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Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)–driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood–brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven medulloblastoma. Cancer Res; 75(1); 134–46. ©2014 AACR.
Medulloblastoma, the most common malignant brain tumor in childhood, has a high tendency to disseminate through the cerebrospinal fluid to the brain and the spinal cord leptomeninges. Dissemination is a known factor of poor survival and occurs in one third of the children at the time of diagnosis and in two thirds by the time of relapse. Affected children are treated with craniospinal radiation and high-dose chemotherapy but the majority of survivors suffer from severe neurocognitive deficits induced by the deleterious effects of treatment on the developing nervous system (1). The discovery of novel and less toxic therapies has been hampered by the poor understanding of the mechanisms of dissemination, and by the failure to account for the genetic divergence between metastatic lesions and their matched primary tumor. Recent studies have shed light into the candidate genes that drive leptomeningeal dissemination in medulloblastoma (2, 3), but therapies that target both the primary and the metastatic compartment have not been identified.
The hepatocyte growth factor (HGF)/cMET pathway is essential for cell proliferation and migration during embryogenesis (4) and, in the central nervous system, it plays a critical role in cerebellar development (5). Aberrant cMET signaling is known to be involved in tumor growth and metastatic behavior of several human cancers (6, 7). The transmembrane receptor cMET is activated through phosphorylation of tyrosine residues upon binding of its ligand HGF, which triggers multiple downstream effector cascades including MAPK and PI3K/AKT that function in various cellular processes including cell proliferation, cell survival, migration, and invasion (8). In medulloblastoma, cMET activation is associated with tumor growth and anaplastic histology (9). cMET signaling is deregulated in medulloblastoma through multiple, independent molecular mechanisms including epigenetic silencing of an upstream inhibitor, the serine protease inhibitor Kunitz-type 2 (SPINT2; refs. 10, 11). Previous studies have shown that cMET inhibition can effectively decrease medulloblastoma cell migration and invasion (12).
Foretinib is an orally available multikinase inhibitor that targets cMET with high affinity (IC50 = 0.4 nmol/L; ref. 13). Foretinib has demonstrated antitumor activity in preclinical models of different tumor types (14–16) and clinical trials are currently ongoing to determine its efficacy in various solid, non–central nervous system tumors (17, 18). To date, the ability of foretinib to penetrate the brain is unknown.
Foretinib also targets other tyrosine kinases with lower affinity, including the platelet-derived growth factor receptor beta (PDGFRβ) with an IC50 of 9.6 nmol/L. Interestingly, PDGFRβ is known to be overexpressed in metastatic medulloblastoma (19, 20), and targeting the receptor reduces proliferation and migration of medulloblastoma cell lines (21). Activation of PDGFRβ occurs through a similar mechanism to cMET receptor activation, in which ligand binding (PDGF-BB) induces receptor autophosphorylation and activates downstream signaling via MAPK and AKT (22).
Therefore, we sought to establish the subgroup-specific role of cMET and PDGFRβ in medulloblastoma, and to test the efficacy of foretinib to cross the blood–brain barrier and to target those pathways, both in the primary and in the metastatic compartments.
Materials and Methods
Tumor material and patient characteristics
All tissues and clinicopathologic information were serially collected in accordance with Institutional Review Boards from contributing institutions. Nucleic acid extractions were carried out as previously described (23).
Expression profiling and molecular subgrouping
Expression of candidate genes was assessed using the R2 software in independent gene expression cohorts (24–32). Expression of reported intermediates of MET signaling was visualized using heatmaps (7). Associations between gene expression and subgroup affiliation were evaluated using one-way ANOVA. P values < 0.05 were considered to be statistically significant.
Analysis of somatic copy-number alterations
Somatic copy-number alterations were assessed on the Affymetrix SNP 6.0 array platform in 1,239 cases. Raw copy-number estimates were obtained in dChip, followed by circular binary segmentation (CBS) in R as previously described (27).
Cell lines and animal models
Human medulloblastoma cell lines (Daoy, ONS76 and D425) were kindly provided by Dr. Annie Huang, Hospital for Sick Children, Toronto, Canada. All cell lines were authenticated and tested by PCR. Daoy-GFP/Luciferase cells were generated as described previously (33). Athymic nude mice were obtained from the Charles River Laboratory. Ptch+/−/SB11/T2Onc mice (2) were generously provided by Dr. Michael Taylor, Hospital for Sick Children, Toronto, Canada.
Cell culture assays for cMET and PDGFRβ signaling
Foretinib was purchased from Selleck Chemicals, dissolved in DMSO (Sigma), and stored at −20°C. Cells were serum starved for 24 hours in media with 0.1% (Daoy and ONS76) and 2% FBS (D425), pretreated with increasing concentrations of foretinib or 1% v/v DMSO for 2 hours, and stimulated with human recombinant HGF (20 ng/mL; Sigma-Aldrich) for 20 minutes or human PDGF-BB (20 ng/mL; Cell Signaling) for 10 minutes.
Migration and invasion assays
The protocols for migration and invasion assays were as described previously (34).
For the radial migration assays, medulloblastoma cells were seeded and allowed to migrate for 24 hours in starved media (0.1% FBS) containing HGF (50 ng/mL) or PDGF-BB (50 ng/mL), in the presence or absence of foretinib. The radius of the migrating cells was measured and compared with the initial radius using a Leica Fluorescent Stereoscope (2.5× magnification).
The invasion assays were performed using Matrigel Invasion Chambers (8 μm pore size; BD Biosciences). Daoy and ONS76 cells were incubated for 16 hours with starved media containing dilutions of foretinib. The number of cells per 6 random fields was determined (×10 magnification) using Volocity software (Perkin Elmer).
The following antibodies from Cell Signaling were used: cMET (1:1,000), phospho-cMET (1:1,000), PDGFRβ (1:500), phospho-PDGFRβ (1:500), AKT (1:1,000), phospho-AKT (1:2,000), p44/42 MAPK (1:1,000), phospho-p44/42 MAPK (1:2,000), PARP (1:1,000), β-actin (1:10,000), anti-rabbit IgG conjugated to horseradish peroxidase (1:5,000), and anti-mouse IgG conjugated to horseradish peroxidase (1:5,000). Western blot analysis and quantification were performed using the Fluorchem Q Imaging System (ProteinSimple).
Cell proliferation assays
Medulloblastoma cells were treated with different concentrations of foretinib or DMSO, and cell viability was determined for the indicated time points by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) absorbance at 490 nm (CellTiter 96 Aqueous One Solution Reagent; Promega).
Active caspase assays
The activity of caspases 3 and 7 was measured using the Apo-ONE Homogeneous Caspase-3/7 Assay (Promega) after 12 hours of incubation.
Foretinib pharmacokinetic studies
Detection and quantification of foretinib were performed using a high-performance LC/MS/MS method (Agilent 1290 HPLC Agilent Technologies/QTRAP 5500 AB SCIEX).
Images of foretinib distribution in various mouse organs were acquired using a matrix-assisted laser desorption/ionization (MALDI) time-of-flight tandem mass spectrometer (AB SCIEX TOF/TOF 5800 System; AB SCIEX).
Medulloblastoma xenografts and transgenic mouse models
All mouse studies were approved and performed in accordance to the policies and regulations of the Institutional Animal Care and Use Committee of the University of Toronto and the Hospital for Sick Children, in Toronto.
Mouse subcutaneous xenografts (Daoy and ONS76) were established in athymic nude mice (Charles River Laboratories). Intracranial xenografts of disseminated medulloblastoma were established by injecting Daoy cells into the fourth ventricle of athymic nude mice. Tumor growth and the presence of metastases were evaluated by weekly bioluminescence imaging using the IVIS Spectrum Optical In-vivo Imaging System (Caliper Life Sciences).
Osmotic pumps (Alzet; model 2004) were implanted in Ptch+/− mice with Sleeping Beauty (SB) transposition (Ptch+/−/SB11/T2Onc) at postnatal days 30 to 35. Pumps loaded with foretinib (6 mg/kg) infused the drug into the cerebrospinal fluid (right lateral ventricle) for 28 days at a rate of 0.25 μL/hour.
The protocol for immunohistochemistry was performed as previously described (35). The following antibodies were used: Ki-67 (1:1,000; Novus), cleaved caspase 3 (1:800; Cell Signaling), phospho-cMET (1:100; Cell Signaling), and phospho-PDGFRβ (1:200; Abcam).
Statistical analysis
Survival curves were generated using the Kaplan–Meier estimate and a log-rank test. The comparison between binary and categorical patient characteristics was performed using the two-sided Fisher exact test. To analyze contiguous variables, the Mann–Whitney U test was used.
Results from experiments were expressed as mean ± SEM. For multiple group comparisons, ANOVA was conducted followed by a post-Tukey test or a post-Dunnett test. Direct comparisons using an unpaired two-tailed Student t test were conducted where appropriate. Statistical analysis was performed using GraphPad Prism 5 Software. We considered a P value inferior to 0.05 as significant.
cMET and PDGFRβ are highly expressed in SHH medulloblastomas
We evaluated the expression of cMET and PDGFRβ in a discovery cohort of primary medulloblastomas from Boston (n = 199; ref. 26). cMET expression was highly upregulated in most SHH medulloblastomas and in a subset of group 3 tumors (Fig. 1A). PDGFRβ was expressed across all medulloblastoma subgroups, with higher levels of expression in SHH tumors (Fig. 1B). We confirmed our results using a multicenter validation cohort of 439 cases profiled on the Affymetrix 133plus 2.0 arrays obtained from the German Cancer Research Centre, Heidelberg (validation cohort; refs. 24, 25, 31, 32, M. Kool and S.M Pfister, unpublished data; Fig. 1C and D).
To identify molecular markers of cMET pathway activation in SHH medulloblastomas, we interrogated three independent datasets using a group of genes known to activate cMET signaling (7, 8). In addition to cMET, GAB1 expression was highly and specifically upregulated in SHH-driven medulloblastomas, across the three nonoverlapping cohorts, when compared with normal cerebellum and with non-SHH medulloblastomas (Fig. 1E–J).
To investigate possible mechanisms leading to cMET and PDGFRβ overexpression, we examined the subgroup-specific copy number aberrations (CNA) encompassing the MET loci (7q31.2) and the PDGFRβ loci (5q31), in a large cohort of 1,239 medulloblastomas (27). There were no focal gains or amplifications of cMET (Supplementary Fig. S1A) and very infrequent copy-number gains affecting the PDGFRβ loci (Supplementary Fig. S1B).
Identification of biologic pathways and processes associated with high cMET and low cMET SHH medulloblastomas
We performed gene set enrichment analysis between tumors with the highest (n = 13) and the lowest (n = 13) cMET expression across a series of 51 primary SHH medulloblastomas (27). Gene sets were compiled from Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), the National Cancer Institute (NCI), Protein Families (PFAM), and Biocarta pathway databases. To visualize significant gene sets (FDR < 0.25; P < 0.01) as interaction networks, we used Cytoscape and Enrichment Map (Supplementary Fig. S2). High cMET SHH medulloblastomas were characterized by gene sets involved in organ development and morphogenesis, cell migration, cell cycle and DNA repair, T-cell differentiation, transcription, and mitochondrial function. Low cMET SHH medulloblastomas were defined by numerous networks including neural development, neurotransmission, amino acid and nucleotide metabolism, ribonucleotide biosynthesis, smooth muscle contraction, and Ras-GTPase activity.
High p-cMET levels correlate with recurrence and poorer survival in SHH medulloblastomas
We stained medulloblastoma tissue microarrays comprised of an independent cohort of 385 patients for the activated cMET receptor or phosphorylated cMET (p-cMET). Eighty percent (104/128) of SHH tumors and approximately 25% (16/62) of group 3 tumors showed high p-cMET staining (Fig. 2A). High p-cMET was associated with older age at diagnosis (Supplementary Fig. S3A and S3B) and desmoplastic histology (Supplementary Fig. S3C and S3D), most likely due to a subgroup-specific enrichment with SHH patients. There was a significant correlation between high p-cMET and an increased 5-year rate of recurrence across all subgroups of pediatric medulloblastomas (P = 0.041; Fig. 2B) and, particularly, across pediatric SHH tumors (P = 0.011; Fig. 2C). There was no association of p-cMET expression and the presence of metastases or TP53 mutational status in SHH tumors (Supplementary Fig. S3E and S3F).
High p-cMET expression in SHH tumors was associated with a significantly shorter progression-free survival (P = 0.007; Fig. 2D), particularly in the pediatric cohort (P = 0.002; Fig. 2E). A trend toward a worse overall survival was also observed in these patients (Fig. 2F and G). Interestingly, considering the metastatic status within SHH medulloblastomas, the prognostic impact of high p-cMET expression was still observed. High p-cMET correlated (P = 0.022) with a poor outcome in nonmetastatic SHH patients (Fig. 2H and Supplementary Fig. S4A). A trend toward a worse survival was observed in patients with high p-cMET and leptomeningeal dissemination at diagnosis (Fig. 2I and Supplementary Fig. S4B). In the pediatric cohort, high p-cMET was correlated (P = 0.014) with a poor progression-free survival (Supplementary Fig. S4C and S4D). Survival differences could not be determined in adult patients with SHH medulloblastoma according to p-cMET status (Supplementary Fig. S4E and S4F). In group 3 medulloblastomas, expression of p-cMET had no prognostic relevance and did not correlate with metastatic status.
Thus, we conclude that activated cMET defines distinct prognostic patient cohorts with higher recurrence rate and poorer prognosis in SHH subgroup of medulloblastomas.
Foretinib inhibits cMET and PDGFRβ pathway activity
On the basis of the elevated expression levels of cMET and PDGFRβ in SHH and group 3 medulloblastomas, we sought to evaluate the antitumoral effect of foretinib against medulloblastoma cell lines representative of these two subgroups. Daoy, ONS76, and D425 cells have transcriptional and cytogenetic features that suggest they are originally derived from SHH (Daoy and ONS76) and group 3 (D425) tumors (36). Furthermore, they express different levels of the tyrosine kinase receptors cMET and PDGFRβ (Supplementary Fig. S5A). First, we evaluated the ability of foretinib to inhibit the cMET and the PDGFRβ pathway activity in the context of HGF or PDGF-BB stimulation. Foretinib potently inhibited the HGF-induced cMET pathway activation, as evidenced by the suppression in cMET phosphorylation and also by the decrease in the phosphorylation of downstream effectors AKT and MAPK (Fig. 3A and B). The inhibitory effect of foretinib in PDGF-BB–induced PDGFRβ pathway activation was moderate (Supplementary Fig. S5B and S5C). Furthermore, a significant antiproliferative effect (Fig. 3C; Supplementary Fig. S6A and S6B) and an induction of apoptosis (Fig. 3D and E; Supplementary Fig. S6C and S6D) were observed in foretinib-treated medulloblastoma cells. Foretinib potently inhibited HGF-mediated migration (Fig. 3F and G; Supplementary Fig. S6E and S6F) and invasion (Fig. 3H and Supplementary Fig. S6G) of Daoy and ONS76 cells for all drug concentrations. In contrast, a significant reduction in migration and invasion mediated by PDGF-BB was only seen with 2.5 μmol/L of foretinib (Supplementary Fig. S6H and S6I).
We then assessed if cMET receptor knockdown by stable shRNA expression would phenocopy the functional effects of foretinib treatment. cMET shRNA 2 was able to knockdown over 70% of cMET expression in both Daoy (Fig. 3I) and ONS76 (Supplementary Fig. S6J). A significant antiproliferative effect was observed in both medulloblastoma cells (Fig. 3J and Supplementary Fig. S6K) stably expressing cMET shRNA compared with nonsilencing control cells. Furthermore, a significant inhibition of HGF-mediated invasion was observed (Fig. 3K and Supplementary Fig. S6L). Interestingly, the relative inhibition of invasion in cMET shRNA expressing Daoy cells mimics the treatment of Daoy cells with 500 nmol/L to 1 μmol/L of foretinib (Fig. 3H)
Collectively, these results suggest that foretinib exhibits a significant in vitro inhibitory activity in medulloblastoma cells, mainly through blockade of the cMET pathway.
Foretinib induces medulloblastoma regression in vivo
We sought to investigate the antitumor activity of foretinib in vivo using subcutaneous xenograft models of SHH medulloblastoma. Daoy and ONS76 cells were implanted in the flank of nude mice, and animals with established tumors were treated by oral gavage with vehicle (DMSO) or foretinib (60 and 100 mg/kg), once every other day for 9 days. Therapy with foretinib significantly induced tumor regression at all drug concentrations administered. At the end of treatment, tumor volumes were reduced by 37% and 46% with 60 and 100 mg/kg of foretinib, respectively, in Daoy xenografts (Fig. 4A and B) and by 50% in ONS76 xenografts (Supplementary Fig. S7A and S7B). Foretinib was well tolerated as mice body weights were maintained during the treatment period for all cohorts (Fig. 4C and Supplementary Fig. S7C).
Medulloblastoma tumor growth inhibition in mice treated with foretinib was associated with concomitant reduction in cMET and PDGFRβ pathway activity (Fig. 4D and Supplementary Fig. S7D). Foretinib treatment resulted in a potent inhibition of cMET phosphorylation in all cohorts (Fig. 4E and Supplementary Fig. S7E) and a moderate reduction in PDGFRβ activation (Fig. 4F). Tumors treated with foretinib also displayed significant dose-dependent decrease in cell proliferation (Fig. 4G and Supplementary Fig. S7F), and increase in apoptosis (Fig. 4H and Supplementary Fig. S7G).
These studies demonstrate that foretinib has a significant in vivo antitumor effect in medulloblastoma allografts, through a potent suppression of the cMET pathway activity and a moderate inhibition of PDGFRβ signaling.
Characterization of foretinib pharmacokinetics and brain permeability
To further evaluate the potential clinical relevance of foretinib in brain tumor treatment, we assessed the pharmacokinetics of the drug and its ability to penetrate into the brain. Nude mice were treated by oral gavage with 30, 60, and 100 mg/kg of foretinib, and blood and the perfused brains were harvested at specific time points. Foretinib was detected in samples from treated animals using high-performance LC/MS/MS. Maximum concentrations of foretinib in the plasma and in the brain of mice occurred 5 hours after oral administration with no difference between dose levels (Fig. 5A and B). The same pharmacokinetic features were previously reported in a phase I clinical trial of foretinib in adult patients with advanced solid tumors outside the central nervous system (17). Furthermore, after 5 consecutive days of treatment with 60 mg/kg of oral foretinib, the penetration of the drug in the brain was approximately 14% (Supplementary Table S1).
We then assessed the distribution of foretinib in different mouse organs using matrix-assisted laser desorption/ionization with time-of-flight mass spectrometer (MALDI-TOF) imaging. Foretinib produces a strong signal (Fig. 5C and D) and five hours after oral administration, when it reaches the maximum plasma concentration, the drug is seen in the liver and also in the renal cortex (Fig. 5E). The concentration of foretinib in the brain after oral gavage was below the threshold detection of MALDI-TOF imaging.
To explore the potential use of foretinib for intrathecal therapy in neuro-oncology, we used osmotic pumps to deliver the drug into the lateral ventricles of mice. After injection of 6 mg/kg of foretinib for 28 days at a rate of 0.25 μL/hour, the drug was distributed through the cerebrospinal fluid to the supra- and infratentorial compartments (Fig. 5F; ref. 37). Foretinib was detected by MALDI-TOF imaging in the right frontal lobe of mice due to its very high concentration at the drug delivery site (Fig. 5G). The drug was well tolerated and the mice did not display any signs of central nervous system toxicity.
Collectively, these studies demonstrate for the first time, to our knowledge, that foretinib crosses the blood–brain barrier and can be safely administered as intrathecal therapy.
Foretinib reduces SHH medulloblastoma growth and dissemination in mouse xenografts
Having established that foretinib can effectively be delivered in the brain, we investigated its efficacy in mouse models of disseminated medulloblastoma. Daoy cells expressing luciferase were orthotopically implanted into the fourth ventricle of nude mice. Animals with a detectable signal by bioluminescence at 3 days after inoculation were treated by oral gavage either with vehicle (DMSO) or 60 mg/kg of foretinib once daily, 6 days a week, for 2 weeks. The weekly evaluation of tumor growth and dissemination by bioluminescence showed a significant reduction in tumor size and metastases in the animals treated with foretinib (Fig. 6A and B), as confirmed by the smaller increase in the total photon flux from luciferase expressing Daoy xenografts (Fig. 6C). Histologic examination [hematoxylin and eosin (H&E) stain] of brains and spinal cords of animals in the control group showed a higher number of metastases in the ventricles and leptomeningeal spaces, as well as surrounding the spinal cord and the nerve roots, when compared with foretinib-treated animals (Fig. 6D and E).
These results demonstrate that foretinib is effective in reducing tumor growth and treating established medulloblastoma metastases in orthotopic mouse models of disseminated medulloblastoma.
Foretinib is effective against the primary and the metastatic compartments in a transgenic model of metastatic SHH medulloblastoma
We then tested the efficacy of foretinib in a recently published metastatic mouse model of SHH medulloblastoma (2). The authors used the SB transposon system where random insertion events in the cerebellar progenitor cells of Ptch+/− mice induce a very aggressive form of medulloblastoma with high incidence of leptomeningeal dissemination by 10 weeks of age (2). SB medulloblastomas express high levels of cMET, HGF, and other cMET pathway activators (Fig. 7A and B). We asked whether early and continuous treatment with foretinib could prevent the formation of metastases and improve survival in this mouse model. Osmotic pumps loaded with 6 mg/kg of foretinib or vehicle (10% cremophor) were implanted in 4 to 5 weeks old mice and delivered the drug for 28 days, at a rate of 0.25 μL/hour. Strikingly, foretinib-treated animals showed a significant increase in survival (Fig. 7C) and displayed medulloblastomas in the cerebellum with a less invasive phenotype when compared with controls (Fig. 7D and E). Moreover, treatment with foretinib reduced the incidence of metastases by 36% (Fig. 7F) and effectively blocked cMET activation (Fig. 7G and H). Mice tolerated intrathecal administration of foretinib, although 4 animals presented with intratumoral hemorrhage in the cerebellum (2 animals in the vehicle control group and 2 animals in the foretinib-treated group).
Taken together, these results demonstrate that foretinib is effective both against the primary and the metastatic compartments in medulloblastoma, by reducing primary tumor invasion and preventing leptomeningeal dissemination in an aggressive mouse model of metastatic SHH medulloblastoma.
We show here that activation of cMET signaling is a hallmark feature of SHH medulloblastomas and correlates with poor outcome in pediatric patients. Targeting the cMET receptor with foretinib, a kinase inhibitor that crosses the blood–brain barrier, significantly reduces primary medulloblastoma growth and invasion, diminishes the incidence of metastases, and increases survival in disseminated mouse models of SHH medulloblastoma. Our study identifies for the first time a subgroup-specific targeted drug with promising efficacy against both medulloblastoma primary tumors and metastases.
We demonstrate that cMET is highly expressed in SHH medulloblastomas although the mechanisms leading to cMET up-regulation in this subgroup remain unclear. Of 332 medulloblastomas recently sequenced, there were no recurrent mutations or amplifications of the cMET gene (32, 38–40). These results suggest that the high expression of cMET is not driven by CNAs but may relate to the specific signaling events or cell of origin of the SHH subgroup. Interestingly, our previous finding that SPINT2, an inhibitor of cMET, is silenced by promoter methylation (10) and the recent publication that cMET is among the most significantly hypermethylated genes in group 4 tumors (41) suggest that cMET regulation in medulloblastomas may be driven by epigenetic factors.
Examination of molecular pathways characterizing SHH tumors with high and low cMET expression revealed distinct patterns of alteration. Although low cMET SHH medulloblastomas were associated with deregulation of biologic processes involved in neurogenesis and neurotransmission, high cMET SHH medulloblastomas were characterized by alterations in a number of cancer-related networks, namely cell migration, cell cycle, DNA repair, and transcription. The activation of distinct biologic pathways in high cMET SHH medulloblastomas supports the existence of a different cell of origin for these tumors, in keeping with a recent study that has shown that a specific population of Nestin-expressing neuronal progenitors in the cerebellum can give rise to SHH-driven medulloblastomas (42).
We identify a gene signature of cMET activators, including cMET and GAB1, unique to SHH-driven tumors. Our results are supported by a previous publication where immunoreactivity for GAB1 was reported to be a surrogate marker for SHH medulloblastomas (43). Furthermore, we demonstrate that the cMET pathway activation status can segregate patients with SHH medulloblastomas into distinct prognostic outcomes. In pediatric patients with SHH tumors, activation of cMET is correlated with an increased rate of relapse and a shorter progression-free survival. Notably, this association is not seen in adult SHH patients confirming the previously reported clinical and molecular distinction between adult and pediatric SHH medulloblastomas (44). Furthermore, p-cMET status does not correlate with the presence of metastases or TP53 mutations, two known markers of poor prognosis across medulloblastoma subgroups (45) and within the SHH subgroup (46), respectively. We show that a simple immunohistochemical analysis of activated cMET provides a high-quality clinical trial biomarker for identification of patients who could benefit from targeted therapy using cMET inhibitors.
Foretinib had dramatic therapeutic effect in SHH medulloblastoma, both in vitro and in vivo. Furthermore, our pharmacokinetic studies demonstrate for the first time that foretinib penetrates the blood–brain barrier and is well tolerated and distributed through intrathecal administration. Foretinib reduces primary medulloblastoma growth and invasion, and has also a potent activity against medulloblastoma metastases. Administration of foretinib to an aggressive metastatic mouse model of SHH medulloblastoma increases survival by 45% and diminishes the incidence of metastases by 36%. These tumors express high levels of HGF, suggesting an autocrine signaling loop that maintains cMET pathway activation. Previous studies on glioblastoma have shown a correlation between HGF autocrine expression by tumor cells and an increased sensitivity to cMET inhibition, which may explain the efficacy of foretinib (47). Interestingly, we show that foretinib also decreases activation of AKT, a downstream effector of both cMET and PDGFRβ signaling, and recently identified as a key contributor to leptomeningeal dissemination in medulloblastoma (2, 3). Therefore, the antimetastatic properties of foretinib may be related to its unique ability to target three key drivers in medulloblastoma dissemination, namely cMET, PDGFRβ and indirectly, PI3K.
Given the high expression of cMET in SHH-driven medulloblastomas, the therapeutic regimen that may offer maximum benefit in this subset of patients is the combination of foretinib with an antagonist of SHH signaling. A significant antitumor effect was reported in a patient with metastatic medulloblastoma after inhibition of smoothened (SMO), a critical component of SHH pathway, although the response was transient due to the emergence of acquired resistance (48). Thus, we anticipate that combining foretinib with a SMO inhibitor may have a synergistic and an antiresistance effect treating cMET-dependent SHH medulloblastomas.
In summary, we show that the drug foretinib is effective treatment in preclinical murine models of metastatic SHH medulloblastoma. Given the dismal outcome and lack of options for these patients, our results provide strong rationale for repurposing foretinib as a targeted agent in SHH-driven medulloblastoma.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: C.C. Faria, B.J. Golbourn, A.M. Dubuc, C.A. Smith, M.D. Taylor, J.T. Rutka
Development of methodology: C.C. Faria, B.J. Golbourn, R.J. Diaz, M. Leadley, D. Reynaud, L. Ermini, M. Post, C.A. Smith, J.T. Rutka
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C.C. Faria, M. Remke, A. Luck, N. Sabha, X. Wu, L. Garzia, X. Wang, M. Leadley, D. Reynaud, L. Ermini, M. Post, S.M. Pfister, S.E. Croul, A. Korshunov, M.D. Taylor
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): C.C. Faria, A.M. Dubuc, M. Remke, S. Agnihotri, S. Olsen, V. Ramaswamy, S.C. Mack, X. Wang, M. Leadley, S.M. Pfister, M. Kool, M.D. Taylor, J.T. Rutka
Writing, review, and/or revision of the manuscript: C.C. Faria, A.M. Dubuc, M. Remke, S. Agnihotri, S.C. Mack, X. Wang, M. Leadley, P.A. Northcott, S.M. Pfister, M. Kool, C.A. Smith, M.D. Taylor, J.T. Rutka
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.C. Faria, A. Luck, P.A. Northcott, C.A. Smith, J.T. Rutka
Study supervision: J.T. Rutka
Other (analytical method development and sample analysis—LC/MS/MS and MALDI-imaging): M. Leadley
Grant Support
C.C. Faria was supported by a fellowship from The Hospital for Sick Children Research Training Centre and the Garron Family Cancer Centre, and by the Programme for Advanced Medical Education, sponsored by Fundação Calouste Gulbenkian, Fundação Champalimaud, Ministério da Saúde e Fundação para a Ciência e Tecnologia, Portugal. This study was supported by the Canadian Cancer Society Research Institute (grant #2011-70051), the Pediatric Brain Tumor Foundation of the United States, the Brain Tumour Foundation of Canada, b.r.a.i.n.child, Meagan's Walk and the Wiley Fund at the Hospital for Sick Children. The CSCCD was supported by the Canadian Foundation for Innovation (CFI).
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.
Mass Spectrometry was performed at the Analytical Facility For Bioactive Molecules (AFBM). The AFBM is part of the Centre for the Study of Complex Childhood Diseases (CSCCD) at the Hospital for Sick Children, Toronto, Canada.
Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
- Received December 18, 2013.
- Revision received September 22, 2014.
- Accepted October 12, 2014.
- ©2014 American Association for Cancer Research.


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IDK if I already did a post on this movie, but every time I think of it, I bust out into hysterics. It's hilarious. I highly recommend watching this movie if you want to laugh!
Weekend at Bernie's
-Larry Wilson and Richard Parker are two young employees trying to make their way up in an insurance company. One is all about charm and the other is all about hard work. One day, Richard Parker comes across a serious financial error on a printout. He takes it to their boss Bernie Lomax. He feigns excitement and invites them to his beach house in the Hamptons for the weekend. His actual plan is to have them killed to keep them silent. But he has already made a mistake: he is fooling around with the girlfriend of his Mafia partner, which is a big no-no in the mob world. The Don has his hit man Paulie go and kill Bernie. When the two discover he's dead, they have to have everyone who comes to his house believing he's still alive
-Andrew McCarthy: Larry Wilson
-Jonathan Silverman: Richard Parker
-Catherine Mary Stewart: Gwen Saunders
-Terry Kiser: Bernie Lomax
-Don Calfa: Paulie
-Catherine Parks: Tina
-Louis Giambalvo: Vito
-Ted Kotcheff: Jack Parker, Richard's dad
-Eloise DeJoria: Tawny
-George Cheung: Gardener
Did You Know?
-When Andrew McCarthy originally read the script, he was reading for the part of Richard. He loved the part of Larry and went to that part instead
-Terry Kiser (Bernie Lomax)'s stunt man suffered a few broken ribs playing the dead man, including being around the surface of the lake
-When Richard knocks out the man Bernie fired, he tells Larry "You can come out now Rambo". The first movie, First Blood, was also directed by Ted Kotcheff. And George Cheung starred in First Blood: Rambo Pt. II, playing a Vietnamese soldier
I'm a girl born in the wrong decade. I belong in the 1960s or the 1970s in my opinion. I bleed tie dye, my theme music is anything 1960s rock or 1970s rock or metal. I'm a hippie through and through. But also a hippie who loves old metal music. I believe that violence never solves anything, so why resort to it to solve problems? With all the wars the world has seen, there should be a clue somewhere in there!
Friday, September 6, 2013
Weekend at Bernie's
Posted by HippieGirl at 4:26 AM
Labels: 1980s pop culture, actors/actresses, cars, comedy movies, funny moments, funny movies, funny people, funny stuff, jobs, laughing, Mafia movies, New York, random thoughts, totally random
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subset: commoncrawl


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Elisabeth Carniel
Institut Pasteur
Elisabeth Carniel (MD, PhD) is Professor at the Institut Pasteur in Paris. As head of the Yersinia Research Unit, she supervises a team working on bacterial evolution, pathogenesis and host-bacteria interactions. As Director of the National Reference Laboratory for plague and other yersiniosis, she is involved in public health and surveillance activities at the national level. She also has international activities, as Director of the WHO Collaborating Center of Reference and Research for Yersinia and as Scientific Advisor at the Institut Pasteur in Cote d'Ivoire.
Research Interest
bacterial evolution, pathogenesis and host-bacteria interactions


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This map features a small Christmas-themed amusement park. It includes multiple minigames, plenty of roller coasters and everything you might need to entertain yourself during the Christmas holidays. All of the creations are very compact and small but it's nonetheless a great theme park worth exploring.
Creator: ShadowBlader21
The spawn is on the parking lot of the amusement park.
You won't get enough of the roller coasters! There are several of them and they look like plenty of fun!
Santa's sleigh. Can you get up there?
Are you up for some miniature golf?
End your visit to the theme park by a duel of fight to the death. It's not exactly the best way to end the day but it's actually more fun than what it sounds dreary.


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If the title is a bit confusing to you, check out how I took a little meat hiatus to start off the year. It has been ten days since my whole-foods plant-based eating officially ended, but I am just now consistently incorporating lean proteins such as chicken and shrimp back into my diet. While I … Continue reading
Tagged with chicken …
Herbs the Word {Lemon Rosemary Red Pepper Chicken}
Rosemary may be my favorite herb. Perhaps I should qualify that with "to cook with" because I really love mint…for mojitos. Herbs make foods flavorful without fuss. I am not one for 'sauces' on my food, so herbs are they way I make good foods better. {Lemon Rosemary Red Pepper Chicken} 2 bone in chicken … Continue reading
More Soup {Green Chili Lime Chicken Soup}
I can't take credit for this yummy soup. I cooked it up with a girl friend this week in Amarillo using her aunt's recipe. Global warming has officially hit Texas when it is 81 degrees in December in the Panhandle. It gets cold at night, and we ate this soup outside under the heater. I … Continue reading
Rainy Day {Chicken Tortilla Soup}
{Chicken Tortilla Soup} 2 baked chicken breasts, shredded or chopped (skin-on adds flavor) 1 quart organic free range chicken broth 1 can tomato sauce 1 can diced tomatoes 1 can tomato paste 1 can sweet corn 1 bunch cilantro 1 clove garlic, chopped 1/3 purple onion, chopped 5-6 corn tortillas 3-4 cups water Spices to taste: … Continue reading


text: BLOOMINGTON, Ind. (AP) -- Indiana forward D.J. White will return for his senior year after leading the Hoosiers in scoring and rebounding last season. White, a second team All-Big Ten selection, averaged 13.8 points and 7.3 rebounds for an Indiana team that finished 21-11 and advanced to the second round of the NCAA tournament. "I believe it is in my best interest to return for my senior season," White said in a statement Tuesday. "I learned a lot from coach (Kelvin) Sampson and the rest of the coaching staff and really improved my game last year. I'm excited to take my game to another level." He will be joined next season by a strong recruiting class featuring guards Eric Gordon, Jordan Crawford and Jamarcus Ellis, forward Brandon McGee and centers DeAndre Thomas and Eli Holman.


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Lone Eagle Landing 8 is located on the Northwest side of Sunriver, in close proximity to the Sunriver marina, airport (with airport tie down) and Sunriver stables. You will be enchanted by the Northwest living meets Country decor that adorns this beautiful 5 bedroom, 4 bathroom Sunriver estate. Watch the game on the giant flat screen from the living room, dining room, kitchen or upper deck. Entertain friends and family in the formal dining area with Deschutes River and woodland views. Star gaze from your bubbling hot tub after an epic day on the slopes, or cuddle up with your sweetheart by the warm fire. This home has everything you need for a perfect Sunriver vacation.
The reverse living layout of Lone Eagle Landing 8 provides the kitchen, dining and living rooms upstairs with a wrap-around upper deck. The entire north side of the home is windows, allowing for a beautiful woodlands view of deer, hawks, elk and eagles (birders rejoice!!) as well as the mighty Deschutes River. Entertaining is fun and easy in the open floor plan that combines the upstairs common areas. There is a generously sized king master upstairs with a large shower and soaking tub en suite. Downstairs you will find another 2 beautifully designed queen master suites as well as two bedrooms that have a common bath one featuring one queen and one that has two twin beds.There is a TV in every bedroom as well!
Outside at Lone Eagle Landing 8 you will find a private hot tub and BBQ on the exterior deck. There is enough parking in the extra-large driveway for multiple family vehicles. Just down the street are Sunriver Stables, the marina and a restaurant right on the water. This home is located in a private part of the Sunriver community, allowing a repast from the rest of the resort, but still close to all of the amenities. This is a PERFECT home to host family reunions with the open floor plan and light and bright feel plus luxurious furnishings and amenities plus A/C!


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Huffington Post Premiere: http://bit.ly/2wo4tl6
Presented here is "Honeysuk," Washington D.C./Baltimore's Sunbathers' new release. FYI, the band's most recent track, a remix of their song "Intimacy" by Belgian melodic house act Curtis Alto, has received over 1 million views since its release in February.
According to Sunbathers' vocalist and synth player Sean Lynott...
"We've gone a long stretch since our last release, but we're excited to break the silence with 'Honeysuk.' The song has become a staple of our live show―an ecstatic moment during the set where the energy between band and audience hits its peak. With the help of Donny Ingram at Dreamcatcher Studio, we feel like we've done a great job of capturing the song's energy in the studio and are excited to have it on wax.
"We regrouped with Jorge Lucas and D.I.Y or DIE Productions—the team behind our 'Intimacy" video—who did a remarkable job of portraying the intertwined, albeit subtle disparity of the song. We think they've created a striking visual, and more importantly, a piece that speaks to the true nature of the song. We're looking forward to seeing how people interpret and react to the video."
The video's director, Jorge Lucas, adds...
"Following the release of Sunbathers' music video for 'Intimacy,' we felt emboldened to take the next video in a radical direction. Unlike 'Intimacy,' we knew we wanted 'Honeysuk' to be less narrative-based, shot in a controlled location, and to feature the band prominently. We first established a visual aesthetic and color palette that suited the song. During a hike one day, not long before the start of filming, the song inspired me to write a story about a man who grew a woman out of soil. This snow-balled into a Pygmalion-like fairytale with a violent conclusion. Thankfully, the band liked my unexpected twist on the lyrics, as I had done on 'Intimacy'. So we forged ahead to tackle toxic and abusive relationships in a story that empowers women to be the masters of their own fate. We filmed the bulk of the video in 13 long hours one day in May in a Brooklyn studio. Throw in some great visual effects from our friends at Third Beacon Studios, and we have a music video we're extremely proud to show the world!"
Leave a Reply.


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2 Bed 1 bath house, could be source of rental income or a starter home. Come and see what the possibilities could be with a little elbow grease!
From I-44 go North on HWY 97 to Stotts City, turn right on Division. Property on the left
A real estate transaction is a multi-faceted process with many moving parts. That's why we offer a wide array of services to help you through the process. Whether you're buying your first condo or selling your third home.
Results from this calculator are designed for comparative purposes only, and accuracy is not guaranteed.
The data relating to real estate for sale on this web page comes in part from the Internet Data Exchange (IDX) of the Southern Missouri Regional MLS, LLC , Inc. Real estate listings held by Brokerage firms other than Murney Associates, Realtors are marked with the IDX logo and detailed information about them includes the name of the listing Brokers. The information being provided is for consumers' personal, noncommercial use and may not be used for any purpose other than to identify prospective properties consumers may be interested in purchasing. The information being provided is not guaranteed, and all information should be verified by the consumer. Any representation that a web site contains all listings shall only mean that the web site contain all listing available to the public through the IDX data feed. There may be other properties offered through a REALTOR® that have not been displayed on this site. © 2019 Southern Missouri Regional MLS, LLC All rights reserved.
Last Updated: May 23, 2018 1:08 PM
Copyright Disclosure


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by greenbamboostudios
Another trainer comes up to us as we are working out and asks, "What did you do to get this boy them big calves?"
My coach tells him that I already came to her looking that way and she didn't have to do anything.
But the truth is that I've had tiny calves my entire life. I just spent the last year working on them three times a week.
And that small exchange motivates me.
The going is getting tougher but I am reminded that I've already got what it takes.


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Drop in to the Army.ca Chat Room.
0 Members and 1 Guest are viewing this topic.
Hi,I've gone through every steps of the recruiting process as a NCM. I'm currently waiting for my medical file to return from Borden, Ontario. The waiting time is not really the issue.The thing is in the meantime, I've started university (might as well do something while waiting) and I'm really starting to think about going to the Military College as an officer.My question is: Is it possible to change during the recruiting process. All my tests would be the same, except the interview (which I'm ready to take again)? Or do I have the cancel my current application and start the thing fresh?Thank you for your advice and your time,P. CuerrierCF Candidate
Can I move up my ED tech and Infantry to first and second and add vehicle tech as my third.
They dont take in consideration the order you put your trade on. No matter wich one is first or second in your trade list, its all depend on the need of the CAF. So if you put 3 trades be prepare to answer question for all those in your interview when it come .
I'm from the caribbean, and has a keen interest in joining the Canadian military,how do I go about filling out my applicantions. Seeing that I'm a non national of Canada would I be considered for same. Note well I'm a serving police officer back in my native country ,Grenada the isle of spice
I imagine calling my recruitment center in Montreal but
I want to apply in MP, weapons engineer and something else.
...but they are not good on the phones after 60 failed called attempts...


text:
Walking Ghost Phase Theme
After endless hours of nausea and feverish visions, the protagonist regains consciousness once more. Having wandered the sewers as far as his exhausted body would carry him, a ray of light finally guides him to the surface.
As he climbs the rusty ladder, he fears facing the destruction that awaits outside; he can smell the toxic fumes that reek through the soil. Knowing that from now on he lives on borrowed time, he feels neither dead nor alive – he has entered the WALKING GHOST PHASE.
While gazing at the rugged wasteland that once used to be a flourishing metropolis, he ponders the purpose of his agony. Along with his ghostly constitution, a strange obsession seems to have risen within his mind:
He must journey to the CORE.
The intro to the upcoming post-apocalyptic odyssee "Walking Ghost Phase"


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Commissioned on the 4/5/2013 located at LMRO north of Heathcote central Victoria.
A new image is uploaded every 20 minutes. Click here for archives. In the image, West is Right, South is to the Bottom while North is to the Top and East to the Left, the camera image is mirrored to reflect the Sky Chart below.
The Sky Chart is updated each time the page is refreshed, image courtesy of Heavens-Above with thanks to Chris Peat.
Syowa (or Showa) Station is a Japanese research station on East Ongul Island in Queen Maud Land, Antarctica.
The Australian Government has research bases at Casey, Mawson, Davis and MacQuarie Island. The webcam pages have some very interesting information including time lapse video. Well worth a visit to this site.
At night, the green laser beam from the Division's atmospheric LIDAR can be seen emanating from the Science Building on the eastern horizon. The laser beam brightens when it is scattered by low clouds.


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A hilarious and heart-warming new musical
With songs by pop icon Cyndi Lauper, Kinky Boots is based on the true story of a young man's struggle to save his family shoe business with an outrageous idea and a fabulous new friend!
With Tony and Grammy winning songs by pop icon Cyndi Lauper, book by Broadway royalty Harvey Fierstein (La Cage aux Folles) and direction and choreography by Tony-Award Winner Jerry Mitchell (Legally Blonde, Hairspray), Kinky Boots is a celebration of love, friendship and the power of believing in yourself.
Full of energy, unmissable – Herald Sun
A fabulous, fabulous show – Channel 9
For all ages; absolutely brilliant – 2GB
The cast is extraordinary – 3AW
A hoot in boots! – The Australian
Don't miss the musical that has captured the hearts of Broadway, the West End and is now playing in Melbourne. Sign up to the waitlist via: www.kinkybootsthemusical.com.au
Tuesday 18 April to Thursday 25 May 2017
More Info
Accessibility services
- Mobility access
Event tags


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Student Friendly Resources
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, 1970- present. (National Agriculture Library).
Updated daily. Contains bibliographic citations with some abstracts covering agriculture, animal husbandry, animal and human nutrition, forestry, plant pathology, plant science, human ecology, agricultural economics and rural sociology. Includes journal articles, books, state extension and experiment station publications and USDA documents.
Alcohol and Alcohol Problems Science Database
, 1960 - present. (National Library of Medicine)
Updated monthly. Covers all aspects of alcohol abuse and alcoholism. Contains approximately 100,000 records, including abstracts and bibliographic references to journal articles, books, dissertation abstracts, conference papers and proceedings, reports and studies, and chapters in edited works.
Anthropological Index Online
, 1970- present. (CSAC)
Updated monthly. Provides basic bibliographic references to over 700 periodicals in the British Museum's Museum of Mankind Library (incorporating the former Royal Anthropological Institute Library). A browsable list of journal titles and abbreviations is also available.
Astrophysics Data System (ADS)
, 1975 - present. (NASA)
NASA-funded project whose main resource is an Abstract Service, which includes three sets of abstracts: 1) astronomy and astrophysics, containing approximately 594m468 abstracts; 2) instrumentation, containing approximately 586,979 abstracts; and 3) physics and geophysics, containing approximately 910,562 abstracts. In addition to the Abstract Service, the ADS provides pointers to astronomical data catalogs and data archives, making data collected by NASA space missions available.
, 1973 - present. (National Library of Medicine)
Updated bimonthly. Covers ethics and related public policy issues in health care and biomedical research (such as euthanasia and other end-of-life issues, organ donation and transplantation, allocation of health care resources, patients' rights, professional ethics, new reproductive technologies, genetic intervention, abortion, behavior control and other mental health issues, AIDS, human experimentation, and animal experimentation). Includes journal articles, monographs, newspaper articles, court decisions, bills, laws, audiovisual materials, and unpublished documents.
Britannica Online
, (Encyclopedia Britannica, Inc.)
Britannica is a free knowledge and learning center for people who seek thoughtful and engaging context to today's affairs. Only Britannica.com lets users simultaneously search the world's most respected encyclopedia, expert reviews of the Web's best sites, timely articles from leading magazines, and related books. Special interactive features extend these resources to create a distinctive, authoritative Internet destination.
, 1963 - present. (National Library of Medicine)
Updated monthly. Provides coverage to cancer literature with more than 1.5 million citations and abstracts from over 4,000 different sources including biomedical journals, proceedings, books, reports, and doctoral theses.
Census Lookup
, 1990 Census. (U.S. Census Bureau)
This service allows users to retrieve data 1990 Census data. With 300 CDs (150 gigabytes) online, it is the largest collection of U.S. Census data on the Internet.
Commerce Business Daily (CBD Net)
GPO Access
CBDNet is the official Free online listing of Government contracting opportunities which are published in the Commerce Business Daily.
Directory of Open Access Journals
ERIC (The Educational Resources Information Center)
It is a national information system designed to provide users with ready access to an extensive body of education-related literature. ERIC, established in 1966, is supported by the U.S. Department of Education, Office of Educational Research and Improvement, and the National Library of Education.
Federal Register Online
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Official daily publication for Rules, Proposed Rules, and Notices of Federal agencies and organizations, as well as Executive Orders and other Presidential Documents. Database contains 1995 to present.
Financial Times- Global Archive
, Search and read over 8.5 million articles from 3,000 periodicals worldwide, most of them for free. Keyword searches may be modified in a number of ways, and users can select to search one, several, or all of the publication groups indexed. Registered users may also save their searches for later reference.
GrayLIT Network
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Handbook of Texas Online
A multidisciplinary encyclopedia of Texas history, geography, and culture. It comprises more than 23,000 articles on people, places, events, historical themes, institutions, and a host of other topic categories. Provided by the Texas State Historical Association in collaboration with the University of Texas at Austin.
HCI Bibliography
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(HCIBIB) Updated frequently. Provides a bibliographic database on Human-Computer Interaction.
HighWire Press- Stanford
HighWire Press is one of the two largest archives of free full-text science on Earth! As of 4/18/00, we are assisting in the online publication of 171,456 free full-text articles and 742,484 total articles.
Internet Movie Database
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(IMDb) Updated weekly. Provides access to information about movies (including those made for television) from across the world, starting with the earliest cinema through the latest releases and titles still in production. Covers over 170,479 titles with over 2,462,516 filmography entries, including major actors, minor bit players and crew members.
, 19th century - present. (Portland State University)
Updated frequently. Provides an index to plays in collections, anthologies and periodicals. Approximately 15,007 locations are currently cited to plays in many languages. The call numbers cited are those assigned by the Portland State University Library and do not necessarily correspond to the holdings of the General Libraries at UT Austin.
Library Chronicle Index
, 1970 to 1989. (The University of Texas General Libraries)
Medieval Feminist Index
, 1994-1997. (Haverford College)
Updated periodically. Covers over 381 international journals as well as book reviews and essays in books about women, sexuality, and gender during the Middle Ages (450 C.E. to 1500 C.E.). Subject coverage for gender and sexuality means that articles on masculinity and male homosexuality are included.
National Archeological Database
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Updated periodically. Contains approximately 240,000 reports on archeological investigation and planning, mostly of limited circulation. This �gray literature� represents a large portion of the primary information available on archeological sites in the U.S.
National Criminal Justice Reference Service
National Criminal Justice Reference Service (NCJRS) is one of the most extensive sources of information on criminal and juvenile justice in the world, providing services to an international community of policymakers and professionals. NCJRS is a collection of clearinghouses supporting all bureaus of the U.S. Department of Justice, Office of Justice Programs: the National Institute of Justice, the Office of Juvenile Justice and Delinquency Prevention, the Bureau of Justice Statistics, the Bureau of Justice Assistance, the Office for Victims of Crime, and the OJP Program Offices. It also supports the Office of National Drug Control Policy.
National Library of Medicine (NLM) Databases
MEDLINE, Pubmed, Taxonomy, AIDSInfo, �
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Political Database of the Americas
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Updated periodically. Provides a comprehensive source of documentary and statistical political information on Latin American politics. Useful for students, academics, policy analysts and government officials.
, 1970- present. (National Library of Medicine)
Updated monthly. Provides worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy.
Population Index On the Web
, 1986- present.
Updated annually. Covers all fields of interest to demographers. Contains selective indexing with abstracts from journals, books, working papers, doctoral dissertations and other sources.
NLM's preferred web-based search engine to access the 9 million citations in MEDLINE and Pre-MEDLINE (with links to participating online journals), and other related databases.
Pubmed General Information
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Updated weekly. PubSCIENCE is a web search system developed by the Department of Energy's (DOE) Office of Scientific and Technical Information (OSTI) to facilitate searching and accessing peer reviewed journal literature in the physical sciences and other energy-related disciplines. To date, publishers of over 1000 separate journal titles have agreed to participate in PubSCIENCE. Citations and abstracts for these journals are added as they are provided. Links to the full-text articles are provided when available, subject to UT subscription status.
Recent Advances in Manufacturing (RAM)
, 1990 - present.
Updated monthly. Provides bibliographic information for manufacturing and related areas. Covers items in over 500 niche and mainstream journals and magazines, and also details of books, videos and conference proceedings.
CiteSeer, Dates of coverage vary.
Updated daily. ResearchIndex is a scientific literature digital library that aims to improve the dissemination and feedback of scientific literature, and to provide improvements in functionality, usability, availability, cost, comprehensiveness, efficiency, and timeliness. ResearchIndex indexes Postscript and PDF research articles on the Web.
, 1965 - present. (National Library of Medicine)
Updated monthly. Collection of online bibliographic information covering the biochemical, pharmacological, physiological, and toxicological effects of drugs and other chemicals. Contains more than 2.5 million bibliographic citations, most with abstracts, indexing terms and CAS Registry Numbers.
U.S. Government Information
Contains full-text of the Congressional Record, Congressional Bills, Public Laws, Federal Register, GAO Reports, and the United States Code.
Updated daily. Catalog of materials held by the General Libraries at the University of Texas at Austin.
Vanderbilt Television News Archive
, August, 1968 - present. (Vanderbilt University)
Updated daily. Indexes the Television News Archive at Vanderbilt University. The archive includes national television evening news broadcasts, as well as special reports and periodic news broadcasts.
World Biographical Index (WBI)
Contains over 2 million short biographical entries for eminent individuals who lived in North and South America, Western and Central Europe, Australia, New Zealand, and Oceania. Each entry contains the name, variations of the name, pseudonyms, the years of birth and death or years mentioned, occupation, source quoted (archive, fiche number and page) and bibliographic information about the sources used. The UT Austin General Libraries owns microfiche copies of some of the archives containing the complete texts of the biographical descriptions. See also:
Patents Databases
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, The World's most complete Universities Index: Over 5500 Links to Higher Educational Institutions in 161 Countries: Africa, America, Asia, Australia, Europe
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Indian Dissertations and Theses
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A keyword searchable database of citations for articles, books, videos and other materials on the South Asian Diaspora.
Southeast Asia Theses and Dissertations
A comprehensive bibliography of all theses completed at the University of California, Berkeley related to Southeast Asia covering the years from 1906-1997.
UCB-UCSF Joint Medical Program Thesis Index
A searchable and browseable index to theses written as partial fulfillment for the requirements of five-year Master of Science/M.D. program.
U. K. (Engeland) Dissertations and Theses
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I have been told some new info is going to be released thats all I can find out.
Dont Know what,when where etc…
this post has had a 2000 hits 766 reads.
I still have No New Info about this
I have been told some new info is going to be released thats all I can find out.
Dont Know what,when where etc…
this post has had a 2000 hits 766 reads.
I still have No New Info about this
maybe good news this week!
Thanks Buzzy, I agree lex lets hope some good news!
Ooh! Hey Buzzy, can I spread the rumor about a rumor. 🙂
Buzzy Says : Sure 🙂
Brandi probably knows what it is too b/c Buzzy has connections!
Buzzy Says: I dont know either someone in the T2s camp told some Info was comming.Maybe we will hear soon or maybe it was BS.
Thanks ck and Buzzy, maybe if it's true we will hear some good news soon!
Buzzy, I really hope this turns out to be good news. Any idea when we'll know or not? Thanks!
why not just say it? whats the rumor please?
A rumor is not actual news 🙁
Yes, Shaztah, here we go again…would like something more than a rumor as I am sure everyone on this site can agree on that at least!:(
Tebow needs to go play somewhere. CFL, Arena league… he just needs to play. If he wants to work his way back into the NFL he has to be playing football. Obviously he deserves a shot, but with coordinators unwilling to change their whole offensive scheme, and the media circus that follows him, nobody wants to take a chance on him. Jacksonville had their opportunity and blew it.
If Tebow REALLY wants to play in the NFL again, he has to play somewhere to get another shot. See Kurt Warner and Warren Moon.
I completely agree with you, however, Arena and CFL may no longer be an option. His ESPN contract has a clause to let him out for an NFL team. Not sure if that include any other professional league.
Good point. Didn't think about that. It's beyond frustrating watching these garbage qb's on teams in the preseason and Tebow is not on a roster. Never seen anything like this in sports and may never see it again. Hope he gets another chance.
Yep, it's beyond frustrating and I don't get it. This guy was successful with seriously flawed mechanics…something that is coachable and apparently, he has fixed. Why would someone not bring him in?
Let's not forget God is using Tim's Football fame for His glory so a comeback after dramatic rejection makes sense plus God likes to make us walk by faith not sight. Just sayin since Tebow is a religious man and thinks God is in control. So I am following Tim's mindset! ps I am a believer too and beliee something is brewing.
You are right about a lot of things especially regarding "Tim's mindset" that nothing is impossible when you have faith/believe!!!
When is the rumor coming out cause we are running out of time and patients
I agree, or this a rumor of a rumor lol. I pray we hear something positive soon.
Randall may be running out of "patients", but the rest of us are also running out of patience. Why would Buzzy lead us on like this. I am sick to my stomach waiting to here something and will soon become one of Randall's patients if we don't hear something soon.
Buzzy Says : well i got a comment or two out of you I was told there was info comming i ask if it was a fact or a rumor i did not get an answer.
Thanks Buzzy……PLEASE keep us posted. we are counting on you to give us some good news. The NFL should be ashamed of not having one of the greatest winners ever on a team while they pander to thugs and others.
Getting sick to my stomach over this. Why would Buzzy give this teaser but not follow up. I am tired of waiting.
Buzzy Says: I guess I am just Mean.
Thanks Buzzy, hopefully something will break soon and we will learn what this rumor is. I pray it is good news, like everyone else here! GO TEBOW!!!!
At least give us a hint on what the rumor is my patients are not happy lol
I am one of randall's most upset patients, so I agree we need some answers soon.
You guys are "cracking me up" ROFL!!!
Unfortunately, I will bet this is just a bad rumor. I like to watch him play, but I just do not think another team will want all the circus that comes along with Tebow.
It wasn't a circus in Denver and it wasn't a circus in NE. The Jets organization is the circus.
Come in let it out what is it we won't be disappointed if it's wrong were use to it
Keep up the pressure Randall!!!!! As one of your depressed patients, I need answers or I am going to get a Rex Ryan tattoo and jump off a building.
Maybe try using correct grammar and punctuation. I don't think it can hurt, but I could be wrong.
who are you directing that comment at??? people make mistakes when they type fast. but we don't expect to get graded by mr. peepers, so scram.
Buzzy Says : Dont get Mad get Even.
I was directing it at Randall but I was also being humorous. However, the mr. Peepers comment was pretty good.
Yea, SB, it made me laugh too!:)
You know if I was trying to be politically correct I wouldn't be on this site hater
Tebow would want us to be nice to each other and yes we all make typos especially when using our phones so focus on the topic Tebow to the NFL!
Yes we are all here to support Tim and each other! Amen, Tebow to the NFL!
I pray each day for same. Tebow is a great role model for all youth. a class guy that everyone should follow. A proven winner. has a winning NFL record. Took an abysmal Denver team to the playoffs despite having the 20th ranked defense. beat the number 1 defense. on and on and on. someone please show courage and sign him.
I agree 100%, I keep praying that any moment we will hear good news! Please let it be soon, I feel like a kid waiting to open my birthday present, lol.
Ditto x 100, Tawk2!!! 🙂
You are soooooooooo right, KingSolomon, and like that name, it fits! 🙂
Praying to who? If there is some higher power, I really do not think he cares about a game, and who plays in it. I just want to watch him play, since he is different type of QB then what is out there now. It gets to be boring. Just my opinion..
Whether a believer or not or if we think God even cares about football (I think he does. Look what he does with Tim's influence in helping others and bringing up the idea of God!)doesn't matter, I am glad we can all unite and agree that Tim is so fun to watch and we hope (and some pray) that he will play again. I do not like the way the nfl is treating him.
Yes he is a better than a lot of backups out there right now, but yet the NFL shuns him.. Is it because he brings an unwanted fan base? Or are they afraid that people will push them to play him if the starting QB is not performing well. Or can it really be that in the grand scheme of things he is really not that good at the pro level? Maybe he just needs to go get a few DUI's, and smack around some woman to have the NFL look at him..( being sarcastic)
Tebow is a better than many starters in the league if given the chance.
Amen and then some!
Tim has a legit fan base that are not just girls with a crush, blind faith Christians or strange tag alongs. We are football lovers that seen a player we enjoy that won many times and entertained all the time we watched. We expect to see him play until or unless he starts to lose all the time and then he would become boring to watch. Then we would think he was a really nice guy who doesnt play well. So what is the problem with that nfl??
Bring us some exciting QBs and maybe we will be entertained by them too!
I guess this the rumor was just a rumor? I too am one of the many fans who loved watching Tim play, he kept me on the edge of the seat. Tim made the game of NFL football more exciting and fun. If Tim had the chance to develop like these other rookies coming into the league he would be still playing. Tim was black balled by the NFL each day that passes with him not on an NFL team just goes to prove the point. No one can't tell me that he is not better than many of the back up quarterbacks playing now.
I agree stefebowfan bring us some QB's that have the it factor and the excitement Tim brought to the game, and I will watch them too.
Lance just posted in another topic here that Tim is about to sign a 25 million dollar contract with the A11FL, he said this is a rumor he heard earlier, anyone know anything about this?
$25 million is probably 25X the budget for all players salary in this league. This isn't even remotely realistic. Its bogus.
Agreed, Tebow Fan.
I guess there was no rumor?
Hey, 933 views and 50 responses later…think you set a record for the TebowZone…Way to go Buzzzzzzy! 🙂
with all due respect, there is nothing to be praising anyone about because most people are really upset that they thought Buzzy had info and he has nothing. So this king of attention is not good. I don't blame Buzzy and I hope he uses his contacts to find something out, but realistically speaking, this post has upset thousands of people and is not the kind of attention you want.
Buzzy says: sorry you think I let you Down calling it a rumor was a poor choice of words.
Buzzy—-you have more info than anyone else, so we will always continue to look to you for information. Keep trying to find something out. You are our only hope.


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Twilight Corporate Tennis
Date: 01-11-2018 - 06-12-2018
Thursday nights commencing 6.30 pm.
Six week competition commencing 1st November 2018 with finals 6th December 2017
Four Team members (Mixed - any combination)
Each player to participate in two sets to six.
Followed by a BBQ (included) with Drinks at bar prices
For paper entry forms click here. For any queries please contact Ali
McMeekin on 0417 509 694 or email@example.com


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Dean's Reign of Winter
Tiefling AC Tank
Maw'veet is a twisted creature, with black veins running up his neck and across his temples, and an overly wide mouth filled with teeth too sharp to be human. Birthed as a part of an experiment by a cult worshiping Shiggarreb to try and reduce the amount of sin that mortals create, he was fathered and partially raised by a Good man, until the cult was found by Chelixian's, slaughtered and Maw'veet was put into training to be a Hellknight enforcer.
Being a fundamentally good person, he didn't want to prop up an evil regime (or really any regime), and so as soon as possible escaped to take up life as, effectively, a hedge knight.


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There's so much to be said about the importance of being kind, positive and supportive to each other. In a world full of horrific news, it seems like we are stuck in a sea of negativity most days. Today, I'm challenging you to be a positive force. Each day we are bombarded with
Summer isn't over yet. Today I'm sharing all my favorite looks from this year, from bright florals and palm prints to crochet classics and straw accessories. These outfits include almost all the looks I wore on my recent trip to Grenada. It's not too late to add a touch of summer to your wardrobe. Many
Summer is all about those easy, breezy thrown together styles. Today, I'm sharing a bohemian look that combines a bright crochet paneled dress, bohemian accessories and espadrille wedges. This style is a perfect combination for a day in the sun or out and about on vacation. I'm also stoked today to give you TWO promo
From its private beach oasis to its turquoise waters, Sandals La Source Grenada is a breathtaking getaway. The peaceful ocean, vibrant flowers and impeccable rooms raises this Sandals resort to the top of my vacation list. Today, I'll reveal my honest opinion of the room, the property, the restaurants and
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Your beach vacation is incomplete without these styles. Today, I'm revealing the best Summer 2018 trends worth adding to your closet. This season calls for hot patterns, high-leg bikinis, straw accessories and espadrille platforms. Incorporate one of these staple pieces into your Summer wardrobe and
You may have seen FabFitFun boxes and wondered what all the hype is about. Today, I'll reveal my honest opinion and provide you with a discount. FabFitFun subscription boxes are taking the market by storm. These seasonal subscription boxes are packed with beauty, health, fashion and fitness goodies. The company has found a way to
Vegas is full of activities, bars and usually bad decisions. Planning a trip can be exciting, but a little overwhelming because there is so much to choose from. Whether it's your first time or you're a frequent visitor, there are a few places you should make time to see while you're there. Here are five
I might have possibly found the most adorable and affordable jewelry boutique. Maroxy & Co is an online store with a wide range of statement jewelry, including necklaces, bracelets and earrings. Their vibe is a mix between
One of my favorite trends this year is the bright, bold and beautiful kimono sleeve. This look can be worn in various ways, whether it's a pop of color, a floral pattern or an incorporation of lace. Today, I'll show you one casual way and one dressy way to add this look to your wardrobe.
If you're looking for a relaxing getaway set on a beautiful island in the Caribbean, look no further than the stunning St. Kitts Marriott Resort & the Royal Beach Casino. The spacious resort offers spectacular views of the island's cascading hilltops and rocky coastline. Today, I'll walk you through the resort's best attributes and provide
This year's Spring outfits are all about bold statement pieces. I've compiled a list of of the season's hottest items, from "bright and bold" to the "classic and simple." Here are some of the best trends that can be easily pulled off. Choose a style and add one of these looks to your 2018 Spring
It's that time of the year when we're craving to jump into Spring clothing, yet the weather pulls us back and forth between the seasons. Today I'm sharing a simple Spring transition outfit. You can easily pull any of these pieces and incorporate them into your Spring wardrobe.
Discover Jamaica's history and ride camels in the Caribbean at Yaaman Adventure Park in Ocho Rios. If you're traveling to Jamaica, spending a day in Ocho Rios is a must. In addition to climbing Dunn's River Falls, our day included an unforgettable trip to the historic Prospect Plantation and camel rides on site. Prospect Plantation


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26 Agu When Youre Overqualified for that Task, just how to Write a Letter
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Everybody dismissed the fact that he was a bully who loved to boss orphans along with a rascal.
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Free credit repair help in Bigfoot, TX might be closer than you think. While the credit repair business counts on a certain amount of profits from customers to support itself, non profit credit repair is also available in most areas. It's designed to help people who otherwise can't afford the cost of Bigfoot debt solutions, repair services, or a credit repair attorney. If you need free credit repair help, contact us for information on a consumer credit counseling service near you. Free help is waiting.
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84 Linsmore Crescent, Toronto, Ontario
$ Click for current price
3 BEDROOMS | 2 (2 full ) BATHROOMS |
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Presented By:
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Licensed In: Ontario
Property Description
1920S Built Character Home With 3+1 Beds, 2 Bath Family Home In The Hottest Part Of Town, Danforth East. Large Principal Rooms & Bedrooms, Original Gumwood & Floors. Renovated Kitchen. 2nd Kitchen Option In 3rd Bedroom. Lived In By The Same Family For Many Years. Stop By The Launch For A Toasty Hot Chocolate On Sat 12-5.
Fridge, Stove, Dishwasher, Washer/Dryer. All Elfs, Window Coverings. Home & Contents All Sold As Is. 3 Hrs Notice. Pre Listing Inspection By Request. Offer Date Wed, Dec 14. Register By 6Pm. Seller Reserves Right To Review Pre Emptive.


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A selection of fun and educational games for kids, freely available on the web. All of these should play in a web browser – no downloads required!
Cyberchase – fun math games from PBS Kids.
Discovery Kids – explore volcanoes, grab a snack with the Meerkats, and more!
Funbrain – educational games for all ages and by grade level.
LEGO – web games for LEGO fanatics.
Ology – games from the American Museum of Natural History. Connect-the-dots, puzzles, quizzes, and more.
PBS Kids – coloring, adventure, math, spelling, you name it.
Peep and the Big Wide World – join Peep and his friends Chirp and Quack (a robin and a duck) to learn about numbers, animals, sounds and more.
Seussville – games featuring favorite Dr. Seuss characters, like The Cat in the Hat, Horton, and the Sneetches.


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We had a taught session on the importance of blogs yesterday. The main problem with Uni doing this wasn't that it was patronising (which it was), it wasn't that they made us use Pebblepad (quite simply the worst blog/networking site I've ever clapped eyes on), it was that that session justified blogging as work. Hence, this counts as productivity. So here I am, blogging on the work that I should be doing during the time I'm spending blogging about it.
Follow that? Nope, me neither.
This is what my bedroom floor looks like. Being in a poky student room, this kind of dominates the floorspace somewhat - I've already stepped in paint on numerous occasions. The idea has been done a thousand times over - paint splatters/splashes/flicks, call them what you will. It's my Jackson Pollock impression, but without the chain-smoking and the alcoholism. I want to scan this sheet and then blow it up so the tiniest splatters are huge.
The brief is another illustration one - an editorial design to front a piece celebrating 15 years of Fairtrade. My initial ideas all centred around champagne/wine bottles:
Rendering the hands proved difficult, and so I feel it would be best to get rid completely, and to use a slightly more celebratory angle on the bottle such as the one on the right. The paint splatters will hopefully fit in behind the bottle - like with the fruit on the left copy, but with more abandon and freedom.
Of course, what I should be doing now is putting those pieces together, rather than wasting time talking about putting them together. I have my excuses lined up:
1. The paint isn't dry, and I don't want paint on my new scanner.
2. Even if it was dry, the software available on my home computer has spent all evening crashing.
3. I'd much rather blog about my problems than try and solve them.
Hopefully, all will be well by Tuesday when this piece will be handed in, and I'll be able to eat a banana without having a panic attack about the slow progress of my work.


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Yesterday I attended MobileMonday Yangon event. There I got chance to hear from an old man, who is investor of Blink Marketing Agency in Myanmar, how to get money from investor. What he said is every simple. Let me share you back.
Don't write your business plan too long.
He said investors don't want to read very long paper. Startups and entrepreneurs don't need to write very long about their business plan. Investor only want to check short-to-the-point facts first. After only they like it, they think of investing. Business angels and most investors are going to take risk. If you can attract them only by a paper, they will take a risk by investing on you.
Don't have too big expectation on your business
Some startups said their business or products will cover for all population in the country. Their customers must be everybody. Actually the facts are not investors are not exciting about. They don't believe you can do it. They don't believe you can make it happen. Just show that you can serve for selected customers. For example, your product may only be for people who live in Yangon or anywhere else. Or your product is for college students. You must have target customers. You cannot sell to everybody. You are a startup. The higher your target, the more money you need. So investors won't invest on you.
The amount should be about 300,000 USD
The investors won't spend more than 300,000 USD in initial period. If the initial investment you need to run your business is more than 300,000 USD, investors will not take risk. You business plan must not spend money carelessly. You need to show by exact information where you are going to spend.
Prove for sustainability
Sustainability is one of the facts investors usually check. For example, they will ask you your next target of after three months, of after six months, etc. You cannot say easily you will hire somebody else to do a task. You need to prove them how you will get someone. Your business plan may be one year-long or two years long. You need to show your investors your monthly target or six months target. It is the best if you can show your business timeline. If they see that your business is sustainable for the time you told in the plan, they will like you.
Author: Aung Kham


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I'm pleased Councillor Sheppard (letter 20 February) doesn't think he's a hypocrite.
He appears in a picture at a bus stop. The press release is about better access to buses. Of course everyone supports better physical access, and indeed I wrote a letter mentioning my support of the proposal.
Now surely Cllr Sheppard would want proper access to buses everywhere, not just where he was photographed on just one route, or how can people get off and on again elsewhere? (This route was not being cut, notice, for some would have called that cynicism).
But apparently he can't see any doublethink involved in supporting better physical access on one route and cutting buses elsewhere, reducing the overall access.
He even says in his letter that if he voted against the cuts he could have played the good guy, but then justifies his voting for the cuts and saying he didn't do the good thing because 'my one vote would not have changed anything.' Do choose your own word to describe this.
Finally this is the same Councillor Sheppard who said, both to me personally and I believe on public record, that if people in rural areas didn't have subsidised buses they could use taxis! That of course is not hypocrisy. Feel free to choose your own word for that, too.
Cllr Peter Gardiner
Lewes District Councillor for Ouse Valley and Ringmer


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Spring has officially sprung and Plus Size Wellness Magazine have included some great spring based information and tips in this our 1st Anniversary issue. We know you are aiming to get healthier this spring and you won't be disappointed with the articles we have inside. Enjoy your read!
Here are 10 spring fitness tips to keep you comfortable while you exercise during the winter thaw. 1. Lighten up Trade your winter parka in for a light, packable waterproof jacket and pants. You need full-body protection against splash-back when you run through puddles, and using lightweight, packable gear ensures that you won't leave it behind to cut weight and then end up wet and cold. You'll also stay dry if it rains, snows or pours freezing rain on you — all of which can happen in the shoulder season. Even better? Being waterproof from head to toe protects you from even the most inconsiderate of puddle-splashing drivers if your workout takes you anywhere near the road. WRITERS & BLOGGERS SUBMIT ARTICLES TO firstname.lastname@example.com 2. Let your footwear work for you Abandon any thoughts of protecting your footwear from mud, slush and puddles. Let those shoes or boots sacrifice themselves to keep your feet dry — that's their job. Most waterproof boots or shoes have a waterproof bootie sewn into the body of the shoe. As long as this bootie isn't pierced and you don't step into water that's higher than its edge, your feet will stay warm and dry. If you think you might end up in over that level, which varies from shoe to shoe, you can extend your waterproof foot protection by using standard gaiters or shorter ankle gaiters. You can also sometimes get by with wearing waterproof pants that cinch down tightly over the tops of your shoes or boots. If temperatures aren't cold enough to pose a hazard to wet feet, you could also just toss on a pair of throwaway sneakers or water shoes, which are made of mesh that lets water in but also lets it drain right out again so you're not squishing around, and then splash away to your heart's content. Allow 3-4 weeks for reply
3. Expect the weather to change It might be winter one day and spring the next, then flip back and forth a few times before it's done. Cope with the changing extremes by leaving room for layering underneath your waterproof jacket and pants. Check the forecast before you go and take extra layers if necessary, or even better yet, just leave an extra top and bottom layer or two in your vehicle or pack all the time. The extra air trapped between layers acts as insulation for your body, and as long as the layers are available, you can remove or add them to fine-tune your comfort. 4. Get a grip Invest in a pair of ice grippers (like Yaktrax or Get-a-Grip) that slip on over your boots or shoes just in case you encounter water-slicked ice. Tuck them into your fanny pack or under the seat of your car so they're always nearby if you need them. Keep an extra-vigilant lookout for icy spots in areas where the snow has been packed down, then exposed to sun followed by shade. Slipping and getting hurt isn't a good way to start the spring season. 5. Stay prepared Having a box in your car or a pack by the door always ready to go helps keep you organized and make sure that what you need is always available. There's nothing quite like leaving the house stoked for a workout only to realize that you left your warm hat, running shoes or ice grippers behind. Tuck your packable pants and jacket, an extra layer for top and bottom, extra socks, your ice grippers and your waterproof shoes with gaiters into the box or pack. If you happen to throw a bottle of water and an energy bar in there too, you'll be your own hero once that post-workout hunger and thirst set in. Also, work out a system for toting winter gear like skis or snowshoes before you leave the house. This means finding a way of strapping, tying, bungeeing or otherwise fastening them to the outside of your pack, not planning to carry them by hand if you hit a snowless spot on the trail. Some packs come ready-made with fancy doodads for toting extra gear on the exterior.
Magazine: Plus Size Wellness Spring 2018 Issue