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Cancer progression involves the seeding of malignant cells in circulation and the colonization of distant organs. However, circulating neoplastic cells can also reinfiltrate the tumor of origin. This process, called "tumor-self seeding," can select more aggressive cells that may contribute to cancer progression. Here, using mouse mammary adenocarcinoma models, we observed that both tumor self-seeding and organ colonization were inhibited by chromogranin A (CgA), a protein present in variable amounts in the blood of cancer patients. Mechanism studies showed that CgA inhibited the shedding of cancer cells in circulation from primary tumors, as well as the reinfiltration of tumors and the colonization of lungs by circulating tumor cells. CgA reduced gap formation induced by tumor cell–derived factors in endothelial cells, decreased vascular leakage in tumors, and inhibited the transendothelial migration of cancer cells. Together, our findings point to a role for circulating CgA in the regulation of tumor cell trafficking from tumor-to-blood and from blood-to-tumor/normal tissues. Inhibition of the multidirectional trafficking of cancer cells in normal and neoplastic tissues may represent a novel strategy to reduce cancer progression. Cancer Res; 72(2); 449–59. ©2011 AACR.
A common feature of most life-threatening tumors is their propensity to seed tumor cells in circulation and to spawn metastasis in distant organs (1). This process requires a complex cascade of events that involve tissue invasion, intravasation, survival in circulation, arrest in target tissues, extravasation, invasion, and organ colonization (2). Recent studies have shown that circulating tumor cells, either derived from primary tumors or from metastatic colonies, can reinfiltrate their tumor of origin (or other tumor masses) in a process that is called "tumor-self seeding" (3, 4). On the basis of data obtained in animal models, it has been proposed that tumor cells acquire, after their excursion outside their site of origin, a more aggressive phenotype that may contribute to accelerate the growth of primary tumors and the breeding of metastatic progenies (3). Studies on the mechanisms that regulate the trafficking of cancer cells in normal and neoplastic tissues may be, therefore, of great experimental and clinical interest.
It has been reported that hematogenous metastasis can originate from the proliferation of endothelium-attached tumor cells (5). Tumor cells can also secrete factors that alter the endothelial barrier function, facilitating their migration across endothelial cells (6). For example, VEGF-expressing tumor cells can promote, via VEGF, the disruption of VE–cadherin–β-catenin complex in the lung endothelium of mice, facilitating their extravasation (7). Furthermore, the enhancement of VE–cadherin–dependent endothelial barrier function with activated protein C has been shown to limit cancer cell extravasation in normal tissues (8). Thus, whereas the presence of vessels with tight endothelial barriers may represent an impediment for the infiltration of normal tissues, the presence of leaky vessels in tumors might facilitate the shedding of cancer cells in circulation and tumor reinfiltration. On the basis of these notions, we have hypothesized that factors that regulate the endothelial barrier in tumors and in normal tissues can also regulate tumor self-seeding and dissemination.
We have previously shown that chromogranin A (CgA), an acidic glycoprotein secreted by normal and neoplastic neuroendocrine cells, neurons and granulocytes (9), can enhance the endothelial barrier function in normal tissues and protect vessels from vascular leakage (10). CgA is released in circulation in normal subjects at about 1 nmol/L levels and in several pathologic conditions, including cancer, at higher levels in the nanomolar range (11). The CgA1-78 fragment, called vasostatin-1 (VS-1), can inhibit the formation of gaps in endothelial cell monolayers and the permeability to macromolecules induced by TNF-α, VEGF, and thrombin (10, 12). Thus, CgA and its N-terminal fragment are efficient inhibitors of the endothelial barrier alterations caused by different inflammatory and proangiogenic stimuli, which are potentially released in the tumor microenvironment.
These notions prompted us to investigate whether circulating CgA might affect the tumor self-seeding process and the dissemination of cancer cells to normal tissues. To this aim, we studied the ability of circulating CgA (exogenous and endogenous) to affect the self-seeding and the dissemination of murine mammary adenocarcinoma tumors. We show that pathophysiologic levels of CgA are sufficient to significantly inhibit both processes. Furthermore, we show that CgA can inhibit the seeding of tumor cells in circulation, the homing of circulating cells to tumors, and the colonization of lungs in mouse models. Finally, we provide experimental evidence to suggest that an important mechanism underlying these effects is the enhancement of the endothelial barrier function against tumor cell–derived propermeabilizing factors.
Materials and Methods
Cell lines, drugs, antibodies, and reagents
Mouse B16-F10 melanoma cells were from American Type Culture Collection and TSA cells were provided by Dr. Giulia Casorati. TSAThy1.1 cells were generated as previously reported. These cells were cultured as described previously (13, 14). Ser-Thr-Ala-CgA1–78 (VS-1; ref. 15), human CgA (hCgA), and murine CgA (mCgA) were prepared by recombinant DNA technology and expression in E. coli cells as described (15–17). Anti-human CgA monoclonal antibody (mAb) 5A8 (epitope CgA53–57), B4E11 (epitope CgA68–71), A11 (epitope CgA81–90; all IgG1k), and anti-Thy1.1 mAb 19E12 were produced and characterized as described previously (14, 16, 18). Sulfate latex beads 4% w/v, 5 μm were from Invitrogen.
Animal models
Studies on animal models were approved by the Ethical Committee of the San Raffaele Scientific Institute and carried out according to the prescribed guidelines. To study the effect of CgA on tumor self-seeding and metastatic dissemination, syngeneic immunocompetent BALB/c mice (8-week-old; Charles River Laboratories) were challenged with TSA or TSAThy1.1 cells subcutaneously (2 × 105 cells) and/or intravenously (4 × 104). Alternatively, C57BL/6 mice were injected, intravenously, with 6 × 104 B16-F10 melanoma cells resuspended in 0.9% sodium chloride. Mice were treated intravenously with hCgA or VS-1 (in 0.9% sodium chloride containing 100 μg/mL of human serum albumin) or with other drugs in 0.9% sodium chloride. Drug doses and treatment schedules for each experiment are reported in figures and figure legends. The presence of disseminated TSAThy1.1 cells in the lungs of BALB/c mice (Thy 1.2) and in recipient tumors was detected by fluorescence-activated cell sorting (FACS) analysis of lungs or tumors, after excision and disaggregation, with an antibody specific for the Thy1.1 antigen (mAb 19E12). Furthermore, the number of TSA and B16 colonies in the lungs of mice was counted with the help of a stereomicroscope.
FACS analysis, reverse transcriptase PCR, antibody detection, and in vitro assays
The methods for Thy1.1 cells detection [FACS analysis, reverse transcriptase PCR (RT-PCR)], antibody binding assay and other in vitro assays (cell proliferation, migration, invasion, transendothelial migration, and permeability) are reported in "Supplementary Methods."
Recombinant hCgA inhibits mouse mammary adenocarcinoma self-seeding
To investigate the effect of CgA on tumor self-seeding, we used a syngeneic mouse mammary adenocarcinoma model based on the subcutaneous implantation of TSA and TSAThy1.1 cells (TSA cells genetically engineered to express the Thy1.1 allele) in controlateral flanks of immunocompetent mice that express the Thy1.2 allele. Immunohistochemical analysis of TSA tumors with an anti-Thy1.1 antibody (mAb 19E12), done 21 days after tumor implantation, revealed the presence of islets of Thy1.1+ cells of different size in TSA tumors (Fig. 1A), indicating that the TSA model is suitable for studies on tumor self-seeding. Quantification of TSAThy1.1 cells that infiltrated TSA tumors in mice was obtained by FACS analysis with the anti-Thy1.1 antibody (Fig. 1B). This assay can accurately quantify TSAThy1.1 cells added either to cultured TSA cells or to cells obtained from TSA tumors (Supplementary Fig. S1A and S1B).
Administration of recombinant human CgA (hCgA, 0.3 μg/day, i.v.) to mice bearing both tumors (a dose that achieves physiologically relevant blood levels) reduced the number of Thy1.1+ cells recovered from TSA tumors (Fig. 1C and D) but not the tumor volume and the TSA/TSAThy1.1 tumor weight ratio. These results suggested that the effect on tumor infiltration was not due to changes in the tumor masses and that hCgA can inhibit the seeding of TSAThy1.1 cells into TSA tumors.
Recombinant hCgA inhibits the seeding of tumor cells in circulation by primary tumors
To dissect the mechanism of action we studied, first, the effect of hCgA on the shedding of cancer cells in circulation by subcutaneous TSAThy1.1 tumors. To this aim, we treated tumor-bearing mice with or without hCgA and we analysed by FACS the presence of Thy1.1+ cells in circulation at day 15. The results showed a reduced number of Thy1.1+ cells in blood samples obtained from mice treated with hCgA, either freshly isolated or incubated for 5 days in cell culture medium containing G-418 (to select TSAThy1.1 cells genetically engineered with the pRS1Neo-Thy1.1 vector; Fig. 2A and Supplementary Fig. S2). The average number of circulating cell, expressed as the percentage of white blood cells, decreased from 0.40 ± 0.2% to 0.03 ± 0.03% in CgA-treated mice. We also analyzed the mRNA extracted from circulating cells at day 15 by RT-PCR with primers selective for aminoglycoside-3′- phosphotransferase (APH, a pRS1Neo-Thy1.1 sequence that is absent in the mouse genome and is present in TSAThy1.1 cells). The results showed reduced levels of APH mRNA in CgA-treated mice (Fig. 2A). These results, together, suggest that hCgA can reduce the seeding of tumor cells in circulation by primary tumors.
Recombinant hCgA inhibits the homing of circulating tumor cells to primary tumors
To further dissect the mechanism of action of hCgA in tumor self-seeding, we then studied the effect of this protein on the homing of circulating TSAThy1.1+ cells (injected into the tail vein of mice) to subcutaneous TSA tumors. Concomitant administration of hCgA reduced the infiltration of circulating Thy1.1+cells into TSA tumors, as measured by FACS. No effect was observed on TSA tumor growth (Fig. 2B). These results suggested that circulating hCgA can impair the infiltration of primary tumors by circulating tumor cells.
Recombinant hCgA inhibits the dissemination of mammary carcinoma cells from primary tumors to the lungs
We then investigated whether hCgA can also inhibit the dissemination of TSAThy1.1 cells from primary tumors to the lungs of mice. TSAThy1.1 tumor–bearing mice were treated daily without or with hCgA (0.3 μg) and the number of tumor cells that infiltrated the lungs was analyzed by FACS at day 25. A reduced number of Thy1.1+ cells was observed in the lungs of mice treated with hCgA, compared with the controls (Fig. 2C). Also in this case, the treatment did not affect the growth of primary tumors (Fig. 2C), suggesting the reduction of Thy1.1+ cells present in the lungs was not caused by reduction of TSAThy1.1 cells in the primary tumors.
Recombinant hCgA inhibits lung colonization by circulating mammary carcinoma and melanoma cells
To assess whether the inhibitory effect of hCgA on tumor dissemination also involved inhibition of lung infiltration and colonization by circulating tumor cells, we studied the effect of hCgA on the formation of tumor cell colonies in the lungs of mice injected with TSA cells into the tail vein. Daily administration of hCgA (see Fig. 3A for a schematic representation of the experiment) decreased the number of TSA colonies in the lungs (Fig. 3B). To verify that this phenomenon was not a peculiarity of TSA cells, we used a similar model based on B16-F10 melanoma cells. hCgA inhibited lung colonization also in this model (Fig. 3C). Notably, hCgA could inhibit tumor cell engraftment when mice were treated from day 0 to 1, or 0 to 4, or even 0 to 11 but not from day 4 to 9 (Fig. 3D), indicating that hCgA could affect the early steps of lung colonization, likely the seeding process. Administration of recombinant VS-1, the N-terminal fragment of hCgA, could also decrease the number of lung colonies in both models (Fig. 3B and C), suggesting that the N-terminal region of hCgA contains a functional site.
These results, altogether, suggested that recombinant hCgA might inhibit the dissemination of tumor cells in mice by affecting not only the tumor tissue compartment (i.e., the seeding of cancer cells into circulation and tumor-self seeding) but also by affecting the engraftment of circulating tumor cells in normal tissues.
Endogenous CgA inhibits lung colonization by circulating mammary adenocarcinoma cells
We then investigated the role of endogenous CgA on the dissemination of cancer cells in mice. To this aim, we studied the effect of the anti-hCgA mAbs 5A8, B4E11, and A11 (16, 18) on lung colonization by circulating TSA cells. Studies on antibody cross-reactivity showed that mAb 5A8, but not B4E11 and A11, could recognize mCgA (Fig. 4A). Thus, mAb B4E11 and A11, which belong to the same IgG1(k) isotype of 5A8, could represent good negative controls. Systemic administration of mAb 5A8, but not of B4E11 and A11, increased the number of lung colonies made by circulating TSA cells (Fig. 4B). These results suggested that normal levels of endogenous mCgA contribute to regulate the engraftment of circulating tumor cells in the lungs.
The effect of omeprazole, a drug known to induce the release of hCgA in circulation in patients (19, 20), was also investigated. Administration of omeprazole to mice (1 mg, i.v.) increased the circulating levels of mCgA from 0.9 ± 0.08 to 1.75 ± 0.27 nmol/L after 4 days (Fig. 4C). Thus, omeprazole is a valid tool for inducing a sustained increase of circulating mCgA in mice.
Repeated administration of omeprazole significantly decreased the number of lung colonies formed by TSA cells (Fig. 4D). This effect was neutralized by mAb 5A8 but not by mAb B4E11 (Fig. 4D), suggesting that it was mediated by mCgA. Thus, a moderate increase of endogenous mCgA, as obtained by pharmacologic treatment with omeprazole, can further reduce the colonization of lungs by circulating tumor cells.
hCgA inhibits the transendothelial migration of mammary adenocarcinoma cells through endothelial cell monolayers
To further investigate the mechanism of action of CgA we studied, first, the effect of hCgA on TSA cell viability, proliferation, migration, invasion, and transendothelial migration in vitro. hCgA did not affect the viability and the proliferation of TSA cells (Fig. 5A and B), whereas it increased the migration of these cells from the upper chamber to the lower chamber of transwell systems coated without or with Matrigel (in migration and invasion assays, respectively; Fig. 5C). No proteolytic processing of CgA occurred during the assays, as indicated by Western blot analysis of cell supernatants (Fig. 5C). Furthermore, hCgA did not alter the production of MMP-2 and MMP-9 by TSA cells, two enzymes that play important roles in tumor cell invasion (Fig. 5D). Finally, hCgA inhibited the migration of TSA cells through endothelial cell monolayers (Fig. 5E). hCgA could also inhibit the transendothelial migration of B16-F10 cells (Fig. 5E) as well as their motility in the migration and invasion assays (Supplementary Fig. S3). The reduced motility may explain the stronger inhibition observed in the transendothelial migration assay, compared with TSA cells. No proteolytic processing of CgA occurred during the assays, and no effect of hCgA on cell proliferation was observed also in the case of B16-F10 cells (Supplementary Fig. S3 A–C).
Exogenous hCgA and endogenous mCgA enhance the endothelial barrier function in TSA tumors
We have previously shown that CgA can enhance the endothelial barrier function in the liver (10). To assess whether CgA can enhance the endothelial barrier function also in tumors, which could be crucial for the regulation of tumor cell trafficking, we investigated the effect of exogenous and endogenous CgA on the penetration of the anti-Thy1.1 antibody (mAb 19E12) in TSAThy1.1 tumors. Tumor-bearing mice were pretreated with hCgA, or with the neutralizing anti-CgA mAb 5A8, and then with mAb 19E12. Tumors were excised, disaggregated, and analyzed by FACS to assess the binding of anti-Thy1.1 antibody to tumor cells. hCgA and mAb 5A8 decreased and increased, respectively, the amount of antibody molecules that reached the tumor cells, compared with controls (Fig. 6A and B). These results suggested that CgA, either exogenously administered or endogenously produced, can regulate the vascular leakage in tumors.
hCgA protects the endothelial barrier against TSA cell–derived propermeabilizing factors
To investigate whether TSA mammary adenocarcinoma can release factors capable to disrupt the endothelial barrier integrity, we carried out endothelial permeability assays with TSAThy1.1 cell supernatants (TSA-SN). TSA-SN induced VE–cadherin−dependent junction disassembly and gap formation and increased the paracellular transport of fluorescein isothiocyanate (FITC)–dextran through endothelial cell monolayers to an extent similar to that induced by TNF, a well known propermeabilizing cytokine. Notably, hCgA inhibited all these effects (Fig. 6C and D).
Using a multianalyte profiling approach, we then characterized the cytokines and chemokines secreted by TSAThy1.1 cells. Interestingly, various cytokines and chemokines capable to disrupt the endothelial barrier integrity were present in the cell supernatant, including TNF, VEGF, and interleukin 1 (IL-1; Supplementary Table S1). Remarkably, these cytokines were detected also in tumor tissue extracts (Supplementary Table S2).
These results suggested that an important mechanism underlying the reduced transendothelial migration of cancer cells is related to the protective effect exerted by hCgA on the endothelial barrier function.
hCgA affects TNF-induced expression of proteins involved in cytoskeleton rearrangement in endothelial cells
As changes in endothelial cell shape and cytoskeleton rearrangement have been implicated in the regulation of the endothelial barrier, we then carried out high-throughput expression profiling of endothelial cells treated with hCgA, alone or in combination with TNF. Both proteins could affect the expression of several intracellular molecules known to be involved in the regulation of the cytoskeleton (Supplementary Fig. S4; ref. 21). For example, hCgA increased the amount of phosphorylated cofilin (as also checked by Western blot analysis, Supplementary Fig. S5), whereas TNF increased phospho-ezrin, MEKKK1, and several other proteins. Notably, hCgA inhibited various TNF-induced effects (Supplementary Fig. S4), suggesting that this mechanism may contribute to the inhibitory effect exerted by hCgA on endothelial barrier function.
hCgA inhibits the secretion of inflammatory cytokines and chemokines in the tumor microenvironment
Finally, we observed that hCgA can reduce the levels of various inflammatory cytokines and chemokines in the tumor microenvironment, such as IFNγ, IL-1α, IL-1β, lymphotactin, and MIP-1β (Supplementary Table S2). As some of these proteins may contribute to promote an inflammatory microenvironment and to increase the leakiness of vessels in tumors, the inhibition of their production in the tumor microenvironment might represent an additional mechanism for the enhancement of the endothelial barrier function by CgA.
The results show that circulating CgA can inhibit the dissemination of cancer cells from primary tumors to the lungs in murine models of mammary adenocarcinoma. Studies aimed at dissecting the mechanism of action have shown that CgA can inhibit (i) the shedding of cancer cells in circulation by primary tumors, (ii) the homing of circulating tumor cells to primary tumors (necessary for the self-seeding process), and (iii) the engraftment in the lungs by circulating tumor cells (another important step of the metastatic cascade). As tumor self-seeding can contribute to select more aggressive and metastatic cancer cells (3), it is possible that all these mechanisms contribute to the inhibitory effects exerted by CgA on the dissemination of cancer cells from primary TSA mammary adenocarcinoma to the lungs.
How does CgA reduce tumor self-seeding and dissemination? The doses of CgA used in our models could not affect the growth of primary tumors. Hence, the effect on metastasis formation was not related to changes in the mass of primary tumors, pointing to other mechanisms. It has been previously shown that tumor cells can secrete factors that alter the endothelial barrier function, which may facilitate their migration across endothelial cells (6, 7). According to this view, we have observed that cultured TSA cells release soluble factors that promote (i) the disassembly of VE–cadherin from adherence junctions, (ii) the formation of intercellular gaps, and (iii) the paracellular transport of macromolecules in endothelial cell monolayers. CgA inhibited all these effects. CgA also inhibited the migration of TSA cells through endothelial cell monolayers. Multianalyte profiling of TSA cell supernatants and tumor tissue extracts showed that various cytokines, including TNF and VEGF among others, were present in TSA cell supernatants as well as in the tumor microenvironment. Remarkably, CgA could counteract the propermeabilizing activity of these cytokines. The hypothesis that CgA enhances the endothelial barrier function also in vivo is supported by the observation that administration of CgA to TSAThy1.1 tumor–bearing mice could inhibit the penetration of an anti-Thy1.1 antibody into tumors, whereas the neutralization of endogenous CgA with mAb 5A8 promoted the penetration of the anti-Thy1.1 antibody. These findings, altogether, suggest that CgA can reduce tumor self-seeding and dissemination by enhancing the endothelial barrier function, which may be critical for the migration of tumor cells from tumor tissue-to-blood and vice versa.
Regarding the mechanism of action, we have shown previously that the CgA fragment VS-1 can inhibit TNF-induced phosphorylation of p38-MAPK, by a pertussis toxin-sensitive mechanism, as well as VEGF-induced phosphorylation of ERK in endothelial cells (12, 22), that is, 2 signaling pathways that have been implicated in endothelial permeability (23, 24). Furthermore, the present results of high-throughput expression profiling of endothelial cells treated with CgA, alone or in combination with TNF, suggest that CgA can affect the expression of many proteins involved in the regulation of cell cytoskeleton rearrangement, a process critical for endothelial cell shape change and vascular permeability.
The results of multianalyte profiling of the tumor microenvironment also suggest that CgA can reduce the levels of various inflammatory cytokines and chemokines (e.g., IFNγ, IL-1α, IL-1β, lymphotactin, and MIP-1β) that may contribute to promote an inflammatory microenvironment and to increase the vascular leakage in tumors. On the basis of these observations, we think that CgA can inhibit tumor cell trafficking through endothelium by improving the endothelial barrier alterations directly, by affecting endothelial cells, and indirectly, by reducing the levels of inflammatory cytokines in tumor tissues. Notably, impairment of transendothelial cell migration and tumor cell dissemination by CgA was observed also with the B16-F10 melanoma model, suggesting that this phenomenon was not a peculiarity of TSA cells.
The biologically active doses of recombinant human CgA used in our experimental models (0.3–1 μg, i.v.) generate circulating levels of 3 to 10 nmol/L. CgA is present in the serum of normal subjects at about 1 nmol/L levels (25). Higher circulating levels (in the nanomolar range) have been detected in patients with neuroendocrine tumors and in subpopulations of patients with breast cancer, prostate cancer, small and non–small cell lung cancer (11, 26–28), or in patients with heart failure, renal failure, hypertension, rheumatoid arthritis, giant cell arthritis, sepsis, and atrophic gastritis, or treated with proton pump inhibitors (9, 25, 26, 29, 30). Thus, the doses used in this study are biologically relevant as they are in the range of those found in patients with nonneuroendocrine tumors.
Notably, we observed that neutralization of endogenous circulating CgA with the anti-CgA mAb 5A8 increases the formation of neoplastic colonies in the lung of mice injected with TSA mammary adenocarcinoma cells, whereas the induction of circulating CgA with omeprazole decreased colony formation in a CgA-dependent manner. These results support the hypothesis that the endogenous CgA plays a role in the regulation of tumor cell dissemination.
As discussed above, our study addresses the role of circulating CgA on metastasis formation by nonneuroendocrine tumors. The role of locally produced CgA, as it may occur in patients with neuroendocrine tumors, was not investigated in this study. Although increased circulating levels of CgA in cancer patients with advanced nonneuroendocrine tumors are associated with worse performance status, advanced stage, and worse prognosis (28), to our knowledge, no information is available on the correlation between CgA levels and circulating tumor cells or with the probability of onset of metastatic disease in patients with early-stage tumors.
In conclusion, the results of this work show that pathophysiologically relevant levels of circulating CgA (as it may occur in patients with nonneuroendocrine tumors) can regulate tumor self-seeding and dissemination of tumor cells in mice, pointing to an important role of this protein. The loss of endothelial barrier integrity caused by tumor cell–derived factors and the inhibitory effects exerted by CgA could represent important mechanisms for the positive and negative modulation of tumor self-seeding and metastatic dissemination processes. These findings suggest that drugs that directly or indirectly improve the endothelial barrier function and reduce the multidirectional trafficking of cancer cells in tumors and in normal tissues may reduce cancer progression in patients.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Grant Support
This work was supported by Associazione Italiana per la Ricerca sul Cancro, and Alleanza Contro il Cancro and FIRB (Italy).
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
- Received September 3, 2011.
- Revision received November 17, 2011.
- Accepted November 23, 2011.
- ©2011 American Association for Cancer Research.


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Gadoutline.library is intended to provide you with a means of describing the general layout of your GUI in a font-independant manner, and take care of the details of determining the exact placement of the individual elements of the display and the drudgery of creating and managing all of the gadgets. In addition, it provides:
Included with version 3 of the library will be a Postscript file which is a tutorial on using the library (WARNING: this file is about 1 meg), new improved example programs, and an additional link library (with source) for supporting multi-window applications and standard event handling, menu and gadget actions, preferences settings and more.
The library draws its name from the primary data structure used to describe the entire gadget layout - a ULONG array 'outline' which is composed of individual 'commands.' A command is used to define a single element of the display - a gadget, the wrapper around a group of gadgets, or an image - and additional 'control' commands are used to control how groups are organized, provide additional information to the library, and mark the end of the array. This array is an entirely static structure; the library only uses it to determine the dynamic data which is needed by the layout and after that it is never referenced again. This brings a number of important consequences:
The new version of the library now fully supports localization through an extension to its internal "translation" hook, and using this hook it is even possible for the caller to design a method of removing all absolute memory references within the static outline so that it could, for example, be loaded off disk when needed by the application.
|Dianne Kyra Hackborn <firstname.lastname@example.com>
|Last modified: Wed Aug 14 14:22:09 PDT 1996

subset: commoncrawl


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Inside the Minds of the Disney Tech Team: Behind the Scenes at Hollywood Studios' 'Wonderful World of Animation'
It's tough for the Disney tech team to top itself, but they've done it with the new nightly spectacular, 'Wonderful World of Animation.'Leave a Comment
If the latest nightly video spectacular is at Disney's Hollywood Studios is…well, spectacular enough to even impress a 38-year park employee, imagine how much you'll enjoy the 12-minute romp through the history of Disney and Pixar animation, dubbed "Wonderful World of Animation," which opened May 1.
Bob Crummett, technical director of Disney Parks Live Entertainment, says the new nightly spectacular—which is broadcast on a canvas that stretched well beyond the façade of the Chinese Theater—"really re-sparked my pixie dust."
"It crosses every generation," says Crummett, part of a team of more than 20 Disney Parks Live Entertainment employees who put the show together. "It's just a very heart-warming show. There are so many fun elements to the show. All of the pieces really come together."
The Disney tech team includes experts in music production, video content creation, production and technical aspects.
Behind Disney's 'Wonderful World of Animation'
The visuals in Wonderful World of Animation are enhanced by pyrotechnics and lighting tricks. For example, at one point, the building is transformed into the Snow White and the Seven Dwarfs pipe organ.
It took the team about 150 programming and preparation hours to put the show together, says Aaron Counterman, principal video systems designer for Disney Parks Live Entertainment.
"We focus not only about topping ourselves from a creative standpoint, but also from a technology standpoint as well," he says. "We look at all of these shows [in other Disney parks] and look around at what new technology is around and try to integrate that into each part of our shows, whether that be lighting, audio, video, lasers, even effects. We try to implement all the new stuff we can.
"We do our best to have that collaborative effort of listening to everyone's opinions. There's always one that's going to win out. Our main goal is to deliver the show director's vision of the show by taking all that technology, production and music and molding it to that the best we can," he says.
Wonderful World of Animation incorporates every Disney animated theatrical release, including Toy Story 4, which was released shortly after CI's behind-the-scenes tour of the show and opportunity to watch it live with Counterman.
The show takes guests on a journey through more than 90 years of Disney animation, starting with Mickey Mouse in Fantasia, before launching into sequences filled with magic, family, adventure, romance, villainy and friendship. It debuted during Hollywood Studios' 30th anniversary celebration.
As with most Disney projection spectaculars, Wonderful World of Animation includes sections that can be updated as new movies are released or other updates are made to the park.
In one segment of the show focused on Beauty and the Beast, the Disney tech team created a window-like effect and "it looks like you could go through that window," says Crummett.
"The projection team, video team and content creators did an amazing job with the animation footage and the content they delivered," he says. "We layered in some laser stars to create a three-dimensional effect of a window on the façade of that building.
"You're going to see short clips from franchises that some of our younger generation may not even be familiar with at all. Some of these are films that were in theaters when I was growing up. As you're watching the show with our guests, you'll hear them make comments," says Crummett.
Wonderful World of Animation ends as it began, with different iterations of Mickey Mouse appearing side-by-side, including his current look in the center. Mickey moves up the building before the virtual curtains part and he walks off into the sunset.
"Guests are really going to see a lot more of that heart of Disney," says Counterman. "They took a lot of time with that animation, going back to Walt's original concepts of what Mickey Mouse was to the Mickey Mouse of today you see in the new animation style. It's a great way to mold them all together into one cohesive show.
"We utilized a lot more of the architecture [with this show than in the past]. We tried to take a lot of care to mold the content to the contours of the building and the elements that are surrounding it," he says.
Technology You've Never Seen Anywhere
Wonderful World of Animation uses up to 10 projectors in seven locations scattered around the center stage area of the park, most of them hidden expertly in plain sight or covertly in places guests would never expect, says Counterman.
In total, the Wonderful World of Animation's canvas measures 11,000-pixels wide and 2,000 pixels deep. As is often the case, the show features AV technology that's never been deployed anywhere, meaning the team is incorporating products that are the first of their kind, says Counterman.
"We try to keep things simple," he says. "Being on the forefront of technology can have its downside too."
Hollywood Studios is one of first Disney Parks to use 4K, says Counterman.
"We definitely dove into that and continue to try to work with that kind of mentality," he says. "Projection mapping is nothing new, but we try to take it and utilize the vast amount of content we have to create these new things."
The Disney tech team worked with the design team on video, lighting, effects, lasers to create the show, says Crummett.
"We gave them the same palette we've used, but asked them to make it something bigger, better and more spectacular," he says. "Given that challenge, all of our designers have really stepped up and created a masterpiece with this show.
"We're always finding inspiration in some of the new products we're putting out there, with some of our new animation features and some of our new live action. I think there's a little bit of a competition [with other Disney parks and teams] and that's good. It keeps everyone on their toes. We're always looking to one up ourselves. It's a good friendly competition," says Crummett.
Highlights and Opportunities
Crummett and Counterman agree the best part of unveiling a new show is watching guests' reactions.
"The best part of the show process for me is definitely that first night," says Counterman. The first time you have the paying park guests who see it and the look on their faces, especially for me seeing the children's reactions and even some of the older adults seeing some of the older animation, particularly for this show, looking back and seeing what they grew up with, is really cool for me.
"The final result is always such an amazing thing to see. After the long hours and lack of sleep when we do these projects, to see all that come into one creative and cohesive thought is just amazing," he says.
"It's satisfying to see our guests enjoy the show," says Crummett. "As we're programming the show, you sit there for hours and hours and hours to get something just perfect in alignment on the façade of the building and you're wondering, 'is this really worth it?' Then at that final moment, you see that product that we're about to deliver to our guests and it's absolutely worth every minute of it."
Like with any technology undertaking, there are always glitches the Disney tech team has to overcome.
"This is gear that lives out in the elements 24/7, 365 days a year," says Counterman. "There's a constant maintenance program that has to happen to make sure we're at our best for our guests. Also, while we're trying to put these new shows in, we're trying to maintain [existing] daily shows."
Crummett focuses on opportunities over obstacles.
"We work primarily overnight when most guests are back at our resorts asleep," he says. "That's when a lot of our other partners and maintenance take care of the park. I've got to be a good partner with our engineering services team. Our horticulture team likes to trim trees at night.
"We were putting some polish on the park for the 30th anniversary as we're trying to open a new show," he says.
What Disney Tech is Next?
Although the Disney Parks Live Entertainment team just recently debuted Wonderful World of Animation, there's really no time to bask in the glory of the show.
"We're always looking at the next thing we're going to be able to do," says Counterman. "It doesn't really stop for us. We go from one open right into something else we're working on. It's about making that product and that experience even better for our guests each time we do it."
Crummett knows the next opportunity is just a phone call or email away.
"I'm excited every time," he says. "There's sometimes you wonder how we're going to pull it off from a technical perspective because our show directors are very creative and we have to bring their vision to reality. Sometimes you just sit there and scratch your head for a few minutes and then it'll come to you. I'm always looking forward to that next opportunity."


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Riding Schooling and Training
Health and Veterinary
Mind Matters
Buying and Selling
Insurance Advice
5 steps to your fittest horse yet
Posted in Riding Schooling and Training Fitness
Whether you're stepping up to the next competition level, bringing your horse back into work or just want to ride him for longer, a proper fitness routine is key
Whether you hack, school or compete your horse, in order to really enjoy your riding, it's important that he's fit for the level of work he's doing. Not only will this keep him going for as long as you want him to, but it also minimises the likelihood that he'll pick up any injuries along the way.
It's important to build your horse's fitness gradually, over a period of weeks or months, to ensure his body has time to adapt as his exercise increases. This may sound like a lot of time and effort but, once you've laid the foundations, you'll soon reap the benefits. Plus, there are a number of ways to keep it varied. Take a look at these fundamentals when formulating your horse's fitness plans.
TOP TIP – If your horse needs to lose some weight, a brisk walk or steady trot will burn more fat than faster canter work.
Step 1 – hill work
When undertaking a new fitness plan, one of the most invaluable weapons in your arsenal is hill work. Taking your horse up and down hills is far more demanding than completing the same distance on a flat surface, so it'll help you get him fit much quicker and by adding less miles on the clock.
While uphill work provides crucial cardio, encouraging your horse to breathe deeply and use his whole body, downhill work uses different muscles and improves his strength and balance.
How to do it Start by trotting your horse up hills and walking him down them. Repeat this at least a few times per session. Encourage your horse to reach into the contact to ensure he's engaging the correct muscles. As he becomes fitter, introduce canter, too. It's important that you build your pace going downhill as well, but start off with walk and slow trot, as he'll find it much harder to balance this way.
TOP TIP – If you're focusing on improving your horse's strength and muscle tone, add plenty of transitions into your hill work, too.
Step 2 – gymnastic exercises
Polework, gridwork and cavaletti are fantastic workouts regardless of your preferred discipline. They'll encourage your horse to become more agile and athletic, improving his core strength.
How to do it Start off with poles on the ground to trot and canter over, before moving onto raised poles and cavaletti. As your horse gets fitter, you can progress to building small grids, bounces and combinations. You can also alter the distance between the poles to encourage your horse to extend and collect his paces. This will help increase his fitness and build muscle mass.
Incorporating gymnastic work into your lungeing routine will reap similar benefits, and you'll be able to see how your horse engages from the ground.
Know your distances
When setting up poles, cavaletti or grids, it's important to get your distances correct…
- Trot poles: 1.2–1.7m
- Canter poles: 2.7–3.4m
- Bounce striding: 3–3.7m
- One stride distance: 6.4–7.5m
- Two stride distance: 10–11m
Top tip – When setting up poles or jumps on a curve, measure the distance from the centre of each pole.
Step 3 – interval training
Interval training is easy to incorporate into your hacks, and is a great way to gradually boost your horse's fitness and stamina.
The point of interval training is to keep your horse's heart rate at 140 beats per minute (bpm) or lower. At this point, his respiratory system is functioning aerobically and he can continue working like this for long periods without getting too tired. When his heart rate reaches 150–160bpm or above, however, his respiratory system starts functioning anaerobically and lactic acid is released into the muscles and he'll tire. This can't be sustained for long periods.
How to do it After you've warmed your horse up, follow this example of an interval training technique once or twice a week, increasing your repetitions as your horse gets fitter…
- three minutes in trot and one minute in walk. Repeat 3–5 times
- two minutes in canter and one minute in walk. Repeat 2–4 times
- two minutes in trot, one minute in walk. Then, cool your horse off
After a few weeks of following this interval training routine, you can work up to longer spells of trot or canter, being sure to bring your horse down to walk in between.
Top tip – A digital watch with a built-in stopclock is invaluable if you're planning to make interval training a regular fixture. It may also be worth investing in an equine heart monitor.
Step 4 – gallops
It's hard to find your horse's fifth gear if you don't have somewhere to really stretch him out, so hiring your local gallops can provide the perfect setting for fast work. If there's a gradual incline, this will really get him blowing, and you can incorporate interval training, too.
Top tip – If your horse is struggling to find his fifth gear, get a lead from a friend with a horse who's a little more turbo-charged
Unlike the tracks on your local hacking route, gallops provide a designated workspace and a horse-friendly surface, so you won't need to worry about concussion from the ground.
How to do it Often venues will have a warm-up track to use for loosening up your horse's muscles, so you'll be able to warm up in trot before stepping it up a gear.
Call the venue beforehand to find out the quietest time to visit if you'd rather ride at a more leisurely pace, and try to avoid peak times such as weekends and evenings.
Uphill climbs on gallops can be quite an intense workout for your horse so only book a trip to the gallops when you know he's on good form and towards the end of his fitness programme.
Top tip – If your horse isn't carrying you forward or you're having to kick on a lot during fast work, you may have asked too much and should review his fitness.
Step 5 – water treadmill
Providing your horse with a low-intensity workout, a water treadmill puts less strain on your horse's joints and tendons than if you were simply working him out in the open.
The saltwater is also renowned for its natural healing effect on wounds, and can be used to help conditions such as tendon or soft tissue injuries, pulled suspensory ligaments and generally for rehabilitation.
How to do it Locate your nearest equestrian therapy centre that hires out its water treadmill. Ask your vet for recommendations, but a physiotherapy-led or referral centre would be best.
Keep sessions short but sweet – just 20 minutes will provide him with an intense workout. Even if you're only able to take him for a few sessions a month, you'll soon see the benefits.
Feeding focus
The food your horse eats will also affect his fitness. A big mistake people make is confusing fat for muscle – you can't increase your horse's topline through feeding alone because you need to build up his muscles. If you simply increase his feed but not his exercise, he might look like he's improving but he won't have the strength or fitness that comes with a proper routine.
That said, condition comes from the inside, so ensuring that your horse has a well-balanced diet to suit his workload is important. Consult a nutritionist for advice.
Things to consider
There are a number of factors to consider that will impact your horse's fitness levels…
- Age Horses in their prime will hold their fitness better than older and very young horses.
- Previous fitness If your horse is used to having time off before being brought back into work, you'll find it easier and quicker to get him fitter than a horse who's getting fit for the first time.
- Previous injuries If your horse is coming back into work after time off with an injury, he'll need to spend more time carrying out slower work to ensure pressure isn't being applied to his previous injury.
It may feel difficult to boost your horse's fitness levels when you're squeezing it in around work but, with so many ways to keep it fun and varied, you'll find yourself bursting to get out. By working smartly, your horse will be striding on for longer in no time.
Are you looking to improve your fitness alongside your horse's? Check out these exercises to maximise your strength and condition in as little as 30 minutes here.


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|Back to Games
Shoot shapes that passively sit around the map to gain xp or kill other players, once you have enough xp to level you will be offered the option to level up several stats such as maximum hp, bullet speed, bullet damage and several others!
In the world of Diep you control a tank and shoot projectiles who's behaviour can be modified through the levelling system to defend yourself and attack opponents. Every 10 levels you will get the choice to modify your overall vehicle and change the way you shoot/play. Like several other io games there is an in game leader board which displays the players score and an icon of the type of tank they are currently using, I'd recommend that new players pay attention to this to begin with so you can get a better feel for strong tank builds. It is highly recommended that you try to move as much as possible as the higher level tanks deal a lot of damage to new players!


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Scottish fashion designer Christopher Kane has opened a pop-up boutique on London's luxurious Bond Street. The shop features ready-to-wear pieces made exclusively for the sleek new store. "I grew up knowing this street, seeing all the big brands on it. I've had to pinch myself now that I'm here. It feels very strange – but brilliant," said Kane at his launch party.
Neutral tones and polished glass accents shine through the 50 sq m pop-up's interior, mirroring the decor of the two-story flagship boutique on Mount Street. Kane's official London flagship, which opened in 2015, will remain open while the pop-up is in place.
Kane is known to "rock" the boat with his designs, frequently surprising fashionistas with his bold creations. His recent collaboration with Crocs includes a collection of natural and lab-grown pebble embellished shoes- yabba dabba doo.
The pop-up will remain open for the rest of 2017 with plans on hosting various cultural events and collaborating with local partners for product launches. Christopher Kane's Pop-Up is located at 15 Old Bond St, Mayfair, London W1S 4PR.


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In February, the State of Florida issued
"After further review of the investigative materials, it was determined that there is insufficient evidence to pursue further legal action in this matter."
It's hard to imagine what the Department might consider sufficient evidence, considering
Clement's been caught fudging on his credentials as well, variously referring to himself as "Dr. Clement" and as a naturopathic doctor. And there are reports of
The CBC and other Canadian media did
Hippocrates and Clement have been operating right under the State's nose for years at the Institute's luxurious Palm Beach County campus. It was only when the Canadian media got involved that the State perked up and took notice in the first place. Even then, it took a complaint I filed with the Department of Health, referencing the Canadian media reports, to get their attention. After two phone calls to the attorney who handled the case for the Department, I haven't been able to get any further information. She hasn't returned my calls. I learned of the Department's reversing its decision only by reading a CBC news report.
Still pending before the Department is a complaint filed (not by me) against Clement with the Dietetics & Nutrition Practices Council, which operates under the auspices of the state Board of Medicine. (Clement is licensed as a Nutritionist by the State.) The allegations of the Complaint are not made public unless a Probable Cause Panel of the medical board determines there is enough evidence to proceed. This does not give me a good feeling, considering.
An complaint against the Hippocrates Health Institute (also filed by me) for operating a health care clinic without the proper license failed as well. (Hippocrates is licensed by the State as a massage establishment.) The state's Agency for Health Care Administration informed me that it had no jurisdiction over Hippocrates because it is a cash-only operation. Only health clinics accepting third-party reimbursement must be licensed.
There is
flimflam artists and snake-oil salesmen have escaped state scrutiny by running clinics that accept only cash.
Unfortunately, as I read the bill, it doesn't close the gap altogether. Non-profit clinics would be exempt under the amended law. Hippocrates is a non-profit. A wealthy one. According to
So, for now, Hippocrates will continue to scam consumers with its quack treatments, Brian Clement can continue his international promotional tours offering to "reverse" cancer, and the State of Florida won't do a thing about it. Or, borrowing the words of Sen. Sobel, flimflam artists and snake-oil salesmen will continue to escape state scrutiny by running cash-only clinics as non-profits in Florida.


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Category: Hotels
Address: 2-4 Saint Margaret Drive, Odd Dorking Road, Epsom, KT18 7LB
Landline: 0333 77...
Website: www.premierinn.com/gb/en/hotels/england/surrey/epsom/epsom-central.html
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The going's always good at Premier Inn Epsom Central. Close to road, rail and bus links, stay with us and you'll be living it up in city or country in no time. Back a winner at Epsom Racecourse. Zip into London to see the sights. Catch a show at Epsom Playhouse. Or go wild at Chessington World of Adventures. And when all the racing around is done, return to our friendly team, relaxing garden, spacious rooms and super-comfy beds.
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Contact Us
Dobies Growing Guides
Vegetable Garden Planner
We're very excited to offer a collection of fantastic day-neutral strawberry plants. Because these plants continue to crop all summer, you'll enjoy a steady stream of delicious strawberries right up until September.
The more fruits you pick, the more your plant will produce, so your dessert dishes will be brimming with fruit for the whole summer and into autumn. Oh happy days. Day-neutral strawberries are insensitive to day length. So they continuously grow fruit as long as the weather is fair.
These plants are easy to grow, and every berry has a wonderfully sweet burst of flavour. These strawberry plants don't just deliver on the fruit front though, they also produce beautiful dark pink, white and pale pink flowers, so they'll create an ornamental talking point on your patio all summer.
They're perfect for containers too, so they're a great choice if you have a smaller outside space yet still want to grow your own fruit.
Your day-neutral plants will establish quickly this summer to produce a steady stream of strawberries throughout the growing season next year, and a lighter crop of fruits this year.
Our collection includes a mix of 3 varieties: F1 Delizz, F1 Toscana and F1 Frisan.
Code: 262572
Code: 262141
F1 Delizz® - Uniform and compact size, sweet and bursting with flavour all summer until September.
F1 Toscana - Unusual dark pink flowers.
F1 Frisan - Beautiful pale pink flowers.
Plug or Potted Plant:Potted
Aftercare - Easy:True
Prefers Full Sun:True
All Dobies products should reach you in perfect condition, just as they left us. If you are dissatisfied in any way with their condition on arrival, please let us know within 14 days. We are only liable for the cost of the goods as quoted on the website plus the cost of delivery if the goods are faulty.
Order online or call 0344 967 0303 For product or any other queries, please email Customer Services Customer Services call 0333 240 5933
Dobies, Long Road, Paignton, Devon TQ4 7SX


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Managing the Ratcheting Risk in Target Setting in the Nigeria Financial Sector
Target setting and performance measurement are very crucial roles of the managers while harnessing the resources of the organization together to achieve its objectives. Ratchet build-up is a risk and counter productive within organization system due to communication gaps among members hence, it must be well managed. The study was a descriptive research which used the data obtained from 239 staff in the marketing departments of the 15 quoted banks operating in Lagos, Nigeria. It documented that communication with subordinates during target setting has insignificant impact on the expected performance (P- Value = 0.074 which is >0.05). Also, bonus award, job rotation and performance measure have significant impact on the expected performance of the subordinates (P-value =.021, .000 and .003) respectively which is <0.05. The study established that communication will encourage ratchet build-up when the workforce have the opportunity to discuss and share experiences among themselves to inter-temporal manage their output. However, it has its positive side when an active interaction with the subordinate is allowed. It helped the superior to determine the level of reliance to be placed on past performance of the subordinate to set new targets.
Keywords: Ratchet, Performance measurement, Target setting, communication, job rotation.
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Hello everyone, Alex here, coming out of mini exile to deliver some new words on Arsenal Football Club.
In recent months I have not had the time nor the inclination to put any thoughts to the keyboard, mainly because so much of the joy of watching Arsenal has left me that nowadays our bad performances pass me by like a fart in a wind tunnel.
But I wanted to pull out a couple of themes following the latest shitshow at Anfield. This is not a blow by blow report of that game but rather a suicide note for the end of Arsene Wenger's Arsenal.
Arsene Wenger is putting his ego before the club
There is no tactical reason on earth to drop your best player for one of your biggest games. The whole point of your best players is that they can deliver on the big occasions. Whether through a sincere but misguided tactical insight or, as it has now emerged, a desire to show Sanchez who's boss, the manager's little folly cost us the game and put even further distance between us and the league leaders.
Arsenal's spinners are now putting out that Sanchez was dropped because of a training ground bust up with the manager and some of his teammates. It would take less of a cynic than me to note that the club really is in a parlous state when it is briefing against its star players in order to protect its underachieving manager.
However, putting that aside for one second, this resolve by the manager to send a message to players through his team selection is all the more galling because it is not applied evenly. More obvious candidates for tactical rotation were Arsenal's first choice "defensive midfielder" Francis Coquelin – the Justin Lee Collins of professional footballers, instantly detestable and with so little talent you wonder how he got there in the first place; or Alex Iwobi whose breakthrough season has been tarnished by the fact he has been played into the ground.
The team is crying out for bold tactical variation and for underperforming players to be given a boot up the jaxie. To see it applied so erroneously is why Sanchez and Perez will be off this summer, why Coquelin and Gibbs won't be, and why Iwobi will only go from a kid with great potential to an overpaid bottlejob under Arsene Wenger.
People were pointing out on Saturday that Arsene had 12 days to prepare for the Liverpool game. What data or tactical insight from his coaching team led to a recommendation to keep Coquelin on the pitch and start Iwobi again ahead of Perez?
The reality is, and everyone can see it, these are the last days of the dictator. I don't mean that literally, Arsene Wenger is obviously not a dictator – this is just football after all.
But in the same way Richard III's tenure ended with him offering up his kingdom in return for a horse, Arsene Wenger's increasingly bizarre decisions (which let's be honest started a few years ago when he refused to upgrade on the likes of Almunia and Sanogo) are nothing to do with the welfare of the club and all about the demonstration of power and control as it ebbs away from him.
Don't blame the talent, they want to win
The difference this year is that he has lost the dressing room. The club can brief that the other players were happy Alexis was dropped but the reality is he is our best player for now. And he has no faith in the manager, just like Van Persie and Fabregas who came before him.
The news that Ozil has also given up and will quit this summer should pile worry on top of worry. Yes these are egos, and their contract demands may be a bridge too far, but what we are seeing play out in Arsenal team after Arsenal team is the best players losing faith in the manager and wanting out. These guys have performed, and won, at the highest level elsewhere and they know Arsene Wenger does not have what it takes. Why shouldn't they throw a tantrum when the team gets beaten 5-1? What is the mentality running through the team, when that is considered the exception and not the rule?
The more Wenger loses his grip, the more we can expect to see this kind of behaviour but it cannot go on forever. Even if the board and Stan Kroenke want him to stay, at some point reality will overcome the fantasy he has constructed in his mind that only he can take this club forward. I genuinely hope it is sooner rather than later. I'm with the majority of people who want him to go out on a high with fans and players alike grateful for the way he has enriched both the club and our lives. But the longer he holds out, the less likely that is to happen. At this point, it's entirely up to him.
Our performance was terrible but it wasn't even in the top 5 worst performances this season
One of Arsene's favourite straw man arguments is to say there is no guarantee that we would win every game with a new manager. I don't remember ever asking for that. All I want is for us to compete again. That means doing something better than last 16 glorious failure in the Champions League and coming within 10 points of the league winners year in year out.
However it also means keeping the number of "what the fuck was that?" performances to 1 or 2 per season. You can expect most top clubs to have a rainy day here or there. Sometimes things don't click or the opposition sets up in a way that takes you by surprise.
But Everton away, Manchester City away, Watford at home, Chelsea away and Bayern Munich are all performances that were worse than the Liverpool game and have all taken place in the last six months. It's incredible really that a team that can point to six performances as underwhelming as a Robbie Williams comeback tour can still be in contention for a Champion's League place.
But here's the rub, fans can accept defeats, what they will not tolerate is paying the highest ticket prices in the land for performances as insipid as those we have seen this season.
Change starts with the manager
The malaise that has been around the club really began when Stan Kroenke took over. Distant, dispassionate and only concerned with the bottom line, he is the very antithesis of a sports fan.
Our board is about as dynamic as the English Indoor Bowling Association's lifetime members' club. Their slavish devotion to Wenger in recent months has shown them to be both cuckolded and completely at odds with the fanbase.
However, beyond trying to move the stadium to Wigan, the reality is no one would care about Stan or Ivan Gazidis or the board if the performances were right.
There are deep-seated issues at Arsenal that will take years to resolve but the first, essential step is to change the manager.
Its cliché but fans really are the lifeblood of a club and you can only take their support for granted for so long. At some point someone in a position of authority at Arsenal is going to need to start listening to fans because the unrest runs much deeper than they realise.
The offer of a 2 year contract, which is reportedly on the table for Arsene, may be the proverbial straw. If it is accepted, I imagine the next two seasons would start to see the club getting hit where it really hurts – declining gate receipts and season ticket sales.
There are no more excuses to hold on to. The money is there, he has spent it and still been found wanting. This is the fourth iteration of a team the manager has had since 2007. The players are different, the opposition is different, their managers are, the kits, balls and even the referees are different.
And yet the performances and outcomes are identical.
The one constant is the manager. Only when he leaves, can Arsenal begin its road to recovery.


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The mega hit show 'Dancing With The Stars' is set to return for its 25th season next week and already fans are wondering which couples have what it takes to win the Season 25 DWTS title. All of the action will get underway on Monday, September 18 when the cast officially hits the ballroom for the first time.
As all of the cast of the upcoming season for DWTS feverishly prepares, Las Vegas odds makers were also busy behind the scenes determining which couple or couples will be the odds on favorite to win the upcoming title. Yes, in case you didn't know it, people can wager on who will win the upcoming season of the ABC hit show.
Online sportsbook giant Bovada has singer/actor Nick Lachey listed as the man to beat in Season 25. The former hubby of Jessica Simpson and singer in the band 98 Degrees has been tabbed as the overwhelming favorite to take home the mirror ball trophy this fall at 4/1 odds.
Right behind the early favorite Nick Lachey in a three-way tie for second place on the Vegas odds board are 1980's pop queen Debbie Gibson, actress Sasha Pieterse, and violinist Lindsey Stirling, currently all listed at 8/1.
Do athletes have an advantage?
Now, before you give the title to the former boy band star, it is important to note that there are several athletes in this season's competition, and if you are familiar with 'Dancing With the Stars', you know that many of the athletes who compete on the show have a tendency to do well.
In fact, in the show's first 24 seasons, 10 current or former athletes have been crowned the champion, despite being outnumbered by actors and singers each season.
Reining champion Rashad Jennings, along with other former NFL stars Emmitt Smith, Hines Ward and Donald Driver have all captured the crown.
Other athletes who have claimed the 'Dancing with the Stars' trophy include Olympians Shawn Johnson, Laurie Hernandez, Apolo Anton Ohno and Kristi Yamaguchi. Indycar driver Hélio Castroneves has also sped away with a 'DWTS' title! When you look at the big picture, it does make sense for an athlete to do well in a competition like this.
Yet every athlete, no matter the sport, is at the bottom half of the odds board heading into the Season 25 debut.
Below is a look at the current odds to win Season 25 of 'DWTS.'
- Nick Lachey 4/1
- Debbie Gibson 8/1
- Sasha Pieterse 8/1
- Lindsey Stirling 8/1
- Frankie Muniz 9/1
- Jordan Fisher 9/1
- Vanessa Lachey 9/1
- Victoria Arlen 10/1
- Derek Fisher 10/1
- Terrell Owens 10/1
- Nikki Bella 12/1
- Drew Scott 12/1
- Barbara Corcoran 25/1


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Get your new smartphone, tablet or smartwatch insured and save your nerves and money! LMT Device Insurance covers – damages, theft, loss, as well as unauthorised use in case of theft or loss – up to 1000 € per claim (only for users of LMT subscription).
Lūdzu, atjaunini pārlūkprogrammu uz FireFox, Chrome, Safari vai Internet Explorer 9. Paldies!


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Robert Klug Memorial Fund
Robert was the most amazing father and friend to so many. He was loved by everyone and always had the biggest smile on his face. He had a heart attack on Tuesday, June 1. We will honor him by giving him a beach paddle out. This fund is to help support his children during this time and help fund the expenses that come along with his death. If you can donate anything in lieu of flowers to help support them through college and life it is greatly appreciated.
DonationsSee top
- Ian Mcpherson
- Chris Hoskins
- Chris Hoskins
- Amber Emerick
- Anonymous
Trace Klug
Laguna Beach, CA
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Evans Halshaw Leasing began trading in 2012 as a sister company of Pendragon Vehicle Management, the fleet management arm of the Pendragon PLC. Evans Halshaw Leasing focuses itself on the B2C (Business to Consumer) and the SME (Small Medium Enterprise) size vehicle market. We pride ourselves on delivery, an unrivalled level of customer service and providing a hassle-free vehicle leasing experience.
Being part of Pendragon PLC gives us unlimited access to the group stock, ensuring that we are able to provide quick turnaround times on lease vehicles, as well as a competitive price.
Based out of our offices in Derby, we have a small team of Relationship Managers- who will be able to help you decide on your next lease vehicle; Consumer Administrators who will provide an impeccable level of service from the point the vehicle is placed on order right through to the delivery of your vehicle and beyond; a Tactical Deal specialist - ensuring we are always competitive in the marketplace and are able to offer you some of the best deals; a Content Manager - making sure our website functions correctly with accurate information; and a Head of B2C to oversee the process and ensure the standards we set ourselves are upheld.
We are very proud to work with some of the UK largest funding partners for our vehicles. In using a number of different funders, we are able to ensure we can offer some of the most competitive rentals in the market. We check our prices regularly and thoroughly ensuring all our customers are offered the best rentals possible.
If you are thinking about leasing a car and want some more information, please call 0333 323 7070 and speak to one of our Relationship Manager's today
All calls are recorded for training and monitoring purposes
Pendragon House
Sir Frank Whittle Road
Mon-Fri 9am-6pm


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Google released the Android 7.0 Nougat update a few weeks back, and it has made its way to a few devices. Unfortunately, Nexus 6 owners are still waiting as there's no word about its roll out.
Recently, the folks at Android Police contacted Google, and it seems Nexus 6 and Nexus 9 LTE users have to wait a few more weeks for the update.
Some people were of the view that Google Nexus 6 will not get the Android 7.0 Nougat update, but it's not correct. Google confirmed to Android Police that it will roll out, but the exact time frame for the update is not yet available. It may take a few more weeks or maybe months for the update to finally reach the Nexus 6 and Nexus 9 LTE.
It's quite surprising as to why the update is delayed for so long for a Nexus device, but it's quite likely that there are some loopholes which the company wants to fix before the operating system is rolled out for the general public.
We'll update you as soon as we get to hear anything more about the roll out of Android Nougat for Nexus 6 and Nexus 9 LTE.
Source: Android Police


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Maximum vehicle height : 2,00 m
Entry : 24h/24 7j/7
Exit : 24h/24 7j/7
Book your parking space online at Epinal on the Q-Park booking site.
Online, you can choose many formulas adapted to your needs! Park downtown in Epinal to be as close as possible to amenities.
The car park is located on rue Saint-Michel and gives access in just a few minutes to the heart of the city centre. Book your parking space online, right next to the car park is the Château d'Epinal, the Place des Vosges or the Ciné Palace cinema. In addition, just a few minutes from the car park, you can access the many shops in the heart of the city.
Thanks to your online reservation, your place is guaranteed even if the car park is full! Go to the Q-Park Saint-Michel car park near the city centre of Epinal and park safely. Your online reservation allows you to access the car park 24 hours a day, 7 days a week.


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So if you'd like to ask me an anonymous question and have me answer it here, on my blog, please visit this link.
never heard of it until now...but I think my social networking skills are stretched to the max with blogging...i should keep it simple!
It doesn't take much, Cadence. Just ask a question. So EASY!
Make your Stick Figure Family at FreeFlashToys.com


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|March 23, 2018
There's no doubt that your 20's is a very precious period of your life. There's a nervous but exhilarating feeling about becoming an adult, leaving home, and being financially independent. Whether you kicked off a career, a university degree, or spent time traveling overseas and gaining life experience, your 20's is a meaningful decade from both a personal and financial point of view. Regardless of what path you go with, the one constant that will consistently remain in your life is money.
The reality of the matter is, the sooner you begin saving money and developing wealth, the better your financial scenario will be in the long term. Regardless of whether you intend to get married, start a family, or purchase a house, there are various financial aspirations that every individual in their 20's should endeavour to accomplish to secure a better a future. In this article, we'll be taking a closer look at these targets and how you can begin constructing healthy financial habits.
Establish a budget
Constructing healthy financial habits starts with understanding how to budget. Being able to spend less money than you earn is the key to saving money, so start taking control of your finances by creating a budget and sticking to it! With a pen and paper, document your monthly income and costs. Analyse your expenditures to uncover which can be cut down, or which can be eliminated altogether. Some ways to lessen your expenditures are electing to eat at home in lieu of eating out and transferring your Cable subscription to streaming services like Amazon instead.
Get rid of your debts
Whether you've travelled the globe or have student loan debts, the quicker you repay these debts, the better. Interest compounds with time, so paying off your debts by reducing expenditures or working a second job can save you thousands of dollars in only a couple of years. These savings can then be invested in a high-interest term deposit for example, which will put you in a substantially better financial position than merely making the minimal monthly repayments on your debts.
Create an emergency fund
Life almost never works out the way you planned, so it is vital to be prepared for any abrupt adjustments that might be necessitated. You may find yourself out of a job, or in an accident that hinders you from working, so having an emergency fund will be able to give you some breathing room when you need it the most. Financial experts highly recommend that all folks should have a dedicated emergency fund that can support their living expenses for three to six months.
Be insured
Insurance protects you financially from any detrimental consequences, for example income insurance in the event you lose your job, medical insurance for unpredictable medical expenses, and vehicle insurance in the event your car is stolen. Though it's not always a good idea to get every form of insurance available, it's undeniably a wise idea to analyse your individual circumstances to see which is best suited to you. For example, medical insurance is recommended for everyone due to the high costs of uninsured medical treatment. Without insurance, an unforeseen incident may cause significant damage to your financial situation.
Invest in a diversified portfolio
If you've managed to save a particular amount of money that is otherwise sitting idle in the bank, look at investing this money in a high-interest term deposit. After you've got more money saved, contemplate buying some property, or investing in gold. The key to a sensible investment portfolio is 'diversification', meaning that you regulate the risks of investment by putting your eggs in different baskets, so to say.
Seek financial help immediately
If, for whatever reason, you've found yourself in financial trouble, the best advice is to seek financial help as soon as possible. A lot of individuals wrestle with financial troubles for several years before seeking help, which puts them in a worse position as their debts will only compound with time. The sooner you get financial advice, the more options are available to you, so if you require any help with your financial situation, speak with the professionals at Bankruptcy Emerald on 1300 818 575, or visit our website for further information: http://www.bankruptcy-emerald.com.au/


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|Networks in Directory
Largest Networks
- Google Ad Network
- Yahoo! Audience Network
- Amobee
- Conversant
- RadiumOne
- Exponential
- Media.net Contextual Ads
- Rocket Fuel
- Gamut
- Acuity Ads
- GumGum
- AdBlade Network
- Xaxis Publisher Network
- Undertone Networks
- Viant
- Bidtellect
- AdSupply
- LiveIntent
- Valassis Digital
- Intergi Games Network
- Solve Media
- true_X_ media
- Federated Media
- Collective Display
- InSkin Media
United Kingdom Ad Networks (59 results)
|24/7 ProfitSocial
|ProfitSocial - The best Smartlink solution from a Direct Advertiser for your quality traffic. The Smartlink contains +150 countries and our in-house and exclusive Dating offers.
|details >
|888 Media
|Headquartered in London, UK, 888 Media is a digital marketing solutions company that provides cost-effective ad solutions for advertisers to reach targeted consumers.
|details >
|Adblade is the largest "premium only" brand safe ad network in the US. Reaching over 130 million monthly unique users on over 400 top media outlets.
|details >
|~~ THE ADSENSE ALTERNATIVE AD NETWORK ~~ Publishers: High eCPM rates with 90% Revenue Share Advertisers: Maximize ROI on your national campaigns
|details >
|AdGaem is a Premium Affiliate Network 100% focused on free-to-play Mobile and Desktop Games.We generate quality gamers internationally for the world's leading F2P Game Publishers.
|details >
|Adit-Media is a performance based boutique ad network. We work with direct clients & Publishers, this way we get the highest rates from our clients and offer the highest Ecpm Rates
|details >
|Digital Advertising & Operations, Display, Rich Media, Online Videos, Mobile Marketing, SEO/ SEM, Website Creation, Social Media, Email marketing, Performance Marketing,etc
|details >
|AdPlay offers innovation driven cloud-based marketing solutions that drive engagement and powerful customer insights in display, mobile, video and social to reach right audience.
|details >
|We are the global leaders and innovators which has helped business of all size reach their goals with our powerful marketing platform.
|details >
|AdsPilot offers global advertising and marketing solutions for online advertisers, media agencies, brand marketers, publishers and ad networks.
|details >
|AdsWick is a next generation ad network with advance technology tested for years and proved to be successful, generates high revenue for your publishers.
|details >
|Adtelligent platform has been designed to solve problems of Desktop, Mobile, and CTV publishers, by supplying them with technology and dedicated services.
|details >
|Adthink Media is an independent Media Group with 16 years history in the Display Advertising landscape. We monetize more than 30M impressions per day, WW. IAB & Special Sizes
|details >
|AdTrue serves over 90 billion ad impressions each month by partnering with over 50k specialized Websites & Apps. High ad quality, high revenue, simple payment term is what we offer
|details >
|Appitate is a CPI/CPA Affiliate Network that unites app-developers and Premium Advertisers with traffic of Publishers. Our team are professionals in mobile and web-promotion.
|details >
|Arbitrage Leads
|details >
|BC Media Group
|BC Media Group has direct relationships with over 325 premium publishers. Both our clients and publishers get unparalleled support from our team.
|details >
|Bcnmonetize is a ROI focused adnetwork, offering more than 50 direct Mobile applications and desktop campaigns. Main GEOs: MENA (AE, SA, KW, OM, EG, BH, MA), ES, GB, US, FR and JP
|details >
|Powerful technology back-end with basic ready-made modules to save time, and overall project cost that will help you get traction
|details >
|ClearPier is Canada's Leading Premium Performance Marketplace and the exclusive representative of a diverse portfolio of the world's top comScore publishers.
|details >
|Clicksor.com serves over 900 million ad impressions each month by partnering with over 100,000 specialized Web sites.
|details >
|Converting Team
|Converting Team is a CPA affiliate network offering unique offers for many of the top verticals with high-payouts across multiple GEOs.
|details >
|CoProsper is a quality affiliate network which has been operating for over 5 years and has achieved a reputation for prompt affiliate support, quick payments & high paying offers.
|details >
|Creafi Online Media
|We are a global PC and mobile display network, serving over 300 million impressions daily on our managed publishers. We offer personal service and transparent, quality, traffic.
|details >
|We have Exclusive Offers owned and operated by us and a lot of direct offers in many different verticals!
|details >


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grocery bag - linen
the fabric body rolls up easily for daily use, and the linen texture gets better with every wash. the detachable leather handles are adjustable and comfy on the shoulders - perfect for wearing as a backpack if you choose!
19" tall / 18" wide / 1 1/8" strap
shown in burnt sienna, cobalt, green white striped cotton, khaki, natural linen and black linen.
SALE! on cerulean blue colour
hand-made in our downtown vancouver studio


text: GBPUSD is facing the resistance of the price channel on the 4-hour chart. As long as the channel resistance holds, the bounce from 1.2658 could be treated as consolidation of the downtrend from 1.3174, and further decline towards 1.2500 is still possible after the consolidation. Key resistance is at 1.2839, only a break of this level could indicate that the downside movement had completed at 1.2658 already, then next target would be at 1.3000 area.


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It is simple to beat the wintertime blues whenever your home is cozier and warmer than the wintry, damp weather conditions outside the house.
Coal, that was previously used to warm up homes, has been substituted by heating engine oil-a free-flowing, easily combustible by-product of petroleum. By exploring http://alcusfuel.com/ you can get more information about home heating oil.
The mandatory quality of heating up oil is usually purchased from distributors who deliver the same in huge tanker vehicles and this oil is warmed in gigantic boilers or furnaces to raise the temperature inside structures, especially homes and office buildings.
Homes that contain boilers have another room specifically created to allow for the boiler because of the enormous size. But you'll hardly ever find a boiler in the present day homes built nowadays and the sole ones you observe around are designed into centuries-old bungalows.
A lot of people's use heating engine oil to warm up their homes during frigid winters which increased consumption has resulted in a primary hike in the purchase price.
Prices of are not often stable and have a tendency to surge during winters. Harsher the wintertime, costlier would be the price tag, rendering it an extremely expensive item for the normal populace.
There are two ways to warming homes in the wintertime, particularly gas and oil heating. The technique of using heating oil for the homes in the frosty seasons is nearly the same as the machine of heating system the homes using gas.


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7735 East Gelding Drive
Suite #5
Scottsdale, AZ 85260
Verve Studios' owner and head coach Amanda Melby Crisalli is a former girl scout and a current leader of a Cadette troop and Junior troop. Learn about digital filmmaking, screenwriting or public speaking from expert Verve coaches. Screenwriting & Public Speaking 3 hrs, Digital Film 4 hrs, Day of Film 7 hrs.


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Perfect for multiple piercings, pairs well with our ball earrings or mini studs. All are 14k yellow gold.
- Dainty 10mm
- Small 16mm
- Medium 21mm
- Large 35mm
Please allow 3-5 business days for your piece to ship. All Skydog jewelry is final sale. If you have any questions please contact firstname.lastname@example.com


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BitBuy is a leading cryptocurrency exchange in Canada best suited for Canadian residents and citizens (and only!). Founded in 2013 with a mission to provide a quick, safe and easy way to buy and sell bitcoin and other top cryptocurrencies, today BitBuy is a fully regulated exchange with oversight from Canadian federal authorities. Its top features include the ability to trade six cryptocurrencies (BTC, ETH, LTC, BCH, XLM, and XRP) directly in the Canadian dollar and BTC based pairs, advanced trading platform, and OTC desk, and excellent customer support service.
- Web address: BitBuy
- Main location: Toronto, Canada
- Daily volume: 152 BTC
- Mobile app available: Yes
- Is decentralized: No
- Parent Company: First Ledger Corp
- Transfer types: Bank Transfer, Crypto Transfer
- Supported fiat: CAD
- Supported pairs: 6
- Fees: Medium
Digital currency for everyone.
Bitbuy makes it simple to buy, sell, and manage your cryptocurrency portfolio. Get started today with our easy-to-follow guide to opening an account. Learn More
Buying Bitcoin, Ethereum, Litecoin, Bitcoin Cash, EOS, XRP, DAI or Stellar XLM has never been more seamless.Trade quickly with Bitbuy Express, or use advanced trading features on Bitbuy Pro. For buying or selling more than $25,000 use Bitbuy OTC.
- Pure Canadian dollar (CAD) exchange. BitBuy accepts Canadian citizens and residents only and is not available in any other country.
- Ease of use.BitBuy offers two platforms – Express and Pro. Pro trading is geared towards experienced traders, while Express lets you purchase cryptocurrencies easily and without friction.
- Ability to buy and sell the top six cryptocurrencies. They include Bitcoin (BTC), Ethereum (ETH), Ripple (XRP), Litecoin (LTC), Stellar Lumens (XLM), and Bitcoin Cash (BCH).
- Regulatory compliance. BitBuy is a regulatory compliant platform that works in accordance with the Financial Transactions and Reports Analysis Centre of Canada (FINTRAC) as a Money Services Business (MSB).
- OTC desk. Large volume traders and institutional investors can make use of BitBuy's OTC trading platform.
- Excellent customer support. BitBuy offers a direct customer support line via phone and responds to emails within 12 hours or less.
Trade with confidence.
Bitbuy is the most secure platform for buying, selling, transferring, and storing digital currency. With 2FA, SSL, and a 95% cold storage security policy, Bitbuy customers can have peace of mind that their cryptocurrency is as safe as possible. Your Bitbuy account comes with a secure cryptocurrency wallet that can be used to send and receive all of your cryptocurrency.


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We've already made a number of improvements to your client area and services, and there are more to follow.
- One-click firewall unblock: Unblock your blocked IP through our client area
- Advanced Security Scans: We've deployed a number of scripts to clean up the servers as some were being reported for spamming and/or phishing, damaging every account hosted on the same IP.
- Centralised DNS: We have now unified all disparate cPanel nameservers under the following ones (ns1.dihostnet.com and ns2.dihostnet.com)
- Hosting Improvements: 500GB DDOS Protection and Free SSL Certificates by Let's Encrypt
Sunday, February 5, 2017