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Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non–small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo. In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107–19. ©2017 AACR.
Approximately half of all cancer patients are treated with radiotherapy, which remains one of the most efficient anticancer strategies, along with surgery and chemotherapy. The efficacy of radiotherapy has improved considerably due to dose escalation and novel irradiation techniques. However, the recurrence and systemic dissemination of the disease after treatment remains a challenge (1). Combination with potential modulators of tumor cell radiosensitivity is one way to improve the efficacy of radiotherapy.
MET is a tyrosine kinase receptor activated by the hepatocyte growth factor (HGF) ligand. MET signaling promotes epithelial cell growth, motility, and migration and thus has a role in organogenesis and wound healing (2, 3). In tumors, MET activation stimulates growth, survival, invasion, and metastatic dissemination (4). Upon HGF stimulation, the MET receptor undergoes autophosphorylation on Tyr1234 and Tyr1235, which activates its kinase activity (2). MET activation is tightly regulated by ligand-dependent activation and receptor internalization and degradation. However, deregulation of the MET/HGF signaling pathway occurs in a wide range of human cancers and includes the overexpression of MET, aberrant ligand production, sustained kinase activation, and MET gene amplification or mutation (4, 5). The tumorigenic potential of several MET mutations has been demonstrated in vivo, strengthening the potential of the MET pathway as a therapeutic target (3, 6).
Preclinical studies have shown that tumor cell lines harboring either MET amplification or an aberrant MET/HGF autocrine loop are highly dependent on ("addicted" to) MET activity for growth and/or survival and are therefore highly sensitive to MET inhibitors (7–17). The efficacy of MET inhibitors does not rely on the expression or activation of MET but instead on the "addiction" or dependency of tumor cells to the MET/HGF axis for survival. Several MET inhibitors are in clinical development. As expected, antitumor efficacy of MET inhibitors has typically been observed when patients have been selected on the basis of a deregulation of the MET/HGF axis, either as a primary tumor driver or as a resistance mechanism to another therapy, as is the case for approximately 15% to 25% of EGFR-mutated non–small cell lung carcinoma (NSCLC) cases with acquired resistance to EGFR inhibition (12).
S49076 is a potent oral ATP-competitive inhibitor of the MET, AXL, and FGFR1-3 receptor tyrosine kinases (RTK) that is currently in phase I/II clinical stage trials (18). AXL belongs to the TAM family of RTKs and is associated with the epithelial-to-mesenchymal transition. AXL is overexpressed in several human cancers and has been linked to invasiveness and metastasis (19). FGFRs regulate several basic biologic processes that are required for tissue development, regeneration, and angiogenesis. Aberrant FGFR signaling has been reported in a number of malignancies and has been implicated in the pathogenesis of cancer (20). MET, AXL, and FGFR activate common signaling pathways, including the PI3K/AKT and MAPK networks, and have all been associated with mechanisms of resistance to conventional and targeted therapies, such as EGFR and VEGF inhibitors. S49076 blocks the autophosphorylation of MET, AXL, and FGFR1-3 at concentrations below 200 nmol/L in cell-based assays. Moreover, S49076 inhibits the growth of MET- or FGFR-dependent cells in vitro and in vivo and blocks HGF-dependent migration of tumor cells (18).
Here, we investigated the effect of S49076 on tumor cells that are not dependent on MET for growth and survival. Three MET-independent models were compared with two MET-dependent models, which were used as a reference. Interestingly, S49076 was active in MET-independent models at clinically relevant doses through the inhibition of Aurora B kinase rather than through the inhibition of MET. Aurora B kinase is a mitotic kinase that promotes kinetochore–microtubule interactions and is required for spindle checkpoint function and cytokinesis. Upon Aurora B inhibition, cells fail to correctly segregate their chromosomes during anaphase and exit mitosis without cytokinesis, thereby producing polyploid cells. The fundamental role of Aurora kinases in cell-cycle regulation and their aberrant expression in a broad range of malignancies have supported the development of Aurora kinase inhibitors (21, 22).
The potential of MET inhibitors combined with radiotherapy remains controversial. Indeed, preclinical studies on combinations of MET inhibitors with irradiation have yielded conflicting results. Two studies have reported radiosensitization for high MET–expressing tumor cells but additive effects for low MET–expressing cells (23, 24). Another study reported additive effects of radiotherapy regardless of the status of MET amplification (15). Different responses to such a combination have been described in glioblastoma and head and neck cancer cell lines (25, 26). In this study, we investigated the combination of S49076 with radiotherapy in vitro and in vivo using subcutaneous xenograft and orthotopic tumor models.
By dissecting the mechanism of action of S49076, we highlight a novel targeting mechanism and provide an extended rationale to guide the future development of this molecule in combination with radiotherapy.
Materials and Methods
Cells and reagents
U87-MG, H441, A549, and H460 cell lines were purchased from ATCC, and H460-luc and A549-luc cells were purchased from Caliper in 2013 (authentication by short tandem repeat analysis, karyotyping, COI testing). The GTL16 and HEK293 Aurora B DN (aspartic acid to asparagine mutation) cell lines have been described previously (18, 27). These cell lines have been tested for MET and Aurora B overexpression by Western blot analysis. All cell lines were frozen in large stock at early passages and were used within 6 months of receipt or resuscitation. The following antibodies were used: MET, pMET (phospho-Tyr1234/1235), H3, and pH3 (phospho-Ser10) from Cell Signaling Technology, Aurora B from BD Biosciences, and GAPDH from Millipore. S49076 and PF-04217903 were synthesized by Servier. AZD1152-HPQA (herein designated "AZD1152") and recombinant human HGF were purchased from Selleckchem and R&D Systems, respectively. Tetracycline induction and the in vitro kinase activity assay were performed as described previously (18, 27). Cells were irradiated with an IBL cesium irradiator.
Proliferation and clonogenic assays
For the proliferation assay, cells were treated with various doses of drug(s) and/or irradiated 2 hours later. The number of living cells was counted manually. For the clonogenic assay, cells were plated at a single-cell density and treated with the drug(s) and/or irradiated 12 hours later. Colonies were stained with crystal violet. The surviving fraction (SF) was estimated: SF = number of colonies formed/number of cells seeded × plating efficiency of the control group (the untreated group for the single-agent experiments and the nonirradiated group for the combination experiments).
Cell-cycle analysis
Cells were fixed in 70% ethanol. DNA was labeled with propidium iodide. Flow cytometry was performed on a FACSCalibur. The results were analyzed using ModFit LT 3.3 software.
MET knockdown
Cells were either transfected with ON-TARGETplus Human MET siRNA SMART pool or with ON-TARGETplus nontargeting pool using DharmaFECT transfection reagents according to the manufacturer's instructions.
Subcutaneous xenografts
In vivo experiments were performed at the Gustave Roussy Institute (Villejuif, France) under animal care license no. D94-076-11. Cells were injected subcutaneously in NMRI nude mice (Janvier). Mice were randomized when tumor volumes reached approximately 100 mm3. S49076 was administered orally, and irradiation was performed locally with an X-ray Varian tube. The tumor volume was estimated according to the following equation: volume = length × width2/2.
For Western blotting and IHC analyses, tumors were excised. One half of the tumor was crushed in PBS and filtered to prepare protein extracts. The other half of the tumor was fixed in 4% paraformaldehyde and paraffin embedded. Sections were processed for pMET and pH3 staining according to standard protocols. The percentage of pH3-positive cells per surface area in nonnecrotic areas was measured using ImageJ v1.41 software.
Orthotopic tumor model
H460-luc or A549-luc cells were injected directly into the lung through the pleura under anesthesia, and tumor growth was monitored by bioluminescence imaging using the Xenogen In Vivo Imaging System 50 (Caliper Life Sciences). Randomization was performed 3 and 5 days after tumor cell implantation for A549-luc and H460-luc grafts, respectively. For the groups treated with irradiation, mice received local irradiations to the chest using an X-ray Varian tube. S49076 was delivered using the same schedule as that used for the subcutaneous xenograft experiments. Mice were euthanized when bodyweight loss exceeded 20% of the initial weight or in the case of severe clinical signs.
Statistical analysis
Statistical analyses were performed using Prism GraphPad software (ns, P > 0.05; *, P < 0.05; **, P < 0.01; ***, P < 0.001; and ****, P < 0.0001). Survival data were analyzed using the Kaplan–Meier method and log-rank test. All other analyses were performed using the one-way ANOVA (pH3 staining) or two-way ANOVA followed by the Sidak posttest for multiple comparisons, unless otherwise indicated. For in vitro experiments, proliferation is depicted as mean ± SEM and clonogenic survival as mean ± SD.
See also Supplementary Materials and Methods.
S49076 demonstrates different mechanisms of action depending on the tumor MET dependency status
We determined the effects of S49076 treatment on five tumor cell lines harboring different mechanisms of deregulation of the MET/HGF axis: two MET-dependent models, namely, GTL16 gastric cancer cells harboring MET gene amplification and U87-MG glioblastoma cells driven by the HGF autocrine loop, and three MET-independent models, namely, H441 NSCLC cells exhibiting constitutive activation of the MET receptor, A549 NSCLC cells, which moderately overexpress MET, and H460 NSCLC cells, which show no activation or overexpression of MET (11, 13, 17, 28, 29). Western blot analysis confirmed strong activation of the MET receptor only in the GTL16 and H441 cell lines (Fig. 1A). As expected, GTL16 and U87-MG cells were highly sensitive to S49076 treatment, as concentrations as low as 10 and 100 nmol/L, respectively, almost completely abolished their proliferation (Fig. 1B). In contrast, the proliferation of MET-independent cells was not affected after treatment with 200 nmol/L S49076 (Supplementary Fig. S1A). However, at 1 μmol/L S49076, the proliferation of H441, A549 and H460 cells was strongly inhibited (Fig. 1B). Similarly, 6 nmol/L S49076 concentration was sufficient to reduce the surviving fraction of GTL16 cells by over 10-fold in clonogenic assay, whereas concentrations above 600 nmol/L were required to reach the same reduction in H441, A549 and H460 cells (Fig. 1C). U87-MG cells were not tested because they display no colony-forming capacity. Cell cycle analyses performed at proliferation-inhibiting concentrations of S49076 showed that GTL16 and U87-MG cells remained largely in G1 phase, which was consistent with the described G0–G1 phase arrest induced by MET inhibition (9, 30). In contrast, we observed an accumulation of tetraploid cells after S49076 treatment in H441, A549, and H460 cells (Fig. 1D), which is typically observed after inhibition of Aurora B kinase activity (27). Because S49076 can inhibit Aurora B in an in vitro kinase activity assay (IC50, 3 nmol/L; Supplementary Fig. S1B), we further examined the possibility of Aurora B as a cellular target of S49076. To test this hypothesis, we used HEK293 cells stably expressing a tetracycline-inducible kinase-dead mutant of Aurora B (Aurora B DN; ref. 27). Expression of Aurora B DN increased the size of the cells, which reflects polyploidization due to inhibition of Aurora B kinase activity. A similar phenotype was observed after S49076 treatment (Fig. 1E). Aurora B kinase phosphorylates histone H3 at serine 10 during mitosis, and S49076 treatment reduced H3 serine 10 phosphorylation to an extent similar to the reduction observed after expression of Aurora B DN without affecting other histone H3 phosphorylation sites (Fig. 1E; Supplementary Fig. S1C). Moreover, a similar degree of proliferation inhibition was observed after either treatment with 1 μmol/L S49076 or expression of Aurora B DN (Fig. 1E). Finally, we knocked down PP1γ, which is the phosphatase that counteracts the phosphorylation activity of Aurora B, using siRNA transfection. Knockdown of PP1γ resulted in an increased level of phosphorylated H3, which was completely abolished by S49076 treatment, resulting in H3 phosphorylation level below detection (Supplementary Fig. S1D). Together, these data support our hypothesis that Aurora B is a cellular target of S49076.
S49076 has dual antitumor activity by targeting MET-dependent cells via MET inhibition and MET-independent cells via Aurora B kinase blockade
To investigate the relative roles of MET and Aurora B in the mechanisms of action of S49076, we compared the effects of S49076 to selective MET and Aurora B inhibitors: the ATP-competitive MET inhibitor PF-04217903 (31) and the AZD1152 Aurora B inhibitor (32). As expected, GTL16 cells showed high sensitivity to PF-04217903 (Fig. 2A and B). The effects of both S49076 and PF-04217903 on proliferation and clonogenic survival correlated with their nanomolar concentration ranges of inhibition of MET (Fig. 2C). A reduction of H3 phosphorylation was observed at concentrations of S49076 higher than those required to inhibit MET phosphorylation (1 μmol/L). This effect was not observed when cells were treated with PF-04217903 (Fig. 2C). In U87-MG cells, MET is neither overexpressed nor activated, and S49076 or PF-04217903 treatment induced only a slight reduction of MET phosphorylation at concentrations over 100 nmol/L. However, we detected a clear reduction in H3 phosphorylation with 1 μmol/L S49076 (Supplementary Fig. S2A). As expected, the MET-independent H441, A549, and H460 cell lines were not sensitive to PF-04217903 treatment (Fig. 2D), and PF-04217903 did not affect their clonogenic survival even at 5 μmol/L (Supplementary Fig. S2B). Treatment with nanomolar concentrations of S49076 or PF-04217903 was able to block phosphorylation of MET whether MET was constitutively activated in H441 cells (Fig. 2E) or activated by HGF stimulation in A549 and H460 cells (Fig. 2F; Supplementary Fig. S2C), suggesting that the lack of cellular effects was not due to impaired inhibition of MET signaling. In these cell lines, 1 μmol/L S49076 treatment also decreased H3 phosphorylation (Fig. 2E and F; Supplementary Fig. S2C). These results suggest that the decreased proliferation and clonogenic survival in MET-dependent cells correlate with the inhibition of MET activation and that S49076 inhibits Aurora B activity in the micromolar concentration range in cancer cell lines independently of their addiction to MET signaling.
Next, we exposed cells to combined treatment with S49076 and PF-04217903. Nanomolar concentrations of PF-04217903 sensitized GTL16 cells to S49076 treatment, as measured by a clonogenic assay (Fig. 3A). This enhanced effect could be explained by the dual targeting of the MET signaling pathway with intermediate concentrations of both compounds. In contrast, treatment with 1 μmol/L PF-04217903 did not affect the sensitivity of H441, A549, or H460 cells to S49076 (Fig. 3B). Then, we downregulated MET using siRNA transfection (Fig. 3C). The proliferation over 72 hours was reduced by half for MET siRNA-transfected GTL16 cells compared with the proliferation in siRNA control cells (Fig. 3D), and the plating efficiency in the clonogenic assay was reduced from 0.35 to 0.1. MET depletion in GTL16 cells enhanced the efficacy of S49076 in the inhibition of cell proliferation and clonogenic survival (Fig. 3D and E). In contrast, no change in the response to S49076 treatment was observed for MET-independent cell lines after MET knockdown (Fig. 3F and G). Thus, cotreatment with the specific MET inhibitor and siRNA experiments support the MET-targeting activity of S49076 in MET-dependent cells. These results also show that S49076 impacts MET-independent cell lines independently of MET activity or expression.
Aurora B is essential for proper cell division. Accordingly, concentrations of the specific Aurora B inhibitor AZD1152 between 10 and 150 nmol/L were sufficient to reduce the surviving fraction to 0.1 for all tested cell lines (Fig. 4A). As previously hypothesized for MET inhibition in MET-dependent cells, we assumed that if S49076 impacts MET-independent cells by reducing Aurora B activity, intermediate concentrations of AZD1152 would sensitize tumor cells to S49076 treatment. This was indeed observed in A549, H460, and H441 cells upon combined treatment with S49076 and AZD1152 with respect to proliferation (Fig. 4B) and clonogenic survival (Fig. 4C). The H3 phosphorylation level was diminished in S49076- and AZD1152-treated cells and was further reduced in cells treated with both compounds (Fig. 4D). In contrast, AZD1152 did not sensitize GTL16 cells to S49076 treatment (Fig. 4E). Taken together, our data suggest that in MET-independent cells, S49076 activity is mediated by the inhibition of Aurora B catalytic activity (Fig. 4F).
Combination of S49076 and irradiation shows additive effects in vitro
Next, we evaluated the combination of S49076 with ionizing radiation (IR) to test whether its efficacy is influenced by MET/HGF axis deregulation. The antiproliferative activity of the combination of S49076 and irradiation was higher than that of the single agents alone in all studied cell lines (Fig. 5A). Similarly, the combination treatment showed an additive effect regarding the clonogenic survival of GTL16, H441, and A549 cells, and S49076 slightly increased the radiosensitivity of H460 cells (Fig. 5B). Thus, the combination of S49076 and IR showed an extended antitumor effect regardless of the MET dependency status of the tumor cell line.
It has been reported that MET expression or phosphorylation is enhanced after irradiation of MDA-MB-231 breast cancer cells and MDA-MB-435 melanoma cells (33, 34). However, this seems to be dependent on the tumor cell line, and no major modulation or conflicting results have been reported for our cell lines of interest (23–25, 35–37). We did not find any significant change in MET expression or phosphorylation levels after IR treatment in our cellular models (Supplementary Fig. S3A). Moreover, MET silencing did not alter the response to irradiation alone or to S49076 plus irradiation, which excludes a potential role for MET in these responses (Supplementary Fig. S3B).
H3 phosphorylation decreased considerably after irradiation at doses as low as 2 Gy regardless of the MET dependency status of the cells (Fig. 5C). This decrease could not be explained by a reduction in mitotic cells because our analysis was performed as early as 2 hours after irradiation. This phenomenon is consistent with other published data (38).
Combination of S49076 and fractionated irradiation significantly delays tumor growth and extends survival in vivo
We first treated subcutaneous tumor xenografts with different doses of S49076 depending on the MET dependency status of the model (3, 6, or 50 mg/kg twice daily) alone and in combination with fractionated irradiation. S49076 and irradiation monotherapy treatments delayed tumor growth in every model (Fig. 6A; Supplementary Table S1). The in vivo S49076 concentration reached levels above 100 nmol/L and 2 μmol/L in the tumors 2 hours after oral administration of a dose of 3 and 50 mg/kg, respectively (Supplementary Fig. S4; ref. 18). Accordingly, reductions in MET and H3 phosphorylation levels in GTL16 and H460 tumors, respectively, were detected by Western blotting and IHC (Fig. 6B–D; Supplementary Fig. S5A). H3 phosphorylation was also reduced after S49076 treatment in MET-dependent tumors (Fig. 6B and D; Supplementary Fig. S5B and S5C). Irradiation did not impact MET activation or protein expression in any of the cell lines tested. Nevertheless, a significant radiation-induced reduction in H3 phosphorylation was confirmed in every tumor model (Fig. 6B–D; Supplementary Fig. S5B and S5C). The addition of S49076 to the radiation treatment further delayed tumor growth in all tumor models compared with single-agent treatments (Fig. 6A; Supplementary Table S1). Interestingly, we observed a trend toward more pronounced inhibition of H3 phosphorylation in the combination groups compared with either single-agent treatment group (Fig. 6B–D; Supplementary Fig. S5B and S5C). At 50 mg/kg of S49076, GTL16 tumors showed extended growth delay, undetectable MET phosphorylation, and further reduction in H3 phosphorylation compared with GTL16 tumors treated with 3 mg/kg S49076. Combined treatment with 50 mg/kg S49076 and irradiation increased the time to relapse (Fig. 6E; Supplementary Fig. S5D–S5F).
To confirm our results in a more pathologically relevant tumor model, we next evaluated the combination of S49076 plus irradiation in an orthotopic model of lung cancer (39). Bioluminescence imaging quantification over time indicated that S49076 treatment and irradiation delayed the growth of luciferase-expressing H460-luc and A549-luc tumor cells in the chest cavity. The combination treatment inhibited tumor growth even further and prolonged survival (Fig. 7). The median survival time was nearly doubled for the combination group compared with the control group for both tumor models and was significantly higher than that for the single-agent treatment groups (P < 0.01).
The combination of chemotherapy and radiotherapy is a therapeutic mainstay in most situations in which radiotherapy is used with curative intent. However, the toxicities induced by chemoradiation therapy are a major limitation. In the setting of radiotherapy, targeted therapies potentially carry the advantage to selectively target aberrant signaling in cancer cells and increase tumor cell killing while sparing normal tissue. However, despite intensive research efforts, combinations of IR and targeted agents, such as EGFR and PI3K/Akt pathway inhibitors, have not fully met expectations for clinical use (40, 41).
The fact that abnormalities in MET signaling correlate with poor clinical outcomes and drug resistance in cancer patients strongly suggests that MET pathway inhibitors could be a promising anticancer therapeutic strategy (12, 42). We and others have demonstrated that highly selective MET inhibitors have no clear potential to treat MET-independent tumors (7, 8, 10, 13–15, 17), suggesting that patients with MET/HGF "addicted" cells must be selected to expect favorable results in clinical trials. Consistently, the MARQUEE and the METLung phase III clinical trials evaluating two MET inhibitors combined with erlotinib in lung cancer, in which true MET-amplified tumors represent only approximately 1% to 5% of the tumors, were halted due to futility (43–45).
The activity of the S49076 compound toward MET, AXL, and FGFR receptors and its efficacy against a panel of MET- and FGFR-dependent cell lines have been reported (18). Here, we sought to evaluate the antitumor effect of S49076 against other cancer models by comparing its activity in MET-dependent and MET-independent cells. We focused our analysis on the MET signaling pathway because all of the cell lines tested did not overexpress AXL and were FGFR independent. As expected, S49076 treatment in the nanomolar concentration range inhibited MET activity. Interestingly, S49076 also inhibited H3 phosphorylation in the micromolar concentration range in all cellular models. For MET-dependent cells, the MET-inhibitory activity correlated with the impact on proliferation and clonogenic survival, and sensitization to S49076 treatment was observed after cotreatment with the specific MET inhibitor PF-04217903 or after MET silencing. The cell-cycle profile observed after S49076 treatment was also in agreement with known phenotypes induced by MET inhibition in this cell type (G0–G1 arrest). These data suggest that the cytotoxic activity of S49076 in vitro against MET-dependent cells is due to MET targeting. The lack of dependency on MET for the H441, A549, and H460 cells was confirmed by the absence of an effect of MET silencing and PF-04217903 treatment on the proliferation and clonogenic survival of these cells. For these non–MET-driven models, S49076 treatment exerted cytotoxic activity in the micromolar concentration range. This effect was independent of MET because the concomitant downregulation of MET protein by silencing or the reduction of MET activity by chemical inhibition did not alter S49076 antitumor activity. In MET-independent cells, treatment with micromolar S49076 concentrations led to cell tetraploidization and decreased histone H3 phosphorylation, and sensitization to S49076 treatment was observed after cotreatment with the Aurora B inhibitor AZD1152. Together, these results led us to the conclusion that the activity of S49076 in vitro against MET-independent cells is mediated by the inhibition of Aurora B. Although S49076 in the micromolar range also alters H3 phosphorylation in MET-dependent cell lines, the inhibition of MET activity in the nanomolar range, which severely impacts proliferation and survival in these cells, predominates and masks the phenotypes induced by Aurora B inhibition.
S49076 treatment delayed tumor growth in all tested models, which was accompanied by a reduction in H3 phosphorylation in MET-independent models. Surprisingly, after 4 days of S49076 administration at 3 mg/kg, H3 phosphorylation was also greatly reduced in GTL16 tumors, although the S49076 concentration in these tumors did not to exceed 200 nmol/L after a single administration of S49076 (18). Consistently, we also observed a clear reduction in H3 phosphorylation in vitro in GTL16 cells treated for 24 hours at concentrations below 200 nmol/L (Supplementary Fig. S6). A relatively long exposure to a low concentration of drug could cause direct inhibition of Aurora B, but we cannot exclude the possibility that the decrease in H3 phosphorylation level is due to an effect on cell-cycle progression. Regarding the former hypothesis, we can assume that in clinical settings, both Aurora B and MET will be targeted even at low doses of S49076 regardless of the tumor type. Regarding the latter hypothesis, a drug concentration over 1 μmol/L in the tumors would be required to block both MET- and Aurora B–driven processes.
Although several early-phase studies are planned to investigate the combination of MET inhibitors with radiotherapy, the issue of tumor selection has become a primary concern. We investigated the efficacy of combined S49076 and irradiation treatment. At least additive effects for the combination treatment were observed with respect to inhibiting proliferation and decreasing clonogenic survival for all tumor models in vitro, which is consistent with published data on the combination of crizotinib and irradiation in NSCLC cell lines (15). Tumor growth was also further reduced by the combination treatment in both subcutaneous and lung orthotopic models regardless of the MET dependency status. In the orthotopic models, the tumor growth delay translated into a survival benefit. Thus, S49076 improves the efficacy of radiotherapy regardless of the tumor type. This finding suggests that patient selection regarding tumor MET dependency status may not be required for this combination treatment in clinical trials. Irradiation reduced H3 phosphorylation in vitro and in vivo, which was consistent with other published data (38). This phenomenon may be a consequence of activation of the PP1 protein phosphatase, which can be activated by IR in an ATM-dependent manner (46, 47). The addition of S49076 to IR treatment showed a trend toward a further reduction in H3 phosphorylation in vivo, which could result from concomitant effects on Aurora B, PP1, and the cell cycle.
In conclusion, the dual targeted mechanism of action of S49076 is unique among MET inhibitors. The targeting of Aurora B kinase by S49076 and the ability of S49076 to improve the efficacy of radiotherapy extend its therapeutic potential, which should be further confirmed in the clinic.
Disclosure of Potential Conflicts of Interest
M.F. Burbridge, V. Cattan, and A. Jacquet-Bescond were employees of Servier at the time of this study. No potential conflicts of interest were disclosed by the other authors.
Authors' Contributions
Conception and design: C. Clémenson, C. Chargari, C. Ferté, M.F. Burbridge, V. Cattan, A. Jacquet-Bescond, E. Deutsch
Development of methodology: C. Clémenson, C. Chargari, C. Ferté, V. Cattan, A. Jacquet-Bescond
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C. Clémenson, C. Chargari, W. Liu, C. Ferté
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C. Clémenson, C. Chargari, M. Mondini, C. Ferté, V. Cattan
Writing, review, and/or revision of the manuscript: C. Clémenson, C. Chargari, M. Mondini, C. Ferté, M.F. Burbridge, V. Cattan, E. Deutsch
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C. Ferté, E. Deutsch
Study supervision: C. Clémenson, C. Ferté, A. Jacquet-Bescond, E. Deutsch
Grant Support
Financial support for this study was provided by the Institut de Recherches Internationales Servier (Suresnes, France).
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.
We thank O. Bawa, E. Louvet, P. Opolon, V. Rouffiac, B. Petit, and Y. Lecluse for their technical assistance and helpful discussions. Animal care was provided by the PFEP at the Gustave Roussy Institute.
Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
- Received February 2, 2017.
- Revision received April 21, 2017.
- Accepted June 5, 2017.
- ©2017 American Association for Cancer Research.


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Through the rain by Toby Andrews
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Toby Andrews has published 7 street photos in UPSP.
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How to Influence Others to Write What You Need
By Susan Varty, Managing Partner
Not everyone can be a subject-matter expert in their industry, and if you work at a large corporation, there are many industries and/or products to cover. As a team member responsible for internal or external content or communications, you may have to rely on others to create what you need.
Writing is time-consuming in the best of circumstances, but (more to the point) it takes a lot persuasion, if you need expert input – or if you need a specialist to write something as part of a project.
I know that my firm helps to solve this problem for you, but here are some practical tips to drive change on your own and get things done when you have limited options:
Draft bullets
Blank pages can be daunting. If you have a vision for what you want, use bullets to create an outline. Bullets cover initial ideas, even if the expert does not use it to write the final piece.
Leave placeholders
Add text or notes highlighted in a different font colour or in brackets as a placeholder for what you need. I call it the "Star Trek method." Star Trek writers used such placeholders for technical references in the script: [Spock, please insert tech speak here]. This is also handy for press releases when you need to draft a quote and attribute it to someone later to expedite approvals.
Set up informal meetings (with food if you can)
If you can, meet face-to-face, drop by the office, offer to bring coffee, etc. Try to meet with experts at your company informally, so you can interview them or ask how you can help write or manage what you need.
Repurpose and/or update
Do you have content written by a expert in the past? Can it can be updated for present needs? It is easier to update content, if only a few new paragraphs are required. Perhaps sections could be repurposed in another format – such as a video.
Interview and record
Conference lines are a great tool on their own to record discussions and they are critical when you cannot meet face-to-face. So, interview experts for the content you need and draft key points they can flush out. You can also share the recording, if you need someone else to write it.
If you have a recording or a video, send it to be transcribed. It may be expensive but it could be worth it to kickstart the writing process so you do not have to start from scratch. It is always easier to remove content from a written transcript to hone in on main points
Give them a voice recorder
Some people may share their thoughts more easily, if you give them a personal recorder to use throughout their busy days. If you cannot provide a device, there are many apps online – or they can call into a conference line on your system and press record (rather than try and share files).
Propose titles
People like choices. Sometimes a thought-provoking title is all they need to get started. So, provide three title options to get ideas flowing and broaden the scope of the conversation.
Give them perks and gamify
Team awards, rewards and competitions are certainly used with the sales team. Why not reuse some of their ideas and "gamify" content generation with your experts?
photo credit: Shanaka KalubowilaAll Posts
HeadStart has been a lifesaver in several occasions. Especially, when we can't afford adding content staff resources to our budget.
HeadStart is an extension of your team to help you finish your content projects. Read about our approach and let's get started. Call 1.647.479.9783 or contact us.


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The Craft Box HelstonApril and her team welcome you to The Craft Box! Based in the heart of Helston we offer a range of crafts designed to captivate children and adults alike. With years of experience and artistic degrees to support them, the craft team are able to tailor activities to suit each individual's ability and interests.
We are also home to a modern café with a shabby chic twist. It's the perfect place to enjoy a delicious barista coffee or speciality italian hot chocolate. We serve Carraro 1927 which is a rich, Italian coffee bean, ground just moments before your coffee of choice is made. All of our staff have professional barista training and previous experience; so whether you choose a flat white or a cappuccino, we guarantee a perfect cup every time complemented by a range of locally handmade cakes.


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THREE, PRICES. •45 inch Pillow Casing, amuslin, only 91-2c per yard Warner's Sample Corsets, only 33c each—to close out. "Renfrew" Dress Ginghams, only 61-2c a yard—worth 12 l-2c. We are quoting extra low prices on all of the "Walker Stock" to close it out. SGHMITT & HEFFLEY. 'Golden Rule, 4th and Market. The Keeley Institute, MfVRION. IND. For the cure of the Liquor.IMorphine.Tobacco, and all other drug addictions. .Absolute Freetoi, Ni Suffering, No Sore Arms, No tapaimeflt of tbe Health. The Institute at Marion, Ind., is authorized toy Dr. Leslie E, Keeley, and the treatment is identical with that given by him at Dwight, (Ills. Write for terms of treatment and other information. All correspondence strictly confidential, THE KEELEY INSTITUTE CO., Marion. Ind. DAILY JOURNAL FRIDAY MOBNING, MARCH 2. Have you eoen those nobby soft hats showp by Putterron. Throe leaders to-day. See our ad. vcrtisement 1 —Goldon Rule. $10.000 worth of flno carpets to seltct from at tbe closing 1 gale of the New Fashion store. Good morningt 4»ve you attended tbe Walker stock sale at tbe Golden Rule? If not, go to-day. Seo the new spring capes by tho hundreds ac the Trade Palace. Ready A atr«a c mm | B Town. The itrongest man who ever pave an exhibition of muscular strength ne'e (i io the olty. Tola muscular Individual la Mr. J VV. Bart, of Clilo (to lately of Wisconsin, who rivals Sandow In •omeof bis exhibitions of- prowess. A* an indication of bis, wonderful strength ht» gave ar ejhtbltl. n alj. R, Hall's place on Wall si reel laat erenUg. During this Informal ext I bltlon he did things which astounded all his spectators. Among other things which bo did ho bunchod a double pack of playing caH» and with a twiai of hl» powerful fingers tore the cards In two He lifted wllb one fingor a 32 gallon barrul' full, a weight wbleh few In the crowd could lift with both hand* He broke a heavy "T" ohaln over tbe muscles of his rlgblarm;ho broke tho same chain by a pull with his tooth and as a crowning: feat broke the biggest cobble stones that could be picked out of tbe street with a single blow of bis wonderful li-t. striking- on the bare muscle of bis hand a blow as effectual as the heaviest blow of a stone m son's sledge. With this same right hand he drove a long i-piko through a two inch board with one blow. In some of his feats Hurt bats challenged Sandow, but as tbe latter bad the most money to guard the challenge tbo-ebas never been a contest between them Mr Hart is visiting friends here and will probably give another exhibition of his wonderful muscle at the same place this evening, W* MIHIJ hVe. wifyul (laW/'ej, Jj«»K«5, uwJ j»»l'«> Wfc MOW lil>* wiHtvF t*xtS, QM(I llVtlvi^wF MS: W» MA* live w f3ut ciuilii voti'no % MIA.M live 5oaf». Next to the foolishness of trying to live without Soap, is Ac great unwisdom of living without SANTA CLAUS SOAP which is acknowledged to be far better than any other kiat. Sold everywhere by enterprising grocers. only by N. K. FAIR BANK & CO., Chicag*. i DREU CITf ON WflLKER & Rf\UCH. BROrtDWftY, FOR flNYTHING YOU WflNT IN BEFORE. AFTER. T have take, the a ff enoy for tbe HERO SHEEP PROTECTOR, and have .* fall Btook of the, coo<b in eight. Theae proteotorB are guaranteed to K lve .firoteet,on to the sneep %i against dogs. We have received our Seeds for the season of 1894, ano have them ready to supply our customers on demand We handle SothingbutLANDRETH'S SEEDS and as all of our old stock has been burnt, our custom- ors may rest assured that they will get fresh, clean goods. We have a full variety of Gar den and Field Seeds also Flower Seeds. We have also a full line of Harness and Carriage Goods, and a fuil line of Turf and Sporting Goods. In fact we have everything that goes with a horse and carnage. Don t forget the old place. 424 BROADWAY Geo. Harrison. made wrappers aro going oil lively. We are determined to close our mammoth atocn of dry goods during the next thirty days at tha Now Fash- Ion store. Perfect health Is seldom found, for impure blood is *o general. Hood's Siirsaparllla really does purify the blood and restores health. The Sherman bat for young men, tho Gujor hat for all ages, the You man, suitable for all faces, sold by Patterson, the Haberdasher. Murray and Mack have abandoned the piece they bavo appeared in tor the last two years, and will win favors in tbe now farce comedy sensation, Finnigau's Ball," at Dolan's tonight. Lovely new spring dress goods just opened from all parts of the globe. Fronch and English goods imported by us from Anthony, Mnhlor & Jo., of Paris, London and Berlli. All at prices to surprise you at the Trad« Palace. See them. The latest, by tbe way, one of the few successful pieces of theatrical proi erty, will be opened for the in fpeotlon of Logansport theatregoers at the opera house this evening. The name of the piece, • Flnnigan's Ball," would suggest plenty of Irish comedy, wit and funny situations, and as the company is headed by two clever comedians, Murray and Mack, mirth more than likely reign supreme. aNEXPENSiVE MEDICAL TREATMENT. The Merroll Humanitarian Idea in Great Favor With the Community -- Medicines Should toe Free and the Best Medical Skill Nearly Free. Dr«, MerroU and MtisUnU, who have been located in our olty over four •aanthg and who have treated 1,240 patients for $6 a month on a positive naraotee U th«y word not satisfied to have their monev returned to them, i»m»a kept their word and out of tkls vast number but six have returned disnat- Ifllfi O(J • During the next two weeks DC*. Morroll and assistants wish allf tbe af- llctad to have aa opportunity of jndglng tbeir abl ity and will thereAore (five Frsa iooiUltaUoa. Kn»«lna«lon and Advice, also one FREE TRECTMENr, "WITH MEIHCIHE. to all atticted with Catarrh, Brojohitls. Liver complaUt, Um, 9,se»se» of Womin, Errors of Youth, Ne*»ous DdbllUy, Lost SparoittnUrHra, Night Etnlnlons, etc Hemomher. this offer holds 'of two wMlesoaly and all afflicted must come tn during office hours, Offloa HUUH: 9 to 12 » m., 2:!JO to 4 and 6:30 to 8pm. The Doctors f»r<j parmviantly (ocital at 411 Broadway, Logansport, Ind. /'At Matter Today—Clear and p/casant. YOU NOTICED THAT AEE INTRODUCING DEPARTMENT IN O OUR BUSINESS, AND THAT IS A DEPARTMENT THAT WE ARE JUSTLY PROUD OF. OUR STYLES ARE THE NEWEST AND MOST APPROVED DESIGNS FROM THE BEST MAKERS. THE HAHEHDASIJEIC SHIRT MAKER, HATTEB AND FURNISHER Rmururd WUto Thank*. It will be rooiBmbered that n. couple of wepks ngo Frank Larger's house on tbe Weet Sirte waa entered by burglars aud jewel y and valuables of considerable amount were taken, urnon? ibeee being Mrs. Larger'a wedding rinp, a diamond ring, earringn, etc., together with Mr. I ergerV pocket book containing bis railroad pasa and others papers of value to him alooo. Theae he expected never to see again along with tbo other iblngs taken, but was greatly surprised the other day to receive by mall tho pocket book and papers which wero aooom pan led by a polite note expressing regret at any inconvenience tho temporary loss of his ticket and papers mlgkt havo occasioned htm and tbanking him very warmly for the jewelry which the thieves trusted that be would not miss much, believing tbat they could derive as much benefit from their po-session as could tho owner. It wan a strange note and Frank is now mo o than ever puzzled to know wbo his very polite and considerate burglars were. Cbamborc-GrUler. Last evening at seven o'clock at the Sheriff's residence, Rev. Tolrmein- stoin, pastor of the German Lutheran church officiating. Miss Mary Grtsley, half-Bister of Sheriff Homburg. was united in marriage to Mr. Samuel L. Chambers, a well known vouog farmer of Clinton township. The wedding waa conducted quietly, only family friends being present, but it was none tbe lees an enjoyable affair. Among the guests waa Maj. Samuel L. Me- Fadln, after whom tbe groom bears hia name and who made a characteristic and fitting address to the newly wedded couple. An elegant supper followed the ceremony Mr. Chambers and bride will at once go to housekeeping on tho Henry Wlpper- man farm in Washington township. Sol Speed ID Jail Here. Detective Morgan went back to Kokomo yesterday morning and re- tut ned at noon with his prisoner, Sol Speed, the colored porter wanted for the Ray burglary, and suspected of the Taylor diamond robbery, whom he landed In the county jail. Sol was inclined to be cross and surly under arrest anfl had nothing to say for himself. lie tried to escape just before hia departure from Kokomo and did break from bis captors, but was soon recaptured aud held to the line. Upon ao affidavit and information hi* case will be brought directly before theclrc It court, b.it the lime forfel* hearing has not yet been set. "Oh, what would the world be to usj "If Children were no more? Don't Neglect the Children "We should dread the desert beyond UH "Worse clun the dark; before" There is no better way to provide lor their Amusement AND Education than by securing for their pleasure and study a series of the superb World's Fair Art Portfolios 256 Offered by this paper. SPLENL ID VIEWS 256 The New G«»C»B»p«nr. The gas committee met yeitarday morning at 9 o'clock with several other citizens present. The committee and citizens started out to raise cash for territory and last evening mt 4 o'clock had secured $3.500. The committee will wot k again today and will raise enough to secure gu terrU tory sufficient lor ten years' oonsump. tion. These subscriptions are cash subscriptions and when the proper amount is raised, which will be done today, some of the be»t territory in the gas belt will be turned over to the committee. The ladi»s-of tbe Christian church will servo supper Friday evening, March 2J. at the home of Mrs. Harrington, No. 19 on 16ib street. Supper 16 cents. . Farm for Bent. Apply at 209 West Broad way. With appropriate descriptions covering EVERY EXPOSITION FEATURE. PART 3 NOW READY HOW TO SECURE THESE SPLENDID PORTFOLIOS Bring or send 6 coupons of different dates, from pag« one, with 10 cents, to the Portfolio Department of the Journal, and you can secure any Port olio tb« week after the issue of each number In sending do not include any other business in your letter, bu« state particularly the number of Portfolio wanted. Address PORTFOLIO DEPARTMENT JOURNAL, LOGANS PORT, INDIANA. IF IN NEED Get your Letter Heads, Bill Heads. Statements, Envelopes and everything you need in the printing line at the JOURNAL OFFICE,
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Well being Insurance Plans, Medical Insurance, Well being Insurance coverage Insurance policies
The Ministry of Health has general responsibility for ensuring that high quality, applicable, price efficient and timely well being services can be found for all British Columbians. The GMC has determined to introduce a Medical Licensing Assessment (MLA) from 2022 to exhibit that those who acquire registration with a licence to practise medicine within the UK meet a standard threshold for secure practice. Candidates ought to be aware that to obtain registration with a licence to practise, medical college students might want to pass each elements of the MLA, pass university finals and demonstrate their health to practise. At Northwestern College Feinberg College of Drugs, we're impressed by possibility and undaunted by complexity. Go inside our world-class laboratories and classrooms and meet our leaders, who're devoted to improving the future of all human well being.
Palliative care is a cemented service supplied by well being care providers globally, and the care given to the terminally sick, as well as the help offered to household and associates, is important to helping patients by way of the challenges of terminal sickness. We have now collated a range of resources and open entry content material as an example the significance of one of the key foundations of palliative care – communication – and to encourage an open dialogue between patient and practitioner.
The College is dedicated to offering college students with up to date medical and health science abilities that are crucial to remodeling healthcare, research and workforce wants. Tropical drugs offers with the prevention and therapy of tropical illnesses. It's studied individually in temperate climates where these ailments are fairly unfamiliar to medical practitioners and their local medical needs. The College's Incapacity Resource Centre (DRC) can present general recommendation and steerage to potential and present disabled college students and people with a SpLD or long-time period well being condition.
The intercalated degree is a one-year BSc course which supplies you the opportunity to review the themes of your choice in better depth across King's and the university's scientific companions. As a multi-college establishment, we offer an unrivalled vary of intercalated degrees from medical and biomedical sciences to humanities topics. The intercalated BSc is a compulsory requirement nonetheless students can request to opt-out; the intercalated BSc is taken between Levels 2 and three of the course.
The gymnasium has been a sacred house for pushing oneself to the restrict and maximizing one's potential because the days of ancient Greece. Every culture has intuitively understood that a healthy body is a central aspect of overall health and wellness. Choose from a wide selection of cutting-edge exercise equipment designed to target a wide variety of muscle teams and health factors. Construct a prime-class health club in your personal home with the whole lot from train bikes to weights and even tech accessories like coronary heart charge screens and pedometers.


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Not every particular person would recognize the structure and method to learning in the standard classroom today. Residual recordsdata, unused and undeleted drivers, and corrupt or unhealthy registry entries will rapidly litter even the latest of computers. Clean, repair, and optimize your system with registry cleaner laptop software. The software will repair your registry, optimise your COMPUTER's performance, defrag the registry and forestall system crashes and freezes.\n\nExpertise has affected and remains to be affecting folks of all age brackets from all around the world. Gone are the days when folks melted for concern of where to get data or information for their usage. "Internet is the world on the computer". Plenty of unhealthy materials are available on the internet.\n\nThis is the most effective sound expertise that is obtainable in the marketplace and it could possibly make computers that run with the Intel 3 chip work like a home theater system with its unbelievable sound quality. This is impressive in that it's going to help to keep from overheating or being especially confused while still sending out the most effective expertise obtainable to a computer.\n\nThere are two forms of retail sales employees: retail salespersons, who sell retail merchandise, corresponding to clothing, furniture, and vehicles; and components salespersons, who sell spare and substitute components and tools, especially automobile components.\n\nThe first suggestion to update your expertise pertains mainly to your laptop or residence COMPUTER. As a substitute of going out and buying a new laptop, it could be price it to hire a Geek Squad kind of company to try to refurbish your current laptop and to also add increased memory to it. The fee for this service is minimal and could lengthen the life of your laptop by several more years without feeling like you might be working on a dinosaur of a COMPUTER. Also, if you may get a techie pal that can assist you at no cost that may be great too.\n\nMedical and health companies managers must direct adjustments that conform to adjustments in healthcare laws, rules, and expertise. Natural sciences managers supervise the work of scientists, including chemists, physicists, and biologists. Social and neighborhood service managers coordinate and supervise social service applications and neighborhood organizations.\n\nNuclear engineers research and develop the processes, instruments, and techniques used to derive benefits from nuclear vitality and radiation. Many of these engineers find industrial and medical uses for radioactive materials—for example, in tools used in medical prognosis and therapy.
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Stafford Library Calendar:
|Thursday 17 October 2019
|Events for day: Thursday 10 October 2019
|<< Previous day Next day >>
|10:30am Animal Story Time
Category : General
Enjoy stories, songs, puppets, and a visit from a surprise animal!
Read more
4:30pm Fireman Story Time
Category : General
Climb and touch a real firetruck! Learn safety tips from our volunteer firefighters. Paint your own toy firetruck. Space is limited, must pre-register.
Read more
Please call 860-684-2852, email email@example.com or click the "Register Online" link at the bottom of the event detail page to sign up for an event. Registration is appreciated for all events.


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Ready for the Bradenton Area River Regatta? Here are 5 things to know before you go
By land and by water, the Bradenton Area River Regatta arrives this weekend to entertain all of Manatee County.
The watersports festival is a chance to see some of the fastest boats in the world zip down the Manatee River.
And there is so much more to enjoy at this year's regatta.
Festivities in Bradenton and Palmetto on Saturday include live music all afternoon, a flyboarding performance, dog shows, a fishing tournament, family fun areas, food, beer and more.
Here are five things to know before you head out to the 2019 Bradenton Area River Regatta.
What's happening and where to see it
The Regatta schedule is packed and some events overlap, so it's best to plan out your schedule ahead of time.
Here's the lineup for the day:
Bradenton events:
▪ DeSoto Little Anglers Fishing Tournament — 8:30 a.m. at the Palmetto Pier;
▪ "Dog Frisbee Shows" — Noon, 2 p.m., 4 p.m. and 6 p.m. on the Bradenton Riverwalk Main Lawn;
▪ Stunt Dog Shows — 11 a.m., 1 p.m., 3 p.m. and 5 p.m. at the Bradenton Riverwalk Ampitheater;
▪ "Distinguished Daredevils Variety Show" — 10 a.m., noon, 2 p.m. and 6 p.m. at the Bradenton Riverwalk Ampitheater;
▪ Pittsburgh Pirates/Bradenton Marauders Family Fun Zone and Area Food Festival — All day at the Bradenton Riverwalk main lawn;
▪ Kristen Smoyer, 2016 World Flyboard Champ — 7:15 p.m. at Pier 22 Restaurant.
Palmetto events:
▪ Vintage Powerboat Show — 10 a.m.-7 p.m. at Riverside Avenue/Riverside Boat Ramp;
▪ Pittsburgh Pirates/Bradenton Marauders Family Fun Zone and Area Food Festival, USF Bulls and Tampa Bay Lightning Street Teams and DeSoto Beer Garden — All day long at Riverside West Park.
On the river:
The powerboat races can be viewed from both sides of the Manatee River. Some prime places to watch are Bradenton Riverwalk, the Palmetto Pier, Riverside Drive and the Green Bridge, which will be closed to vehicle traffic all day.
▪ Powerboat race test runs — Formula 3 at 10 a.m. and Formula 2 at 10:30 a.m.;
▪ Qualifying heats — Formula 3 at noon;
▪ USF Ceremonial Band — 1 p.m. at the base of the Green Bridge;
▪ Qualifying heats continued — Formula 2 at 2 p.m.;
▪ Championship races — Formula 3 at 3 p.m. and Formula 2 at 3:45 p.m.;
▪ Zambelli Fireworks Spectacular — 6:45 p.m.
Fireworks will be visible from both sides of the river, and this year, the Green Bridge will remain open to pedestrians during the display.
Who's playing?
Music kicks off at noon in Bradenton and Palmetto and goes all day long. So pick a stage and settle in or go show-hopping and create your own lineup.
Bradenton Riverwalk Pavillion Stage
Noon — Couch Music Foundation Education Students;
1 p.m. — Penny Fountain;
1:45 p.m. — Trevor Bystrom Band;
2:45 p.m. — "Tribute to Abba" by Shaman Band
4 p.m. — Under the Moon and Friends;
4:30 p.m. — Sam Woolf;
5:15 p.m. — We the Kings.
Palmetto Main Stage
Noon — Couch Music Foundation Education Students;
1 p.m. — 301 Travelers;
2 p.m. — Matt Walden;
3 p.m. — Brandi Sparks;
4 p.m. — "Tribute to George Strait" by Andy Pursell Band;
5:15 p.m. — Andy Pursell Band.
Come prepared
If you plan to spend all day at the festival, it's best to know the lay of the land.
Good news: You are allowed to bring your own coolers.
Bad news: You are not allowed to bring your own alcohol, but there will be a beer garden near the Palmetto main stage. Law enforcement may check coolers.
You can bring your own food to the event, but there will be lots of tasty offerings on site.
Pets are also OK, but they should be well-behaved and leashed.
And how about the weather? At the moment, this Saturday is forecast to be pleasant, with highs in the 70s, lows in the 60s and only a small chance of rain. However it is Florida, so having some sunscreen and a poncho on hand is never a bad idea.
Where to park
There's lots of free parking throughout downtown Bradenton and Palmetto.
Some good bets in Bradenton are the Riverwalk parking lot off of Third Avenue West (east of Manatee Performing Arts Center) and the lot off of Riverfront Boulevard (by Mattison's City Grille).
Check the City of Bradenton's website for more public parking locations.
In Palmetto, look for parking on Riverside Drive.
Also keep in mind that the Green Bridge will be closed from 4 a.m. Saturday to 1 a.m. Sunday, so you will have to use the DeSoto Bridge if you plan on traveling back and forth.
Where to party
There are several Regatta celebrations happening around Bradenton this weekend.
A few highlights:
Meet the drivers at Mattison's
Mattison's City Grille on Bradenton Riverwalk will host a pre-Regatta party on Friday night where guests can meet powerboat drivers and crews participating in the big day. The boats will be there too, and local bands will perform.
Details: 6 p.m. Friday. Mattison's City Grille, 101 Riverfront Blvd., Bradenton. mattisons.com.
Regatta day drinks and dining at Pier 22
For those who want some suds on the Bradenton side of the river, Pier 22 is hosting a beer garden on Regatta day from 10:30 a.m. to 3:30 p.m. The restaurant offers prime views of the water.
On Saturday night, Regatta fans are invited to dine al fresco for the fireworks show and a second performance by flyboarder Kristen Smoyer. This time, she'll be decked out in neon lights.
Details: 6:30 p.m. Saturday. Pier 22 Restaurant, 1200 First Ave. W., Bradenton. Reservations recommended. pier22dining.com.


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Pcchips A13G NVIDIA Windows Chipset Driver
PC Chips PCChips A13G+ v Motherboard - NVIDIA GeForce , Socket WITH WINDOWS 7 PROFESSIONAL AMD PHENOM PROCESSOR WITH. Placa mãe PCChips A13G V Motherboard Pcchips P21G V ChipSet VIA P4M Socket Also Supports: A13G (vA), NVIDIA nForce(tm) Browse all PC Chips > BIOS Download do Driver da Placa-Mãe PCCHIPS A13G para Windows XP.
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Not only was there no mention of a wider effort, the complaint itself hung from a settlement that Microsoft Chairman Bill Gates described as a 'nothing.
This week the DOJ will file its first round of arguments before an appeals court explaining why that court must uphold a lower court's decision to force Microsoft to offer its Internet browser separately from its OS. Just last week, a group of 10 state attorneys general met with federal prosecutors to coordinate strategy on their separate investigations of Microsoft's business practices.
That meeting followed Pcchips A13G NVIDIA Windows Chipset Feb. The DOJ will go far beyond its limited goals and launch a wide-ranging attack against Microsoft's business practices. Lande, who helped sue Microsoft over its earlier bundling of Windows with the Microsoft Disk Operating System on behalf of the developers of the competing DR-DOS, said he believes the DOJ can show that the company that produces more than 90 percent of the PC OSes sold can exert far-ranging control over the market for personal computer software.
Once DOJ attorneys do that - a slam dunk, in Lande's opinion - they need only show the company has used that power to maintain market share, dictate prices or otherwise compete under conditions that favor Microsoft. Gate A20 Option Fast This item defines how the system handles legacy software that was written for an earlier generation of processors. Advanced Chipset Features Page Chapter 3: You should leave the items on this page at their default values unless you are very familiar with the technical Pcchips A13G NVIDIA Windows Chipset of your system hardware.
If you change the values incorrectly, you may introduce fatal errors or recurring instability into your system. Page 32 Chapter 3: Ide Prefetch Mode Chapter 3: Onboard Fdc Controller Chapter 3: I had to shut down blindly because as soon as I disabled the onboard video, the monitor, of course, went black, but when I rebooted with that setting even with a monitor still plugged Pcchips A13G NVIDIA Windows Chipset the onboard VGA portit finally came up with the monitors attached to the PNY PCI card.
I haven't tried any of this with the 64 bit version of Win7. I'll leave that for another week when I don't have anything to do.
I haven't noticed any benefit of running 64 bit Win7 vs 32bit so I'll leave it installed with the 32 bit Win7 RC1 for now.


text:
The Juan Cuadrado Files
April 16: Liverpool emerge as favourites to land Cuadrado before the transfer window even opens.
June 1: New Barcelona boss Luis Enrique puts Cuadrado on his summer wishlist.
June 29: Cuadrado pledges to decide where his future lies after the World Cup.
July 12: Brendan Rodgers is given £75m from sale of Luis Suarez to spend. Cuadrado is one of his targets.
July 21: United are linked with a £29m bid for Cuadrado after being impressed with his displays at the World Cup
July 30: Cuadrado's agent gives suitors big hope of signing him after revealing Barcelona's interest has cooled.
August 5: Louis van Gaal drops a big hint he could be in the Colombia star.
August 8: Fiorentina admit they are not confident of keeping Cuadrado at the club.
August 11: Chelsea winger Marko Marin undergoes a medical at Fiorentina. He looks set to replace Cuadrado.
According to Spanish newspaper Sport, United agree personal terms with the winger.
But Barcelona are still pondering one last bid for Cuadrado. A successful move would take their spending beyond £150m.
And in a dramatic twist, Chelsea could also be keen. Jose Mourinho is pondering his own big move.
August 12: Fiorentina star Borja Valero begs Cuadrado to stay in Florence.
But Cuadrado has other ideas. He wants to snub Chelsea and United to explore a move to Barca.
Fiorentina want the Colombian's future sorted by August 20.
August 13: United's bid to sign Cuadrado looks set to fail with the player holding out for talks with Barcelona.


text: Sublet.com is a Gallo Matese apartment rental service that advertises Gallo Matese apartments, sublets, subleases, roommates & houses for rent. Gallo Matese Apartment rentals, sublets, subleases, roommates and potential Gallo Matese renters have not been screened, verified or evaluated. Individuals utilizing this rental service to find Gallo Matese apartments, sublets, subleases, roommates or tenants take full responsibility for their actions & understand that the owners of the site take no responsibility for any consequences of using this service.


text:
2017 Publisher Introduction Program Fellowships
Thank you to the publishers from Black Inc, Pan Macmillan, Random House, Scribe Publishers, Text, UQP and UWA Publishers for making the selection, and congratulations to the writers who will receive a fellowship.
The writers who will receive a PIP Fellowship 2017 and the Publishers who will read their work are:
Frances Chapman for her young adult novel The Dreamer of Dreams
Guitarist Taylor Donadi yearns for success, but when fame beckons she must choose between the music, and the dream.
Janet Lee for her fiction novel Burning Jane Austen's Letters
Historical fiction set in Hampshire, 1843, when Cassandra Austen is sorting and destroying Jane Austen's letters.
Michelle Marquardt for her young adult novel Always Greener
To escape starvation on a distant, hostile world, a fifteen-year-old girl must confront the terrible secrets in her community.
Fiona Reilly for her narrative non-fiction The Uncharted Kingdom
A rollicking, dangerous journey of self-discovery in search of 'The Real China', with children in tow.
Alison Gibbs for her fiction novel Repentance
A literary novel set in 1976 in the fictional town of Repentance, NSW
Scott Pearce for his fiction novel Faded Yellow By The Winter
A mythic novel about boys and men, Australian Rules Football and living off the land.
Bruce Fell for his fiction novel Love Care and Forgiveness
Terminally-ill convicted murderer, Darren Ashley Circus, reflects on the life of his official visitor, Sister Marion West.
Polly Jude for her young adult fiction novel Head Space
A young adult novel dealing with suicide and growing up
Hayley Lawrence for her young adult fiction novel Inside the Tiger
A girl from an elite Sydney boarding school writes to a Thai death row prisoner and falls for him, destroying them both.
Anne Hotta for her collection of short stories Mending Heart
In this collection of short stories set in Australia and Japan, the protagonists struggle to overcome their dilemmas.


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Hoploclasts – Stupid people
Virginia lawmaker who brandished AK-47 in session is disbarred felon
(Daily Caller)
Nathan: This thuggish politician (a Democrat, as it happens) has a rap sheet a gangbanger would envy, had to be asked to take his finger off the trigger as he waved it around, and had to have violated multiple laws. His actions can be, in my opinion, considered threatening and therefore terroristic – if a soldier can be arrested for two stray 9-mm rounds in his first aid bag, just sixty miles away, and if a grade-schooler can be detained and interrogated for three hours without her parents because she had a Little Pony bubble-gun. This man belongs in prison and not in the House of Delegates.
Stupid people
Ob-gyn journal urges mandatory screening of women for abuse
(CNSNews.com) This power-trip behavior by men, according to the Feb. 2013 issue of Obstetrics and Gynecology, includes explicit attempts to impregnate a partner against her will or force her to have sex against her will; control the outcome of a pregnancy by forcing its continuation or abortion; and sabotaging birth control methods by "hiding, withholding, or destroying a partner's oral contraceptives; breaking or poking holes in a condom on purpose or removing a condom during sex in an attempt to promote pregnancy; not withdrawing when that was the agreed upon method of contraception; and removing vaginal rings, contraceptive patches, or intrauterine devices."
Nathan: Funny, eh? At the same time as ONE batch of idiots claims that women are fully capable of ground combat: as tankers, infantry, and field artillery, another group says that they are so weak and require so much protection that special procedures must be created for medical services to protect them from their "partners." Frankly, most men immorally interested only in "getting a piece" are the MOST worried about their "female partner" getting knocked up, NOT "trying to promote pregnancy." This strange twisting of worldview into some sort of frantic action fantasy shows the psychology of this society and the "medical profession" as it decays into nothing but a government bureaucracy dedicated to maintaining a political clientele and power.
The "messiah's" minions – Nazgul
Court: White House NLRB Appointments Violated Constitution
(CNSNews) On Jan. 4, 2012, Obama unilaterally named three people to the National Labor Relations Board (NRLB). The Senate—by a unanimous agreement of all 100 senators—had said that it was in fact still in session that day and not in the recess. — Yet despite the Senate's unanimous declaration that it was in session, Obama unilaterally determined the Senate was in fact in "recess" on Jan. 4, 2012 and that he could therefore use the Constitution's recess appointment power to directly appoint his three choices to the five-member National Labor Relations Board, thus denying the Senate its constitutional power to confirm or reject them. —Obama's action was challenged in federal court by Noel Canning, a Pepsi distributor. The company argued that when the NRLB ruled against it in a dispute decided in February 2012, the board did not have its legally-required quorum of three members because Obama's three recess appointments were not constitutional.
Nathan: It seems to me, as an outside observer, that this man willfully and intentionally violated the Constitution, broke the law of the land, and in addition, was incredibly disrespectful of Congress. It would, to me, appear that we have an impeachable offense and that the President of the Senate (also known as the Vice President) should have this man arrested and stripped of all powers while the House approves a bill of impeachment and sends it to the Senate, which should be able to speedily find him guilty and remove him from office, since at least two-thirds of those currently in that body were there when he tried this smarmy little lawyer's trick of his.
Mama's Note: Leaving Biden on the throne, of course. That might get very interesting, as all of the big city "mayors" and other heavyweights jockeyed to push him around.
Home front – Stupid people – Politics 2013
Three strategies to block gerrymandering of Electoral College
(The Nation, by John Nichols) "As Republican National Committee chairman Reince Priebus promotes one of the most blatant assaults on democracy in modern times — a scheme to gerrymander the Electoral College so that the loser of the popular vote could win key states and the presidency — the number-one question from frustrated citizens is: What can we do about it? After so many assaults on voting rights and the electoral process itself have been advanced, it is easy to imagine that Priebus, Karl Rove and their team could get away even with so audacious an initiative as the rigging of presidential elections. Priebus is counting on precisely that cynicism, as well as the neglect of the story by major media, to enable the plan to have Republican legislatures and governors in key swing states (Florida, Michigan, Ohio, Pennsylvania, Virginia and Wisconsin) arrange for the distribution of electoral votes not to winners of the popular vote statewide but to the winners of individual congressional districts.
Nathan: This is a commentary, but it is news and about news. The reason I'm including this is because the hypocrisy of the Democrats is worse than ever in this. Nebraska is the only state that currently has such a system, and the Democrats have praised it over and over again as a wonderful example of getting around that nasty Electoral College. Now that the GOP has found this idea, it is suddenly evil – stealing our votes. Garbage. I believe the entire idea is wrong; it destroys one more vestige of the dead Republic. (Indeed, I think not only should a presidential candidate get a majority – not just a plurality – of electoral votes, but should also carry a supermajority of states: three-quarters. If none does, ALL the candidates should be disqualified and the election done over again. but that is dreaming.) Why cannot people see through the lies and hypocrisy of BOTH old parties?
Whitewashing the past – Bogus heroes (or Stupid people)
Note to a childhood hero
(The Libertarian Enterprise by AX Perez) "Dear Dr. King, Thought I'd let you know how things have gone in the 44, nearly 45 years since you've passed. The good news is that state supported racism is a thing of the past in the United States. I would also like to inform you that your example inspired other people to make a stand and peacefully seek respect for their rights. … The bad news is that the bureaucrats have seized control of the enforcement of the laws enforcing what you accomplished. Instead of being judge by the content of one's character or achievement, one must prove they are of the correct race and gender to meet quota, then they may compete based on ability, assuming someone doesn't decide to come up with another politically determined criteria." (01/21/13)
Nathan: This is a real disappointment, coming from one of TLE's stable of writers especially. ANY Libertarian who believes that Martin Luther King Jr. was a lover of freedom or liberty, or anything OTHER than a communist, is so incredibly blinded – if not just plain STUPID – that they should not be allowed to write for ANY "libertarian" publication and should be publicly branded as a dangerous hypocrite. King's efforts led DIRECTLY to this result that Perez so decries, as they were intended to do. His writings make this clear; those who knew him who are not trying to establish his deity, know it. He was a dangerous man and as much a danger to the nation then as his "disciples" are today. And besides, "state-supported racism" is NOT gone from the United States: it has just changed from racism against minority blacks to racism against majorities (Anglos) and other minorities (AmerInd, Asian-origin, etc.). The state is still evil, just in another way – and just as King wanted it. To give Perez the benefit of the doubt, MLK was a "childhood hero" – time to put away childish things however, and it is childish and naive to think that MLK is a hero or a supporter of liberty.
Self-defense – Stupid people
Great-Grandmother Fires at Thug 11 Times After Brazen Mid-Morning Robbery in Detroit
(The Blaze.com)
Mama's Note: How in the devil did she get a "permit" in Detroit? And she obviously needs some serious training and range time. Eleven shots and she has no idea where they went? YIKES.. Thank goodness nobody innocent was hurt – though if her characterization of her fellow passengers is accurate… maybe they should be.
Nathan: As the story says, this is no advertisement to visit Detroit. The good guys are as dangerous as the villains! Of course, the kid that tried to rob her was incredibly stupid to try, just looking at her. And her actions are also – very stupid indeed.


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Elevcon: Announcement and call for papers
The 23rd Congress of the International Association of Elevator Engineers (IAEE) is from 16 to 18 June 2020 in Prague, Czech Republic.
The Elevcon congress and exhibition of industry innovations are planned for three days at Grandior Hotel Prague, a hotel situated in the city center of Prague. Since 1986 the Elevcon congress takes place every two years in Europe.
"We plan an outstanding programme of presentations by leading experts from all over the world within the vertical transportation industry and we hope you will contribute to the success of the congress, either by presenting a paper or simply by your participation", writes Ami Lustig, IAEE President and President and Elevcon 2020 Chairman & Programme Manager: "You are cordially invited to share your experience, knowledge, and opinions with your professional colleagues by presenting a paper at the upcoming Elevcon 2020."
Guidelines will be provided
The abstract of an original paper on all topics relevant to vertical transportation technologies should be no longer than 100 words, with 10 words title, classification of the topic, authors' name(s), company, address, email and phone numbers. Proposals for workshops are welcomed as well. Workshops should discuss topics that involve the audience rather than being mini-sessions.
The official language of Elevcon 2020 will be English and will be used in all presentations and printed material. Once the abstract is accepted, guidelines for paper preparation and further information will be provided. The written papers will be included in the Elevator Technology 23 book, proceedings of Elevcon 2020.


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|Oracle FAQ
|Your Portal to the Oracle Knowledge Grid
Home -> Community -> Mailing Lists -> Oracle-L -> Re: Oracle view riddle I am being asked , help me out here.
Run autotrace or sql_trace and determine if the execution plans are different. If they are the same, increase the sql_trace level and find out what the wait events are.
-- Daniel W. Fink http://www.optimaldba.com IOUG-A Live! April 27 - May 1, 2003 Orlando, FL Sunday, April 27 8:30am - 4:30pm - Problem Solving with Oracle 9i SQL Thursday, May 1 1:00pm - 2:00pm - Automatic Undo Internals Ehresmann, David wrote:Received on Wed Apr 02 2003 - 13:13:46 CST
>So why would the sql statement used to create a view run faster
>(significantly) than selecting from that view built with the same sql
>David Ehresmann
-- Please see the official ORACLE-L FAQ: http://www.orafaq.net -- Author: Daniel W. Fink INET: optimaldba_at_yahoo.com Fat City Network Services -- 858-538-5051 http://www.fatcity.com San Diego, California -- Mailing list and web hosting services --------------------------------------------------------------------- To REMOVE yourself from this mailing list, send an E-Mail message to: ListGuru_at_fatcity.com (note EXACT spelling of 'ListGuru') and in the message BODY, include a line containing: UNSUB ORACLE-L (or the name of mailing list you want to be removed from). You may also send the HELP command for other information (like subscribing).
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Ages: 6-15 years (16+ years eligible to volunteer. See volunteer link below for more information). Students need to be 6 BEFORE camp begins. Proof of age required.
Dates: July 9th-August 1st, 2019 (Tuesdays, Wednesdays, Thursdays only)
Time: 10:00am-3:30pm
Cost: Registration is $25 per student for the month of July. Includes camp T-Shirt, class supplies and meals.
Meals: Registration includes lunch and a light snack.
Subjects: Students will engage what we loosely like to call "creative art" subjects taught by various instructors. This year's subjects include storytelling through art, bible, poetry/percussion/songwriting and more!
Scholarships: Please email email@example.com if your student is in need of a scholarship to cover the cost of camp registration.


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Training & Placement
EFFORTS is offering job-oriented Short term Programs along with 100% placement. Short term courses in the following areas of expertise
Besides the regular training by our Expert Qualified Faculty, we send the students for compulsory Industrial Training for a period of 12 weeks to different STAR category hotels, some are listed under.
Every candidate gets an Industrial training exposure of 12 weeks. This training aims at giving them the understanding of how the industry works and what can they expect. Some of the hotels with whom we are empanelled are as follows:
The establishment promotes an overall development of the personality of its candidates through Seminars, Workshops and Guest Faculty lectures from various Hotels and Institutes all over the country.
After the successful completion of the course students of EFFORTS are ready to take the Hospitality and Tourism Industry head on and are guided and assisted to get placed immediately after the finishing of the course. Students will get placements in leading Star Hotels, Resorts, Tourism Sector, Travel Agencies, Air Ticketing Agencies, Airlines, and Call Centers etc. The students are trained enough to apply their professional skills to be self-reliant and even start their own ventures.


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14 thoughts on "Admin Section"
Hey All of WLBW,
Welcome to the wonderful new website that DJ Johnny has put together for us. His hard work and sleepless nights putting all this together is inspirational. Thanks Johnny site looks great. Well Done from the team at WLBW.
Thanks Suzy!
We finally got there after some delays
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The lack of sober mind and reasonable judgment may be one more symptom. Except for the various physiological discomforts, the patients are disturbed by the regular mental problems. As a rule, people with Down syndrome are joyful, excited by the world around, always willing to party, and seem restless; there are episodes in their lives when the mood can change to the opposite. Each time these patients face a dilemma or the need to make a weighted decision, they simply get lost and turn nervous.
The patients with Down syndrome are slow learners. It is difficult for them to demonstrate research skills, critical thinking, or valuable analysis as they lack judgment and sober mind. In separate cases, the patients manage to cope with these problems and educate more or less effectively. The symptoms of slow learning include delayed speech or time-consuming motor development.


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|"Mark Grover (JIRA)" <j...@apache.org>
|[jira] [Commented] (SENTRY-131) bin/sentry script doesn't find config-tool.sh under some circumstances
|Wed, 05 Mar 2014 22:32:52 GMT
[ https://issues.apache.org/jira/browse/SENTRY-131?page=com.atlassian.jira.plugin.system.issuetabpanels:comment-tabpanel&focusedCommentId=13921537#comment-13921537 ] Mark Grover commented on SENTRY-131: ------------------------------------ Seems unrelated. Can someone please verify? > bin/sentry script doesn't find config-tool.sh under some circumstances > ---------------------------------------------------------------------- > > Key: SENTRY-131 > URL: https://issues.apache.org/jira/browse/SENTRY-131 > Project: Sentry > Issue Type: Bug > Affects Versions: 1.2.0 > Reporter: Mark Grover > Assignee: Mark Grover > Fix For: 1.3.0 > > Attachments: SENTRY-131.1.patch > > > The sentry binary script makes an assumption that the config-tool.sh script is under SENTRY_HOME/bin/ which in turn assumes that the sentry jars are under SENTRY_HOME/lib. > This is not a fair assumption in my opinion because the binary scripts and jars don't have to be under the same top level directory. I think a better way to do this would be to to have SENTRY_HOME/lib point to where the jars are, but don't assume that config-tool.sh is under SENTRY_HOME/bin. We can look for config-tool.sh in the same directory that the sentry script is present in, since they always are/should be. -- This message was sent by Atlassian JIRA (v6.2#6252)
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This decision came as a beacon light of hope to millions of disinherited people. This problem of poverty is not only seen in the class division between the highly developed industrial nations and the so-called underdeveloped nations; it is seen in the great economic gaps within the rich nations themselves.
It came as a bright interlude in the long and sometimes turbulent struggle for civil rights: Jose Bogolasky Memorial Prize in International Air Law awarded on the recommendation of the Institute of Air and Space Law to the student or students in the Masters or Diploma program in the Institute of Air and Space Law achieving the highest standing in public international air law.
The New Abolitionists Boston: It seeks to secure moral ends through moral means.
Property Law Prize awarded to a graduating student who achieves high standing in the Law of Property throughout the program. She holds the James A. The movement does not seek to liberate Negroes at the expense of the humiliation and enslavement of whites. This resignation, Hardy explains, was completely voluntary and was not the result of another altercation.
Give as a gift Publisher's Summary What ever happened to good government? Prizes and scholarships for post-graduate studies Use our online web form to apply for one of these post-graduate scholarships.
The important thing to remember is that this is your map: Google Maps in the Classroom GoogleMaps is not simply a tool to direct you to your favorite restaurant. Most importantly, this project allows students the opportunity to produce a multimedia project in order to contemplate the concepts of audience, style, and structure.
Yet, at least one-fifth of our fellow citizens — some ten million families, comprising about forty million individuals — are bound to a miserable culture of poverty.
They had known each other sinceand Edith had taught English at Bryn Mawr College near Philadelphia, sharing a house for 20 years with Russell's old friend Lucy Donnelly. In the final analysis, the rich must not ignore the poor because both rich and poor are tied in a single garment of destiny. Price rite providence application essay an essay of dramatic poesy pdf editor jochen lawrenz dissertation help.
Just thirty years ago there were only three independent nations in the whole of Africa. Here was the Point of View that made me look at what I did not want to see.
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Herschorn Prize Discretionary Prize awarded to the highest ranking graduating student who intends to enter the Notarial Profession.Biography of Nobel Prize Winner, William Butler Yeats. Biography of Nobel Prize Winner, William Butler Yeats William Butler Yeats was not just an extremely well-known Nobel Prize winning author, he was a very influential Irishman in the political and social fields of the time.
This arrived in my inbox yesterday from the John Button Foundation. Lowy Institute's executive director, Michael Wesley, and visiting fellow, Hugh White, are both on the shortlist of this year's $20, John Button Prize for writing on public policy and ideas for Australia's future.
His philosophical essay "On Denoting" has been considered a "paradigm of philosophy". Russell was awarded the Nobel Prize in Literature "in recognition of his varied and significant writings in which he champions humanitarian ideals and freedom of thought".
John Slater. Bertrand Russell, Bristol: Thoemmes Press, John Glover Roberts Jr. (born January 27, ) is an American lawyer serving as the 17th and current Chief Justice of the United States since He was nominated by President George W.
Bush after the death of Chief Justice William Rehnquist and has been described as having a conservative judicial philosophy in his jurisprudence. In a remote corner of El Salvador, investigators uncovered the remains of a horrible crime — a crime that Washington had long denied.
The villagers of El Mozote had the misfortune to find themselves in the path of the Salvadoran Army's. tom howard/john h. reid fiction and essay contest Welcome to the 27th annual Tom Howard/John H.
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Adoption Literature for Children and Young Adults: An Annotated Bibliography
Book Description
This extensive annotated bibliography covers the literature published since 1900 suitable for children and young adults dealing in some fashion with adoption. The 503 titles annotated in this volume are divided into fiction and nonfiction by reading level. A comprehensive subject, as well as title and author index, assures access to the books cited within the bibliography. Although most ... More
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About Susan G. Miles (Author) : Susan G. Miles is a published author. Published credits of Susan G. Miles include Adoption Literature for Children and Young Adults: An Annotated Bibliography (Bibliographies and Indexes in Sociology)... more
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South London Club Card holders receive 15% off tickets. Raastawala is a pop-up Indian street food experience in South East London.
South London Club Discount: 10% off food Located at the end of Creekside and on the borders of Greenwich and Deptford, The Birds Nest is a hub of artists and musicians.
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