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Goniothalamin Inhibits Growth of Human Lung ... - ACS Publications
Goniothalamin Inhibits Growth of Human Lung ... - ACS Publications
Mar 10, 2011 - Goniothalamin Inhibits Growth of Human Lung Cancer Cells through DNA ..... In our study, the cell migration in wound healing (Figure 5)...
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ARTICLE pubs.acs.org/JAFC
Goniothalamin Inhibits Growth of Human Lung Cancer Cells through DNA Damage, Apoptosis, and Reduced Migration Ability Chien-Chih Chiu,† Po-Len Liu,‡ Kuang-Jing Huang,§ Hui-Min Wang,|| Kuo-Feng Chang,† Chon-Kit Chou,† Fang-Rong Chang,^ Inn-Wen Chong,# Kang Fang,z Jia-Shing Chen,£ Hsueh-Wei Chang,*,§,^ and Yang-Chang Wu*,^,@ †
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan § Department of Biomedical Science and Environmental Biology, Center of Excellence for Environmental Medicine, Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan ^ Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan # Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan z Department of Life Science, National Taiwan Normal University, Taipei 106, Taiwan £ Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan @ Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan
ABSTRACT: We evaluated the possible anticancer performance of a natural compound, goniothalamin (GTN), against human lung cancer using as a non-small cell lung cancer (NSCLC) cell line, H1299, as the model system. Cellular proliferation was significantly inhibited by GTN. Using an improved alkaline comet-nuclear extract (comet-NE) assay, GTN was found to induce a significant increase in the tail DNA. Wound healing and zymography assays showed that GTN attenuated cell migration and caused a reduction in the activity level of two major migration-associated matrix metalloproteinases, MMP-2 and MMP-9. It can be concluded that the DNA-damaging effect of GTN against lung cancer cells leads to growth inhibition as well as a depression in migration ability. Therefore, GTN has potential as a chemotherapeutic agent against lung cancer. KEYWORDS: Goniothalamin, non-small cell lung cancer, comet assay, cell migration, matrix metalloproteinase
' INTRODUCTION Lung cancer is a leading cause of cancer-related mortality and has become a global health problem. Non-small cell lung cancer (NSCLC) causes more than 80% of all lung cancers, and the majority of NSCLC patients are unsuitable for surgery.1 The development of chemotherapeutic drugs that target lung cancer seems to have reached a plateau.2 Fortunately, many anticancer agents derived from natural products3-5 have the possibility of improved therapeutic effects against lung cancer. Goniothalamin (GTN) is one of the plant bioactive styryllactones found within the family Annonaceae, and it has been mainly isolated from the genus Goniothalamus.6 GTN has been reported to induce cytotoxicity in a variety of cancers, including cervical,7 gastric, kidney,8,9 breast,7,10 leukemia,11-14 ovarian, melanoma, and colon cancers.15 Some of these studies have demonstrated that the cytotoxicity induced by GTN occurs via apoptotic cell death.11-14,16,17 Accordingly, we proposed a hypothesis that GTN is also a potential anticancer drug against lung cancer. To test this hypothesis, we used Goniothalamus amuyon-derived GTN18,19 to investigate the anticancer potential of the drug against a human NSCLC cell line, H1299, based on cell survival, an improved comet assay [comet-nuclear extract (comet-NE)],20,21 changes induced in the cell cycle, apoptosis, and assays related to cell migration. r 2011 American Chemical Society
' MATERIALS AND METHODS Cell Cultures and Drug Information. A human NSCLC, H1299, was cultured in Dulbecco's modified Eagle's medium (DMEM) (Gibco, Grand Island, NY) supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin, 100 μg/mL streptomycin, 0.03% glutamine, and 1 mM sodium pyruvate. The cells were incubated at 37 C in a humidified atmosphere containing 5% CO2. GTN from G. amuyon, prepared as described earlier,18,19 was freshly dissolved in the dimethyl sulfoxide (DMSO) before being used to test the effects of the drug. Assessment of Growth Proliferation. Cell growth was determined by the trypan blue dye exclusion assay as described earlier.20,21 Briefly, cells were treated with the vehicle control (DMSO) or various doses of GTN for 24 and 48 h. Subsequently, the cells were exposed to 0.2% trypan blue and counted using a hemocytometer. Assessment of DNA Damage. The comet-NE assay was performed as described previously,20-22 except that the NE was derived from human gingival fibroblast cells. Briefly, 1 105 H1299 cells in suspension were added to 1.2% low-melting-point (LMP) agarose and subsequently transferred onto a precoated slide. A third layer (1.2% LMP gel) was added to the second gel and put on ice for solidification. The slides were soaked in freshly prepared ice-cold cell lysis solution Received: November 25, 2010 Accepted: February 23, 2011 Published: March 10, 2011 4288
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at 4 C for 2 h and then rinsed with deionized water 3 times. For NE digestion, a 20 μL excision mixture containing 0.6 μg of NE, 50 mM N-2hydroxyethylpiperazine-N0 -2-ethanesulfonic acid (HEPES)-KOH (pH 7.9), 70 mM KCl, 5 mM MgCl2, 0.4 mM ethylenediaminetetraacetic acid (EDTA), 2 mM ATP, 40 mM phosphocreatine, and 2.5 mM creatine phosphokinase was added to each slide. The slides were then incubated at 37 C for 2 h in a humidified space with a coverslip. The slides were denatured and resolved by electrophoresis. Afterward, the DNA damage was analyzed.22 Using a fluorescence microscope (TE2000-U; Nikon, Tokyo, Japan), the migration of DNA from the nucleus of each cell was measured with a computer program (http://tritekcorp.com) to calculate percent tail DNA,20-22 which corresponds to the percentage of DNA in the comet tail (sum of intensities of pixels in the tail); i.e., head percent DNA = (head optimal intensity)/(head optimal intensity þ tail optimal intensity) 100. Tail percent DNA = 100 - head percent DNA.
Assessment of Cell Cycle Distribution and Sub-G1 Population. To determine the phase distribution of the DNA content of the cell, propidium iodide (PI) staining was performed as described earlier.23 Briefly, cells were treated with solvent vehicle or 0.5, 1, 2, 5, and 10 μM GTN for 24 and 48 h. After treatment, the cells were collected, washed twice with phosphate-buffered saline (PBS), and fixed in 70% ethanol overnight. After centrifugation at 700 rpm for 5 min at 4 C, the cell pellet was stained with 10 μg/mL PI (Sigma, St. Louis, MO) and 10 μg/mL RNase A in PBS buffer for 15 min at room temperature in the dark. The samples were assayed using a FACScan flow cytometer (Becton-Dickinson, Mansfield, MA) and CellQuest software (Becton-Dickinson). Assessment of Apoptosis. To further confirm apoptosis in GTN-induced H1299 cells, annexin V staining (Pharmingen, San Diego, CA) was performed as described before.23 A total of 1 106 cells per 100 mm Petri dish were treated with vehicle or GTN for 24 h. Subsequently, cells were labeled with 10 μg/mL annexin V-fluorescein isothiocyanate (FITC). The apoptotic cells were analyzed using flow cytometry. Assessment of Cell Migration. In brief, a total of 5 105 H1299 cells were seeded onto 12-well plates, treated with GTN or DMSO, and then grown to complete confluence. A yellow 200 μL plastic pipet tip was used to create a clean 1 mm wide wound area in the H1299 confluent culture. After incubation for 24 and 48 h, the wound gaps were photographed. The wound areas were then examined and calculated using the software "TScratch".24 Gelatin Zymography. The gelatin zymography was performed using 10% polyacrylamide gels containing 0.1% gelatin. After electrophoresis, the sodium dodecyl sulfate (SDS) present was removed by treating with Triton X-100 (2.5%), followed by incubation in a Trisbased buffer containing NaCl, CaCl2, and ZnCl2 at 37 C overnight. The gel was then stained with Coomassie Brilliant Blue, and gelatinase activity was detected as unstained gelatin-degradation zones within the gel. The signals were analyzed using Gel Pro, version 4.0, software (Media Cybernetics, Silver Spring, MD). Statistical Analysis. All data are presented as the mean ( standard deviation (SD). Student's t test was used to test the significance of the mean difference between two groups.
' RESULTS GTN Induced Growth Inhibition in H1299 Lung Cancer Cells. As shown in Figure 1, the trypan blue assay showed that the
relative cell proliferation at various concentrations of GTN (0, 1, 2, 5, and 10 μg/mL) after 24 and 48 h were 51.79 ( 5.92, 35.14 ( 5.09, 22.29 ( 6.04, and 9.30 ( 7.37 (n = 3) and 38.04 ( 3.82, 16.08 ( 1.14, 3.15 ( 0.17, and 0.45 ( 0.64 (n = 3), respectively. Treatments with GTN caused growth inhibition that was significant and dose-dependent (p < 0.05 at a dose of 1 μg/mL and p < 0.01 at doses of 2, 5, and 10 μg/mL for control versus GTN
Figure 1. Proliferation of H1299 lung cancer cells is inhibited by GTN. Cells were incubated with various concentrations of GTN (0, 1, 2, 5, and 10 μg/mL) for 24 and 48 h. The proliferation was determined by the trypan blue assay. The data are expressed as the mean ( SD n = 3. (/) p < 0.005 and (//) p < 0.001 against the vehicle.
treatment). The IC50 values of the GTN-treated H1299 lung cancer cells at 24 and 48 h were 1.15 μg/mL (5.75 μM) and 0.83 μg/mL (4.15 μM), respectively. GTN Induced DNA Damage in H1299 Lung Cancer Cells When Measured by the Comet Assay. In the comet assay using H1299 cells (Figure 2A), no "tail" was found in the vehicle control (0.1% DMSO alone), whereas the "tail" grew following GTN treatment (2, 5, and 10 μg/mL for 2 h). Figure 2B shows that the values for the average percent of tail DNA of the GTN treatments (2, 5, and 10 μg/mL for 2 h) were 58.47 ( 18.47, 58.47 ( 18.47, and 90.69 ( 4.38 (n = 50), respectively (p < 0.001). Accordingly, GTN was able to induce DNA damage in H1299 cells in a significant and dose-dependent manner. These results suggested that DNA damage is involved in the antiproliferation effect of GTN on H1299 lung cancer cells. GTN Induced Sub-G1 Accumulation in H1299 Lung Cancer Cells Using Flow Cytometry. As shown in Figure 3, the subG1 populations at concentrations of 0, 1, 2, 5, and 10 μg/mL GTN were 0.80 ( 0.07, 4.05 ( 0.38, 18.37 ( 0.67, 76.76 ( 0.04, and 98.76 ( 0.19 (n = 3), respectively. The sub-G1 population induced by GTN was slightly increased at a dose of 1 μg/mL (p < 0.05) and became significantly increased at the higher doses of 5 and 10 μg/mL (p < 0.001). It can be concluded that the GTNinduced sub-G1 population of H1299 lung cancer cells was significantly increased by GTN and that this occurred in a dose-responsive manner. GTN Induces Apoptosis of H1299 Cells Measured by FlowCytometry-Based Annexin V Staining. To determine whether GTN inhibits cell survival by inducing apoptosis, flow-cytometrybased annexin V staining was performed. H1299 cells cultured with different concentrations of GTN for 24 h were stained with annexin V to detect the externalization of PS on the cell membrane. After treatments with vehicle control or 1, 2, 5, and 10 μM GTN for 24 h, the percentage of apoptotic cells was calculated and shown in Figure 4. These results showed that GTN significantly induced apoptosis of H1299 cells in a doseresponse manner (p < 0.01 and 0.001 as indicated). GTN Attenuated Migration of H1299 Lung Cancer Cells in the Wound Healing Assay. Figure 5A shows that the migration of H1299 lung cancer cells was dramatically inhibited by GTN. Figure 5B showed that the migration ability of H1299 cells treated with various GTN concentrations at 0, 1, 2, 5, and 10 μg/mL 4289
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Figure 2. Comet-NE assays of H1299 lung cancer cells after treatment with GTN. (A) PI staining of the control (DMSO) and GTN-treated cells (1, 2, 5, and 10 μg/mL for 2 h). The circular spots in pink are the nuclei, and the tails indicated the DNA damage. (B) Average of tail percent DNA for the various GTN-treated cells. (/) p < 0.001 against the vehicle.
Figure 3. GTN induces an accumulation in the sub-G1 population in H1299 lung cancer cells. Cells were treated with the indicated doses, 1, 2, 5, and 10 μg/mL, of GTN for 24 h, respectively. (A) Accumulation of the sub-G1 population in GTN-treated H1299 cells and vehicle controls at 24 h. (B) Quantification analysis. Data are presented as the mean ( SD (n = 3). Different letter notations indicate the statistical significance between the drug treatment and vehicle (a versus b and a versus c indicate p < 0.005 and 0.001, respectively).
was 100, 72.74 ( 1.28, 41.12 ( 0.99, 31.01 ( 2.43, and 7.30 ( 1.76% (n = 3), respectively. This indicates that cellular migration in H1299 lung cancer cells was inhibited by GTN in a doseresponsive manner. GTN Inhibited MMP-2 and MMP-9 Activities in H1299 Lung Cancer Cells Based on Gelatin Zymography. The activity levels of MMP-2 and MMP-9 are shown in panels C and D of Figure 5, respectively. The fold changes in the MMP-2 activity at GTN concentrations of 0, 1, 2, 5, and 10 μg/mL were 1, 0.86 ( 0.07, 0.67 ( 0.04, 0.46 ( 0.02, and 0.40 ( 0.18 (n = 3), respectively. The fold changes in MMP-9 activity at GTN concentrations of 0, 1, 2, 5, and 10 μg/mL were 1, 0.68 ( 0.25, 0.51 ( 0.25, 0.35 ( 0.26, and 0.25 ( 0.17 (n = 3), respectively. These results show that GTN significantly attenuates MMP-2 and MMP-9 activities in H1299 cells in a doseresponsive manner.
' DISCUSSION The cytotoxic effect of GTN has been demonstrated in many types of cancer. For example, the IC50, IC25, and IC10 values for GTN-treated vascular smooth muscle cells (VSMCs)16 after 72 h are 4.4 μg/mL (22 μM), 1.5 μg/mL (7.5 μM), and 0.5 μg/mL (2.5 μM), respectively. After 72 h of treatment with GTN, the IC50 values of HL-60 (a human promyelocytic leukemia cell line) and CEM-SS (a T-lymphoblastic cell line) are 4.5 and 2.4 μg/ mL, respectively. In this study, we obtained a novel finding that
GTN has a cytotoxic effect on H1299 lung cancer cells. In addition, the effect of GTN is time-dependent based on the 24 and 48 h results. Because the normal human lung cells are not available in our lab, the test of cancerous lung cells was performed in the study. However, some studies have been discussed about the possible cytotoxicity of GTN upon the normal cells. For example, Tian et al. indicated that GTN and its derivative showed less toxicity on normal mice hepatocyte compared to human hepatocellular carcinoma (HCC) HepG2 and that the IC50 values of them on normal mice hepatocyte were about 3 times that on HepG2.25 The study by Wattanapiromsakul et al. indicated that GTN exerted a promising cytotoxicity against colon cancer, breast cancer, and lung cancer cells but that the cytotoxic evaluation of GTN to normal cells revealed moderate toxicity against mouse skin fibroblast ST3 and human fibroblast HF cells.26 Accordingly, these studies suggested that the cytotoxicity of GTN toward cancer cells and normal cells may be discrepant. However, we still cannot exclude the possibility that GTN may cause cell damage in normal lung cells. Although GTN has been found to be cytotoxic against many types of cancer,7,8,10-15,27 the detailed mechanisms have rarely been addressed, except in terms of apoptosis. Recently, DNA damage has been reported to be involved in the GTN-induced cytotoxic effect; this was based on the percentage of cells with DNA damage using VSMCs16 and leukemia cell lines,12,28 as measured by the comet assay.29 Consistent with these findings,12,28 in this study, we have demonstrated that GTN induces DNA damage in GTN-treated H1299 lung cancer cells based on the comet-NE assay (Figure 2). There are an about 60, 40, and 20% changes in tail length at IC50, IC25, and IC10, respectively. Our results support the idea that GTN induces DNA damage in a dose-dependent manner in H1299 lung cancer cells prior to cytotoxicity. According to the study by Inayat-Hussain et al., they demonstrated that GTN induced DNA damage and that reactive oxygen species (ROS) leads to apoptosis in human lymphocyte Jurkat T-cells. Additionally, the DNA damage induced by GTN is independent of topoisomerase IIR inhibition.12 Furthermore, our preliminary result showed that GTN induced phosphorylation of γ-H2AX, a hallmark of DNA double-strand break (DSB) (data not shown). When these observations are taken together, they suggest that GTN seems to cause DSB of DNA damage via ROS generation but not inhibit topoisomerase IIR directly. Our study has also shown that there is a dose-dependent accumulation in the sub-G1 population of cells (Figure 3) after 4290
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Figure 4. GTN induced apoptosis of H1299 cells. (A) Cells cultured with different concentrations of GTN for 24 h were stained with annexin V/PI to detect externalization of PS from the cell membrane. (B) Quantification analysis of annexin V staining. (/) p < 0.01 and (//) p < 0.001 for the control versus GTN-treated cells, respectively.
Figure 5. GTN inhibits cell migration in H1299 lung cancer cells. (A) A total of 5 105 cells were seeded onto a 12-well plate, and the cells were scraped to create a clean 1 mm wide wound area within the confluent culture. Cells were treated with the indicated doses of 0, 1, 2, 5, and 10 μg/mL GTN for 16 h. Afterward, the wound gaps were photographed using an inverted phase-contrast microscopy. (B) Quantification analysis. (C and D) Gelatin zymography assays of MMP-2 and MMP-9 activities. (/) p < 0.05 and (//) p < 0.001 against the vehicle.
GTN treatment of H1299 lung cancer cells but without clear cell cycle arrest occurring. These sub-G1 accumulations had been confirmed to be apoptosis based on the annexin V staining result (Figure 4). However, we cannot exclude the possibility for the involvement of necrosis and autophagy, and it needs to be further investigated in the future. In breast cancer cells (MDA-MB-231), GTN has been reported to significantly induce cell cycle arrest at G2/M phase and then apoptosis occurred.30 Although activation of the DNA damage response pathways is known to involve both cell cycle arrest and apoptosis, they are regulated by distinct cellular machinery. Moreover, apoptosis may happen independently of cell cycle arrest under certain conditions.31,32 For instance, a low paclitaxel dose (10 nM) caused apoptosis without cell cycle arrest, but the same drug caused G2/M arrest at higher doses (>50 nM).32 Similarly, we found that GTN induced a dose-dependent accumulation of the sub-G1 population and an apoptotic annexin V
signal for H1299 cells. Therefore, the cell cycle arrested at a specific phase is not an essential event always associated with increased apoptosis.33 To further clarify the relationship between the higher dose GTN treatment and cell cycle arrest in H1299 lung cancer cells, we perform the annexin V staining assay and the result showed that a higher dose (5 and 10 μg/mL) of GTN triggered a significant apoptotic cell death of human lung cancer H1299 cells, whereas a lower dose (2 μg/mL) of GTN only induced a moderate accumulation of apoptotic population. Accordingly, these results suggest that the induction of apoptosis by GTN is a dose-dependent manner (Figure 4). The extracellular matrix (ECM) plays an important role in tumor proliferation and migration.34 Many anticancer therapies are based on killing cancer cells by generating high ROS.35 A low level of intrinsic ROS may induce activation and releases of MMP-2 and MMP-9, which are responsible for cancer metastasis.36 4291
dx.doi.org/10.1021/jf200566a |J. Agric. Food Chem. 2011, 59, 4288–4293
Journal of Agricultural and Food Chemistry Because GTN has been reported to be capable of modulating the redox status of cells and this is known to lead to apoptosis in breast cancer cells (MDA-MB-231),30 we examined cell migration, MMP-2 activity, and MMP-9 activity (Figure 4) in H1299 cancer cells. In our study, the cell migration in wound healing (Figure 5) and transwell studies (data not shown) of H1299 lung cancer cells was markedly inhibited by GTN, even at the lowest (non-cytotoxic) dose. Therefore, these studies suggested that GTN has potential for inhibiting MMP-mediated lung cancer progression. To the best of our knowledge, this is the first demonstration that GTN dramatically attenuates the migration ability of cancer cells by inhibiting MMP-2 and MMP-9 activities.
' AUTHOR INFORMATION Corresponding Author
*Address: Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan. Telephone: þ886-7-3121101, ext. 2691. Fax: þ886-7-3125339. E-mail:
[email protected]
(H.-W.C.); Address: Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan. Telephone: þ886-422053366, ext. 1233. Fax: 886-4-22060248. E-mail:
[email protected]
mail.cmu.edu.tw (Y.-C.W.). Funding Sources
We thank the National Science Council of Taiwan for Grant NSC98-2314-B-037-035, the Kaohsiung Medical University for Grants KMU-Q-097-046 and M-M100003, and other Grants KMU-EM-99-1.4 and DOH100-TD-C-111-002.
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dx.doi.org/10.1021/jf200566a |J. Agric. Food Chem. 2011, 59, 4288–4293
Journal of Agricultural and Food Chemistry
(29) McKelvey-Martin, V. J.; Ho, E. T.; McKeown, S. R.; Johnston, S. R.; McCarthy, P. J.; Rajab, N. F.; Downes, C. S. Emerging applications of the single cell gel electrophoresis (comet) assay. I. Management of invasive transitional cell human bladder carcinoma. II. Fluorescent in situ hybridization comets for the identification of damaged and repaired DNA sequences in individual cells. Mutagenesis 1998, 13, 1–8. (30) Chen, W. Y.; Wu, C. C.; Lan, Y. H.; Chang, F. R.; Teng, C. M.; Wu, Y. C. Goniothalamin induces cell cycle-specific apoptosis by modulating the redox status in MDA-MB-231 cells. Eur. J. Pharmacol. 2005, 522, 20–29. (31) Liu, M. J.; Yue, P. Y.; Wang, Z.; Wong, R. N. Methyl protodioscin induces G2/M arrest and apoptosis in K562 cells with the hyperpolarization of mitochondria. Cancer Lett. 2005, 224, 229–241. (32) Pushkarev, V. M.; Starenki, D. V.; Saenko, V. A.; Yamashita, S.; Kovzun, O. I.; Popadiuk, I. D.; Pushkarev, V. V.; Tronko, M. D. Effects of low and high concentrations of antitumour drug taxol in anaplastic thyroid cancer cells. Exp. Oncol. 2009, 31, 16–21. (33) Haas-Kogan, D. A.; Kogan, S. C.; Levi, D.; Dazin, P.; T'Ang, A.; Fung, Y. K.; Israel, M. A. Inhibition of apoptosis by the retinoblastoma gene product. EMBO J. 1995, 14, 461–472. (34) Ryschich, E.; Khamidjanov, A.; Kerkadze, V.; Buchler, M. W.; Zoller, M.; Schmidt, J. Promotion of tumor cell migration by extracellular matrix proteins in human pancreatic cancer. Pancreas 2009, 38, 804–810. (35) Ding, H.; Han, C.; Guo, D.; Chin, Y. W.; Ding, Y.; Kinghorn, A. D.; D'Ambrosio, S. M. Selective induction of apoptosis of human oral cancer cell lines by avocado extracts via a ROS-mediated mechanism. Nutr. Cancer 2009, 61, 348–356. (36) Belkhiri, A.; Richards, C.; Whaley, M.; McQueen, S. A.; Orr, F. W. Increased expression of activated matrix metalloproteinase-2 by human endothelial cells after sublethal H2O2 exposure. Lab. Invest. 1997, 77, 533–539.
dx.doi.org/10.1021/jf200566a |J. Agric. Food Chem. 2011, 59, 4288–4293
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Caroline Gumble from Make UK (formerly known as EEF) gave an informative, interesting & thought provoking speech at the joint lunch event last Friday hosted by Felixstowe Chamber of Trade of Commerce & Suffolk Chamber of Commerce.
It was the first time that the Suffolk Chamber had put on event in Felixstowe and the sun shone and the sea looked its best, till the fog rolled in towards the end of lunch. It was a great opportunity for networking across the county, and Felixstowe Ferry Golf Club was a friendly and welcoming venue to the business community of Suffolk.

subset: commoncrawl


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Darkovibes – Come My Way ft. Mr Eazi MP3 DOWNLOAD.
Ghanaian highly talented hitmaker, Darkovibes comes through with a new song titled "Come My Way".
The new Killbeatz-produced number had a feature from the Nigerian Award-winning singer, Mr Eazi who also added a nice verse.
Finally, Come My Way comes in a sequel to his following song "Mike Tyson" featuring Nigerian artist, Runtown.
Listen, download & share your thoughts below.


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SSE has announced plans to sell up to a third of its 50% stake in gas distribution network business SGN. The company said it was likely to return the cash to shareholders.
In results for FY2015/16 SSE said customer energy account numbers in GB and Ireland had fallen from 8.58 million to 8.21 million, but the decline was slowing. It hoped to grow other domestic businesses, it said, revealing plans for a national expansion of its home services business. It also said it wanted to 'build scale' in its broadband and telephony businesses. It promised new products, but also a reduced cost to serve by upgrading its web and digital customer communication channels.
The company said it had now installed 200,000 smart meters.
On generation, SSE said three wind farms – Dunmaglass, Clyde Extension and Bhlaraidh – would start up with Renewables Obligation subsidy in 2017. Next year will also see the start of construction at the Beatrice offshore wind farm.
Thermal generation "continued to be challenging" SSE said, but it expected that lower wholesale gas prices and the closure of coal-fired plants would see a trend towards more gas-fired generation continuing. As a result "SSE will continue and retain and develop options for new stations at Keadby 2 in Lincolnshire and Seabank 3 near Bristol". It expects to take a final investment decision on a second 'multifuel' unit at Ferrybridge this year.


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Slender is a first-person horror game. The goal is only eight manuscripts to search for thin and paranormal beings. There is a game called Slenderman, which is based on one of these issues, but it is not so scary or successful.
How to play sweet
The more you know about the basic hypotheses of the game, the faster you drain your health will be. So be careful not to see the enemy and determine your torch batteryDue to limited, occasionally, you need to be turned off to save. In addition, more sprints, with lower stability, so you only need sprint when needed.
Is it afraid
It is very nice to create a very important atmosphere. You feel like you, flashing the lantern and the cricket sound while you scroll through the hand-written woods. and limiting the general purpose of collecting 8 pages of manuscripts and therefore, few games are limited.
Easy game management: Mouse- View W, A, S D move to the left to move – Sprint Click the left mouse button – Drag the right button on the right page – QE flashlight – Increase / decrease technical problem
Note that WinZip or WinRAR is required to unpack the downloaded product.
Since the beginning of the "Slack", there were some spinoffs of different quality levels. If we try to get the worst thing we've tried with Softonic staff, so be sure to check it out:
Slender scary terrifyingIt's a game, Listen to whether you've heard about the Myth of Man.
A subtitle for the match has been added ("Eight pages") to separate from future versions.
Upgrade the main menu and add music. It also has links to trendy men and YouTube series info.
Multiple clarity sources (locked up to defeat every game).
It has been added to the shade (except significant in bright areas).
Increasing speed increases gradually when more pages are collected.
Cooling is considered offensiveAfter jogging / sprinting and reducing the residual leap rate. when it is
Start jogging / sprint, but immediately cut a 5% stamina. This will allow you to move
Strikes for a longer time, but jog / sprinkler causes you to get stuck again and again
to go fast (to effectively eliminate used assets).
The maximum distance seen decreases when more pages are collected; this is to keep up the same challenge
Those who wear clothes do not exclude them. For the same reason, the remote ShadowIt's not longer.
The Options menu will be added to skip the entry automatically.
Adding paused function, but you can stop static if it does not allow pause
in response to human vision).
An error occurred when the page tried to light up the page.
Delete one of the hidden modes (only time spent by the authors).
|49 4 User votes
- Slender: The Eight Pages Rosie FastDL Torrent
- Slender: The Eight Pages download
- Slender: The Eight Pages 32bit-64bit Harvey Torrent Download


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'So when I read the list of elected representatives on our Council, of 32 members there were only two women. I wondered how they could possibly assert their presence in the chamber?'
SO I knew we were home when the Customs Officer who was supposed to be searching the van for Syrian refugees, stuck her head in the door and said, did ye have a great time? O we did, we did! Welcome home, says she with a big grin.
You would think the old Irish charm would wear thin, but it never does. You could be saluting people on the highways and byways of Europe and never a Buenos Dias or even a wink back. We were hardly off the ramp in Ringaskiddy but fellas were giving us the customary nod and women were smiling. It's just how we are.
I rang a friend. What's new? Well, she said, the usual, women being bullied, murdered and dispatched. Could it be any more depressing and in the rain too?
I began to catch up with the litany of pain expressed by Majella Moynihan, the Garda who was wrongfully disciplined for giving birth. A reminder, yet again, of what so many women have dealt with behind closed doors. There is something so heartbreaking about the bullying of a young woman by an established group of powerful men. Our police force! Men who were supposed to have our backs and protect us. But the inevitable breaking of the mother child bond, ruining her life forever, was devastating.
I remembered how a group of us in Waterford used to send flowers to the wronged and the marginalised women of Ireland in the 1980s. Eileen Flynn, the New Ross teacher, sacked for "having an affair with a married man." Joanne Hayes in Kerry, wrongfully accused of killing her baby. And in the 1990s Roisin McAliskey, the pregnant daughter of Bernadette who gave birth in prison in England. It just went on and on.
But sending flowers was never going to be enough. It still isn't.
We have to get more women into all of the rooms where ignorance of women's bodies and hatred of women leads to such horror. If you are not around the table how can you really make the world a better place for women? We've been saying this for years but why is it still not happening?
Where were the women in the room when they were testing the efficacy of a range of common drugs? Apparently they only tested them on men and have no real idea what their impact on women's bodies might be? Even though we are prescribed them all the time? Or who was it who finally realised that heart attacks in women happen in a different way and all the previous information and warnings were only relevant for men? Where were women when they designed crash test dummies only based on male bodies, shapes and weight. And by the way could we have a breast friendly seat belt designed sometime soon please!
It took Sheryl Sandberg, the most powerful woman in the Facebook room to address the special needs of pregnant women. It happened because she had to park miles away from the building where her next meeting was taking place. A heavily pregnant Sandberg had to run across three car parks to get there on time. Why don't we have parking for pregnant women nearer to the door she suggested? Bingo. It changed because she was in the room.
During the last few weeks the Dáil has decided that mothers will have permission to breastfeed their babies anywhere as needed. There will also be special facilities for adoptive leave and a new Dáil creche. Would this have happened without women becoming more of a presence?
If women are a small minority, it is much too hard to sway the room. You need a critical mass of women to provide enough safety and numbers to effect change. So when I read the list of elected representatives on our Council, of 32 members there were only three women. I wondered how they could possibly assert their presence in the chamber? It reminded me of the sad image of a group of men from Waterford Council taking a stand against women's right to choose during the Referendum on the Eighth Amendment. Why do we continue to vote for men who haven't a clue about women's bodies and lives?
It's a good thing that Breda Brennan was elected Metropolitan Mayor! Straight away her first statement was to call for more inclusion and youth participation. She also wants to connect with carers and community groups. But we must have many, many more women in those rooms where decisions are made, to bring knowledge and experience of women's real experiences to the table.
By the way, the top image of today was President Trump in another room full of men discussing policy on Maternity Care in his new Health Bill. Not a woman in sight! Sigh…
Catherine Drea blogs at Foxglovelane.com


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2019 Kia Telluride
While it's still just a concept, rumors state the wildly glamorous Kia Telluride Principle, which debuted at the 2016 Detroit Auto Show, has been given the green light for production.
The 2019 Kia Telluride guarantees to be a cutting-edge, full-size SUV that presses technological boundaries without jeopardizing luxury. Telluride is a three-row, seven-seat hybrid vehicle with a muscular, upright position and distinct rear-hinged back entrances that open in tandem with the front doors to a 90-degree angle for ease of entry. The first 2 rows are fitted with four black-leather captain's chairs, behind which sits a folding three-seat bench. The middle seats recline nearly flat and feature fold-away footrests for ultimate comfort.
2019 Kia Telluride Design
The Telluride Concept can be found in with a far different look than we're utilized to from Kia. This SUV was massive at 70.9 inches tall, 79.1 inches large and 196.9 inches long, and its customized Sorento wheelbase was 121.3 inches long.
On top of being big, the Telluride boasted an upright style with plenty of bodylines to draw one's eye from one end to the other. It also boasted vertical taillights, hood scoops, double exhaust, and a bigger variation of Kia's Tiger Nose grille. Obviously, there are a few things that will not make it to the production Telluride, like the rear-hinged rear doors, but we anticipate the rest to be pretty near to the concept.
2019 Kia Telluride Interior
Inside, the Telluride had much of that principle feel. One thing we anticipate to make the shift to production will be its seven-passenger capability that includes 2 second-row captain's chairs and a third-row bench. We likewise anticipate all the current technology, like Android Auto and Apple CarPlay, a premium audio system, heated seats, a big touchscreen, and more.
2019 Kia Telluride Engine
The Telluride Concept flaunted a powerful hybrid powertrain that boasted a 270-horsepower 3.5-liter V6 and a 130-hp electrical motor with a combined 400 hp. On top of its huge power, this powertrain might deliver up to 30 miles per gallon highway, according to Kia's price quotes. While this sounds fantastic, we anticipate something more standard, like perhaps Kia's turbocharged 3.3-liter V6 or the 5.0-liter V8.
2019 Kia Telluride Pricing & Release Date
There is still nothing official on the Telluride's release, however it'll apparently be around for the 2019 or 2020 model year. Offered its likely positioning in the lineup, try to find the production Telluride to sit almost the Sorrento in pricing, which ranges from $26,890 to $47,290 (location costs included). The Telluride's competitors might consist of models like the Mazda CX-9, Jeep Grand Cherokee, and Dodge Durango.
Incoming search terms:
- 2019 Kia Telluride


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Cockroaches are among the most unwanted pests. They have a reputation for living in unclean homes, but these insects will actually stay anywhere with food and shelter. Since they spread a number of diseases, it's best to respond quickly to cockroach issues.
Cockroaches are among the most unwanted pests. They have a reputation for living in unclean homes, but these insects will actually stay anywhere with food and shelter. Since they spread a number of diseases, it's best to respond quickly to cockroach issues.
More Information
Biology & Behavior
Cockroaches are oval, flattened, fast moving insects. They have long, hair like antenna and a broad, saddlelike plate called a pronotum that covers the head. Adult stages of most species have wings, with the front pair of wings being thick and leathery. Cockroaches go through gradual metamorphosis in three stages consisting of egg, nymph, and adult. The eggs are laid in bean like egg capsules called ootheca, which may contain several dozen eggs. These egg capsules are often dropped around food sources or secured to surfaces. Some cockroaches carry the ootheca during its development. The immature stages are called nymphs. Several nymphal stages occur, each separated by a molt. The nymphs generally appear similar to the adult stage, but they lack wings and are smaller. Typically it requires 2 to 3 months to complete a life cycle. Cockroaches are among the oldest insects known, with fossils dating back 200 million years. As a group, the cockroaches have shown exceptional ability to adapt to and survive in a wide range of environments. Most cockroaches can develop on a wide range of food and their flattened body form allows them to move into most areas. Cockroaches have also developed a resistance to many commonly used insecticides. Cockroaches can enter buildings and containers of all kinds. They also may enter around loose fitting doors, windows, and through utility lines, and they may travel through sewers. Once within a home, cockroaches tend to prefer warm, dark, moist shelters and are often found near kitchens and food handling areas. Since cockroaches are nocturnal they are rarely seen during the day. Aside from their reputation as a household nuisance, they may soil areas with their salivary secretions and excrement, leaving an unpleasant odor. Cockroaches and cockroach parts also produce allergic reactions in some humans. Cockroaches have not been found to be direct carriers of human disease. However, their feeding on filth or disease organisms is why they often contaminate food and utensils. They are suspected of helping to spread diseases such as dysentery, diarrhea, and food poisoning. Most cockroaches are tropical or subtropical in origin and possess generally harmless habits. A few have developed into serious pests, including several species of cockroaches that have been introduced into Utah. The habits of common cockroaches are as follows.
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DAVENPORT, Iowa -- Scott County has been added to the Presidential Disaster Declaration after part of the downtown was severely flooded.
The declaration was originally granted on March 23. Scott County was added to the list in mid-May, according to the office of Iowa Governor Kim Reynolds.
This means that Scott County residents can now apply for the Federal Emergency Management Agency's Individual Assistance Program. Through this program, help is provided to homeowners, renters, and businesses.
Click here to apply or call 1-800-621-3362 or I-800-462-7585 TTY.
Because Scott County is now part of the presidential declaration, they are no longer eligible for the Iowa Individual Assistance Program.


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The mystery of the disappearance of Sanxingdui culture
Researchers will determine the age of the 'Giant of Cerne Abbas' geoglyph
The mystery of the Anasazi, the mystical "tree of life"
Druids of Scotland used lightning in their rites
All Dead Sea scrolls turned out to be fakes
Shocking video with bodybags in New York while Israel prepares for the Messiah
The poles are shifting, the magnetic field is turning over and it will be very unpleasant for our civilization!
Indian Indigo boy warning on the imminent start of war
Red mushroom cloud over Portugal and Bats falling dead in Israel
Post apocalypse. The best vehicles for self-isolation
New World Order may be just around the corner now
Nibiru appeared on Google maps. A pretext?
The scandalous Blue Beam project. The coming of Antichrist or a Great Deception?
A wave of conspiracy theology swept the planet
Coronavirus – A Secret Plan to Prepare the World for the Apocalypse
Olivia Rosane, EcoWatch Waking Times It looks as if firefighters in Australia have succeeded in saving a secret grove of prehistoric trees belonging to a species that dates back to...
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Any cookies that may not be particularly necessary for the website to function and is used specifically to collect user personal data via analytics, ads, other embedded contents are termed as non-necessary cookies. It is mandatory to procure user consent prior to running these cookies on your website.


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In recent years many global firms--including Starbucks, Google, and Amazon--have come under fire for avoiding paying faxes in one country by shifting their profits to a country with lower tax rates, Attention has been largely focused on companies avoiding tax in developed countries, but our new WIDER Working Paper documents a strong relationship between economic development and the prevalence of multinational tax avoidance: countries with low incomes and poor governance are more exposed to tax dodging. This is particularly worrying given the urgent revenue needs and already limited tax bases of developing countries.
Multinational tax avoidance costs hundreds of billions of dollars
Multinational Arms reduce their lax bills substantially by shifting profits from countries with high taxes to countries with low taxes. The various profit-shifting techniques are fairly well understood. Transfer mispricing, aggressive financial structures, and the strategic allocation of intangible assets, give multinational firms a large degree of flexibility to decide where their profits should be taxed.
Recent evidence suggests that the resulting loss of government revenue is likely to be counted in hundreds of billions of dollars every year.
More tax dodging in less developed countries
While almost all studies of multinational tax avoidance focus on developed countries, a rich dataset with financial information on 210,000 corporations in 102 countries allows us to take a global perspective.
We document that the profits reported by corporations depend systematically on their incentives to shift profits to foreign affiliates.
Concretely, if we consider two corporations in the same country with similar inputs of capital and labour, the one whose parent company faces the lower tax rate tends to report the lower profits. This pattern is clearly consistent with tax motivated profit-shifting: the lower the tax rate of the parent, the larger the tax saving from shifting profits by means of transfer pricing or otherwise.
Interestingly, the relation between reported profits and the incentives for profit-shifting varies systematically with the level of economic and institutional development. In countries with low incomes and poor governance, the sensitivity of corporate profits to profit-shifting incentives is much stronger.
Evidence of tax avoidance in the raw data
Figure 1 provides an illustration of aggressive profit-shifting in low-and middle-income countries. For...


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Coolfire Solutions, a St. Louis-based creator of a situational awareness delivery platform, raised $11.5m in Series B financing.
An undisclosed strategic investor led the round along with significant follow-on investment from Clayton Venture Partners, the venture capital arm of Enterprise Holdings, and IrishAngels.
The company intends to use the funds to accelerate sales, marketing and product development for commercial industries.
Led by Don Sharp, Chief Executive Officer, Coolfire Solutions provides the Ronin Platform, a real-time situational awareness delivery platform, built to integrate data from any source and transform it into actionable intelligence. Ronin, developed initially for the U.S. Military, is now being widely adopted by innovative industry leaders such as Enterprise Rent-A-Car.


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This article does not cite any sources. (October 2008) (Learn how and when to remove this template message)
In botany, a photoassimilate is one of a number of biological compounds formed by assimilation using light-dependent reactions. This term is most commonly used to refer to the energy-storing monosaccharides produced by photosynthesis in the leaves of plants.
Only NADPH, ATP and water are made in the "light" reactions. Monosaccharides, though generally more complex sugars, are made in the "dark" reactions. The term "light" reaction can be confusing as some "dark" reactions require light to be active.[citation needed]
Photoassimilate movement through plants from "source to sink" using xylem and phloem is of biological significance. This movement is mimicked by many infectious particles - namely viroids - to accomplish long ranged movement and consequently infection of an entire plant.
|This botany article is a stub. You can help Wikipedia by expanding it.


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Just reading the word 'exercise' can provoke a whole cascade of self-addressed questions: Am I doing too little? Am I doing too much? Am I healthy? What exercise is best for me? Physical exercise, to be specific, is any activity that requires physical effort, and so enhances or maintains physical fitness and health. From marathons to evening walks, exercise can be performed for various reasons. This can be both physical, e.g. increasing athletic strength or weight-loss, but also mental. This is as exercise triggers a release of chemicals in the brain, such as serotonin, endorphins and dopamine. This can dull pain, better your mood and remove stress.
Michael Mosley Does cold water swimming have health benefits?
Michael Mosley


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The King's Home
November 2, 2013
November 2, 2013 This combination of the King's Ranch Campuses and Hannah Homes provide 24 hours a day, seven day s a week care. There are nine residential youth homes and two youth campuses. Hannah Homes has nine residential group[Read More...]
Alzheimer's of Central Alabama (ACA)
October 4, 2013
On October 4, 2013 Ontime Electric donated money to the Alzheimer's of Central Alabama (ACA). We donated in honor of Dale Evan's who is the sister of Doug Demdedicis ( both are to the right of the picture.) Doug shot[Read More...]
We Support Samford University!
August 30, 2013
AUGUST 30, 2013 OnTime Electric proudly supports Samford University Football Program! Goodluck on your 2014/2015 Season!! Go Bulldogs! 2014 SAMFORD FOOTBALL SCHEDULE 8/30/14 . 6P.M. Vs. TCU 9/11/14 . 6 30 P.M. Vs. Stillman College @ Samford 9/20/14 . 2P.M.[Read More...]
We're Moving!
August 27, 2013
August 27,2013 OnTime Electric is moving from Homewood to Old Rocky Ridge Road! We are in the process of building our own two story building, and we are so excited! The new building will give us much more room to[Read More...]
Congratulations to our OnTime Members
August 22, 2013
AUGUST 22, 2013 Thank you, Mike Scott, for 2 years of service here at OnTime Electric. Your hard work doesn't go unnoticed. We appreciate everything you do for the company. Thank you Nicole Murry for your hardworking commitment this year. We[Read More...]
Morgan's Blood Drive & Ride
August 17, 2013
August 17, 2013 Everyone meet Morgan Grace. She is the 3 month old daughter of one of our technicians named Tony Fields. Morgan Grace has a very rare condition that causes a child to develop without the lower part of[Read More...]
The Clay House Children's Center
June 24, 2013
Vestavia Hills Chamber of Commerce Luncheon
June 1, 2013
Press Release: June 2013 Vestavia Hills Chamber of Commerce Luncheon Guest Speaker Governor Robert Bentley The Governor addressed State of Alabama Issues.
Hoover Day
May 4, 2013
Celebrate Hoover Day! May 4th, 2013.
Business Break -David Crouch
April 27, 2012
4-27-12 Adkins On-Time 1 from Kerry Adkins on Vimeo.


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10 Tweets That You Can Fully Relate To If You Grew Up In Saudi
Living in Saudi Arabia comes with a lot of perks, privileges and experiences one most likely, would never see elsewhere. Growing up in the Kingdom, similarly, is an even greater extent to all those positive attributions.
Wherever you've decided to move to, it is a sure thing that certain things will remind you of the beauty and simplicity of having grown up in the Kingdom.
These tweets are just some of the examples of that beauty:
1. The 'Where are you from?' question doesn't ever get any easier to answer
No seriously.
2. You understand the religion, the Kingdom's culture and the people more
In other words, we've all had to adapt and learn to be open-minded sine Saudi is such a melting pot of cultures.
Growing up, I never really saw Muslims, as different. They were hospitable when me, and my family, resided in Saudi. Now that I am in my homeland, I am very much willing to do the same for them, when they decide to go here. #Protect_A_Muslim_Day
— Allan Joseph Aggabao (@aj_aggabao) March 12, 2018
3. You had to always have fesh fash, drink your suntop & play with the adorable sticker book
'fesh fash' 'salad snacks' 'ricco ricco' 'suntop' (w/ the sticker book) – the junk of my/our youth growing up in Saudi Arabia ☺ YUMMY
— noma afiouni (@opiumgrace) April 26, 2011
4.You especially couldn't go wrong with Lipton Tea
Green, Black, Red tea. Lipton is the ultimate OG.
Can't go wrong with a bit of Lipton Tea. #SaudiMemories
— ???????? (@AbidaZahar) April 11, 2017
5. How beautiful and serene being here felt.
Close to Maghrib Salaah in Madinah! The umbrellas close in!#SaudiMemories pic.twitter.com/XXKswzZdYu
— AJ (@AJ_AKH) May 25, 2013
6. Petrol prices were never an issue
#SaudiMemories 12 litres of petrol for the equivalent of £1.. In UK, 12 litres is about £15-17
— AJ (@AJ_AKH) January 20, 2013
7. When you see Saudi companies reppin' elsewhere and get a sense of pride
Like Al Baik in Indonesia or an Almarai ad in Egypt.
Omg just saw a billboard for Al-Marai milk on 6th of october bridge! Men emta it's been here? #Saudimemories
— Ethar El-Katatney (@etharkamal) October 27, 2010
8. During summer, washing your face or showering had you running to the side of the bathroom
If you grew up in Saudi, you just know. Summer heat= boiling hot water even when the tap is on cold.
yung tubig sa spray, shower, gripo. shiet boiling water HAHAHA #SAUDIFEELS
— Ohlala (@DiscretlyBoring) July 14, 2017
9. You're always looking for that authentic local kabsa taste everywhere you go
Because kabsa is more than just a dish, it is a way of life.
Perks of living in an area with so many Arabs. Authentic kabsa chicken for dinner! #Saudifeels pic.twitter.com/wcC5BJP9oe
— janina sarmiento (@janinamariee) March 26, 2015
10. If you lived in the Aramco compounds, you're always going to be remember the great memories
READ MORE:The 8 Signs And Photos Will Bring Back A Whole Lot Of Your Memories


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2015 Porsche Cayman GTS Returns with a Vengeance
Fans of the Porsche Cayman model have a lot to be excited as the new model year approaches. The model has been updated and upgraded in a number of ways for 2015, and we have the scoop here for you today. Starting on the exterior, the eye is immediately drawn to new matte-black accents on both the front and rear fascias. This touch is matched by similar black-finishes on both the front and rear lights, and the model also includes black, 20-inch Carrera S rims to complete the sinister look. And under the hood, an incredibly powerful 340 horsepower engine resides. Have a look at the video below for more details.
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Avatar 2,3,4,5 and Three star wars movies are Announced
Walt Disney Studios has pushed the arrival of the first of James Cameron's four Avatar continuations by a year, reports said on Tuesday. Avatar 2 will currently be out on December 17, 2021, rather than December 18, 2020. The ensuing titles have comparatively been delayed, with the new discharge dates for Avatar 3, 4 and 5 pegged for 2023, 2025 and 2027.
"The organization is changing the introductions of different movies it acquired subsequent to purchasing the greater part of 21st Century Fox's film and TV resources in a $71.3 billion super merger," Variety noted. Likewise in the pipeline are three more Star Wars films, which will pursue the December 20 discharge Star Wars: The Rise of Skywalker. The first of these motion pictures is booked for December 16, 2022, while the other two are gotten ready for December 20, 2024, and December 18, 2026.
"We're eager to set up a vigorous and different slate that establishes the framework of our long haul technique, uniting a broadness of movies from Disney, Pixar, Marvel, Lucasfilm, Fox, Fox Searchlight, and Blue Sky Studios to make an exceptional accumulation of true to life encounters for gatherings of people far and wide," Cathleen Taff, the studio's leader of dramatic appropriation, was cited as saying.
Steven Spielberg's report on West Side Story will be out on December 18, 2020, while the Emma Stone-starrer Cruella will be out on December 23, 2020.
In different changes, The New Mutants, the X-Men motion picture featuring Game of Thrones star Maisie Williams, will be out on April 3, 2020, rather than 2019. Gambit, another Fox turn off from the X-Men films, has been dropped from the logbook for the present.
Advertisement Astra, featuring Brad Pitt as a space explorer, will be discharged on September 20, 2019. Artemis Fowel, in view of the top of the line books, has been pushed by a year to May 29, 2020.


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Top rated gambling apps
Best Real Money iPhone Casinos & Gambling Apps Find the highest rated iPhone casinos ranked by our users for great games, speedy payouts, security and software quality. The Best of the Best. Now, it's already quite true that many online gaming apps have the features spoken of above. Of course, these can't all be considered to be the best iPhone gambling apps for So, something else has to differentiate between them in order to locate the best of the best in this area. The House of Fun has only one goal in mind – to create the best casino apps in existence! The House of Fun is home to a huge selection of online casino games that are specifically designed to give you the ultimate casino experience right at your fingertips.
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It Is Interesting about casino
- The casino is the most common place in which suicides are committed
- The center of the casino is Las Vegas. Every year 40 million gambling people from all over the world come here.
The iPhone device is perhaps the most popular handset in the world right now. This is probably due to the fact that it is a product of the Apple company. After all, big names sell big products. It is for this reason that most of them will offer up an iOS download version of their platform before they move on to versions for other devices.
However, with the market for such apps constantly growing, new and existing gaming platforms will aim to bring forth new and impressive apps. The year will no doubt be riddled with companies launching their own mobile versions of their sites. We intend to take an in-depth look at these apps and provide you with a complete review and rating for them.
Of course, anyone can do this. However, we want to build upon that idea and really keep you informed on the nitty gritty. This will start with its external appearance, and move on through the usability of the app, the design of it, the games included within and much more. It is, after all, one thing to provide a downloadable app with a beautiful appearance. Of course, it has to be aesthetically pleasing at the same time, and ergonomically usable.
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Он довольно быстро сориентировался в Лебяжьем, и Маша вышла на крыльцо и провела его в дом на второй этаж. Женщины отдались ему на месте, вдвоём обслуживая его стоячий член ртом, а затем и чем поприятнее, после чего получили дозу мужского семени. Affectionate fingers and a gentle tongue will bring you to frenzied roarand then will bring you t I want a hot man because I am hot and insatiable. Прелестные совратительницы обнажают свои тела и тем самым сводят мужчин с ума.
Drove it through the base of Jake's spine. The two stood embraced, in a pool of warm fresh blood. Обладатель здоровенного агрегата долго таранил её чёрную дыру, пока в итоге не кончил на упруги булки.
There are hundreds of mobile casino apps that are available for players on the market. This is why it can be quite difficult for them to make up their minds and select one casino app. This is why, since our aim is to help players and make their mobile gambling experience as easy and as smooth as possible, we came up with a list that contains some of the top casino apps in the industry.
This list contains the names of these apps and a brief description on each and every one of them. Royal Panda Casino made its entrance into the world of mobile gambling with the help of real players that wanted to make a difference in gaming. This is why players will enjoy a hassle-free mobile gaming experience through a very simple and a user-friendly software and casino interface.
Players will also enjoy a remarkable selection of NetEnt and Microgaming games. This includes table games like European Roulette Pro, Blackjack and others. Players will also be able to take advantage of numerous promos and bonus offers that are dedicated to new players as well as loyal and existing ones such as the loyalty program and the regular competitions.
Royal Panda was is powered by one of the biggest names in the online gambling industry, NetEnt. Players can either choose to create a new account for the mobile casino or they can log into the mobile casino with the same account that they use to access the online casino. Royal Panda Mobile Casino is certainly a recommended mobile casino, as it knows how to satisfy its players and how to keep them happy. This includes a constantly updated supply of promos and offers as well as an outstanding selection of mobile casino games.
The mobile casino is compatible with almost every smartphone and tablet out there. This is why iPhone players and Android players can enjoy this casino on the go, as well as Windows Phone users.
Gambling commision forms
This message is displayed if 1 your browser is not standards-compliant or 2 you have you disabled CSS. Read our Policies for more information. Please enter your e-mail address to sign up for updates or to access your subscriber preferences. Welcome to the new Charity Gaming forms page. The new forms listed below comply with the new statute that took effect on July 1, Please review the License Types and Related Activities section on the website to determine which licenses best suit the needs of your organization.
The numeric identifiers for the old forms have been replaced with alpha symbols on the new forms, and the applications are now license specific to help simplify the application process. Get information about Charity Gaming. View the Indiana Statutes and Rules concerning gaming. Sign up for the Voluntary Exclusion Program. View the Monthly Revenue reports. View the yearly riverboat evaluation reports.
Become a supplier to an Indiana gambling operation. Text Reader What's this? Calendar Raffle License Application No longer used.
Free Roulette
Free Roulette
The thrill of watching the spinning red and black Roulette wheel has long served to grip many avid gamblers around the g...Read More
Play Blackjack
Free Blackjack
With its great payouts, easy-to implement strategy and simple rules, Blackjack has become one of the most popular casino...Read More


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Item Detail
Item is New without tag & wash care.it has label attached to it.
Size: Small
Bust:19" across (laying flat) 20"across (Stretched)
Length:30" Shorter part 26" Longer part
Color :Green
Fabric :Rayon & Polyester
V neck.
Long Sleeves.
Fabric patchwork on back & shoulder.
Slit on both side toward the hem.
High & low hem.
Raw edge.
Top is semi sheer & comes without inner
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8ware DVI-A (Analogue) to VGA HD15F Adaptor
The DVI to VGA adaptors allows you to connect your VGA monitor to the DVI port on your computer. Please note this is for use with Analogue DVI connections only.
Estimated Availability
10 or less units in stock
*Our stock is a mix of Supplier and HT Stock.
All shipments are subject to our standard delivery policy.
TaxEx. GST:$3.23
GST Amount:$0.32
DetailsTech Code:AW583
Manufacturer Number:GC-17MA15F
Images may differ slightly from actual product


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Maguari-Table Cover - Have A Nice (Brown)
Vendor : Maguari Textile
Special Price PKR 499.00 Regular Price PKR 1,200.00
Categories: Defalut catagory , Kitchen Accessories , bumper sale , Maguari , Maguari store
Availability: In stock
Maguari-Table Cover - Have A Nice (Brown)
Colored table cover. The size of the tablecloth is 140*160cm . Our table cloths have a very high attractive colors so that they can be used on any table with Beautiful look. Your tables will look elegant with these beautiful table covers.
|Product Brand
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The bugg is also on xbox one !
i report it to and they say.
"Thank you for contacting us regarding Train Sim World.
The version in RT is newer and features improvements we...
i do think its weird because why will the dots it self seeing sharp en when the dots turn on it will be a mess i think DTG was to cheap on this one
im playing on the Xbox One X and de destination board look off and not sharp
and the BR1442-6 talent2 !!!
ps4 can zoom in ?
it would be nice to have a zoom in function for Xbox/ps4
- replace (tap) toggle corsur with the zoom in/out and swam the corsur 'zoom in/out...
it would nice if i
TrainSim-Dmitri will the DB BR 146 later added to RSN in a fix or update?
TrainSim-Dmitri will the olders routes also get a update so we can set the destination display on ?
TrainSim-Dmitri why will Xbox and PS4 not get the 20% off for pre-ordering ??
When will get xbox or ps4 the sale's ??
Train Sim World®: Thalys is an all new route that brings to life the experience of driving Thalys passenger trains on one of the...
Nice, so later in this year we can see the Rapid Transit & Nec New York add-ons releasing on the Xbox one ?
will the add-ons ( NEC New York, Rapid Transit ) coming to xbox if so when can we expect a release ?
Separate names with a comma.


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Send a message to set-up a video call for a free quote
Director Mr P Oliver & Director Mr M Docherty, M Docherty
Hello and welcome to Home Cert Ltd. We are NICEIC Approved Contractors and we have worked on a plethora of projects ranging from small to large, we have much experience, tacit knowledge and know-how to apply to your electrical requirements and projects. We offer an extensively wide range of services from domestic small installations right up to complete commercial fit out projects. This includes:
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City & Guilds- Level 3 Award in the Periodic Inspection, Testing and Certification of Electrical Installations- Level 3 Certificate in the Requirements for Electrical Installations
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Gravina's Window Center of Littleton is a window replacement company headquartered in Littleton and serving the Denver Metro Area. We always offer a free estimate on new windows and doors. As an A+ Better Business Bureau Rated Company, family owned and operated window dealer, we constantly strive for excellence with outstanding installation in Infnity fiberglass window and door replacements.
Infinity from Marvin Replacement Windows
With energy costs getting higher, it may be necessary now, more than ever, to invest in replacement windows. Inefficient and drafty windows and doors affect your home in many different ways. But don't worry! We have the window solution for you.
Infinity from Marvin Replacement Windows and Doors
Over the years, we have found that when homeowners insist on replacing with vinyl windows, they are just putting a bandaid on their problem — an expensive one at that. Vinyl windows expand and contract under Colorado weather conditions — making vinyl windows challenging to open and close. This warping and shifting affect their performance and durability. Time and time again we see people needing to replace their windows again. If they had only replacement them with something stronger. Infinity created Ultrex fiberglass with one goal in mind: develop the most durable window material in the industry. It's not only eight times stronger than vinyl — it resists expanding and contracting in any weather. So you get a secure, snug fit that will endure. When customers choose Infinity from Marvin replacement windows, they know they will never have to worry about how they perform. Infinity from Marvin windows with Low-E Glass and Argon meet Energy Star requirements. Backed by Marvin Windows, homeowners are getting windows that are "Built for Life!" Infinity fiberglass windows are the most durable fiberglass replacement window on the market.
If you're starting to think about replacing your windows or are in the planning stages of your project, we can help you explore your options, answer any questions, or create a quote. It is the perfect window for your home. Replace your windows with Infinity from Marvin and breathe easy.
A family tradition since 1973.
Gravina's Window Center of Littleton is a Family Owned and Operated Window Replacement Company, Built on Family Values Since 1973
Infinity from Marvin Windows Dealer | Window Replacement
From patio doors to window replacement, choosing the best fiberglass windows is a no brainer. Our Infinity fiberglass replacement windows and Infinity patio doors are designed to fit your project plans perfectly. You can count on each fiberglass window replacement to be durable, energy-efficient and secure. Available in a variety of sizes and shapes. As Infinity's oldest replacement window company in the country, Gravina's Window Center of Littleton offers the full line of Infinity from Marvin replacement windows. Made of Ultrex® fiberglass, Marvin's patented pultruded fiberglass, Infinity windows combine the best strength, comfort and energy savings on your utility bills for Denver homeowners.
Infinity Windows Brochure
Partners with Infinity from Marvin Windows and Doors
The value of any Infinity from Marvin® window or door goes far beyond the quality of its materials and construction. Infinity windows and doors are built to last, long into the future. There's a reason you won't find Infinity from Marvin windows and doors in the big box stores. It's only through independent window installers like us that can offer an unparalleled level of support and expertise. Choosing and installing replacement windows properly involves a lot more than people can imagine. We work only with homeowners to find the best solution to make beautify your home and improve it's curb appeal.


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Fire Pit Dining
Perfect for winter sunshine and cool summer evenings you can dine intimately or like royalty with family and friends on our unique range of gas operated fire pit dining sets. Ranging from 4 to 8 seats, square or rectangular, you can mix and match our exclusive stylish dining chairs to your own taste, quality and comfort. Made from all weather proof premium HDPE (High Density Polyethylene) rattan. We offer top quality rattan dining sets for unbeatable prices.
Please Note - Our Fire Pits do not come with Propane Gas.
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The United States' Role in Causing the Nicaraguan Revolution
The Nicaraguan revolution of 1979 is an event that many American citizens may not know about. What is likely less understood is the United States' role in the cause of this revolution. The US actually played a very important role in causing the Nicaraguan revolution. The US did three major things that strongly influenced the revolutionaries to revolt against the government. The US helped create the National Guard of Nicaragua, a group that abused citizens and blatantly disregarded for human rights. The US was also complicit in the assassination of Augusto Cesar Sandino, a citizen who fought against US Marine occupation in the 1930's. Finally, the US supported the Somoza family, a series of three dictators who held Nicaragua from 1939 until 1979 when the revolution occurred. The United States involvement is not limited to these three occurrences, but these three examples are important causes of the revolution. To provide a better understanding of the revolution and the United States' involvement in Nicaragua, the historic setting is necessary.
The first case of US involvement in Nicaragua was the Walker Affair, of 1856. William Walker ventured to Nicaragua from the United States in 1855 on the invitation of Nicaraguan Liberals, who hoped his assistance could help them win a war against the Conservatives of Nicaragua. Walker easily defeated the conservatives because of his "aid of private American financing, superior firepower, and no small amount of luck" . At the end of this war, however, instead of handing over the regime to the liberals he had helped, he made himself the president of Nicaragua . Once he was president, Walker legalized slavery and made English the official language of Nicaragua, a historically Spanish speaking country. Clearly out of touch with many Nicaraguans, Walker is still hated in Nicaragua today . In 1857, the US arranged for Walker to surrender and leave Nicaragua, only to have him return to Central America in 1860; however, he was tried by the Hondurans and put to death . Walker was only the first of many more interactions between the United States and Nicaragua.
The US marine occupation began in 1912 and continued to 1925, ended, and then occurred again from 1926 till 1933. During this time period, there were a variety of reasons for the US occupation of Nicaragua. The most prominent reason seemed to be the geography of Nicaragua. Holding Nicaragua gave the United States an area that would allow, first of all, US influence over more of Central America, as Nicaragua is right in the middle of Central America, and, second of all, it was seen as an area suitable for a transoceanic waterway . Since Nicaragua borders both the Pacific Ocean and the Caribbean Sea, a canal connecting the two would be fairly feasible. The existence of this canal could bring great profits to US investors and US companies. This US occupation eventually led to the creation of the...


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Choice of Universal Studios, Disneyland, Disney's California Adventure, LA Tour, Palm Springs Shopping, San Diego.
(incl. tax and fees)
Posted by: kishan on 2014-03-17
In Los Angeles, it is suggested to have the possibility to provide flexible options to do evening tours to Hollywood/LA city tour, covering some locations along with theme parks.