transcription and protein secretion in a time-dependent manner. To investigate the signal transduction pathway involved in regulating VEGF expression, mitogen-activated kinase (MAPK) specific inhibitors, SB203580 (p38 MAPK inhibitor), PD98059 (ERK1/2 inhibitor) and JNKi (c-Jun N-terminal protein kinase inhibitor) were applied. The results showed that only PD98059 blocks VEGF expression, suggesting an important role for ERK1/2 in regulating VEGF expression in A549 cells. As well, ERW inhibited the activation of extracellular signal-regulated kinase (ERK) in a time-dependent manner. Co-culture experiments to analyze in vitro tubule formation assay revealed that A549 cell-derived conditioned medium significantly stimulated the formation of vascular tubules in all analyzed parameters; tubule total area, tubule junction, number of tubules, and total tubule length. ERW counteracted the effect of A549 cell-conditioned medium and decreased total tube length (p<0.01). The present study demonstrated that ERW down-regulated VEGF gene transcription and protein secretion through inactivation of ERK.
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Affiliation(s)
- Jun Ye
- Graduate School of Systems Life Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8581, Japan
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Gridelli C, Maione P, Rossi A, De Marinis F. The role of bevacizumab in the treatment of non-small cell lung cancer: current indications and future developments. Oncologist 2007; 12:1183-93. [PMID: 17962612 DOI: 10.1634/theoncologist.12-10-1183] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The majority of non-small cell lung cancer (NSCLC) patients present with advanced disease, and despite the improvement in efficacy and safety outcomes with platinum-based chemotherapy, this standard cytotoxic approach has reached a therapeutic plateau, with the prognosis for this clinical condition remaining poor. Advances in the knowledge of tumor biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment. Bevacizumab, an anti-growth factor vascular endothelial growth factor (VEGF) monoclonal antibody, is the antiangiogenic agent at the most advanced stage of development in the treatment of solid tumors and also in NSCLC treatment. Bevacizumab, combined with platinum-based chemotherapy, has been demonstrated to improve efficacy outcomes over chemotherapy alone in the treatment of nonsquamous advanced NSCLC in two phase III randomized trials. These represent the first evidence of improvement in treatment outcomes of chemotherapy with targeted therapies in the first-line treatment of advanced NSCLC. Future clinical developments of bevacizumab in NSCLC treatment will include the combination of this agent with other targeted therapies in advanced disease (especially with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor) and the integration of this agent into combined modality approaches for the treatment of early-stage and locally advanced disease.
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Affiliation(s)
- Cesare Gridelli
- Division of Medical Oncology, S.G. Moscati Hospital, Contrada Amoretta, Avellino, Italy.
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Ye J, Li Y, Hamasaki T, Nakamichi N, Kawahara T, Osada K, Teruya K, Kato Y, Toh K, Abe M, Katakura Y, Noguchi K, Shirahata S. Catalyser-21(TM), a mineral water derived from leaf soil, inhibits tumor cell invasion and angiogenesis. Cytotechnology 2007; 55:61-70. [PMID: 19002995 PMCID: PMC2104553 DOI: 10.1007/s10616-007-9073-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2007] [Accepted: 03/30/2007] [Indexed: 12/11/2022] Open
Abstract
Catalyser-21(TM) is a mineral water derived from natural leaf soil containing various organic and inorganic substances. Previous reports suggested a possibility that Catalyser-21(TM) has antioxidative potential and could inhibit angiogenesis and cancer cell invasiveness. Angiogenesis is a prerequisite for cancer cells to spread to surrounding tissues. Vascular endothelial growth factor (VEGF) is a major angiogenic factor in the formation of blood capillaries by cancer cells to supply nutrients and oxygen for their sustained growth. Matrix metalloproteinase-2 (MMP-2) is another key enzyme for cancer cell metastasis. To assess the anti-angiogenic activity of Catalyser-21(TM), we first examined cell viability using a human cervical cancer cell line, HeLa, and a fibrosarcoma cell line, HT1080. The results showed that Catalyser-21(TM) decreased the viability of both cell types in a dose-dependent manner. Flow cytometric analysis proved that Catalyser-21(TM) scavenges intracellular H(2)O(2) in both cell types. RT-PCR demonstrated that both VEGF and MMP-2 gene transcription was suppressed after Catalyser-21(TM) treatment. Both Matrigel and tubule formation experiments showed an effect of Catalyser-21(TM). These results suggest that Catalyser-21(TM) has potential as an anti-tumor agent.
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Affiliation(s)
- Jun Ye
- />Graduate School of Systems Life Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
- />Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Science, Xiamen University, Fujian, China
| | - Yuping Li
- />School of Life Sciences, Nanchang University of Science and Technology, Nanchang, 330006 Jiangxi Province China
- />Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
| | - Takeki Hamasaki
- />Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
| | - Noboru Nakamichi
- />Functional Water Cell Analysis Center Co. Ltd, Fukuoka, 812-0000 Japan
| | - Takeshi Kawahara
- />Integrated Department of Sciences of Functional Foods, Graduate School of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano, 399-4598 Japan
| | - Kazuhiro Osada
- />Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
| | - Kiichiro Teruya
- />Graduate School of Systems Life Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
- />Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
| | - Yuko Kato
- />Department of Industrial Chemistry, Faculty of Engineering, Tohwa University, 1-1-1 Chikushigaoka, Minami-ku, Fukuoka, 815-8510 Japan
| | - Kazuko Toh
- />Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
| | - Masumi Abe
- />Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
| | - Yoshinori Katakura
- />Graduate School of Systems Life Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
- />Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
| | - Katsumi Noguchi
- />Noguchi General Institute Co. Ltd, 4-5-8 Kokyu, Miyazaki, 880-0913 Japan
| | - Sanetaka Shirahata
- />Graduate School of Systems Life Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
- />Department of Genetic Resources Technology, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581 Japan
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Rossi A, Maione P, Ferrara C, Del Gaizo F, Guerriero C, Nicolella D, Palazzolo G, Falanga M, Colantuoni G, Gridelli C. New angiogenic agents and non-small cell lung cancer: current results and future development. Target Oncol 2007. [DOI: 10.1007/s11523-007-0060-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Chandrasekaran V, Ambati J, Ambati BK, Taylor EW. Molecular docking and analysis of interactions between vascular endothelial growth factor (VEGF) and SPARC protein. J Mol Graph Model 2007; 26:775-82. [PMID: 17560152 DOI: 10.1016/j.jmgm.2007.05.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2006] [Revised: 05/01/2007] [Accepted: 05/02/2007] [Indexed: 12/29/2022]
Abstract
The extracellular module of SPARC/osteonectin binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-stimulated proliferation of endothelial cells. In an attempt to identify the binding site for SPARC on VEGF, we hypothesized that this binding site could overlap at least partially the binding site of VEGF receptor 1 (VEGFR-1), as SPARC acts by preventing VEGF-induced phosphorylation of VEGFR-1. To this end, a docking simulation was carried out using a predictive docking tool to obtain modeled structures of the VEGF-SPARC complex. The predicted structure of VEGF-SPARC complex indicates that the extracellular domain of SPARC interacts with the VEGFR-1 binding site of VEGF, and is consistent with known biochemical data. Following molecular dynamics refinement, side-chain interactions at the protein interface were identified that were predicted to contribute substantially to the free energy of binding. These provide a detailed prediction of key amino acid side-chain interactions at the protein-protein interface. To validate the model further, the identified interactions will be used for designing mutagenesis studies to investigate their effect on binding activity. This model of the VEGF-SPARC complex should provide a basis for future studies aimed at identifying inhibitors of VEGF-induced angiogenesis.
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Affiliation(s)
- Vasu Chandrasekaran
- Laboratory for Molecular Medicine, Office of Research, University of North Carolina at Greensboro, Greensboro, NC 27402-6170, USA
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Dallard BE, Ruffino V, Heffel S, Calvinho LF. Effect of a Biological Response Modifier on Expression of Growth Factors and Cellular Proliferation at Drying Off. J Dairy Sci 2007; 90:2229-40. [PMID: 17430922 DOI: 10.3168/jds.2006-653] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Agents that increase natural protective mechanisms have been proposed for the prevention and treatment of intramammary infections. Staphylococcus aureus is a major pathogen causing primarily subclinical chronic mastitis that responds poorly to antibiotic therapy. The objectives of this study were to describe the effects of a single intramammary infusion of a lipopolysaccharide-based biological response modifier (BRM) on mammary epithelial cellular proliferation and expression of insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor (VEGF) in uninfected and Staph. aureus-infected bovine mammary glands during involution. Three groups of 12 cows, 6 Staph. aureus-infected and 6 uninfected, were infused with BRM or placebo in 2 mammary quarters and killed at 7, 14, and 21 d of involution. The proportion of infected quarters, mammary cell proliferation, and IGF-I and VEGF expression were evaluated. Biological response modifier treatment decreased the proportion of Staph. aureus-infected mammary quarters at 7 d of involution, but a similar number of isolations were observed at 14 and 21 d of involution in either treated or control quarters. The percentage of proliferating mammary epithelial cells was higher in infected than uninfected quarters at every observation period, irrespective of the treatment administered, whereas uninfected BRM-treated quarters showed increased cell proliferation at 7 d of involution. Insulin-like growth factor-I expression in uninfected quarters was not affected by treatment and showed a decrease at 21 d of involution. Expression of IGF-I was greater in infected than uninfected quarters at every observation period, irrespective of the treatment received. Expression of VEGF was greater in BRM-treated uninfected quarters at 7 d of involution compared with controls. In infected quarters, VEGF expression was lowest in BRM-treated quarters at 7 d of involution and increased throughout the observation period. Conversely, untreated infected quarters showed the highest VEGF expression at 7 d and decreased at 21 d of involution. Mammary cell proliferation and expression of IGF-I and VEGF were increased in Staph. aureus-infected quarters. Increased mammary cell proliferation and VEGF expression were observed in BRM-treated quarters during the first week of involution.
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Affiliation(s)
- B E Dallard
- Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral, Rvdo. Padre Kreder 2805, (3080) Esperanza, Santa Fe, Argentina
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Beckert S, Farrahi F, Aslam RS, Scheuenstuhl H, Königsrainer A, Hussain MZ, Hunt TK. Lactate stimulates endothelial cell migration. Wound Repair Regen 2006; 14:321-4. [PMID: 16808811 DOI: 10.1111/j.1743-6109.2006.00127.x] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The significance of the high lactate levels that characterize healing wounds is not fully understood. Lactate has been shown to enhance collagen synthesis by fibroblasts and vascular endothelial growth factor (VEGF) production by macrophages and endothelial cells. VEGF has been shown to induce endothelial cell migration. However, it has not been shown whether accumulated lactate correlates with the biological activity of VEGF. Therefore, we investigated the effect of lactate on migration of endothelial cells. Human umbilical vein endothelial cells and human microvascular endothelial cells were cultured to subconfluent monolayers in standard six-well tissue culture plates. Following a 24-hour serum starvation, cells were treated with the indicated concentrations of l-lactate. Cell migration was assessed using a modified Boyden chamber. VEGF protein in the cell culture supernatant was measured by enzyme-linked immunoassay. Lactate-enhanced VEGF protein synthesis in a time- and dose-dependent manner. Lactate added into the bottom well did not stimulate cellular migration from the upper well. However, lactate when added together with endothelial cells to the bottom well of the Boyden chamber increased cellular migration in a dose-dependent manner. This effect was blocked by anti-VEGF and by cycloheximide. Lactate enhances VEGF production in endothelial cells, although lactate, itself, is not a chemoattractant. We conclude that the lactate-mediated increase in cellular migration is regulated by VEGF.
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Affiliation(s)
- Stefan Beckert
- Department of Surgery, University of California, San Francisco, California, USA, and Department of General Surgery, University Hospital Tübingen, Germany.
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Gridelli C, Rossi A, Maione P. New antiangiogenetic agents and non-small cell lung cancer. Crit Rev Oncol Hematol 2006; 60:76-86. [PMID: 16843002 DOI: 10.1016/j.critrevonc.2006.01.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2005] [Revised: 01/27/2006] [Accepted: 01/27/2006] [Indexed: 01/02/2023] Open
Abstract
New blood vessel formation, known as angiogenesis is a fundamental event in the process of tumor growth and metastatic dissemination. Due to its central role in tumor angiogenesis, the vascular endothelial growth factor (VEGF) and its receptor have been a major focus of basic research and drug development in the field of oncology, including the treatment of non-small cell lung cancer (NSCLC). Approaches targeting VEGF include monoclonal antibodies and vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). Bevacizumab (Avastin) is an anti-VEGF recombinant humanized monoclonal antibody. A very recent randomized phase III trial demonstrated a statistically significant advantage in median survival favouring the combination of bevacizumab plus chemotherapy versus chemotherapy alone in the treatment of advanced non-squamous NSCLC. This study represents the first evidence of superior efficacy of targeted therapy combined with chemotherapy over chemotherapy alone in the treatment of NSCLC. ZD6474 is an orally bioavailable inhibitor of VEGFR-2 tyrosine kinase. First evidences of antitumor activity and its excellent toxicity profile make it a promising targeted agent for the treatment of NSCLC. A recent phase I/II study examined the combination of Epidermal Growth Factor Receptor (EGFR)-TKI erlotinib and bevacizumab in patients with non-squamous stage IIIB/IV NSCLC. Data on antitumor activity of this combination have to be considered very promising. Clinical trials of multiple targeted therapy may represent the second generation studies in the treatment of NSCLC.
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Affiliation(s)
- C Gridelli
- Division of Medical Oncology, S.G. Moscati Hospital, Contrada Amoretta, Avellino, Italy.
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45
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Cantarella G, Risuglia N, Dell'eva R, Lempereur L, Albini A, Pennisi G, Scoto GM, Noonan DN, Bernardini R. TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells. Br J Cancer 2006; 94:1428-35. [PMID: 16622457 PMCID: PMC2361261 DOI: 10.1038/sj.bjc.6603092] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.
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Affiliation(s)
- G Cantarella
- Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria, 6, Catania 95125, Italy
| | - N Risuglia
- Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria, 6, Catania 95125, Italy
| | - R Dell'eva
- Laboratory of Experimental Oncology, National Cancer Research Institute, Genova 16100, Italy
| | - L Lempereur
- Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria, 6, Catania 95125, Italy
| | - A Albini
- Laboratory of Experimental Oncology, National Cancer Research Institute, Genova 16100, Italy
| | - G Pennisi
- Department of Chemical Sciences, University of Catania, Catania 95125, Italy
| | - G M Scoto
- Department of Pharmaceutical Sciences, University of Catania, Catania 95125, Italy
| | - D N Noonan
- Laboratory of Experimental Oncology, National Cancer Research Institute, Genova 16100, Italy
| | - R Bernardini
- Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria, 6, Catania 95125, Italy
- Department of Experimental and Clinical Pharmacology, University of Catania, Viale Andrea Doria, 6, Catania 95125, Italy. E-mail:
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Hopf HW, Gibson JJ, Angeles AP, Constant JS, Feng JJ, Rollins MD, Zamirul Hussain M, Hunt TK. Hyperoxia and angiogenesis. Wound Repair Regen 2006; 13:558-64. [PMID: 16283871 DOI: 10.1111/j.1524-475x.2005.00078.x] [Citation(s) in RCA: 155] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We hypothesized that tissue hyperoxia would enhance and hypoxia inhibit neovascularization in a wound model. Therefore, we used female Swiss-Webster mice to examine the influence of differential oxygen treatment on angiogenesis. One milliliter plugs of Matrigel, a mixture of matrix proteins that supports but does not itself elicit angiogenesis, were injected subcutaneously into the mice. Matrigel was used without additive or with added vascular endothelial growth factor (VEGF) or anti-VEGF antibody. Animals were maintained in hypoxic, normoxic, or one of four hyperoxic environments: hypoxia -- 13 percent oxygen at 1 atmosphere absolute (ATA); normoxia -- 21 percent oxygen at 1 ATA; hyperoxia -- (groups a-d) 100 percent oxygen for 90 minutes twice daily at the following pressures: Group a, 1 ATA; Group b, 2 ATA; Group c, 2.5 ATA; Group d, 3.0 ATA. Subcutaneous oxygen tension was measured in all groups. The Matrigel was removed 7 days after implantation. Sections were graded microscopically for the extent of neovascularization. Angiogenesis was significantly greater in all hyperoxic groups and significantly less in the hypoxic group compared with room air-exposed controls. Anti-VEGF antibody abrogated the angiogenic effect of both VEGF and increased oxygen tension. We conclude that angiogenesis is proportional to ambient pO(2) over a wide range. This confirms the clinical impression that angiogenesis requires oxygen. Intermittent oxygen exposure can satisfy the need for oxygen in ischemic tissue.
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Affiliation(s)
- Harriet W Hopf
- Wound Healing Research Laboratory, Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94143, USA.
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Gridelli C, Maione P, Rossi A, Ferrara C, Colantuoni G, Del Gaizo F, Nicolella D, Guerriero C. Targeted therapies in the treatment of advanced non-small cell lung cancer elderly patients. Target Oncol 2006. [DOI: 10.1007/s11523-005-0006-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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Minardi D, Lucarini G, Mazzucchelli R, Milanese G, Natali D, Galosi AB, Montironi R, Biagini G, Muzzonigro G. PROGNOSTIC ROLE OF FUHRMAN GRADE AND VASCULAR ENDOTHELIAL GROWTH FACTOR IN pT1a CLEAR CELL CARCINOMA IN PARTIAL NEPHRECTOMY SPECIMENS. J Urol 2005; 174:1208-12. [PMID: 16145371 DOI: 10.1097/01.ju.0000173078.57871.2d] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE Conventional renal cell carcinoma (RCC) is characterized by rich neovascularization and shows a fine vascular network around tumor cells. Nephron sparing surgery has been established as a method of choice or necessity for localized tumors. We investigated the importance of microvessel density (MVD), vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (Flk-1) immunohistochemical expression in a large series of small conventional clear cell renal carcinomas treated with partial nephrectomy and assessed the prognostic value of their expression in terms of patients survival at long-term followup. MATERIALS AND METHODS A total of 48 patients with a mean age +/- SD of 58.2 +/- 9.5 years who had conventional single RCC were considered. Median tumor diameter was 2.92 +/- 0.82 cm (range 1.3 to 5). Disease was grades 1 to 4 in 15, 29, 2 and 2 patients, respectively. Median followup was 92.9 months (range 17 to 186). RESULTS Four patients (3.9%) had died of metastatic renal cancer at a median followup of 23.5 months, of whom 1 had a grade 2, 1 had a grade 3 and 2 had grade 4 RCC. Patients with MVD expression higher than the median (44.4 vessels per mm) did not show a significant difference in survival compared to patients with MVD expression lower than the median. Patients with VEGF expression higher than 25% in the histological specimen showed worse survival than patients with VEGF expression lower than 25%. Different Flk-1 expression did not determine a significant difference in survival. On univariate analysis of patient survival in relation to the different considered factors Fuhrman grading was the most important factor for survival. CONCLUSIONS Our study shows that recurrence and death are possible even in patients with small renal tumors. MVD, VEGF and Flk-1 expression do not depend on tumor size in pT1a RCC. Therefore, to date Fuhrman grading appears to be the only factor predictive of survival even in small RCC. Thus, Fuhrman grading is predictive of mortality. While VEGF is not predictive of survival as a single parameter, based on its percent of expression (lower or higher than 25%) it can determine 2 groups that are different from the prognostic point of view.
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Affiliation(s)
- D Minardi
- Institute of Urology, Polytechnic University of the Marche Region Medical School, Ancona, Italy
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Ng I, Tan WL, Ng PY, Lim J. Hypoxia inducible factor-1α and expression of vascular endothelial growth factor and its receptors in cerebral arteriovenous malformations. J Clin Neurosci 2005; 12:794-9. [PMID: 16165361 DOI: 10.1016/j.jocn.2005.02.005] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2004] [Revised: 02/28/2005] [Accepted: 02/28/2005] [Indexed: 11/30/2022]
Abstract
BACKGROUND Vascular endothelial growth factor (VEGF) and its tyrosine kinase family of receptors (VEGFR) (Flt-1, Flk-1, Flt-4) have been implicated in vascular angiogenesis and remodelling in cerebral arteriovenous malformations (CAVM). In this study, we investigate the role of hypoxia inducible factor-1 (HIF-1alpha) in CAVM and its relationship to VEGF and VEGFR. METHODS Surgical specimens from 26 patients undergoing CAVM resection were studied for HIF-1alpha , VEGF, Flt-1, Flk-1 and Flt-4. The mean age was 34.08 +/- 14.18 years. Twenty-one patients presented with intracerebral haemorrhage. RESULTS VEGF, Flt-1 and Flt-4 were expressed in all specimens. Flk-1 was expressed in 15 of 26 patients. HIF-1alpha was expressed in 15 of 26 patients. HIF-1alpha expression was significantly associated with VEGF, Flt-1 and Flk-1 expression (p < 0.05) CONCLUSIONS HIF-1alpha is expressed in human CAVM. The expression of HIF-1alpha is significantly related to VEGF and VEGFR expression, suggesting a possible role for its induction and role in maintaining angiogenesis and vascular remodelling.
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Affiliation(s)
- Ivan Ng
- Section of Cerebrovascular Surgery, Department of Neurosurgery, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.
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50
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Mastrangelo F, Grimaldi S, Tecco S, Festa F, Perfetti G, Salini L, Stuppia L, Angelucci D, Dolci M, Tete S. Immunohistochemical Evaluation of VEGF Inflamed Cystic Radicular Lesions and in Keratocysts. EUR J INFLAMM 2005. [DOI: 10.1177/1721727x0500300303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Vascular Endothelial Growth Factor, also known as Vascular Permeability Factor, is a multifunctional cytokine hyperexpressed during angiogenesis and in numerous physiological and pathological processes characterised by an increase of vascular permeability. The aim of this study was to evaluate the angiogenetic processes which are accompanied by an expansion of cystic radicular lesions and of keratocysts of the jaw bone. 12 subjects were chosen with an average age of 43 years, of whom 8 were males and 4 females. After an accurate history and physical examination, the patients underwent surgery for removal of the cysts. The samples taken were histologically and immunohistochemical examined. The histological exam confirmed the diagnosis of radicular cysts and keratocysts. The immunohistochemical examinations were positive for VEGF in all the lesions analysed, even though they had different immunostaining. Using a semi-quantitative method, in the radicular cyst samples it was possible to highlight a wider expression of the vascular component, both in the inflamed area and the adjacent stroma. The lesions with keratin content showed newly formed and modest vascularisation both in the area showing slight inflammation, where the cellular component was prevalent, and in the adjacent areas showing no inflammation. Therefore, angiogenesis could take on a primary role in the development of cystic lesions of the jaw. However, the differences of expression of the VEGF protein suggest the need for wider monitoring to better evaluate a possible use of such a protein as a diagnostic marker.
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Affiliation(s)
- F. Mastrangelo
- Department of Odontostomatology, University “G. D'Annunzio” Chieti, Italy
| | - S. Grimaldi
- Department of Odontostomatology, University “G. D'Annunzio” Chieti, Italy
| | - S. Tecco
- Department of Odontostomatology, University “G. D'Annunzio” Chieti, Italy
| | - F. Festa
- Department of Odontostomatology, University “G. D'Annunzio” Chieti, Italy
| | - G. Perfetti
- Department of Odontostomatology, University “G. D'Annunzio” Chieti, Italy
| | - L. Salini
- Department of Odontostomatology, University “G. D'Annunzio” Chieti, Italy
| | - L. Stuppia
- Department of Odontostomatology, University “G. D'Annunzio” Chieti, Italy
| | - D. Angelucci
- Department of Odontostomatology, University “G. D'Annunzio” Chieti, Italy
| | - M. Dolci
- Department of Odontostomatology, University “G. D'Annunzio” Chieti, Italy
| | - S. Tete
- Department of Odontostomatology, University “G. D'Annunzio” Chieti, Italy
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