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Basic Research Team « Normal and pathological angiogenesis »
Dr Gilles PAGES, DR1 INSERM, Team Leader
Our projects have focused on the ERK signaling pathway ; modulation of its activity, its role in tumor development (use of ERK1-/- mice) and its role in tumor angiogenesis (regulation of VEGF expression). We have highlighted regulators of VEGF expression that can serve as markers of tumor aggressiveness especially in the case of head and neck and breast cancers. We have established an original link between telomeric activity and the ERK signaling pathway. We are also interested in phenomena that could explain the varying efficiencies of Avastin/Bevacizumab (BVZ) depending on cancer origins. On models of breast and prostate cancers, the clinical efficiency of associations Taxol / BVZ could be explained by a direct effect on tumor cells expressing both VEGF and its receptor VEGF-R2. Clear cell renal cell carcinomas (RCC) express VEGF and pro-angiogenic factors of the family of ELR+CXCL cytokines. CXCL7 and CXCL8 (interleukin 8) are associated with increased mortality in patients. Monoclonal antibodies targeting CXCL7 and 8 are currently developed. In xenograft models of RCC tumors, BVZ accelerates tumor growth and induces the development of the lymphatic network that can explain the acceleration of the metastatic spread observed in patients.
Background of the team and self analysis
The group was created in 1999 when we moved from the Centre de Biochimie Parc Valrose to the Nice Cancer Centre, Centre Antoine Lacassagne (CAL). Our objectives were to decipher the links between activation of the ERK pathway and abnormal angiogenesis, two mains actors implicated in tumor development. Our localization at the CAL incited us to develop translational research aiming at reinforced the links with clinicians. My team was implicated in the discovery of new pertinent direct targets of ERK and on the molecular links between ERKs and regulation of VEGF expression at transcriptional and post transcriptional levels. Discussions with clinicians and our expertise on angiogenesis have oriented our thematic on the failure of anti-angiogenic therapies. The identification of the phosphorylation of the telomere binding factor TRF2 by ERK has established a new link between telomeric activity and activation of a major signaling pathway involved in tumor development.
Strengths : a strong interaction with clinicians and a solid expertise in the mechanisms of angiogenesis and on the ERK signaling pathway; the access to tumors samples in collaboration with different cancer centers (Nice, Lyon, Montpellier, Grenoble); the access to platforms (Animal house, imagery); the capacity to raise funds from national and international agencies, charities and private companies for manpower and consumables; the capacity to initiate clinical assays for an optimal transfer of the fundamental results to the clinic; valorization of the results of translational research through the filing of patent. Previous members of the team have obtained permanent positions at the University of Nice as assistant professors (Julie Milanini-Mongiat, Cercina Onesto), INSERM researcher (Sandrine Marchetti), clinic responsible (Laurence Legros) and researcher at the Pasteur Institute of Tunis (Khadija Essafi-Benkhadir). Olga Bermudez a PhD student who has defended her thesis in October 2009 realized currently a post doc with opportunity to develop her own team in Germany. The recent will of Dr Pascal Colosetti (engineer INSERM) to join my team.
Research Projects
« Normal and pathological angiogenesis »
The phenomena of angiogenesis are finely controlled through an equilibrated balance between pro and anti-angiogenic factors. Any imbalance leads to abnormal angiogenesis often associated with tumor progression. Despite an undeniable effect on progression-free survival of anti VEGF (Bevacizumab, BVZ), only a marginal effect on overall survival was observed. Our project aims to elucidate the partial failure of anti-angiogenic through the approach "from bedside to bench". Our recent findings have shown that ELR + / ELR-CXCL cytokines are major players implicated in tumor evasion to BVZ. The anti-angiogenic forms of VEGF are also interesting targets since they are recognized by BVZ with the same affinity than VEGF. We have also evidenced that a specific phosphatase, PTPRk is specifically down-regulated upon BVZ treatement and induced over activation of major tyrosine kinase receptor including EGF-R and c-Met. The aims of our project will be both fundamental and translational and we will focused on: i) redundant angiogenic ELR+CXCL, regulation of their expression and development of specific antibodies targeting the most pertinent one; ii) test the efficiency of EGF-R/c-Met inhibitors in case of resistance to BVZ; iii) the regulation of expression of anti-angiogenic forms of VEGF in tumor cells, the means of forcing their expression, their role as pro-apoptotic factors or growth inhibitors and targeting only pro-angiogenic forms of VEGF; iiii) Influence of ERK on the balance between pro and anti-angiogenic forms of VEGF. The molecular players involved in maintaining an equilibrated angiogenic balance would serve as pertinent prognosis markers of cancers aggressiveness. Moreover, the targeting of the most relevant pro-angiogenic cytokines (CXCL VEGF) represents a significant therapeutic challenge.
Clear cell renal cell carcinomas (RCC) are vascularized tumors that arise due to mutations in the von Hippel-Lindau gene leading to over-expression of VEGF. Hence RCC should be one of the most responsive tumors to anti-angiogenic therapies. Bevacizumab (BVZ), a humanised monoclonal antibody targeting VEGF has obtained approval for treatment of RCC in association with interferon-a (1). Despite the increased time to progression, no significant effects of BVZ on overall survival have been observed (AVOREN study) (2). The limited effectiveness raises an economic issue, given the high cost of treatment with BVZ. Moreover, some recent papers describe a new phenomenon called treatment evasion and the selection of more aggressive cells with increased metastatic potential (3-4). The aim of our study was to gain insight into the absence of persistent effects of anti-angiogenic therapies (5). Our hypothesis states that this could be due to the presence of anti-angiogenic forms of VEGF called VEGFxxxb, which result from alternative splicing (6) or to the production of redundant angiogenic cytokines. We have focused on the specific regulation of the VEGF/VEGFxxxb balance and on the targeting of cytokines of the CXCL family that have angiogenic and anti-angiogenic potency depending on the presence or absence of the amino acid triplet ELR (ELR+CXCL (1,2,3,5,6,7,8), pro-angiogenic; ELR-CXCL (4,9,10) anti-angiogenic) (7). ELR+CXCL stimulate their G-protein-coupled receptors CXCR-1 and CXCR-2, which activate of the ERK pathway (8). The pro-inflammatory chemokine CXCL8/interleukin-8 promotes angiogenesis, tumorigenesis and metastasis and is over-expressed in many tumors (9) including RCC (10). Ras-dependent secretion of CXCL8 enhances tumor progression by promoting neo-vascularisation (11). Hence, tumor cells may use diverse pro-angiogenic chemokines to mediate angiogenesis and to promote tumor progression. Our goals are :1) To determine the pertinence of targeting CXCL rather than VEGF for RCC2) To highlight new cytokines implicated in mechanisms of evasion to anti VEGF3) To demonstrate that VEGFxxxb are implicated in absence of enduring efficacy to BVZ4) To understand the molecular mechanisms implicated in repression of VEGFxxxb in tumor5) The development of new therapeutic strategies aiming at decreasing the activity of CXCL, at increasing expression of VEGFxxxb or specifically targeting the pro-angiogenic VEGF6) Patenting therapeutic antibodies issued from our fundamental research.
A) Determination of pertinent ELR+CXCL or others cytokines implicated in RCC aggressiveness and anti-angiogenic treatment evasion
Excessive amounts of intra-tumor CXCL7 and 8 are independent markers of increased mortality. RCC cells secreted high amounts of CXCL8. CXCL7 is produced by tumor cells when implanted in mice whereas it is not produced in culture conditions. These results on human samples and on tumor development in mice have highlighted CXCL7 and CXCL8 as major cytokines implicated in increased RCC aggressiveness.
A.1 The role of antibodies directed against CXCL7 and 8 to prevent tumor growth
RCC cells expressing the reporter gene luciferase will serve to follow tumor development in live animal and the role of commercially available anti CXCL7/CXCL8 antibodies on tumor shrinkage and on the vascular and lymphatic networks.
A.2 Development of anti angiogenic therapies targeting the action of CXCL cytokines
A.2.1 Monoclonal antibody strategy
CXCL7 and CXCL8 share common sequences. We are developing monoclonal antibodies that could target both cytokines (Dr Michel Pierres, antibody platform, cancéropole PACA). Polyclonal ascites against GST-CXCL8 (collaboration with Professor Anny Cupo, IPMC Sophia Antipolis) contains antibodies that prevent CXCL8 and CXCL7-dependent activation of the CXCR2 (CXCR2 expressing cells were obtained from Dr Venkatakrishna Shyamala (Chiron Corporation California)). These experiments represent a proof of concept showing that CXCL7 and 8 share common immunogenic epitopes. We will analyze the capacity of antibodies produced from 4 independent monoclonal hybridomas against GST-CXCL8 to block the CXCL7,8-dependent activation of CXCR2. Their therapeutic activities will be tested on tumor development in mice. If efficient, they will be humanized for phase I clinical assays.
A.2.2 Inhibition of the CXCR2 receptor
We will use repertaxin (12), a noncompetitive allosteric inhibitor of the inflammatory chemokine receptors CXCR1 and CXCR2 (collaboration DOMPE company L'Aquila Italy). It is currently in clinical assays for inflammatory diseases. RCC cells express different CXCL cytokines including CXCL1, 2, 3, 5 and 8 and CXCR2 receptor, hence maintaining an autocrine loop. Repertaxin should block tumors development by inhibiting cell proliferation and angiogenesis. If validated in preclinical models, clinical studies would be proposed.
A.3 Identification of new cytokines implicated in evasion to anti-VEGF
Treatment of RCC in mice with BVZ accelerates tumor growth. These artificial conditions putatively mimic the progression phase observed when patients became refractory to treatment. A transcriptomic analysis on RCC cells recovered from tumors that have grown in the presence of BVZ has revealed an increased expression of CKLF1, a potent chemoattractant for neutrophils, monocytes and lymphocytes (13). CKLF1 could induce an inflammatory situation encountered in the tumors. We have obtained the cDNA encoding CKLF1 from Dr Ma (School of Medical Science, Peking). RCC cells conditionally expressing CKLF1 in response to tetracycline will be created and implanted in nude mice. Since RCC tumor growth slowly (one month after inoculation) tumors should be visible sooner upon CKLF1 induction or latter upon inhibition of CKLF1 by shRNA.
B) The role of VEGFxxxb isoforms in resistance to anti VEGF/Regulation of expression and therapeutic approaches
VEGF and VEGFxxxb are express at a 50/50 ratio in normal cells (14). An increase of the VEGF/VEGFxxxb ratio led to the development of an abnormal vascular network in tumors (6). BVZ has the same affinity for VEGF and VEGFxxxb (15) underlying inefficiency of the drug if VEGFxxxb are present. In normal epithelial cells, the VEGF/VEGFxxxb ratio depends on SR splicing factors; ASF/SF2 promotes pro-angiogenic forms and SRp55 promotes the anti-angiogenic forms (16). However, the factors controlling this ratio in cancer cells are not known. SR proteins are involved in tumor pathology. ASF/SF2 is carcinogenic because i) it is overexpressed in breast kidney and lung tumors; ii) its overexpression is transform fibroblasts iii) tumors generated with these cells are vascularised (17). This project aims to elucidate the contribution of VEGFxxxb isoforms in the failure of antiangiogenic therapies and propose therapeutic alternatives. SR factors, by affecting the VEGF/VEGFxxxb balance, could represent predictors of failure or success of treatment. Identification of predictive markers of tumor response to antiangiogenic therapy should help in selecting patients to be treated in order to prevent side effects at the origin of tumor escape and dissemination.
B.1 VEGF/VEGFxxxb ratio and SR proteins in rcc: towards the identification of bio-markers prognostic and/or predictive of response to anti-angiogenic drugs
B.1.1 In situ approach on samples of patients
B.1.1.1 Expression of isoforms VEGFxxxb and SR proteins
Expression of VEGF and VEGFxxxb isoforms in RCC will be studied and a correlated with overall survival. Amounts of SR proteins and the kinases regulating their activity (CLK/STY, SRPK1/2) in normal and tumor tissues will be correlated with disease-free survival or overall survival. Statistical analysis of these results will be conducted by Dr. Emmanuel Chamorey (CAL statistic department).
B.1.1.2 Correlation ratio VEGF / VEGFxxxb and response to therapy Sunitinib
We have initiated a prospective clinical study which aimed to correlate the amount of plasma VEGF and VEGFxxxb and response to treatment with Sunitinib in patients with RCC. This multi-centres trial (SUVEGIL, Nice, Montpellier, Toulouse, Mougins) has been approved by the "protection of person committee" (CPP). Plasma levels of VEGF/VEGFxxxb will be determined by ELISA and correlated with clinical response (RECIST Criteria).
B.1.2 Molecular actors controlling the ratio VEGF/VEGFxxxb
B.1.2.1 Role of proteins ASF/SF2 and SRp55 on the VEGF / VEGFxxxb ratio
The expression of VEGF and VEGFxxxb isoforms will be analyzed in cell models over-expressing or knock-down for proteins ASF/SF2 or SRp55. Preliminary results showed that modulation of SRp55 expression affects the VEGF/VEGFxxxb balance.
B.1.2.2 Tumorigenicity in nude mice
The above cell models will allow testing the ability of ASF/SF2 or SRp55 to modulate tumor growth and tumor angiogenesis in nude mice. The time of onset of tumors, the incidence of occurrence and tumor size will be assessed. The degree of vascularization and VEGF/VEGFxxxb ratio will be evaluated on cuts and shreds of tumors.
B.2 VEGF/VEGFxxxb balance and SR proteins in RCC: towards the establishment of new therapeutic strategies
B.2.1 Monoclonal antibodies specific of pro-angiogenic VEGF isoforms
6 amino acids located in the C-terminal differentiate pro and anti-angiogenic forms (CDKPRR). Although cysteine is involved in a disulfide bridge, the other five amino acids are clearly exposed as shown by the three-dimensional structure (18). Moreover, monoclonal antibodies specific of VEGFxxxb were obtained after immunization with a peptide of 6 amino acids (SLTRKD) (15). An immunization program was initiated with specific peptides corresponding to the CDKPRR sequence. Antibodies present in the immune ascites specifically recognize VEGF but not VEGFxxxb forms. Monoclonal will be developed with the antibody platform of the cancéropole PACA. These antibodies will be validated; i) by their capacity to specifically recognized VEGF by ELISA; ii) by their capacity to block VEGF-induced proliferation of HUVEC; iii) by their efficacy to inhibit tumor growth in nude mice. Mice RCC cells are available for testing the efficiency of our antibodies in immune-competent animals. Preclinical insight into the mechanisms of development of kidney cancer is limited by the paucity of preclinical models. Recently, Guys et al have developed a model of RCC development in mice by using streptozotocin (19). The effect of prophylactic immunisation against VEGF on the incidence of spontaneous tumor development will be tested.
B.2.2 Combination anti-angiogenic + inhibitors of kinases (TG003 or siRNA SRPK1 / 2) and / or anti-angiogenic + chemotherapy
B.2.2.1Effect of chemotherapy on the ratio VEGF/ VEGFxxxb
Our hypothesis stipulates that chemotherapeutic agents by modifying the VEGF/VEGFxxxb ratio would alter the intrinsic response to anti-VEGF therapies. We will test in vitro effects of chemotherapy used in combination with BVZ on the VEGF/VEGFxxxb ratio and the level of expression of proteins ASF/SF2, SRp55, SRPK1/2 and CLK/STY. According to the results, these proteins will be neutralized by RNA interference and the effects on the VEGF/VEGFxxxb ratio and on tumor cell survival analyzed. Evaluation of tumor growth in nude mice with different combinations of chemotherapeutic agents +/- BVZ will be tested in models overexpressing/knockdown for ASF/SF2 or SRp55.
B.2.2.2 Targeting CLK/STY and SRPK1/ 2: Development of new therapeutic strategies
The role of CLK and SRPK in the control of the VEGF/VEGFxxxb ratio will be analyzed in our cell models over-expressing or knock down for our proteins of interest. CLK/STY will be inhibited by commercially available pharmacological inhibitor TG003 (20). SRPK will be neutralized by RNA interference. Inhibition of CLK and/or SRPK through inhibition of ASF/SF2 could synergize with the effect of anti-angiogenic. This section provides a direct application of these fundamental results in the clinic. We will test the ability of combinations BVZ/TG003 and Sunitinib/TG003 to modulate the VEGF/VEGFxxxb ratio and to inhibit tumor growth in nude. These combinations will also be tested with specific anti VEGF antibodies.
B.2.2.3 Relationship between ERKs, the VEGF/VEGFxxxb ratio and SR factors
RCC cells present with constitutive ERK activity. The presence of four consensus sites for phosphorylation by ERK on ASF/SF2 and SRp55 suggests that their activity could depend on the RAS/RAF/MEK/ERK signaling pathway. The constitutive activation of ERKs would cause an imbalanced VEGF/VEGFxxxb ratio by activating and/or increasing the expression of ASF/SF2 and by inhibiting the activity and/or expression of SRp55. The stability and/or activity of these proteins may depend on direct phosphorylation by ERKs as for the SAM68 splicing factor (21). Mutation of these sites may have constitutive (mutation to aspartic acid) or dominant negative activity (mutation alanine) and modulate the VEGF/VEGFxxxb ratio. If true, a new relationship between ERK and angiogenesis would be established.
B.3 VEGF/VEGxxxb ratio: The relationship between mRNA stability and splicing
Alternative splicing that generates mRNAs encoding the pro/anti-angiogenic forms of VEGF changes the 3' non-coding sequences (3'UTR) and coding regions of mRNA. Comparison of 3'UTR sequence reveals the presence of 44 additional bases in the mRNA encoding the pro-angiogenic forms. This sequence forms a hairpin structure characteristic of protein/RNA interaction domains and contains an "Enhancer Splicing Element (ESE)" capable of binding ASF/SF2 (16). This domain could lead to the degradation of pro-angiogenic VEGF mRNA and maintain an equilibrated VEGF/VEGFxxxb ratio in normal cells. Preliminary experiments have shown that these 44 bases confer instability to the reporter gene luciferase. Proteins interacting with this area would represent key factors implicated in the maintenance of a balanced VEGF/VEGFxxxb ratio. The loss of destabilizing protein(s) or the gain of stabilizing protein(s) interacting with this domain constitutes criteria of abnormal angiogenesis. These proteins might therefore become relevant prognosis markers.
The anti-angiogenic drugs exceptionally improve overall survival. This finding was depressing for both therapeutic purposes and economic impact as huge sums were invested by pharmaceutical companies and these treatments are very expensive for patients or for health insurances. Our project propose to determine the molecular mechanisms involved in this semi-clinical failure and find new ways to improve existing treatments or propose new therapeutic options. Our project should: 1) identify biomarkers predictive of response or non-response to anti-angiogenic drugs for a more relevant prescription of existing therapies, 2) test the relevance of combinations currently used in clinical practices, 3) propose new combination therapies, 4) propose new targets for developing more efficient therapies.
1. B. Escudier et al., Lancet 370, 2103 (Dec 22, 2007).2. B. Escudier et al., J Clin Oncol 28, 2144 (May 1, 2010).3. J. M. Ebos et al., Cancer Cell 15, 232 (Mar 3, 2009).4. M. Paez-Ribes et al., Cancer Cell 15, 220 (Mar 3, 2009).5. J. C. Yang et al., N Engl J Med 349, 427 (Jul 31, 2003).6. S. J. Harper, D. O. Bates, Nat Rev Cancer 8, 880 (Nov, 2008).7. D. Raman, P. J. Baugher, Y. M. Thu, A. Richmond, Cancer Lett 256, 137 (Oct 28, 2007).8. J. Vandercappellen, J. Van Damme, S. Struyf, Cancer Lett 267, 226 (Aug 28, 2008).9. K. Xie, Cytokine Growth Factor Rev 12, 375 (Dec, 2001).10. J. Mestas et al., J Immunol 175, 5351 (Oct 15, 2005).11. A. Sparmann, D. Bar-Sagi, Cancer Cell 6, 447 (Nov, 2004).12. R. Bertini et al., Proc Natl Acad Sci U S A 101, 11791 (Aug 10, 2004).13. W. Han et al., Biochem J 357, 127 (Jul 1, 2001).14. D. O. Bates et al., Cancer Res 62, 4123 (Jul 15, 2002).15. A. H. Varey et al., Br J Cancer 98, 1366 (Apr 22, 2008).16. D. G. Nowak et al., J Cell Sci 121, 3487 (Oct 15, 2008).17. R. Karni et al., Nat Struct Mol Biol 14, 185 (Mar, 2007).18. C. Wiesmann et al., Cell 91, 695 (Nov 28, 1997).19. M. E. Gruys et al., Cancer Res 61, 6255 (Aug 15, 2001).20. T. Fukuhara et al., Proc Natl Acad Sci U S A 103, 11329 (Jul 25, 2006).21. N. Matter, P. Herrlich, H. Konig, Nature 420, 691 (Dec 12, 2002).
(June 2012)
Research Team
Research Team
PAGES Gilles, DR1 INSERM, Team Leader Tel : +33 (0)4 92 03 12 32, E-mail :
MARTIAL Sonia, CR1 CNRS
NDIAYE Papa-Diogop, Thèse en sciences
PAROLA Julien, Technicien (Centre A. Lacassagne)Tel : +33 (0)4 92 03 12 31, E-mail :
(Oct 2016)
DistinctionsJune 2017
Dr Gilles Pagès received the Price Albert I of the National Academy of Medicine in Paris for his research on the "L'angiogenèse tumorale ; du mécanisme moléculaire à la découverte de nouveaux traitements visant à détruire les vaisseaux sanguins tumoraux".
Ce travail est axé sur une démarche «de la paillasse au lit du malade» et «du lit du malade à la paillasse» avec une volonté d'appliquer les connaissances des laboratoires à des approches thérapeutiques de précision."
June 2017
Gilles Pagès
joined the Administrative Council of the "European Vascular Biology Organization" : http://www.evbo.org/about-evbo/council-members)
June 2016
Maeva DUFIES
post-doctorante dans l'équipe du Dr Gilles Pagès, a reçu un prix de 10 000 Euros par le Groupe Pasteur Mutualité pour son projet de recherche : "Rôle du facteur VEGFC dans les propriétés métastatiques acquises en réponse aux traitements anti-angiogéniques dans le cancer du rein".
March 2016
Gilles Pagès
is the new President of the French Association for Angiogenesis :
December 2013
Sandy Giuliano
was distinguished with a Price from the NOVARTIS Foundation for her research project.
Abstract PRIMe Sandy Giuliano :
Research Project PRIMe Sandy Giuliano :
FP7 Marie Curie Research Project
Dr. Marilena Lupu-Plesu
FP7 Marie Curie Research Project
VELYMPH is a Marie Curie project of the 7th Frammework Programme (FP7) of the European Commission, coordinated by the Centre National de la Recherche Scientifique (CNRS) - Institute for Research on Cancer and Aging, Nice (IRCAN), CNRS "UMR 7284", in Nice, France.
The concept of VELYMPH is to significantly catalyze the career development of an experienced researcher, Dr. Marilena Lupu-Plesu, via training-through-research in academic and nonacademic brain-gain environments. This approach is expected to significantly widen and diversify the experienced researcher's competencies in terms of multi/interdisciplinary and intersectoral expertise, transferable skills and expansion of scientific collaborations. VELYMPH is further aiming to build capacity within CNRS via generation of innovative research data, knowledge transfer, strengthened contact network and enhanced international visibility.
The scientific aim of VELYMPH consists of the investigation of the involvement of pro-(lymphangiogenic) cytokines into the metastatic properties aquired following various anti-angiogenic treatments currently applied to patients with carcinomas. This aim is linked to clinical observations indicating resistance to anti-angiogenic therapies, phenomenon in which we propose that certain pro-(lymph)angiogenic cytokines, such VEGF-C, may be involved and thus might constitute predictive markers of treatment efficiency and novel therapeutic targets.
VELYMPH is as a model of inter/multidisciplinary and intersectoral approach. It integrates knowledge from Cell and Cancer Biology, Molecular Biology, Radiobiology, Cell and Molecular Pharmacology, Biochemistry, Clinical Pathology, Medical and Radiation Oncology, in order to advance fundamental research on angiogenesis to the development and market transfer of reliable anti-angiogenic therapies for the patients in need. The close scientific interplay between the academic, clinical and industry sectors within VELYMPH's framework fosters biomedical research and developments at both fundamental and clinical levels, beyond cancer therapy.
Herein, we propose to provide a wealth of useful information regarding the involved participants and our activities.
Tumor angiogenesis and growth factors that induce proliferation of tumor blood vessel cells are major therapeutic targets. Tumor neovascularization is principally driven by VEGF. The treatment of choice for many types of carcinomas is currently represented by tyrosine kinase inhibitors, such as sunitinib, which block the activity of VEGF receptors (Eisen T et al., 2012). Despite of an increased time to progression, there are no convincing effects on the overall survival (Escudier B et al., 2010). The remaining tumor cells acquire invasive properties and evade treatment, presumably through the selection pressure exerted by the therapeutic agents (Lu KV et al., 2012; Paez-Ribes M et al., 2009; Ebos JM et al., 2009). While these agents should only target the endothelial cells, tumor cells aberrantly express the VEGF receptors and become "addicted" to signaling pathways mediated by such receptors. Therefore, we propose to identify the most important players involved into the acquired resistance to antiangiogenic therapies and to promote them as predictive markers of anti-angiogenic treatments efficiency, as well as pertinent therapeutic targets.
The originality of our study consists of an insightful approach to investigating pro(lymph)angiogenic factors regulation and interplay with different actors of the metastatic process, to unravel the associated molecular mechanisms. Through our research, the general concept of anti-angiogenic ther-py should be refined since it is inexact, because most of tumor cells express receptors targeted by anti-angiogenic drugs; this might contribute to tumor cells adaptation to anti-angiogenic treatments via alternative activation of downstream signaling pathways.
VELYMPH has been designed to open up the best career possibilities for the involved experienced researcher; it is expected to enhance her creative and innovative potential by expanding her knowledge in the break-through field of angiogenesis within inter/multidisciplinary and intersectoral brain-gain environments. VELYMPH also offers the optimum foundation to extrapolate the experience researcher's knowledge from pro-angiogenic to anti-angiogenic approaches and vice-versa. Moreover, VELYMPH is expected to open new collaboration opportunities for all participants. Their pre-established collaborative networks have been already engaged in VELYMPH via scientific twining actions that shall enrich the participants with a pool of new knowledge, diversify their research directions, and allow them to better face the current and future scientific challenges; this shall further open up new perspectives for joint grant applications, increasing their international visibility, competitiveness, and contributions to an "Innovation Union".
Communication and Public engagement
Promotional activities have been foreseen within VELYMPH in order to increase its visibility to the end-users, citizens, academia, civil society organizations, industry and policy makers, via the following communication channels: VELYMPH's website, including a public area; outreach activities; flyers and brochures; lectures at external scientific events; articles/interviews via conventional media channels.
Specifically, VELYMPH's outreach activities aim at communicating to the society at large about the Marie Curie actions and the knowledge generated during our project development, in order to raise the level of the general scientific awareness.
Our results dissemination strategy has been tailored to target groups (scientific community, clinicians, students, interested stakeholders, general public). To further facilitate VELYMPH's research data registration, discovery and open access, the VELYMPH has been enrolled into the European Commission Open AIRE public platform (www.openaire.eu).
Targeted dissemination of VELYMPH's results is being achieved through: preparation of dissemination materials for scientific purposes and the general public (i.e. presentations, brochures, leaflets, flyers, e-newsletters); participation to public events, workshops and conferences; publication of results in high-impact, ISI journals; outreach activities and press releases; concertation with related EU and national initiatives such as other projects, networks of excellence and graduate school programs (i.e. EU "Labex Signalife", www.signalife.unice.fr).
For more details, please follow the Results Dissemination section.
Project Full Title
The project title endorsed by the European Commission is "Investigation of VEGF-C involvement in the acquired metastatic properties of renal cell carcinoma following anti-angiogenesis treatments"
Framework Programme
FP7 / Marie Curie actions
VELYMPH is funded by the European Commission under the 7th Framework Programme of the European Union.
Marie Curie action-code
Scientific Panel
Centre National de la Recherche Scientifique (CNRS)
3 Rue Michel-Ange, 75794, Paris, France
Web: www.cnrs.fr
Project Reference No.
Grant Agreement Number
Start Date
End Date
24 months
VELYMPH brings together an experienced researcher, Dr. Marilena Lupu-Plesu, its supervisor, Dr. Gilles Pagès, internationally recognized for his contributions to the field of angiogenesis research, and CNRS, an academic institution well-known for its scientific excellence, which have been carefully chosen to collectively constitute a consortium capable of fully executing VELYMPH.
CNRS "UMR 7284", the Institute for Research on Cancer and Aging, Nice (IRCAN, www.ircan.org) is a world-class institute fully supported by the CNRS, INSERM and Univ. of Nice Sophia Antipolis. It has developed a strong partnership with the Anti-Cancer Center and Univ. Hospital of Nice, centered on innovative approaches in the field of personalized medicine applied to Oncology. It hosts the "Normal and pathological angiogenesis" team coordinated by Dr. Gilles Pagès, whose research focus is to unravel the molecular pathways underlying tumor angiogenesis.
IRCAN hosts 15 independent, junior and senior research groups that conduct cutting-edge inter/multidiscipli-nary research studies funded by the following bodies: (i) European organizations – the European Commission FP7 Programme, European Research Council, European Molecular Biology Organization and European Foundation for the Study of Diabetes, as well as (ii) national organizations – CNRS, INSERM, INCA, "Agence Nationale de la Recherche" (ANR) , "Fondation ARC pour le Recherche sur le Cancer", "Ligue Contre le Cancer", "Alliance Nationale pour les Sciences de la Vie et de la Santé", "Association Française Contre les Myopathies", "Fondation de l'Avenir", "Fondation pour la Recherche Médicale", "Fondation de France", Galderma, L'Oréal and Roche.
Marilena Lupu-Plesu, Ph.D. performed her Ph.D. research/post-doctoral studies at the Fred Hutchinson Cancer Research Center, Seattle, WA, US and Oregon State University, OR, US. After her studies in the US, she returned to Romania, at the Institute of Cellular Biology and Pathology "Nicolae Simionescu" - Centre of Excellence of the European Community, with the support of a Marie Curie international reintegration grant, as an independent researcher, principal investigator, project coordinator/manager (including EU FP7 and international grants), and leader of the "Angiogenesis and Cardiovascular Remodeling" group.
Leadership has been exerted during daily supervision and mentoring of team members/international visiting trainees, and direct coordination of project consortiums. In addition, Dr. Plesu has expertise in organization of international scientific events and project coordination meetings. Her decision-making skills have been refined during work as an expert evaluator of scientific grants, reviewer for peer-review journals, as well as member in the European Commission FP7 "People" Program Committee and the Managing Boards of professional associations. She has been often selected to present her work at scientific events world-wide, and published in international journals as a first and, lately, as a senior author.
Dr. Plesu's previous studies have addressed various aspects of adult stem and progenitor cells biology, cell therapy for vascular repair and regeneration, transplantation biology, histocompatibility testing, graft-versus-host disease prevention and treatment, and hematopoietic cell transplantation for the treatment of hematological malignancies and Duchenne muscular dystrophy.
With VELYMPH's support, Dr. Plesu is reinforcing a position of professional maturity. Her current research is aiming at the investigation of pro-(lymphangiogenic) cytokines involvement into the aquired metastatic properties following various anti-angiogenic treatments, with a focus on VEGF-C transcriptional regulation. Her goal is to identify novel predictive markers of anti-angiogenic treatments efficiency and to promote them as pertinent therapeutic targets.
Contact :
Marilena Lupu-Plesu, Ph.D.
Marie Curie Fellow
"Normal and Pathological Angiogenesis" Team
Institute for Research on Cancer and Aging, Nice (IRCAN)
University of Nice-Sophia-Antipolis
33, Avenue de Valombrose
06189 Nice, Cedex 2, France
Tel.: + 33-492031227
Web: http://ircan.org/
Dr. Gilles Pagès, Ph.D. has specialized in tumor angiogenesis for more than 10 years. His group has acquired a solid reputation in the fields of cell signaling (Pagès G. et al, PNAS 1993, 880 citations; Pagès G. et al, Science 1999, 350 citations) and regulation of VEGF expression. Papers of the group are highly cited (Milanini J. et al, J.Biol.Chem.1998, 236 citations; Milanini-Mongiat J. et al, J.Biol.Chem. 2002, 158 citations).
In 2008, Dr. Pagès created an "Interface Contract" between the National Institute of Health and Medical Research (INSERM) and the Anti-Cancer Centre of Nice to further advance translational research. The close interplay with clinicians has already led to publications at the interface of fundamental with clinical research (Legros L. et al, Blood 2004; Onesto C. et al, B.J.Cancer 2006; Beauclair S. et al, Ann.Oncol. 2007).
Dr. Pagès received several awards from the Roche Company, Association for International Cancer Research, and "La Ligue Nationale Contre le Cancer". His group is involved in two clinical trials on the role of sunitinib and pazopanib in patients with RCC and glioblastoma, respectively. Dr. Pagès' established expertise on xenografting and transgenic mice has led to 17 productive international collaborations with laboratories in Germany, Italy, Japan and USA. Two relevant patents have been generated on the role of CXCL cytokines in renal cell carcinoma, and novel hybridomas for the production of new mononoclonal antibodies against CXCL1, 7 and 8.
Dr. Pagès has extensive teaching/training experience, as an Assistant Professor of Molecular Biology at the Univ. of Nice and "Ecole Polytechnique Universitaire de Nice", coordinator of Master/Ph.D. programs and supervisor of postdoctoral fellows. His Hirsch factor is 40.
Contact :
Dr. Gilles Pages, Ph.D.
DR1 INSERM, Team Leader
"Normal and Pathological Angiogenesis" Team
Institute for Research on Cancer and Aging, Nice (IRCAN)
University of Nice-Sophia-Antipolis
33, Avenue de Valombrose
06189 Nice, Cedex 2, France
Tel: +33-492031231
Fax: +33-492031235
Web: http://ircan.org/
Events and News
Meet us in Paris at the 6th Congress of the French Society of Angiogenesis, 24-25 Septembre 2015 (http://www.angiogenese.fr/2015_introduction.html) and at the 26th National Congress of the French Society of Oncological Radiotherapy, 8-10 Octobre 2015 (http://www.sfro.org/17-professionels.html).
Results dissemination
Modulation of the anti-(lymph)angiogenic response in squamous cell carcinoma cells following proton versus photon irradiation. Marilena Lupu-Plesu, Audrey Claren, Jérôme Doyen, Julien Feuillade, Joël Hérault, Gilles Pagès, the 6th Congress of the French Society of Angiogenesis, 24-25 Septembre 2015, Paris, France:
Modulation de la réponse angiogénique/lymphangiogénique dans le temps en fonction de l'irradiation par protons ou photons. Audrey Claren, Marilena Lupu-Plesu, Jérôme Doyen, Julien Feuillade, Joël Hérault, Gilles Pagès, the 26th National Congress of the French Society of Oncological Radiotherapy, 8-10 Octobre 2015, Paris, France:
Links :
What is FP7?
What are Marie Skłodowska-Curie actions?
What is the Marie Skłodowska-Curie individual fellowship program?
Centre National de la Recherche Scientifique
«Normal and pathological angiogenesis» Research Team
French Society of Angiogenesis
Contact :
Administrative Coordination
Mrs. Sandra Pittavino
Centre National de la Recherche Scientifique
Delegation Cote d'Azur
Rue Albert Einstein – CS 10 269 250
Sophia Antipolis Cedex 06905
Tel.: +33-492954194
Fax: +33-492960339
- Cupo, A et Pagès, G. 2010. Prognosis and treatment of clear cell renal cell carcinoma: réference 10305243.7
- Pagès, G. Méthode de prédiction de la réponse à un traitement avec un agent bloquant HER2 : 2011 FR1155128 (PCT/EP2012/060807).
- Grépin, R, Pagès, G : Anti-CXCL1, CXCL7 and CXCL8 antibodies and their applications. Reference EP 13305642 (2013)
- Pagès, G : Méthode de prédiction de la réponse à un traitement avec un agent bloquant HER2 : (2011) FR1155128 (PCT/EP2012/060807).
- Pagès, G : Méthode de prédiction de la réponse à un traitement avec un agent bloquant HER2 : (2011) FR1155128 (PCT/EP2012/060807).
- Picco, V, Gilson, E et Pagès, G. Détection de la phosphorylation du facteur de liaison au Télomère TRF2 comme méthode pronostique de l'activité tumorale. (Dépôt en cours)
Original Publications Dr Gilles Pagès
20151. Giuliano S, Cormerais Y, Dufies M, Grépin R, Colosetti P, Belaid A, Parola J, Martin A, Lacas-Gervais S, Mazure NM, Benhida R, Auberger P, Mograbi B, Pagès G.Resistance to sunitinib in renal clear cell carcinoma results from sequestration in lysosomes and inhibition of the autophagic flux.Autophagy. 2015 Oct 3;11(10):1891-904. 2. Guyot M, Pagès G.
VEGF Splicing and the Role of VEGF Splice Variants: From Physiological-Pathological Conditions to Specific Pre-mRNA Splicing.
Methods Mol Biol. 2015;1332:3-23. doi: 10.1007/978-1-4939-2917-7_1.
20141. Giuliano S, Guyot M, Grépin R, Pagès G.The ELR+CXCL chemokines and their receptors CXCR1/CXCR2: A signaling axis and new target for the treatment of renal cell carcinoma.Oncoimmunology. 2014, Apr 9;3:e28399.
2. Grépin R, Guyot M, Giuliano S, Boncompagni M, Ambrosetti D, Chamorey E, Scoazec JY, Negrier S, Simonnet H, Pagès G.
The CXCL7/CXCR1/2 axis is a key driver in the growth of clear cell renal cell carcinoma.
Cancer Res., 2014 Feb 1;74(3):873-83.
3. Griseri P, Pagès G.
Control of pro-angiogenic cytokine mRNA half-life in cancer: the role of AU-rich elements and associated proteins.
J Interferon Cytokine Res., 2014 Apr;34(4):242-54.
4. Grépin R, Ambrosetti D, Marsaud A, Gastaud L, Amiel J, Pedeutour F, Pagès G.The relevance of testing the efficacity of anti-angiogenesis treatments on cells derived from primary tumors : a new method for the personalized treatment of renal cell carcinoma. PLoS One, 2014, Mar 27;9(3):e89449.
- Giuliano S, Pagès G., Mechanisms of resistance to anti-angiogenesis therapies. Biochimie. 2013 Mar 15. doi:pii: S0300-9084(13)00088-6. 10.1016/j.biochi.2013.03.002. [Epub ahead of print]
- Grepin, R., Guyot, M., Jacquin, M., Durivault, J., Chamorey, E., Sudaka, A., Serdjebi, C., Lacarelle, B., Scoazec, J. Y., Negrier, S., Simonnet, H., and Pagès, G. (2012) Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines, Oncogene 31, 1683-1694.
- Caujolle, J. P., Maschi, C., Freton, A., Pagès, G., and Gastaud, P. (2012) Treatment of neovascular glaucoma after proton therapy for uveal melanomas with ranibizumab injection: preliminary results, Ophthalmic Res 47, 57-60.
- Goplen, N., Karim, Z., Guo, L., Zhuang, Y., Huang, H., Gorska, M. M., Gelfand, E., Pagès, G., Pouyssegur, J., and Alam, R. (2012) ERK1 is important for Th2 differentiation and development of experimental asthma, FASEB J.
- Guerin, O., Etienne-Grimaldi, M. C., Monteverde, M., Sudaka, A., Brunstein, M. C., Formento, P., Lattanzio, L., Maffi, M., Tonissi, F., Ortholan, C., Pagès, G., Fischel, J. L., Lo Nigro, C., Merlano, M., and Milano, G. (2012) Contrasted effects of the multitarget TKi vandetanib on docetaxel-sensitive and docetaxel-resistant prostate cancer cell lines, Urol Oncol., sous presse
- Krishna-Subramanian, S., Hanski, M. L., Loddenkemper, C., Choudhary, B., Pagès, G., Zeitz, M., and Hanski, C. (2012) UDCA slows down intestinal cell proliferation by inducing high and sustained ERK phosphorylation, Int J Cancer 130, 2771-2782.
- Saulnier, N., Guihard, S., Holy, X., Decembre, E., Jurdic, P., Clay, D., Feuillet, V., Pagès, G., Pouyssegur, J., Porteu, F., and Gaudry, M. (2012) ERK1 regulates the hematopoietic stem cell niches, PLoS One 7, e30788.
- Chang CF, D'Souza WN, Ch'en IL, Pagès G, Pouyssegur J, Hedrick SM. (2012) Polar Opposites: Erk Direction of CD4 T Cell Subsets. J Immunol. 2012 sous presse.
- Guérin O, Etienne-Grimaldi MC, Monteverde M, Sudaka A, Brunstein MC, Formento P, Lattanzio L, Maffi M, Tonissi F, Ortholan C, Pagès G, Fischel JL, Lo Nigro C, Merlano M, Milano G. (2012) Contrasted effects of the multitarget TKi vandetanib on docetaxel-sensitive and docetaxel-resistant prostate cancer cell lines. Urol Oncol. 2012 Sous presse.
- Griseri, P., Bourcier, C., Hieblot, C., Essafi-Benkhadir, K., Chamorey, E., Touriol, C., and Pagès, G. (2011) A synonymous polymorphism of the Tristetraprolin (TTP) gene, an AU-rich mRNA-binding protein, affects translation efficiency and response to Herceptin treatment in breast cancer patients, Hum Mol Genet 20, 4556-4568.
- Bermudez, O., Jouandin, P., Rottier, J., Bourcier, C., Pagès, G*., and Gimond, C*. (2011) Post-transcriptional regulation of the DUSP6/MKP-3 phosphatase by MEK/ERK signaling and hypoxia, J Cell Physiol 226, 276-284. (Co senior auteurs)
- Bourcier, C., Griseri, P., Grepin, R., Bertolotto, C., Mazure, N., and Pagès, G. (2011) Constitutive ERK activity induces downregulation of tristetraprolin, a major protein controlling interleukin8/CXCL8 mRNA stability in melanoma cells, Am J Physiol Cell Physiol 301, C609-618.
- Anand, P. K., Tait, S. W., Lamkanfi, M., Amer, A. O., Nunez, G., Pagès, G., Pouyssegur, J., McGargill, M. A., Green, D. R., and Kanneganti, T. D. (2011) TLR2 and RIP2 Pathways Mediate Autophagy of Listeria monocytogenes via Extracellular Signal-regulated Kinase (ERK) Activation, J Biol Chem 286, 42981-42991.
- Cisse, M., Braun, U., Leitges, M., Fisher, A., Pagès, G., Checler, F., and Vincent, B. (2011) ERK1-independent alpha-secretase cut of beta-amyloid precursor protein via M1 muscarinic receptors and PKCalpha/epsilon, Mol Cell Neurosci 47, 223-232.
- Cisse, M., Duplan, E., Guillot-Sestier, M. V., Rumigny, J., Bauer, C., Pagès, G., Orzechowski, H. D., Slack, B. E., Checler, F., and Vincent, B. (2011) The Extracellular Regulated Kinase-1 (ERK1) Controls Regulated {alpha}-Secretase-mediated Processing, Promoter Transactivation, and mRNA Levels of the Cellular Prion Protein, J Biol Chem 286, 29192-29206.
- Jager, J., Corcelle, V., Gremeaux, T., Laurent, K., Waget, A., Pagès, G., Binetruy, B., Le Marchand-Brustel, Y., Burcelin, R., Bost, F., and Tanti, J. F. (2011) Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptin-deficient mice from insulin resistance without affecting obesity, Diabetologia 54, 180-189.
- Satoh, Y., Kobayashi, Y., Takeuchi, A., Pagès, G., Pouyssegur, J., and Kazama, T. (2011) Deletion of ERK1 and ERK2 in the CNS causes cortical abnormalities and neonatal lethality: Erk1 deficiency enhances the impairment of neurogenesis in Erk2-deficient mice, J Neurosci 31, 1149-1155.
- Ortholan, C., Durivault, J., Hannoun-Levi, J. M., Guyot, M., Bourcier, C., Ambrosetti, D., Safe, S., and Pagès, G. (2010) Bevacizumab/docetaxel association is more efficient than docetaxel alone in reducing breast and prostate cancer cell growth: a new paradigm for understanding the therapeutic effect of combined treatment, Eur J Cancer 46, 3022-3036.
- Denner, L., Bodenburg, Y. H., Jiang, J., Pagès, G., and Urban, R. J. (2010) Insulin-like growth factor-I activates extracellularly regulated kinase to regulate the p450 side-chain cleavage insulin-like response element in granulosa cells, Endocrinology 151, 2819-2825.
- Giaime, E., Sunyach, C., Druon, C., Scarzello, S., Robert, G., Grosso, S., Auberger, P., Goldberg, M. S., Shen, J., Heutink, P., Pouyssegur, J., Pagès, G., Checler, F., and Alves da Costa, C. (2010) Loss of function of DJ-1 triggered by Parkinson's disease-associated mutation is due to proteolytic resistance to caspase-6, Cell Death Differ 17, 158-169.
- Guihard, S., Clay, D., Cocault, L., Saulnier, N., Opolon, P., Souyri, M., Pagès, G., Pouyssegur, J., Porteu, F., and Gaudry, M. (2010) The MAPK ERK1 is a negative regulator of the adult steady-state splenic erythropoiesis, Blood 115, 3686-3694.
- Imamura, O., Pagès, G., Pouyssegur, J., Endo, S., and Takishima, K. (2010) ERK1 and ERK2 are required for radial glial maintenance and cortical lamination, Genes Cells.
- Krishnamoorthy, S., Jin, R., Cai, Y., Maddipati, K. R., Nie, D., Pagès, G., Tucker, S. C., and Honn, K. V. (2010) 12-Lipoxygenase and the regulation of hypoxia-inducible factor in prostate cancer cells, Exp Cell Res 316, 1706-1715.
- Lee, S. J., Pfluger, P. T., Kim, J. Y., Nogueiras, R., Duran, A., Pagès, G., Pouyssegur, J., Tschop, M. H., Diaz-Meco, M. T., and Moscat, J. (2010) A functional role for the p62-ERK1 axis in the control of energy homeostasis and adipogenesis, EMBO Rep 11, 226-232.
- Essafi-Benkhadir, K., Grosso, S., Puissant, A., Robert, G., Essafi, M., Deckert, M., Chamorey, E., Dassonville, O., Milano, G., Auberger, P., and Pagès, G. (2009) Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness, PLoS One 4, e4478.
- Patitucci, M., Lugrin, D., and Pagès, G. (2009) Angiogenic/lymphangiogenic factors and adaptation to extreme altitudes during an expedition to Mount Everest, Acta Physiol (Oxf) 196, 259-265.2008
- Formento, J. L., Etienne-Grimaldi, M. C., Francoual, M., Pagès, G., Onesto, C., Formento, P., Chamorey, E., Dassonville, O., Poissonnet, G., and Milano, G. (2009) Influence of the VEGF-A 936C>T germinal polymorphism on tumoral VEGF expression in head and neck cancer, Pharmacogenomics 10, 1277-1283.
- Fremin, C., Bessard, A., Ezan, F., Gailhouste, L., Regeard, M., Le Seyec, J., Gilot, D., Pagès, G., Pouyssegur, J., Langouet, S., and Baffet, G. (2009) Multiple division cycles and long-term survival of hepatocytes are distinctly regulated by extracellular signal-regulated kinases ERK1 and ERK2, Hepatology 49, 930-939.
- McGargill, M. A., Ch'en, I. L., Katayama, C. D., Pagès, G., Pouyssegur, J., and Hedrick, S. M. (2009) Cutting edge: Extracellular signal-related kinase is not required for negative selection of developing T cells, J Immunol 183, 4838-4842.
- Bermudez, O., Marchetti, S., Pagès, G*., and Gimond, C*. (2008) Post-translational regulation of the ERK phosphatase DUSP6/MKP3 by the mTOR pathway, Oncogene 27, 3685-3691. (*Co senior auteurs)
- Body-Malapel, M., Dharancy, S., Berrebi, D., Louvet, A., Hugot, J. P., Philpott, D. J., Giovannini, M., Chareyre, F., Pagès, G., Gantier, E., Girardin, S. E., Garcia, I., Hudault, S., Conti, F., Sansonetti, P. J., Chamaillard, M., Desreumaux, P., Dubuquoy, L., and Mathurin, P. (2008) NOD2: a potential target for regulating liver injury, Lab Invest 88, 318-327.
- Nakazawa, T., Shimura, M., Ryu, M., Nishida, K., Pagès, G., Pouyssegur, J., and Endo, S. (2008) ERK1 plays a critical protective role against N-methyl-D-aspartate-induced retinal injury, J Neurosci Res 86, 136-144.
- Tronson, N. C., Schrick, C., Fischer, A., Sananbenesi, F., Pagès, G., Pouyssegur, J., and Radulovic, J. (2008) Regulatory mechanisms of fear extinction and depression-like behavior, Neuropsychopharmacology 33, 1570-1583.
- Yasuda, T., Sanjo, H., Pagès, G., Kawano, Y., Karasuyama, H., Pouyssegur, J., Ogata, M., and Kurosaki, T. (2008) Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion, Immunity 28, 499-508.
- Essafi-Benkhadir, K., Onesto, C., Stebe, E., Moroni, C., and Pagès, G. (2007) Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing vascular endothelial growth factor mRNA degradation, Mol Biol Cell 18, 4648-4658.
- Beauclair, S., Formento, P., Fischel, J. L., Lescaut, W., Largillier, R., Chamorey, E., Hofman, P., Ferrero, J. M., Pagès, G*., and Milano, G*. (2007) Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity, Ann Oncol 18, 1335-1341 (* Co senior auteurs).
- Pagès, G. (2007) Sp3-mediated VEGF regulation is dependent on phosphorylation by extra-cellular signals regulated kinases (Erk), J Cell Physiol 213, 454-463.
- Cane, G., Moal, V. L., Pagès, G., Servin, A. L., Hofman, P., and Vouret-Craviari, V. (2007) Up-regulation of intestinal vascular endothelial growth factor by Afa/Dr diffusely adhering Escherichia coli, PLoS One 2, e1359.
- Fremin, C., Ezan, F., Boisselier, P., Bessard, A., Pagès, G., Pouyssegur, J., and Baffet, G. (2007) ERK2 but not ERK1 plays a key role in hepatocyte replication: an RNAi-mediated ERK2 knockdown approach in wild-type and ERK1 null hepatocytes, Hepatology 45, 1035-1045.
- Ha, U., Lim, J. H., Jono, H., Koga, T., Srivastava, A., Malley, R., Pagès, G., Pouyssegur, J., and Li, J. D. (2007) A novel role for IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus pneumoniae, J Immunol 178, 1736-1747.
- Bourcier, C., Jacquel, A., Hess, J., Peyrottes, I., Angel, P., Hofman, P., Auberger, P., Pouyssegur, J., and Pagès, G. (2006) p44 mitogen-activated protein kinase (extracellular signal-regulated kinase 1)-dependent signaling contributes to epithelial skin carcinogenesis, Cancer Res 66, 2700-2707.
- Onesto, C., Hannoun-Levi, J. M., Chamorey, E., Formento, J. L., Ramaioli, A., and Pagès, G. (2006) Vascular endothelial growth factor-A and Poly(A) binding protein-interacting protein 2 expression in human head and neck carcinomas: correlation and prognostic significance, Br J Cancer 94, 1516-1523.
- Deniaud, E., Baguet, J., Mathieu, A. L., Pagès, G., Marvel, J., and Leverrier, Y. (2006) Overexpression of Sp1 transcription factor induces apoptosis, Oncogene 25, 7096-7105.
- Nie, D., Krishnamoorthy, S., Jin, R., Tang, K., Chen, Y., Qiao, Y., Zacharek, A., Guo, Y., Milanini, J., Pagès, G., and Honn, K. V. (2006) Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells, J Biol Chem 281, 18601-18609.
- Hilmi, C., Guyot, M., and Pagès, G. (2012) VEGF spliced variants: possible role of anti-angiogenesis therapy, J Nucleic Acids 2012, 162692.
- Grepin, R., and Pagès, G. (2010) Molecular mechanisms of resistance to tumour anti-angiogenic strategies, J Oncol 2010, 835680.
- Bermudez, O., Pagès, G., and Gimond, C. (2010) The dual-specificity MAP kinase phosphatases: critical roles in development and cancer, Am J Physiol Cell Physiol 299, C189-202.
- Essafi-Benkhadir, K., Pouyssegur, J., and Pagès, G. (2010) Implication of the ERK pathway on the post-transcriptional regulation of VEGF mRNA stability, Methods Mol Biol 661, 451-469.
- Pagès, G. (2009) MAP kinase phosphatase-1: a link between cell signaling and histone phosphorylation. Focus on "Histone H3 as a novel substrate for MAP kinase phosphatase-1", Am J Physiol Cell Physiol 296, C233-234.
- Grépin R, Pagès, G. (2009) The vascular endothelial growth factor (VEGF): a model of gene regulation and a marker of tumour aggressiveness. An obvious therapeutic target? J Soc Biol. 2009;203, 181-92.
- Gimond C, Marchetti S, and Pagès G. Differentiation of mouse embryonic stem cells into endothelial cells: genetic selection and potential use in vivo. Methods Mol Biol 330: 303-329, 2006.
Publications issued of international congresses
- Griseri P, Essafi-Benkhadir K, Bourcier C, Pagès G European society of human genetic, Vienna 2009. Supplement European Journal of Human Genetics Vol 17 Supplement 2
- Corcelle V, Jager J, Pagès G, et al. DIABETES & METABOLISM Volume: 35 Special Issue: Sp. Iss. 1 Pages: A23-A23 Published: MAR 2009
- Bermudez O, Jouandin P, Rottier J, Pagès, G and Gimond, C. Conference Information: 34th Congress of the Federation-of-European-Biochemical-Societies, JUL 04-09, 2009 Prague, CZECH REPUBLIC, FEBS JOURNAL Volume: 276 Pages: 230-230 Supplement: Suppl. 1 Published: JUL 2009
- Corcelle V, Jager J, Pagès G, et al. Conference Information: 45th Annual Meeting of the European-Association-for-the-Study-of-Diabetes, SEP 30-OCT 02, 2009 Vienna, AUSTRIA, DIABETOLOGIA Volume: 52 Pages: S52-S52 Supplement: Suppl. 1 Meeting Abstract: 112 Published: SEP 2009
- Jager J, Corcelle V, Aouadi M, Pagès, G et al. Conference Information: 16th European Congress on Obesity, MAY 14-17, 2008 Geneva,SWITZERLAND,INTERNATIONAL JOURNAL OF OBESITY Volume: 32 Pages: S39-S39 Supplement: Suppl. 1 Published: MAY 2008
- Marchetti S, Jouandin P, Pagès G, and Gimond, C. Conference Information: 20th Meeting of the European-Association-for-Cancer-Research, JUL 05-08, 2008 Lyon, FRANCE, EJC SUPPLEMENTS Volume: 6 Issue: 9 Pages: 93-93 Published: JUL 2008
- Bermudez,O, Marchetti, S, Pagès, G and Gimond, C. BULLETIN DU CANCER Volume: 95 Issue: 6 Pages: 596-596 Meeting Abstract: 39 Published: JUN 2008
- Tanti JF, Jager J, Corcelle V, Pagès, G et al. DIABETOLOGIA Volume: 51 Pages: S258-S259 Supplement: Suppl. 1 Meeting Abstract: 640 Published: SEP 2008
- Pagès, G et al 20th EORTC-NCI-AACR Symposium on Molecular Targets and EJC SUPPLEMENTS Volume: 6 Issue: 12 Pages: 18-18 Published: OCT 2008
- Ortholan C, Durivault J, Viera A, Pagès, G. Conference Information: 6th International Symposium on Target Anticancer Therapies, MAR 20-22, 2008 Bethesda, MD
Source: ANNALS OF ONCOLOGY Volume: 19 Pages: 30-30 Supplement: Suppl. 3 Published: 2008.
- Ortholan C, Durivault J, Viera A, Pagès, G. Conference Information: 6th International Symposium on Target Anticancer Therapies, MAR 20-22, 2008 Bethesda, MD
- Jager J, Corcelle V, Aouadi M, Pagès, G et al. Conference Information: 16th European Congress on Obesity, MAY 14-17, 2008 Geneva,SWITZERLAND,INTERNATIONAL JOURNAL OF OBESITY Volume: 32 Pages: S39-S39 Supplement: Suppl. 1 Published: MAY 2008
- Bost, F, Aouadi, M, Laurent, K, Pagès, G et al 15th European congress on obesity Budapest Hungary 2007 and INTERNATIONAL JOURNAL OF OBESITY Volume: 31 Pages: S26-S26 Supplement: Suppl. 1 Published: MAY 2007.
- Bost F, Jager J, Aouadi M , Laurent K, Pagès G, Pouyssegur J, Binetruy B, Le Marchand Brustel Y Tanti JF . 15th European Congress on Obesity2007 Budapest, HUNGARY
INTERNATIONAL JOURNAL OF OBESITY Volume: 31 Pages: S26-S26 Supplement: Suppl. 1 Published: MAY 2007.
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text:
We will be commemorating Maundy Thursday by working through a "Christian Passover Feast". We will meet at the church at 6.30pm to begin eating at 7pm. Cost $20 per person. For more details contact Sue on 0468342476 or speak to Kath.
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Earlier Event: March 25PALM SUNDAY SERVICE
Later Event: March 30GOOD FRIDAY SERVICE


text:
This color in the gorgeous Cinnia yarn is called "Rådyr" in Danish - meaning roe deer, and I fell head over heels for it. Capreolus means roe deer in Latin.
The yarn inspired me to design a warm little cardigan for the littlest humans. It is worked seamlessly and have little details that makes the knitting fun and the finished garment that little bit more special.


text: Writer-adventurer Richard Grant's Crazy River: A Plunge Into Africa describes the first descent down the unexplored Malagarasi River in Tanzania, known by the locals as "the river of bad spirits". The journey begins with Grant encountering thieves in Zanzibar and crossing the Indian Ocean in a small cargo boat before he reaches the river itself. Once he has begun his descent he faces all kinds of unexpected and dangerous situations including dodging bullets, navigating through swamps and avoiding hippos and crocodiles; and all on a raft! Crazy River is a daunting yet thrilling tale full of the challenges, excitement and escapades faced by any modern-day adventurer.


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Lee Ray Medina of San Angelo was indicted on the charge of "Driving While Intoxicated Felony Enhanced".
The range of punishment for this crime is 2 – 20 years and up to a $10,000 fine.
Lee Ray Medina faced his punishment after over two years from the circumstances that led to his arrest on April 4, 2015.
Law enforcement officers from the Tom Green County Sheriff's Office and the Texas Department of Public Safety were dispatched to a one vehicle crash on State Highway 208. The vehicle had crossed a lane of traffic and off the roadway, then rolled and eventually came to a stop in an area off the roadway.
The driver of the vehicle, Lee Ray Medina, was removed from the vehicle and transported to Shannon Medical Center. Containers of alcoholic beverage were located inside the vehicle and around the crash site. A small of bag of marijuana was also located in the vehicle.
This was not Ray Lee Medina's first encounter with law enforcement, as he had previously been convicted of the felony offense of "DELIVERY OF A CONTROLLED SUBSTANCE", (COCAINE), Felony "TAMPERING WITH A WITNESS" charge, and a misdemeanor "EVADING ARREST" case.
The prior conviction history enhanced his punishment range to a second-degree felony.
After taking all facts and evidence into consideration, the jury sentenced Medina to 14 years in prison.
The Associate Judge had this comment in regard to the case:
"The citizens of Tom Green County deserve to feel safe while traveling on the roadways of our county. The District Attorney's office will continue the fight to keep our roads safe by prosecuting those individual who gamble with the safety and lives of the citizens of Tom Green County by engaging in dangerous behaviors such as driving while intoxicated."


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Every once in a while students are normally encouraged to think hard about the topics that they are about to write on their papers. Most students take this for granted, but there really are some very good reasons why you need to pay attention to the topic. A good topic will start earning you marks from the moment someone starts reading it. Even without opening your paper, the topic is worth earning or docking you points, and it is because of this reason that you need to make sure that you pay attention to the topic that you choose.
There are so many students who have come to learn about the importance of having a good topic, and you do not need to learn this the hard way. Herein we will showcase some really good topics that you should consider writing on, and perhaps you can learn from the same.
These are some topics that you can really relate to. There is a good reason for you to think about using some of them, or you can alternatively come up with something similar.
Once you have come up with a useful topic like the ones available herein, the next thing that you need to do is to work on the structure of your paper. Having a good topic is the first step towards success, but it does not end there. Once you have a good topic you will need to further proceed and make sure that you get the best out of it.
Professional online paper writing service - mypaperwriter.com - hire an expert paper writer today.
Stuck with your paper? Just ask: "write my paper" here and your paper will be written.
Struggling with admission essay? You can buy an essay here - professional essay writing service.
Native English-speaking writers from US can assist you with your essays.


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Call for Submssions: The Sundance Documentary Fund
The Sundance Documentary Fund is very competitive, generally receiving between 1500 and 2000 applications per year and making some 40-60 awards annually. A panel of film professionals and human rights experts conduct a review of each docket. Proposals are evaluated on effective storytelling, originality, artistic approach, global relevance and timeliness, and potential for social engagement. Films supported have included My Country, My Country; Why We Fight; Iraq in Fragments; Trouble the Water; If A Tree Falls and Give Up Tomorrow.
· Development grants range from $10,000-$20,000 and clips, samples, trailers and teasers are highly encouraged.
· Production & Post-production grants range from $20,000-$50,000. Production & Post-production proposals should include a rough cut of approximately 20-75 minutes, ideally conveying the vision for the film. Shorter cuts or unedited source footage are generally not competitive against the longer rough cuts submitted.
How To Apply
The Sundance Documentary Fund postmark deadline is February 9, 2012 for both development and production proposals. To apply, register online by visiting http://www.sundance.org/programs/documentary-fund/. If you chose to apply we will look forward to reviewing your proposal. Decisions take approximately five months from the deadline.


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OK, returning from abroad today and looking to the first weekend in town since August 7 where my health will permit me to surf and this is what I see (courtesy of SurfLine):
ZERO to ONE?!?!?! Both Saturday & Sunday? Report - ankle to knee & poor???
After this weekend, traveling again, the next two weekends. My next shot at water time is October 16. I haven't gone this long in years!!
Anticipation? More like FRUStration!
Wednesday, September 22, 2010
Posted by Hank H H at 3:27 AM
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Jim and Lynne have worked in the trenches with parents of all kinds – single parents, adoptive parents, parents of teens, parents of kids with intense behavior challenges, parents in blended families, parents of wealth and parents in poverty, and any other kind of parent you can think of. In other words, they have a lot of experience! You're going to get a lot out of this chat. Grab a pen and paper!
What We Chat About:
The result of believing half-truths
How to make a plan to deal with the problem behavior
The identity messages we accidentally communicate to our kids
Links Mentioned:
12 Misbehaviors and the God-given Gifts Beneath Them
Discipline that Connects Parenting Course
Discipline that Connects Book
Connect with Jim and Lynne:
Connected Families // Instagram // Facebook
Episode Sponsors:
FabFitFun: get $10 off your first box when you use promo code STRUGGLE
Prep Dish: get your first two weeks free by visiting prepdish.com/msw
Easy Kicks: join the sneaker club now at EasyKicks.com
Brooklinen: $20 + free shipping with code MSW
Ways to support the show:
Share the Struggle!
Find me on Instagram because I want to hear YOUR thoughts! If you've been encouraged, share the episode with another mom. The struggle is real. We might as well do this together!
***Some links above take you to Amazon. When you click through, anything you purchase there will help offset the costs associated with producing the show. It doesn't cost you any extra, and it helps me out. Everybody wins! Thank you for your support!


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Locking Compass Set
- Brand: Staedtler
Create a perfect circle for every occasion with Locking Compass Set. This compass offers a safety point metal tip that works on all paper, as well as a lead insert which tightens to stay put.
Plus the handy plastic case features a five inch ruler along the edge. Secure your circle size, and use it for art, drafting, geometric, architectural design, and more!
Set Contains:
- 1 - Compass
- 1 - Case with Ruler Edge
- 1 - Extra Lead with Case
Item not available in Hobby Lobby Stores.
Check your local store for availability.
Inspired?Share it:


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Skating in Washington Park (Springfield, Illinois USA)
View Single Post
August 17th, 2006, 03:02 PM
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Senior Member
Join Date: Aug 2006
Location: seattle, WA USA
Posts: 3,997
Dave, talk about scenic! But whre are you hiding that gem, as in, which state?
Hey Janneman, your country is amazing too. If i didn't say it before, it's just becuase i'm green with envy. It;s so nice, it drives me to be a bad sport. So there, happy?
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"OK, STOP! THAT'S A BIT UNNERVING. You can talk about someone else now." – Chief Public Relations Officer, Jonathan Blum, Yum! Brands
The very first time I trained a team in strengths at Yum! Brands, this was the leader's response after he asked me to explain his talents to him. He hadn't identified with any of them, and even worse, was against the idea of strengths development in general. But once I gave him a general picture of his habits, ways of thinking, delegating tasks – all based on how I interpreted his results – he was won over. He even became one of my biggest supporters. That was in 2004 and I've been sharing the life changing benefits of strengths-based development since then.
However, my own journey in the strengths world didn't start much earlier than that first training meeting mentioned above. My dear friend, Samir, had been one of the lucky few to be trained by Gallup as an internal coach at Yum!. He immediately shared the book, Now, Discover Your Strengths with me, and I was hooked as soon as I took the test. I had always been a "people-person" but when I saw my results, it was like I received a personal user's manual for the first time. I had a vocabulary to explain myself to people. I wasn't just a "people-person" I had #WOO (Gallup's term for Winning Others Over). I was a social butterfly, but one with purpose. I love(d) expanding my network and having a rolodex in my head. I promise you, if you need a contact, if I don't know the right person, I know the person who knows the right person. Two degrees of separation is about the limit for me. And I don't mean just here in Peru, where I live, but around the world.
And with my #Communication, #Positivity and #Relator, I loved telling stories, sharing stories, listening to others and complimenting everyone! I could always find something positive in everyone and truly enjoyed recognizing them for it. I suppose it should be no surprise that I ran the nation's most revered Recognition Program at Yum! Brands, the one written about by Ken Blanchard. My love of recognition got me a mention in CEO David Novak's book about the time I recognized him. I was even a loaned executive for Yum! Brands, helping other businesses implement recognition programs.
So, you know, a "people-person".
Knowing my strengths even saved my job. You can read more about that here, but the general story is that I had been in my new position as Employee Programs Coordinator for roughly six months with a supervisor who had a reputation for being difficult. After a particularly difficult meeting with him, I gathered up the courage to let him know that we needed to revise our relationship or I would need to find another job. The story has a happy ending. We reviewed our strengths, discussed our needs and how we could each give our best. What had been one of the most difficult working relationships I had ever had turned into one of the most rewarding.
And here it is 2017. I became a Gallup Certified Strengths Coach in 2015. I was among the first coaches to certify in Spanish and since that day, I've never looked back. I am in my element. I love what I do and a deeply enjoy sharing the knowledge I have with others. I believe we all have a role to play and when we know what that role is, we can maximize our contribution to the world. I seek to create a world where talents are recognized, we all have the chance to live up to our highest potential and happiness is contagious.
Eager to know more? Just book a conversation with me and let's work together to figure out your next best steps. No obligations no requirements.


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Today, there was a nice change of pace on our journey through the Holy Land. We started off the day with our typical routine of eating breakfast, having a devotion by the sea and then loading up the buses to head to our first site. On our way up the mountain to Susita, the leaders of the trip decided to join in the American culture of April Fool's Day. They got out of the bus and began to inspect it, acting as if the bus had died. They proceeded to get everyone off of the bus and begin to walk up the mountainside, while a bunch of the guys attempted to push the bus up the hill. This set the tone for the way the rest of the day was going to happen, a day full of joy and laughter.
We learned about Jesus healing the demon possessed man and how deeply He cares about each of us. We got a tour of an ancient Roman city and learned about all of the distractions that this brought into the faith. After that, we spent an afternoon in a park, soaking up the sun and taking part of Sabbath. The place that I felt God the most today was on our boat ride across the Sea of Galilee. The story of Jesus walking on water has always been one of my favorite stories. I was overwhelmed imagining this story coming to life right next to the spot that we were on the sea. The song "Oceans" began playing as I stared out into the sea, and the lyrics became a prayer for me.
"And I will call upon Your name
And keep my eyes above the waves
When oceans rise
My soul will rest in Your embrace
For I am Yours and You are mine"
It was in that moment that I realized how much God loves us and cares for us. No matter what storms we might be going through in life, no matter what problems we are facing, there is nothing that our God can't overcome. When we call upon the name of God, He draws near to us and is able to calm the storms. I am able to rest in God's embrace, and that's exactly what the Heartland community was able to do today.
Jake O'Connor, Heartland Intern


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Tammy Roberts (Medical Herbalist)
I founded Motivating Health (Formerly Tamara's Herbal & Natural Therapies) in 2003 after completing my diploma in Medical Herbalism through Southern Cross Herbal College.
Previous to this I spent the early years of my life starting and running my own Successful Health Food Takeaway shop in the Carbow Arcade in Gosford known as the Natural Approach. (And of course we did not sell Coke or Soft Drinks).
My full list of Qualifications now is:
- Dip Med Herb (Diploma of Medical Herbalism)
- Diploma of Herbology
- NET (Neuro Emotional Technique)
- NIS (Neurological Integration)
- Diploma Iridology
- Diploma Food Therapy
- Diploma Pharmaceutical Drugs
Further; to maintain my professional registration I am obligated to accrue a set number of continuing education credits every year. This allows me to stay well educated and up to date with new and relevant research and more importantly allows me to maintain my professional indemnity insurance which is important for the protection of my patients.
I work hard for my patient's health but also believe I need to lead by example, therefore I live by what I teach my clients. How can I look my clients in the eye if I ask them to do something I wouldn't or couldn't do?
How could I talk to a weight loss client if I need to lose weight myself & couldn't or wouldn't?
I have been operating from the same address since 2006 and I am proud to say that my business and list of clients grows every year.
By the time you read this the clinic will be operating as "Motivating Health". This merges Tamara's Herbal & Natural Therapies and Fitness Factory Erina with Weight Loss & Detox Centre. Both Lance and I agree this now forms a super clinic that is unique to the Central Coast.
- The service and expertise with which we offer is second to none.
- Our case files are full of many success stories.
- Be sure to view some testimonials provided by just a few of my many satisfied clients.
Lance Roberts (Elite Personal Trainer) & Weight Loss Specialist
I founded Fitness Factory Erina in January 2010 (Now Motivating Health) after having completed my personal training certification in 2008. Prior to that I was a project manager for a wonderful business in the construction industry called Ultrafloor Pty Ltd and prior to that I was managing director in my Own Environmental Services Company which I founded with Tammy in 1992.
Having been a keen sportsman all of my life and having an obvious addiction to exercise I made the obvious decision to get myself fully qualified as a fitness professional. "I wanted to join Tammy in following our vision which is: "changing lives by improving health through natural therapies, exercise & weight loss" this allowed me to add a fitness & exercise arm to Tamara's Herbal & Natural Therapies which as mentioned is now Motivating Health.
During 2010 I started to realize that although my fitness clients were getting fitter and enjoying our style of exercise, the clients who were using exercise alone to lose weight, were struggling. This prompted a mini restructure where we completely re wrote the way we manage our weight loss clients. While exercise is still important we induct our weight loss clients into our weight loss program before we start the exercise. Food is 70% of the weight loss process, Exercise is 20% and mental approach and preparation while we suggest is 10%, it could easily be considered the most important ingredient of all.
As a personal trainer & weight loss specialist I live by my philosophies to prove that they work. I maintain my fitness levels through regular cardio style training and strength training. I also manage my diet in the same manner that I coach my weight loss clients. I also like to maintain a particular body fat percentage.
We lead by example, our clients are never asked to try anything we haven't done! You will never asked to do something I wouldn't do!
- Certificate III & IV in Fitness
- Member of Fitness Australia
- Fitness Australia Level 3 Accredited & Registered
- REHAB Trainer Certified
- Punchfit Trainer
- Member Australian Fitness Network
- First Aid & CPR
- Professional Indemnity Insurance
- Weight Loss Specialist
- Heart Foundation Heartmoves Accredited
Alex Koltsis
Alex is our Senior Female trainer. She is highly qualified and we completely trust her and her skills as a trainer. She excels in working with clients with injuries.
- Bachelor Degree Exercise & Sports Science
- Masters Degree (Strength & Conditioning)
- Certificate III Fitness
- Certificate IV Fitness
- Tennis Australia (Tennis Hot Shots Coaching Course) Level 1
Interested? Find out more!


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Agate Wind Chime/Mobile
Single Color Agate Wind Chime (multiple colors available)
Slices of genuine agate in one color family come together in this harmonious wind chime. Perfect outdoors or indoors. Genuine agates are unique, and each agate mobile is one-of-a-kind, though it will closely resemble the examples pictured here. Each mobile/wind chime includes 7 agate slices.
Please select your color at checkout.
Total length is approx 18 inches.


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Set Dates & Guests
Know Before You Go...
Located in a secure gated community, the amenities at Schooner Bay are limitless. Let us take care of everything from car rentals and airport transfers to groceries and locating a private chef. This three bedroom apartment is spread out over two levels allowing for part of the family to sleep in, while the rest of them go about their morning activities. The huge porch spans the entire property, making it perfect to sit outside and enjoy the ocean view. If you want to take a dip, there is a large, communal pool set amongst tropical landscape. There is nothing missing, so bring the family and visit this fabulous property just a short walk from Speightstown.
Andrew , 214-350-6220 x9104
Luxurious beachfront penthouse apartment!
This exclusive, luxurious 2 storey beachfront penthouse apartment is available for rent in this leading development.
Laid out over 2 floors, offering 3,322 sq. ft. of luxury living space - this apartment offers the idyllic beachfront experience.
The bathrooms include marble tiles throughout - in particular the master bathroom and the main guest bedroom include twin sinks, whirlpool bath and separate corner shower. All bedrooms include ensuite bathrooms, and central air conditioning.
Sea views can be enjoyed from the covered terrace off the living room - and views of the communal pool and gardens, as well as attractive views to the East are also available. Being a low density building of only 4 floors, ceiling heights are higher than most new buildings on the West Coast, which adds to the luxury and exclusivity of this unique residence. The wide covered terrace - ideal for watching the sunset or dining in the warm tropical evenings spans the entire property, offering plenty of space for family and friends. The furnishings are exquisite and are included in the sale of this property.
Schooner Bay is located on the edge of the up and coming Speightstown, which includes several coffee shops and elegant restaurants - there is also a police station, several banks, a large supermarket and boutiques stores. Speightstown is water front and is away from the main highway, reflecting the charm of Old Barbados.
Peace and quiet - Privacy and Exclusivity.
The communal gym at Schooner Bay includes the following equipment:
Multi Gym
Free weights
Rental Note:
Special dates and rates apply for bookings over the Christmas Holiday Season.
Please ask your WhereToStay.Com representative for more information
|Apr 15, 2019 to Dec 14, 2019
5 Night Minimum
|1-2 people
|3-4 people
|5-6 people
|Dec 15, 2019 to Dec 19, 2019
7 Night Minimum
|1-2 people
|3-4 people
|5-6 people
|Dec 20, 2019 to Jan 10, 2020
14 Night Minimum
|1-6 people
|Jan 11, 2020 to Apr 14, 2020
7 Night Minimum
|1-2 people
|3-4 people
|5-6 people
|Apr 15, 2020 to Dec 14, 2020
5 Night Minimum
|1-2 people
|3-4 people
|5-6 people
Notes on Rates:
- All rental rates are based on two persons per bedroom.
- This property charges rates in US Dollars (USD).
- Rates do not include: tax of 10%, Barbados room levy (lesser of 2.5% or $10/room/night), island charges of 1.5%.
- Rates are subject to change.
Choosing the right villa is just the first step in creating the perfect vacation experience. We help you plan every element of your villa vacation, from rental cars to spa treatments, completely personalized to you.
- spa services
- chef/cook services
- butler service
- car rental
- restaurant reservations
- activity and sightseeing
- ferry/airport transfers
- grocery provisioning
- laundry service
- Bedroom 1
- 1 King, Air Conditioning, Ceiling Fan, Terrace/Balcony
- Ensuite Full Bath with Shower, Tub
- Bedroom 2
- 1 King/Twin, Air Conditioning, Ceiling Fan, Terrace/Balcony
- Ensuite Full Bath with Shower, Tub
- Bedroom 3
- 1 King/Twin, Air Conditioning, Ceiling Fan
- Ensuite Full Bath with Shower
Beds & Baths
Main House
- 1 Housekeeper: 3-days per week
- BBQ Outside (Gas)
- Beach Chairs
- Beach Towels
- Beach Umbrellas
- Beachfront
- Book Library
- Cable TV
- Ceiling Fans
- Common Pool
- Family
- Fridge
- Gated Community
- Gazebo
- Hot Tub
- Internet Access/WiFi
- Microwave
- Oven/Stove
- Resort Fitness Facilities
- Resort Villas
- Staff Favorites
- Telephone
|Air Conditioning
|A/C throughout villa
|Speightstown, St. Peter, Barbados
|Sq Ft.
|Transfers are not included in the cost of the rental.
|Special rates apply for Christmas and New Year
|(5.00 out of 5)
|Traveler Satisfaction
|100% Traveler Satisfaction
|# of Reviews
|1 for Schooner Bay #306
A lovely stay
Schooner Bay #306, Barbados villa review
We stayed at Schooner Bay #306 for 10 days in March with 3 adults and one toddler. The pictures are accurate and the furniture and beds are very comfortable. The cleaning lady, Rose, was very nice and accommodating with our daughter's nap time. The grounds are lovely and its an easy 5 minute walk to Speightstown for groceries, the fish market and any essentials. There are a couple good restaurants within walking distance, and you can walk down the beach to cobbler's cove, but you'll otherwise need a car or cab if you want to go out.
It is definitely a quiet place, we never felt crowded around the pool or beach. The pool and grounds around it are very nice and well maintained each day. The ocean directly out front isn't swimmable because of the reef, but a 3 minute walk gets you to lovely soft sand, and resident turtles to snorkel with. Some snorkel tours do come each day but they're not intrusive at all, unlike at Paynes Bay where we've previously stayed. We rented a paddle board and were able to keep it by the pool hut, but had to carry it down the beach a bit to be able to enter the water. Overall, we enjoyed our stay at Schooner Bay and would definitely return to this complex.
Andrew at wheretostay.com was really amazing at helping us secure this condo at the last minute and was readily available for help and advice.


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Create Your State
This is one segment of our Video Tutorial Series, part of our "Changemaker's Toolkit" on createyourstate.org.
Welcome to our neighborhood!
Our Early Story
This video features the talented, all female powerhouse formally known as Distraction. These students have since reformed as "The Change." This video was filmed entirely on Mercer Street, and was a great collaboration with Stages Music School.


text: A mission to obtain some intel on the location of Cesium 137 will challenge the abilities of this team. One of their targets will do something that will change the game for all of them. Eighteen months later, this team finds themselves at an embassy in Indocarr. While figuring out their game plan, a local arrives seeking asylum in exchange for information about the locations of Cesium that they are so desperate to find. Only he won't give them the information needed to unlock the information until he is safely out of the country. In order do to this, they must transport him 22 miles to meet up with the transport that could do just as he requested. It's never that simple though. This mission will come at a high cost in order to access the necessary information contained on the drive. The Indocarr gov't also wants this information so now the team is not only fighting the bad guys that want the info, they are also fighting the local authorities as well. The locals have been ordered to stop this man from leaving Indocarr at any cost. As you can imagine, it's absolute chaos as they try to navigate this short distance. Will the team reach the transport before the countdown clock runs out? or Will the Indocarr gov't stop them in their tracks? That's where the story gets even more complicated. This will keep you on the edge of your seat with an intensity that you can feel. Even up to the very moment that one side succeeds… It's much more complicated than it seems… This is one that must be experienced to be understood, just hang on because it's going to shock you like never before.


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Presidential address
It is an honour and a privilege to accept the office of President of the
Institute of Refractory Engineers. Something that would never have
crossed my mind when I joined as a member, many years ago in South
Africa. Moving to the UK has given me a new perspective of the
importance of the IRE and made me even more aware of the need for this
institute to exist. Countries like China and India are getting more
actively involved into refractories, mainly because the industry has
largely moved into those areas. However, the UK is still seen as a major
contributor to the standards relating to refractories and we should
still be very proud of that.
The IRE has been surviving over the last 20 years even though every
presidential speech mentioned declined member numbers and difficult
times. Just another testimony that the institute has an important part
to play in the future of the refractory industry.
Over the last number of years great efforts have been made by every
newly elected president to try and make it more relevant for the current
times. We think of the introduction of the website and the efforts made
to have a chat room for members to share their views and experiences.
Then later, the expansion of the website to include advertising.
Increased energy had to be put into ensuring a successful conference is
held every year, as well as trying to revive the branches which seems to
become less attractive in today's lifestyles.
New ideas are coming forward regarding the use of social media as many
nowadays live with their mobiles in their pockets. However, time is
precious for everyone and even though social media may be utilised to
extend the reach of the IRE, the way in which it needs to be set up and
maintained will be the challenge I foresee during my time in office. New
strategies will have to be found to promote the objectives set out by
the IRE, objectives that are still just as valid, in my mind, as 50
years ago. Objectives such as to foster and promote the skills and
science of refractories engineering. All I know is that exciting times
lie ahead of us, and I am looking forward to the changes that will most
certainly take place.
Jan DuPlessis


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The Club's Officers for 2019/20
A selection of photos from Saturday's Presentation evening.
Second batch of photos from the 2018 Presentation Evening
The final selection of photos from the 2018 Presentation Evening.
Available to members and non-members - pre-booking at the Pro Shop.
Pictures courtesy of Totally Abersoch
Thursday 11th April 2019
Official Opening of the Simulator Room
Ladies European Tour Professional Amy Boulden.
Photos by John Wormold - Totally Abersoch


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Week two and it was time to say goodbye to the wonderful city of Chicago and hit the national parks!
Hiking in Badlands National Park / Me & Polly at Mt. Rushmore
The Old Trail Town, Wyoming / Hiked up Mt. Washburn in Yellowstone National Park
Amazing view of Grand Prismatic, Yellowstone / Grand Teton National Park
After thunderstorms and rain galore, we arrived at Badlands National Park for a short hike where we saw the sun set which was amazing. The next day we visited Mt. Rushmore and Crazy Horse – I have to say I was so impressed with Crazy Horse, I didn't know it was a family project so that was pretty cool to see and experience. Then it was on to Cody, Wyoming to see a rodeo (which was surprisingly really good) and to see the Old Trail Town. Yellowstone was the second national park we visited (we even saw bears!), hiked up Mt. Washburn and visited beautiful springs like Grand Prismatic and Mammoth Hot Springs. Towards the end of the week we headed to Grand Teton and Jackson Hole, which is one of the most prettiest towns I've ever seen and a group of us white water rafted! Even though it was only week two, it seems like we are such a close knit family and get on so well! It will be hard when everyone goes their seperate ways.
Stay up to date with all the latest goings-on with my USA trip on instagram – @sazwatson.
Keep up to date on the following channels:


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The broadest definition of ecommerce is 'the conduct of transactions by electronic means In this introductory course we will focus specifically on purchases of goods and services from online stores on the Web, and a fictional eenterprise.
Ebook covering ecommerce web design, search engine placement, shopping cart software programs, internet marketing, and international merchant accounts.
Complete Going Beyond ECommerce Technologies, Los Angeles, California, U. S. A. Juanita Ellis Author Juanita Ellis has been at the forefront in working with corporations in the areas of convergence, computer Security and ebusiness. The Complete ECommerce Book covers diverse industry topics from the basic concept of eCommerce to an analysis of the creative process, to building and maintaining a successful web based business.
This is a stepbystep manual with precise, lean information to support your daily activities. The book gives a sound introduction to the fascinating world of ECommerce.
Readers with an economic background will learn which technologies help to change and improve business. Readers with a computer science background will learn, how business needs have to be incorporated into the development and operation of information systems. Download E Commerce Notes Download free online book chm pdf Free Ecommerce Books by admin Published Updated Here is a list of online books about Ecommerce in various formats available for free Electronic commerce, in a broad sense, is the use of computer networks to improve organizational performance.
Increasing profitability, gaining market share, improving customer service, and delivering products faster are some Online Textbooks for Free. Bookboon's free online textbooks for students are focused and to the point.
They are all written by highly respected professors from top universities in the world and cover topics such as economics, statistics, IT, engineering and natural science. Sid is an entrepreneur, an eCommerce expert and Marketing Manager at LemonStand. If we encounter a man of rare intellect, we should ask him what books he reads Ralph Waldo Emerson The fact that youre reading this blog means you want to learn more about eCommerce. Whether youre a new Find ECommerce Textbooks at up to 90 off.
Plus get free shipping on qualifying orders 25. Choose from used and new textbooks or get instant access with eTextbooks and digital materials.
Phone: (917) 104-5897 x 1345
Email: [email protected]


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There's more than one way to skin offshore earnings. TPC's Steve Rosenthal explains how Congress could slow tax-motivated departures like corporate inversions and preserve the tax base: Levy an exit tax. "If a US company voluntarily departs (or is acquired by a foreign company in a hostile takeover), we could charge the US company the tax due on its deferred earnings, just as we collect the deferred tax on IRAs of people who relinquish their US citizenship."
Could a carbon tax benefit companies and households? In TPC's latest Tax Fact, Donald Marron, Eric Toder, and Lydia Austin illustrate what would happen to households if Congress split carbon tax revenues equally between a corporate tax rate cut and a "dividend" paid to each American. Low- and high- income households would come out slightly ahead, while those in the middle would come out slightly behind. By contrast, using carbon tax revenues to buy down corporate taxes would be more regressive, but do a better job reducing the macroeconomic drag of the energy levy.
In the United Kingdom, pressure builds for a sugar tax. Parliament's Health Committee cites "clear evidence that measures to improve the food environment" must be used to tackle obesity. State-run health services spend $7.65 billion a year treating obesity and its related medical issues. The committee calls for strong controls on price promotions of unhealthy food and drink and a tax on full sugar drinks.
The Islamic State has a (violent, predatory) tax system. The New York Times reports that militants charge tolls; issue traffic tickets; require rent for government buildings; bill for water and electricity usage; tax income, crops, and cattle; and fine individuals for smoking or wearing the wrong clothes. ISIS collects nearly $1 billion a year. The revenue stream is strong enough that the Islamic State could cover its costs even if the US and its allies cut off oil revenue.
On the Hill. There'll be hearings today in the Senate Finance Committee and the House Ways & Means Tax Policy Subcommittee on the Organization for Economic Cooperation and Development's report on base erosion and profit shifting. House and Senate conferees continue work on a longer-term highway funding bill. House and Senate negotiators are also trying to reach a deal on expired tax breaks—one that could be included in the highway bill due December 4 or the omnibus spending bill due December 11.
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- © Urban Institute, Brookings Institution, and individual authors, 2016.


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March 19th - April 2nd
7:30pm - 8:30pm
Week 1: March 19th
Incense Making Intro
We will cover the basics of incense making, discuss health benefits, and make incense cones from herbs aligned with the Full Moon and Equinox.
Week 2: March 26th
Incense Sticks
We will make Palo Santo incense sticks and discuss how to use this plant in an ethical way. Q&A Included.
Week 3: April 2nd
Making Traditional Loose Incense with Resins
We will make a loose incense blend from herbs aligned with the New Moon and discuss how this method used by our early ancestors laid the foundations for aromatherapy and ritual.
$15 per class
$40 for all 3 classes
RSVP preferred but not required
Event Facilitaor: Chase Fincher