text:
(WASHINGTON) -- The Clinton administration asked the Supreme Court today to revive a law aimed at shielding children from Playboy Television and other sexually explicit cable TV channels. The law, struck down by a lower court, is Congress' attempt to limit "graphic, sexually explicit adult programming that is available on cable television to children with merely a flip of the dial," Justice Department lawyer James A. Feldman said. But the lawyer for Playboy Entertainment Group called the 1996 law "a case of regulatory overkill" that would restrict programming even to households without children. The law violates the Constitution's free-speech guarantee, and a decision to uphold it could "open a wide avenue" for regulation of other new technologies, said Playboy Entertainment lawyer Robert Corn-Revere. Under the law, cable systems could show sex-oriented networks only during overnight hours if they did not fully scramble the signal for nonsubscribers. Picture and sound occasionally get through to nonsubscribers when a cable channel's signal is only partly scrambled. A Florida woman complained to Congress that she found her 7- and 8-year-old children "transfixed" by sex scenes on an imperfectly scrambled channel. A decision on whether the law went too far is expected by late June. Feldman urged the justices to compare the measure's limits on speech with the "evil it's addressing." Government lawyers had submitted to the court examples of sex-oriented programming that children could see and hear. "I wouldn't even read the descriptions in public," said Justice Antonin Scalia. "It seems to me obscenity," which is not constitutionally protected. But Justice John Paul Stevens noted that the law did not address programming on other cable channels that are not primarily sex-oriented. "We see an awful lot of strong language on WGN," Stevens said. "I'm often shocked at what I see on television." Corn-Revere said the law would restrict all of his client's programming. "There is no distinction between hard-core pornography ... and safe-sex information if it's shown on Playboy Television." Corn-Revere said the law contained an alternative that requires cable channel operators to block any channel, free of charge, if a customer requests it. But Justice Stephen G. Breyer questioned having an alternative in which people have to take action to stop the signal from coming into their homes. Breyer said that in today's world, "many, many thousands of children come home from school and there's no one there" to know what they are watching on television. The law was enacted as part of the 1996 Communications Decency Act. Cable operators that don't fully scramble or block sex-oriented networks for nonsubscribers can show those "indecent" programs only between 10 p.m. and 6 a.m. Playboy challenged the law as a violation of the Constitution's First Amendment, which protects freedom of speech. Indecent material is constitutionally protected, while obscene material is not. A federal court struck down the law in December 1998, noting that another part of the law already requires cable operators to completely block any channel upon a customer's request. The trial court said giving customers adequate notice of that choice would be a less-restrictive alternative to banning all daytime adult-oriented programming. The Supreme Court cited free-speech protections in 1996 when it struck down parts of a federal law aimed at restricting children's exposure to indecent programs on some cable channels. The justices ruled the government cannot force cable operators to segregate all indecent programs on a single leased channel, nor can it let cable operators opt out of carrying public-access channels that feature indecent programs. In 1997, the court ruled that Congress' effort to keep pornography off the Internet violated the First Amendment. The 1996 law made it a crime to put "indecent" or "patently offensive" words or pictures online where they could be found by children.
50 Shades of Grey ~ Cinema Seen
XRCO 2015 Hall of Fame
Interview with Ela Darling
Derrick Pierce Interview
The News Rack: Naked Swingers
Interview of Holly Heart
ED Expo to Big Easy
Hof on Phoenix Hooker Bust
I Know You
Cal/OSHA vs Evil Angel
Layla Price at Foxxx Booth
Star.XXX Blasts Off
Puma Swede on Jukeboxx Live
Nikki Phoenix Party
Viva Las Vicki
Freedom Acres Open House
Kendra Lust in Detroit
Starr Sisters in Houston
Nikki Phoenix Update
MWA: 10th Anniversary Column
Vegas Heat Party
XBIZ Rooftop Party
Welcome 2015!
Canadian Foot Porn
Actress as an Artist
Pushed Into the Corner
Tod Hunter Press Releases
Global Adult Industry Association
Pornography Feminism
Merry XXXmas, Happy Xanukkah
Rock'N'Sexxxy 12/10/2014
Karlie Montana Interview
Deep Vision ThunderRama
Hackin Jack vs Chainsaw Chick
BBW Eliza Allure Interview
Tara Lynn Foxx Retires
Treacherous ~ Reviewer Rated
Bright Lights, Lonely Nights
Taormino Speaks at Goucher
Cumisha Amado at Sagebrush
Vivid Radio 1st Anniversary
The Gardener ~ Reviewer Rated
BoodiGo: Privacy & Porn
Shades of Scarlet ~ Reviewer Rated
AINews: Skow Among Best
Heaven & Hell Halloween Party
These Things We Do ~ Reviewer Rated
Farrah Abraham at Hustler Hollywood
Sex Workshop Hustler San Diego
Halloween Art Show
O Awards Pre-Noms Open
Trophy Girl Casting Call
Cum in Me Baby 4 ~ Reviewer Rated
More Phoenix Mainstream
BoodiGo Partners PornGuardian
BoodiGo Supports ASACP
BoodiGo Blocks Child Porn
Boodigo Adult Search Engine
AVN Show Discounts End Today
Inside The Industry 10/08/2014
Amber Lynn at Wasteland
Nikki's Fit as Phoenix
Vivid Extends Patrick Hosting
Fake Test Results
Angelyne on Amber Lynn's RNSU
Red Cardinal Wraps Betrothed
Siri Wins Round 2
J.Lo Doc Johnson Offer
Stripclub Microbrewery on CNN
Father's Day ~ Reviewer Rated
Our Father ~ Reviewer Rated
Nikki Phoenix Album Released
Passport to Hustler Event
Fox News Wasteland
Asianmodelpalooza 14
Nikki Phoenix Appearances
Nikki Phoenix Karaoke XXX
Nina Elle Retains Star Factory
Tasha Reign Grads UCLA
Tera Patrick Hosts Vivid Radio
It's Just Work
Traci Bryant Goes Legal
CET Free Panel Month
Miss LA Karaoke XXX
Freedom Acres Location
Summer Lovers
Nikki Delano at Centerfolds
Karen Summer Returns
Advertise on AINews
Cytherea Auctions Fan Scene
Entertainment is Entertainment is Entertainment
Pornstar Graduates Law School
AHF Against AB 999
CraigsErotica Letter to Senators
Amazon Crushes Small Business
Letter of Equality
ASACP Service Recognition Award
Suit Filed Challenging Measure B
ASACP Ready For Internext
Octomom Loses Civil Suit
ASACP at XBIZ 360
Crakmedia ASACP Corporate Sponsor
Mo Reese Statement
CAM4 Newest ASACP Sponsor
Mo Reese FSC Nom
Amber Lynn Seeks FSC Board
Suit Against Measure B
Law Puts Con in Condom
No on B: Here's Why
NO on B Campaign
NO on B Bus Tour
GFY: Vote No on B
Margold on Erection Election
Alex Chance in Documentary
Yahshua: No On B
No On 35 Rally
Why No On B
Measure B Threatens Freedom
Measure B Protest Video
No On B Raffle
Alia Janine: No On B
AHF Vilifies Porn
No on B Event
Alia Janine Against Measure B
Fight Measure B
Takedown Piracy Removes 10,000,000
John Stagliano Keynotes CatalystCon
Hirsch Blasts Trueman
Hirsch Cautions GOP
LATATA Files Injunction
Child Porn Hotline Increased
Vette Scores on AFF
Nicole Houde Assault Arrest
YouJizz Sued
Dickinson Defends Travolta
Kardashian/Humphries Divorce Deposition
Three Stooges Porn Controversy
Suing: Wasn't Sexy Enough
Lords of Acid Censored
Nate Glass on CNBC
Law & Politics Section Index


text:
Fax: +81-3-5696-4264.
Cancer Therapy
CS-706, a novel cyclooxygenase-2 selective inhibitor, prolonged the survival of tumor-bearing mice when treated alone or in combination with anti-tumor chemotherapeutic agents
Article first published online: 20 NOV 2007
DOI: 10.1002/ijc.23250
Copyright © 2007 Wiley-Liss, Inc.
Additional Information
How to Cite
Senzaki, M., Ishida, S., Yada, A., Hanai, M., Fujiwara, K., Inoue, S.-I., Kimura, T. and Kurakata, S. (2008), CS-706, a novel cyclooxygenase-2 selective inhibitor, prolonged the survival of tumor-bearing mice when treated alone or in combination with anti-tumor chemotherapeutic agents. Int. J. Cancer, 122: 1384–1390. doi: 10.1002/ijc.23250
Publication History
- Issue published online: 21 JAN 2008
- Article first published online: 20 NOV 2007
- Manuscript Accepted: 30 AUG 2007
- Manuscript Received: 22 MAR 2007
- colorectal adenocarcinoma;
- combination therapy
- Top of page
- Abstract
- Material and methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
The potent chemopreventive activity of cyclooxygenase-2 (COX-2) inhibitors has been demonstrated in a number of preclinical studies, but their potency in antitumor activity is still in dispute. In this report, we demonstrate the potent antitumor activity of a novel COX-2 inhibitor, CS-706 in mouse colorectal adenocarcinoma colon 26 tumor-bearing mice treated with or without antitumor chemotherapeutic agents. Daily oral administration of CS-706 at doses of 3–100 mg/kg from the day of tumor inoculation (Day 0) inhibited tumor growth dose-dependently, and the maximal inhibition was 67% at a dose of 100 mg/kg. In contrast, celecoxib, a well-known COX-2 inhibitor, did not inhibit tumor growth at doses up to 100 mg/kg. Furthermore, CS-706 at a dose of 1 mg/kg or above markedly prolonged the survival time of tumor-bearing mice. Administration of 30 mg/kg CS-706 from Day 7 combined with a single intravenous treatment of 10 mg/kg cisplatin on Day 7 completely regressed the tumors in all tumor-bearing mice examined, whereas only in 1 of 10 mice tumor was regressed with cisplatin treatment. Similar combination effects were observed with 10 mg/kg CS-706 and 60 mg/kg 5-fluorouracil (5-FU). Moreover, 10 mg/kg CS-706 significantly inhibited angiogenesis induced by implanted chambers with colon 26 cells in a dorsal air sac assay in mice. Collectively, these results suggest that CS-706 is a potent antitumor agent, especially in combination with conventional chemotherapeutic agents, and that the anti-angiogenic activity of CS-706 may contribute at least in part to its marked antitumor activity. © 2007 Wiley-Liss, Inc.
Cyclooxygenase (COX) is a key enzyme of prostaglandin synthesis and plays an important role in a variety of biological responses, including inflammation and pain. There are 3 isoenzymes of COX, namely COX-1, COX-2 and COX-3. COX-1 is constitutively expressed in most tissues including gastric mucosa and platelets to regulate the turnover of epithelial mucosa1 and platelet coagulation.2 Contrary to COX-1, COX-2 expression is regulated by inflammatory stimuli such as TNF-α and IL-1β. COX-3 (also known as COX-1b) is a splicing variant of the COX-1 gene that is reported to be a target molecule of acetaminophen.3
Among them, COX-2 is suggested to be involved in carcinogenesis. COX-2 overexpression is often detected with high frequency in colorectal polyps and in various kinds of tumor tissues, including colorectal, lung,4 pancreatic5 and breast cancers.6 In a genetically engineered animal model, Liu et al. reported a higher frequency of mammary tumors developing when COX-2 expression was forced in mammary epithelial cells under the mouse mammary tumor virus (MMTV) promoter.7 This result suggests that COX-2 may even act as an oncogene. Therefore, numerous experimental and clinical studies have recently been conducted in order to examine the chemopreventive activity of COX-2 inhibitors such as celecoxib and rofecoxib.8–14
Celecoxib, which is a well-known COX-2 selective inhibitor widely used as a nonsteroidal anti-inflammatory agent, showed an inhibitory effect on colorectal polyp formation in a Min mice model8 and in azoxymethane-induced colorectal tumors in F344 rats.9 The chemopreventive activity of COX-2 inhibitors has been demonstrated not only in experimental colorectal carcinogenesis but also in other tumor carcinogenesis models such as prostate,10 skin11 and breast12, 13 carcinogenesis models in mice or rats. In clinical trials, because celecoxib treatment significantly inhibited the formation of colorectal polyps in familial adenomatous polyposis (FAP) patients,14 it was approved as an adjunctive treatment to surgery for FAP in the US. In addition to its effect on FAP, it was reported that a treatment of 200 or 400 mg of celecoxib twice daily reduced the incidence of recurrent adenomas in the Adenoma Prevention with Celecoxib (APC) trial with 2,000 or more patients who had adenomas removed before study entry.15 Moreover, a case–control study demonstrated that both daily 200 mg celecoxib and daily 25 mg rofecoxib significantly reduced the risk of breast cancer in clinical trials.16 In addition to the chemopreventive activity of COX-2 inhibitors, recently, a few reports have shown the significant tumor growth inhibitory activity of COX-2 inhibitors against various tumors in animal models.17–19 With regard to celecoxib, various pilot studies in cancer patients in both monotherapy and combination therapy with antitumor agents have been conducted, but with very limited success.20, 21 In contrast to great number of reports that evaluate the chemopreventive activity of COX-2 inhibitors, there still are few reports that evaluate their tumor growth inhibitory activity in detail.
CS-706 is a novel COX-2 inhibitor with IC50 values of 2.2 μM (95% confidence interval 1.3–3.4) and 0.31 μM (95% confidence interval 0.15–0.63) for COX-1 and COX-2 inhibition, respectively, when measured in human whole blood.22 It has been demonstrated that CS-706 showed potent antiinflammatory activity in various animal models,22 and ongoing Phase II studies in the US have revealed its safety profile and its potent analgesic activity with regard to dental pain.23, 24 Here, we show the detailed examination of the antitumor activity of CS-706 against mouse colorectal adenocarcinoma colon 26 subcutaneously implanted in CDF1 mice in comparison with that of celecoxib. We also investigated the antitumor activities of CS-706 in combination with chemotherapeutic agents such as cisplatin or 5-fluorouracil (5-FU).
Material and methods
- Top of page
- Abstract
- Material and methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
CS-706 and celecoxib were synthesized in Sankyo (Tokyo, Japan). Cisplatin and 5-FU were purchased from Nippon Kayaku (Tokyo, Japan) and Wako Pure Chemical Industries (Osaka, Japan), respectively. Sodium carboxymethyl cellulose was purchased from Iwai Chemicals Company (Tokyo, Japan). For the inhibition assay of vascular endothelial growth factor (VEGF) production, lipopolysaccharide (LPS) from Escherichia coli Serotype 055:B5 was purchased from Sigma-Aldrich (Tokyo, Japan) and dimethyl sulfoxide (DMSO) was purchased from Wako Pure Chemical Industries.
Cell lines and culture
The mouse tumor cell line, colorectal adenocarcinoma colon 26 derived from Balb/c mice, was obtained from the Japanese Foundation for Cancer Research (Tokyo, Japan) as solid tumors. The cell culture line was established by isolating tumor cells from solid tumor tissue by mincing and trypsinizing. Colon 26 tumor cells were maintained in RPMI Medium 1640 with L-glutamine (Invitrogen, Tokyo, Japan) containing 10% fetal bovine serum (FBS, HyClone, Logan, UT). The established colon 26 tumor cell line highly produced prostaglandin E2, and expressed COX-2, of which expression was confirmed by western blot (data not shown). RAW 264.7, a mouse monocyte/macrophage cell line, was purchased from American Type Culture Collection (Manassas, VA). RAW 264.7 cells were maintained in DMEM with L-glutamine (Invitrogen, Tokyo, Japan) containing 10% FBS.
CDF1 mice, an F1 hybrid of Balb/c and DBA/2 mice, were purchased at the age of 6–8 weeks from Charles River Japan (Yokohama, Japan), and specific pathogen-free female BALB/cA Jcl-nu mice (nude mice) were purchased at the age of 6 weeks from CLEA Japan (Tokyo, Japan). Diet pellets (FR-2, Funabashi Farms, Funabashi, Japan) and water were given to the mice ad libitum. All the animal care and experiments were conducted under the standard operational protocol of the Sankyo Institutional Animal Care and Use Committee.
Evaluation of antitumor activity of CS-706 in tumor-bearing mice
The colon 26 cell suspension of 1 × 106 cells/0.1 ml was inoculated subcutaneously into the right axillary region of the CDF1 mice. CS-706 and celecoxib were suspended in vehicle (0.5% carboxymethyl cellulose solution) at appropriate concentrations and orally administered to the mice. The compounds were daily administered from Day 0 or from Day 7 after tumor inoculation according to the study protocols.
In the experiment where administration was started from Day 0, the mice were inoculated with tumors, divided into experimental groups (n = 10) on the same day, and administered with CS-706 or celecoxib at the doses of 1, 3, 10, 30, and 100 mg/kg. In the experiment where administration was started from Day 7, the mice were divided into experimental groups (n = 10) on Day 7, when the average tumor reached around 300 mm3 (note that over 95% of the tumors were in the range of 200 mm3 and 400 mm3, average volume: 292 ± 54 mm3). Then, CS-706 at doses of 3 and 30 mg/kg was daily administered.
In our preliminary study, the maximum tolerated dose of cisplatin (intravenously (i.v.), 1 shot) and 5-FU (orally, 3 times per week) were determined to be 10 and 60 mg/kg, respectively, in the colon 26 tumor-bearing (TB) mice. We therefore used 10 mg/kg of cisplatin and 60 mg/kg 5-FU in the following experiment. The grouping of the mice was performed on Day 7, as mentioned earlier, and then cisplatin (i.v., 1 shot, on Day 7) alone or in combination with CS-706 or celecoxib (at doses of 3 and 30 mg/kg, from Day 7, everyday) was administered. 5-FU (orally, from Day 1 to Day 13, every 3 days) was administered alone or in combination with CS-706 (at dose of 10 mg/kg, from Day 0).
The tumor volume (mm3) was calculated as a × b2/2, where a and b are the largest and the smallest perpendicular diameters, respectively. The tumor growth inhibition (TGI %) was calculated as (1 − T/C) × 100, where T and C are the mean tumor volume of the compound-treated mice and the mean tumor volume of the vehicle-treated mice, respectively. The tumor growth rates (TGR mm3/day) in each mouse were represented as the slope of the tumor volume in order to analyze the inhibitory effect of the compounds. The slopes of the tumor volume were calculated by linear regression analysis. To evaluate the life-prolonging effect of the compounds, the median survival time (MST days) after tumor inoculation for each group was determined from the survival times of the mice according to a Kaplan-Meier plot using SAS System Release 8.2 (SAS Institute, Cary, NC). The increase in the life span (ILS %) was calculated as (TMST/CMST − 1) × 100, where TMST and CMST are the MST of the compound-treated mice and the MST of the vehicle-treated control mice, respectively. A mouse that exhibited no palpable tumor for more than 2 weeks was regarded as a complete regression (CR).
Measurement of anti-angiogenic activity of CS-706 in vivo
To evaluate the anti-angiogenic activity of CS-706 in vivo, we used a dorsal air sac (DAS) assay.25, 26 Millipore chambers covered with Millipore filters of 0.45 μm pore size were filled with Hank's Balanced Salt Solution (HBSS, Invitrogen, Tokyo, Japan) or colon 26 cell suspension, and implanted subcutaneously into dorsal air sacs created by the injection of an appropriate volume of air under the skin of nude mice (Day 0). In our preliminary experiments, we optimized the cell concentration and suspension volume in the chamber and found that 3 × 106 cells/0.15 ml is appropriate. For a negative control to evaluate the effect of the chamber itself, an air sac was formed on the mice without the implantation of any chambers, and these mice were designated as the sham-operated group. The mice with colon 26 cell-filled chambers were then administered vehicle (0.5% carboxymethyl cellulose solution) or CS-706 at a dose of 10 mg/kg orally for 4 days from Day 0, and the mice with HBSS-filled chambers or the sham-operated mice received neither CS-706 nor vehicle. Each experimental group included 12 mice. The preparation and administration of the compounds was performed in the same way as in the experiment to evaluate antitumor activity. On Day 4, the mice were sacrificed and the area of neovascularization was photographed. The skin of the mice in the sham-operated group was also resected at the region where it was supposed that a chamber would be implanted. An observer who was blinded to the randomized sample numbers evaluated the total lengths of the vessels in each mouse using Win ROOF Ver. 3.1 (Mitani Corp., Fukui, Japan), by tracing the vessels in the neovasculature. The vessel length was represented as pixels. The percent inhibition of the vessel length (VLI %) was calculated as (1 − (TV − HV)/(CV − HV)) × 100, where TV, HV and CV are the mean length of the compound-treated group, the mean length of the HBSS-control group and the mean length of the vehicle-treated group, respectively.
Production of VEGF by RAW 264.7 cells
RAW 264.7 cells were seeded at 1 × 104 cells/well in 96-well plates 24 hr before the compound addition. Then, CS-706 at final concentrations ranging from 0.01 to 300 nM and LPS at a final concentration of 1 μg/mL was added into the appropriate wells. CS-706 and LPS were diluted with DMSO and physiological saline, respectively, and the final concentration of DMSO was 0.1%. DMSO alone at the final concentration of 0.1% was added to the wells as a negative control. The 96-well plates were placed in a CO2 incubator for 24 hr and then the culture supernatant was collected and kept at −80°C until use in the following assay. The number of samples in each group was 4–8. The concentrations of VEGF and prostaglandin E2 (PGE2) in the culture supernatant were measured directly using enzyme-linked immunosorbent assay (ELISA) kits, according to the manufacturer's directions. We used AN′ALYZA M mouse VEGF Quantitative Colorimetric Sandwich ELISA (TECHNE Corp., Minneapolis, MN) for mouse VEGF and Prostaglandin E2 EIA Kit-Monoclonal (Cayman Chemical, Ann Arbor, MI) for PGE2.
Statistical analysis
We used a Dunnett's test and a log-rank test based on the joint-ranking method for evaluation of the inhibitory activity on tumor growth and life-prolonging activity, respectively, to compare the vehicle-treated or chemotherapeutic agent (cisplatin or 5-FU) alone groups to the compound-treated group. The time to death of the CS-706-treated mice was compared with that of the celecoxib-treated mice by a Cox proportional hazards model with a continuous variable "Log Dose" as the covariate. Applying this model, the hazard ratio for every 10-fold increase in the dose of each compound was estimated and the hazard ratio of the CS-706-treated mice was compared with that of the celecoxib-treated mice by a Wald's test. A t-test and a Dunnett's test were performed for evaluation of the inhibitory activity on cytokine production and on colon 26-induced angiogenesis in the DAS assay. A p value of less than 0.05 was considered to be statistically significant. We abbreviated the 95% confidential intervals in the Table in order to prevent the Table from becoming too jumbled.
- Top of page
- Abstract
- Material and methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
Effect of CS-706 on tumor growth and survival of colon 26 tumor-bearing mice
When CS-706 was daily administered from Day 0 after tumor inoculation, CS-706 dose-dependently inhibited tumor growth at doses above 3 mg/kg, and a 67% maximal tumor growth inhibition (TGI) was observed at the highest dose of 100 mg/kg on Day 14 (p < 0.05, Fig. 1a and Table I). It is noteworthy that 100 mg/kg CS-706 achieved CR in 1 of the 10 mice. On the contrary, celecoxib showed very weak inhibition of tumor growth up to 100 mg/kg, and the TGI by celecoxib at the dose of 100 mg/kg was 8% on Day 14 (Fig. 1b and Table I). CS-706 at doses of 1–100 mg/kg markedly prolonged the MST of tumor-bearing mice, and the ILS were more than 110% at doses examined (Table I). Celecoxib also prolonged the MST at doses above 10 mg/kg, though the ILS at a dose of 10 mg/kg was only 41% (Table I). Because the CS-706 treatment significantly decreased the hazard ratio more than the celecoxib treatment (Cox regression analysis and Wald's test, p < 0.05), CS-706 was demonstrated to have more potent life prolonging activity as compared with that of celecoxib.
Tumor growth | Survial time | CR | ||||
TGR (mm3/day) | TGI (%, Day 14) | MST (Days) | ILS (%) | |||
| ||||||
TB control | 220 | – | 18.5 | – | 0/10 | |
CS-706 | 1 mg/kg | 182 | 15 | 42.51 | 130 | 0/10 |
3 mg/kg | 1272 | 39 | 39.01 | 111 | 0/10 | |
10 mg/kg | 1152 | 45 | 46.51 | 151 | 0/10 | |
30 mg/kg | 1132 | 48 | 44.01 | 138 | 0/10 | |
100 mg/kg | 682 | 67 | 47.01 | 154 | 1/10 | |
Celoxib | 1 mg/kg | 245 | −14 | 33.0 | 78 | 0/10 |
3 mg/kg | 219 | −5 | 24.5 | 32 | 0/10 | |
10 mg/kg | 252 | −13 | 26.01 | 41 | 0/10 | |
30 mg/kg | 201 | 7 | 39.01 | 111 | 0/10 | |
100 mg/kg | 179 | 8 | 35.01 | 89 | 0/10 |
Similar superior antitumor activities of CS-706 were also demonstrated in the experiments where CS-706 was administered from Day 7 when the average tumor volume reached around 300 mm3. CS-706 treatment from Day 7 at a dose of 30 mg/kg significantly inhibited the growth of tumors on Day 14 by 43% (p < 0.05), and prolonged the MST with an ILS of 98% (p < 0.05, supplementary Fig. 1).
Antitumor effects of CS-706 combined with a chemotherapeutic agent
A single treatment of 10 mg/kg cisplatin on Day 7 showed marked tumor growth inhibition (TGI: 79% on Day 25) and significant prolongation in the survival time of the tumor-bearing mice by 107% ILS (Figs. 2a and 2c). However, when cisplatin was given in combination with CS-706 (3, 30 mg/kg), the tumor growth inhibitory activity and life-prolonging activity of cisplatin were markedly potentiated in a dose-dependent manner. Especially when combined with 30 mg/kg CS-706, all the tumors were completely regressed in the cisplatin and CS-706-treated tumor-bearing mice, although the cisplatin alone-treated group showed only 1 CR (Figs. 2a and 2c). Similar results were also observed when 30 mg/kg celecoxib was administered in combination with cisplatin, but with much weaker activity and only 2 CRs (Figs. 2b and 2d). These results clearly demonstrated that CS-706 showed a marked combination antitumor effect with cisplatin. In addition, the antitumor activity of CS-706 with cisplatin seemed to be more potent than the activity of celecoxib with cisplatin.
Similar results were also obtained in the combination treatment of CS-706 and 5-FU. When 10 mg/kg CS-706 (from Day 0 after tumor inoculation, everyday) was administered in combination with 60 mg/kg 5-FU (from Day 1 to Day 13, every 3 days), the life prolongation was remarkably enhanced (ILS: 213%, p < 0.05) when compared with 5-FU alone (ILS: 59%, supplementary Fig. 2). Moreover, 2 of 10 mice in combination treatment of CS-706 and 5-FU showed CR, whereas no tumor-free mice were observed under 5-FU treatment alone (supplementary Fig. 2). These results also demonstrated the marked combination effects of CS-706 with 5-FU.
Inhibitory effects of CS-706 on angiogenesis induced by implanted chambers with colon 26 cells
A DAS assay was performed in BALB/cA Jcl-nu (nude) mice to examine the inhibitory activities of CS-706 on neovascularization induced by implanted chambers with colon 26 cells. In the skins of the nude mice in the sham-operated group and in the HBSS-control group, the mean length (±SEM) of the neovascularity were 40 (±40), and 166 (±50) pixels/mouse, respectively (Fig. 3). In contrast, the implantation of chambers with colon 26 cells to the mice remarkably increased the neovascularization, and the mean vessel length of the neovascularity was 1,971 (±276) pixels/mouse. CS-706 treatment at a dose of 10 mg/kg inhibited neovascularization, and the mean vessel length of the CS-706-treated neovascularity was 1,222 (±194) pixels/mouse with 41% inhibition (p < 0.05, Fig. 3).
Inhibitory activity of CS-706 against VEGF production in vitro
We then studied the inhibitory activity of CS-706 against production of VEGF that is one of the important factors for angiogenesis. Mouse monocyte/macrophage cell line RAW 264.7 cells activated with 1 μg/ml lipopolysaccharide (LPS) produced 157.6 ± 11.01 pg/ml of VEGF (mean ± SEM, Fig. 4a), whereas control RAW 264.7 cells produced less than 10 pg/ml of VEGF without LPS stimulation (Fig. 4a). The addition of CS-706 at the concentrations of 0.1–300 nM inhibited production of VEGF in LPS-stimulated RAW 264.7 cells, and the inhibitory activity of CS-706 against VEGF production reached a plateau of approximately 50% at concentrations above 30 nM.
In the parallel experiments, we determined PGE2 production in RAW 264.7 cells. CS-706 potently inhibited the LPS-induced PGE2 production in a concentration dependent manner at concentrations above 0.3 nM, and 30 nM CS-706 nearly completely inhibited the PGE2 production (IC50 = 2.8 nM, Fig. 4b). Note that the addition of 1 μM PGE2 increased VEGF production in RAW 264.7 cells, and the increased VEGF production was not inhibited by 300 nM CS-706 (data not shown). On the other hand, it has been shown that LPS induces VEGF production via a Toll-like receptor-NF-κB pathway27 other than the PGE2 pathway. These results suggested that CS-706 partially inhibited the VEGF production through the inhibition of PGE2 production.
- Top of page
- Abstract
- Material and methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
In this report, we have demonstrated that daily oral treatment with CS-706, a novel COX-2 inhibitor, exhibited potent tumor growth inhibitory activity (Fig. 1a) and life-prolonging activity (Table I) in colon 26 tumor-bearing mice. Furthermore, when administered together with conventional chemotherapeutic agents such as cisplatin or 5-FU, the combination activity of CS-706 was very marked and synergistic (Figs. 2a and 2c and supplementary Fig. 2). It is noteworthy that all the tumors in the tumor-bearing mice, i.e. 10 of 10 tumor-bearing mice, regressed completely by 30 mg/kg CS-706 treatment in combination with a single dosing of 10 mg/kg cisplatin, while 10 mg/kg cisplatin-alone treatment regressed the tumor for only 1 mouse, out of 10 mice (Fig. 2).
CS-706 showed potent life-prolonging activity not only in mice treated from Day 0 but also in mice treated from Day 7 (established tumors about 300 mm3 in average tumor volume, Table I and supplementary Fig. 1b). In addition, CS-706 with cisplatin resulted in increased survival in established tumor bearing mice (Fig. 2c). These results indicate the potent therapeutic activity of CS-706.
Concerning the antitumor mechanisms of the COX-2 inhibitors, there are numerous reports on the possible antitumor mechanisms of celecoxib or rofecoxib both in vitro and in vivo, including the induction of apoptosis of tumor cells,28, 29 the direct inhibition of tumor cell proliferation,30, 31, 32, 33 the inhibition of COX-2-induced increase in tumor invasiveness34 and the inhibition of COX-2-induced tumor-angiogenesis.35 In our preliminary in vitro experiments, we confirmed that CS-706 at concentrations up to 10 μM did not show any cytotoxic effect on colon 26 cells in a 3-day exposure, though it potently inhibited the production of PGE2 in a 24-hr exposure (data not shown). In addition, 10 μM CS-706 induced neither apoptosis nor cell cycle arrest in the cultured tumor cells. Furthermore, CS-706 did not modulate TNF production in LPS-stimulated macrophages and did not activate peroxisome proliferator-activated receptor (PPAR) γ (data not shown), although a great number of reports have demonstrated that other COX-2 inhibitors or NSAIDs have such activities.36, 37 However, as shown in Figures 3 and 4, CS-706 inhibited angiogenesis induced by implanted chambers with colon 26 cells in a dorsal air sac model in vivo, and also attenuated the production of VEGF in LPS-stimulated RAW 264.7 cells, probably through the inhibition of PGE2 production. Consequently, it is anticipated, as also indicated with other COX-2 inhibitors in various tumor models,35 that the inhibition of angiogenesis may be involved at least in part in the significant tumor-growth inhibitory activity demonstrated by CS-706. The synergy in antitumor activity observed in the combination studies with either cisplatin or 5-FU may be explained by the different mechanism of action between CS-706 and these conventional cytotoxic agents.
Since the importance of anti-angiogenic activities is also shown in the growth and progression of metastatic tumors,38, 39 we examined if CS-706 had an anti-metastatic activity in mouse experimental metastasis model. In a mouse Lewis lung carcinoma (LLC) model, in which LLC cells were subcutaneously inoculated, and the resultant tumors were excised to allow metastasis, CS-706 inhibited the number of lung nodules (data not shown). In other preliminary studies, in which mice were subcutaneously inoculated with colon 26 tumor cells, we often found metastatic nodule in lungs. These results may support the marked survival prolongation of the tumor-bearing mice as results of the decreased growth and progression of metastatic colon 26 cells by CS-706. The antimetastatic mechanisms of CS-706 are now under examination.
In the present studies, we found that the antitumor activity of CS-706 was very marked when compared with that of celecoxib. Our preliminary results demonstrated that the COX-2 inhibitory activity of CS-706 was only about 3 times as potent as that of celecoxib in a human whole blood assay. Furthermore, our preliminary pharmacokinetic studies using 10 mg/kg CS-706 and 10 mg/kg celecoxib demonstrated that the Cmax and AUC0–24 hr of CS-706 was approximately half as high as that of celecoxib in mice. From these results, it is indicated that the COX-2 inhibitory activity of 10 mg/kg CS-706 was almost equivalent to that of 10 mg/kg celecoxib in mice in this calculation. Therefore, it is difficult to explain the potent antitumor activity of CS-706 demonstrated with or without chemotherapeutic agents, when compared with that of celecoxib at the same/above dose, solely by differences in COX-2 inhibitory activity. Next, we examined whether there is an alternative mechanism such as COX-1 that might be involved in the differing strengths of the antitumor effects. In our preliminary experiments, we measured the inhibition of human whole blood COX-1 activities in the presence of CS-706 and celecoxib. The COX-1 inhibitory activity of CS-706 was only around 4 times as potent as that of celecoxib. The inhibitory profiles of COX-1 by CS-706 and celecoxib seem to be similar to those of COX-2. We then carried out in vivo experiments to determine the accumulation of each compound. The radioisotope labeled compounds, [14C]CS-706 and [14C]celecoxib were orally administered to rats and the radioisotope activities were counted in various tissues. Importantly, the isotope levels were comparable in all the tissues examined.40 The above results may suggest unique characteristics of CS-706 or the possible involvement of an unknown mechanism in the potent antitumor activity of CS-706, and this mechanism will need to be clarified in the future.
It has been shown that the colon 26 tumor-bearing mice were cachectic41 at the late stage of tumor-bearing. In addition, PGE2, either produced by colon 26 cells or inflammatory macrophages, is known to be one of the well-known cachectic molecules.42 It may be that CS-706 was very effective in prolonging the survival of colon 26 tumor-bearing mice through inhibiting the colon 26-mediated cachexia. Studies on the effect of CS-706 on colon 26 tumor-induced cachexia are now in progress.
Although the precise mode of action of the marked antitumor activity of CS-706 when compared with that of celecoxib in colon 26 tumor-bearing mice is not clear yet and needs further clarification, CS-706 is expected to be a potent antitumor COX-2 inhibitor in clinical situations in combination with conventional chemotherapeutic agents.
- Top of page
- Abstract
- Material and methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
We would like to thank Naomi Shimazaki, Fumie Tanzawa and Shigeru Ushiyama for their assistance in the assays and for their constructive criticism.
- Top of page
- Abstract
- Material and methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
- 1Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1. J Clin Invest 1997; 99: 1367–79., , , , .
- 2Why there are two cyclooxygenase isozymes. J Clin Invest 2001; 107: 1491–5., .
- 3COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci USA 2002; 99: 13926–31., , , , , , .
- 4Expression of cyclooxygenase-2 in human lung carcinoma. Cancer Res 1998; 58: 4997–5001., , , , , .
- 5Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res 1999; 59: 987–90., , , , , , , , , , .
- 6Cyclooxygenase-2 gene expression in human breast cancer. Int J Oncol 1997; 10: 503–7., , , , , .
- 7Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J Biol Chem 2001; 276: 18563–9., , , , , , , , .
- 8The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res 2000; 60: 5040–4., , , , .
- 9Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res 2000; 60: 293–7., , , , , , , .
- 10Suppression of prostate carcinogenesis by dietary supplementation of celecoxib in transgenic adenocarcinoma of the mouse prostate model. Cancer Res 2004; 64: 3334–43., , , , , , , .
- 11Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol Carcinog 1999; 25: 231–40., , , , , , .
- 12Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res 2000; 60: 2101–3., , , .
- 13Chemoprevention of mammary carcinogenesis in female rats by rofecoxib. Cancer Lett 2003; 202: 131–6., , , , , , .
- 14The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 2000; 342: 1946–52., , , , , , , , , , , .
- 15Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006; 355: 873–84., , , , , , , , , , , , et al.
- 16Reduction in the risk of human breast cancer by selective cyclooxygenase-2 (COX-2) inhibitors. BMC Cancer 2006; 6: 27., , .
- 17Tumor growth inhibition by simultaneously blocking epidermal growth factor receptor and cyclooxygenase-2 in a xenograft model. Clin Cancer Res 2005; 11: 6261–9., , , , , , , , , .
- 18Cyclooxygenase-2 inhibitors suppress the growth of gastric cancer xenografts via induction of apoptosis in nude mice. Am J Physiol 1998; 274: G1061–7., , , , , , ,
- 19Anti-cancer effects of COX-2 inhibitors and their correlation with angiogenesis and invasion in gastric cancer. World J Gastroenterol 2004; 10: 1971–4., , , , .
- 20Targeting cyclooxygenase-2 in recurrent non-small cell lung cancer: a phase II trial of celecoxib and docetaxel. Clin Cancer Res 2005; 11: 6634–40., , , , , , , , .
- 21A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma. Clin Cancer Res 2005; 11: 5504–14., , , , , , , , , , , , et al.
- 22Preclinical pharmacology of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects. Eur J Pharmacol, Sep 11, 2007, (Epub ahead of print)., , , , , , , , .
- 23A randomized double-blind one-week study comparing effects of a novel COX-2 inhibitor and naproxen on the gastric mucosa. Dig Dis Sci 2007; 52: 442–50., , , , , , , , , .
- 24Pain relief model for a Cox-2 inhibitor in patients with post-operative dental pain, Submitted for publication., , , , , .
- 25UFT and its metabolites inhibit the angiogenesis induced by murine renal cell carcinoma, as determined by a dorsal air sac assay in mice. Clin Cancer Res 1999; 5: 2185–91., , , , , , , .
- 26Angiogenesis and tumor proliferation/metastasis of human colorectal cancer cell line SW620 transfected with endocrine glands-derived-vascular endothelial growth factor, as a new angiogenic factor. Cancer Res 2004; 64: 1906–10., , , , , , , , , .
- 27VEGF expression in human macrophages is NF-kappaB-dependent: studies using adenoviruses expressing the endogenous NF-kappaB inhibitor IkappaBalpha and a kinase-defective form of the IkappaB kinase 2. J Cell Sci 2003; 116: 665–74., , , , , .
- 28The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. J Biol Chem 2000; 275: 11397–403., , , , , .
- 29Celecoxib inhibits proliferation and induces apoptosis via prostaglandin E2 pathway in human cholangiocarcinoma cell lines. World J Gastroenterol 2003; 9: 1302–6., , , , .
- 30Rofecoxib inhibits cyclooxygenase 2 expression and activity and reduces cell proliferation in Barrett's esophagus. Gastroenterology 2002; 123: 60–7., , , , , .
- 31In vitro and in vivo effects and mechanisms of celecoxib-induced growth inhibition of human hepatocellular carcinoma cells. Clin Cancer Res 2005; 11: 8213–14., , .
- 32Celecoxib inhibits prostate cancer growth: evidence of a cyclooxygenase-2-independent mechanism. Clin Cancer Res 2005; 11: 1999–2007., , , , , , , , .
- 33Celecoxib exhibits the greatest potency amongst cyclooxygenase (COX) inhibitors for growth inhibition of COX-2-negative hematopoietic and epithelial cell lines. Cancer Res 2002; 62: 2029–33., , , , , .
- 34Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997; 94: 3336–40., , .
- 35Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 2000; 60: 1306–11., , , , , , , , , .
- 36Pharmacological modulation of TNF production in macrophages. J Microbiol Immunol Infect 2004; 37: 8–15., , , .
- 37Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem 1997; 272: 3406–10., , , , .
- 38Tumour angiogenesis and metastasis. Eur J Cancer 1991; 27: 679–80., .
- 39Significance of angiogenesis in tumour progression and metastasis. Eur J Cancer 1995; 31: 1101–4..
- 40Covalent binding of radioactivity from [14C]rofecoxib, but not [14C]celecoxib or [14C]CS-706, to the arterial elastin of rats. Drug Metab Dispos 2006; 34: 1417–22., , , , , .
- 41Experimental cancer cachexia induced by transplantable colon 26 adenocarcinoma in mice. Cancer Res 1990; 50: 2290–5., , , , , , , , .
- 42Induction of muscle protein degradation by a tumour factor. Br J Cancer 1997; 76: 1035–40., , .
Supporting Information
- Top of page
- Abstract
- Material and methods
- Results
- Discussion
- Acknowledgements
- References
- Supporting Information
This article contains supplementary material available via the Internet at http://www.interscience.wiley.com/jpages/0020-7136/suppmat .
Filename | Format | Size | Description |
ijc23250-Suppl-Fig1-final.tif | 2514K | Supporting Information file ijc23250-Suppl-Fig1-final.tif | |
ijc23250-Suppl-Fig2-final.tif | 2768K | Supporting Information file ijc23250-Suppl-Fig2-final.tif |
Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

subset: commoncrawl


text:
About this business
- Website
- extremewakejetski.com
Sharon .
2 years ago
So much fun, an hour is not enough!!!
Emma F.
2 years ago
I had a very good time and would recommend this place.
From Our Editors
Able to hold three passengers without dissolving, the Yamaha WaveRunners at Extreme Wake Jet Ski Rental churn through water along gulf beaches from Clearwater to St. Petersburg. For those seeking a little guidance beyond a rental, Extreme Wake also leads tours. These excursions can pass by sandy beaches, lighthouses, and dolphins as they shoot plumes of ocean water into the air. Additionally, the company's free shuttle ferries customers to and from their holding pods at nearby hotels.


text:
My daughter is 13 mos old now, and she has been enjoying these books since she was about 9 mos old. She gets excited and starts to clap along at the beginning of Barnyard Dance. That's definitely her favorite, but she also has fun with Pajama Time. I bought this set for my nephew as I think they are a great addition to any new baby's library.
I bought this set to read with my 6-month-old son. He loves "helping" turn the pages so board books are a must. Three great Boynton classics.
If you have never read her books...you are missing out! They are so much fun for the little people (kiddos) AND you :-) Makes a great gift. I love her sense of humor. Great value, too!!
This item will be delivered to you via USPS Trackable Media Mail or UPS Mail Innovations and will take from 2 days to 3 weeks from the time the item leaves our warehouse. *
Items must be returned in new or unused condition and contain all original materials included with the shipment. More details
FINAL SALE EXCLUSION: Items marked as FINAL SALE are not returnable unless the problem you experience is the result of our error.
* For your protection, all orders are screened for security purposes. If your order is selected for review, our Loss Prevention Team may contact you by phone or email. There may be a two business day delay to process your order.
** Most Oversize orders are delivered within 1-4 weeks. Some orders may take 6 weeks to be delivered.


text:
I stayed in this lovely house for only one night but it was enough to spent a relly good time with the family. They were really helpful by sharing their experience in the island and telling me the best spots in the southern coast of Bali. It was a shame I couldn't stay more days with them.
Indonesia >
Bali >
Nusa Dua Peninsula >
Price Range (Based on Average Rates):
Number of rooms: 6
- Also Known As:
- Hally-Bali Pecatu


text:
United Cerebral Palsy
United Cerebral Palsy Interview Questions
Interview Experience
Interview Experience
Getting an Interview
Getting an Interview
Interview Difficulty
Interviews for Top Jobs at United Cerebral Palsy
- Recreation Assistant (1)
- House Manager (1)
- Director (1)
- Application Details
I applied online – interviewed at United Cerebral Palsy.
Interview DetailsOn line job notice. Sent resume. Had first interview with HR , second interview with HR and VP of programing, and the last interview with the VP of programing and the CEO. Each interview was held on a different day. I was told there were other interviews in place for the position.
Negotiation Detailsno negotiation on yearly salary. Really no negotiation with any aspect of the job.Accepted OfferPositive ExperienceDifficult Interview - Application Details
I applied through other source – interviewed at United Cerebral Palsy in April 2010.
Interview DetailsThe hiring and interview process was intense for the simple fact that they only picked 10 out of 30. You had to stand out because of the big crowd. You also had to have good people skills. You then got interviewed by 3 different people & you had to go thru a 2 week training.
Interview Questions- There were no unexpected questions View Answer
Negotiation DetailsNAAccepted OfferPositive ExperienceAverage Interview - Application Details
I applied through other source. The process took a day – interviewed at United Cerebral Palsy.
Interview DetailsStraightforward and easy.
Negotiation DetailsAll dictated by the employer.Accepted OfferAverage Interview - Application Details
I applied through an employee referral. The process took 3 days – interviewed at United Cerebral Palsy in July 2010.
Interview DetailsMy First Information is regarding my interview is that they asked me first about my qualification
Interview Questions- what you expect that how will treat with you company View Answer
Negotiation DetailsOn the basis of current inflation and my experience.Accepted OfferNeutral ExperienceAverage Interview
Is this helpful? The community relies on everyone sharing – Add Anonymous Interview Review


text:
For status updates, visit lucyburns.org.
Ballotpedia's coverage of elections held on March 3, 2015, was limited. Select races were covered live, and all results will be added once the merger is complete.
EMC Research
From Ballotpedia
EMC Research is a polling company based in California. It has a specialty practice in polling relative to parcel tax elections.[1]


text:
Scotty ATL - Aint No Competition
Artist: Scotty ATL
Producer: J Baker
Album: Untitled (TBD)
Avg Rating: 2.6 ( 7 votes )
I don't mean to brag, but my Call Of Duty game play is on point. It's only been 24 hours since Black Ops 2 was released and I am basically already an expert. I might need to stop playing because there is nobody (yes, that is a challenge to Booth Nation) who can beat me. ATL newcomer Scotty knows this exact feeling because on his new single he lets listeners know that when it comes to the rap game there Aint No Competition. Producer J Baker composes a bangin', squeaky beat that rides perfectly behind Scotty to back up his many braggadocios claims. No Competition is the lead single off the emcee's forthcoming, untitled mixtape with DJ Burn One, which will drop later this month.
Scotty ATL DownloadsIndieStreet Banger
Written by Lucas G. on 11/14/12
Submit your Rating
First DJ Booth Appearance:
"Fade Away" (2011)
You Might Like...
blog comments powered by DisqusTRENDING NOW
- 1 Listen Album Review: Big Sean's "Dark Sky Paradise"
- Could Kanye's Rapper Reparations Idea Actually Work?
- Every Rapper is Going to Die & So Will I
- Rap Quiz: Bet You Can't Guess The Album Cover Pt. 6
- An Anti-Elitist Guide to Respecting Gucci Mane
- Breaking Down the Sordid Details of the Lil Wayne vs. Cash Money Lawsuit
- Oh My God, If Drake Dies Is He A Legend?
- Fine, You Got Me: Your Favorite Rapper's First Tweet
- 2014 Best of the Booth Award Winners (The Complete List)
- Your Favorite Indie Rapper is Secretly Signed to a Major Label


text:
Hot DealSilver Wonder by Victor Jamnitzky - Trick $100.00 $39.95 Save: 60% off Reward PointsNo points earned yet on current order. Log in to see how many reward points you have already earned Categories
LoginTestimonialsThanks for all that you do
I had to post this ...... you are all so easy to do business with , always responding to questions quickly without a constant battle. , and your... Great Service MJM has been great for me to deal with. Always helpful and excellent customer service! |


text:
Join Now
Join ePHOTOzine, the friendliest photography community.
Upload photos, chat with photographers, win prizes and much more for free!
Taken today in my back garden. This cheeky little monkey (I mean squirrel) has found a way to nick the wild bird food.
I reckon he'll be back with his mates tomorrow!
Thanks for looking
Camera: | Olympus E-410 |
Lens: | 40-150mm |
Recording media: | JPEG (digital) |
Title: | Cheeky! |
Username: | Paul65 |
Uploaded: | 10 Apr 2008 - 6:25 PM |
Tags: | Humour, Humour / fun, Nuts, Squirrel, Wildlife / nature |
VS Mode Rating |
102 (75% won) These stats show the percentage of wins and the rating score that your photo has achieved. You can go to the VS Mode by clicking on this icon. Signup to PlusBecome a plus member to see which photo this has won or lost against in the vs mode |
Votes: | 4 |
Voters: | robway · graceland · BethMN · ringyneck · |
Views: | 16 |
Unique Views: | 4 |
There are no comments here! Be the first!
- Original Poster Comments
- Your Posts
Add a Comment
ePHOTOzine, the web's friendliest photography community.
Upload photos, chat with photographers, win prizes and much more.


text:
Age: 11 years old Favorite swimmer: Doesn't have one Favorite event: 100 Backstroke Future swim goals:… [more]
Age: 11 years old Favorite swimmer: Rebecca Soini Favorite event: 500 Free Future swim goals: Qualify… [more]
Bangor, ME – 2014 Haunted Hat Meet Results are now available in the Meet Info/Results Section. For… [more]
Get the best seat in the house by signing up to be a timer, marshall or official for this Sundays sprint… [more]
We need timers, marshals and officials for this Sundays Sprint meet. It takes 13 timers, 4 marshals,… [more]
Bangor, ME – 2014-2015 Winter Season will begin on September 2nd. All Swimmers at 4:30PM. See you all… [more]


text:
Hot DealMovements by Moom Magic $54.95 $18.35 Save: 67% off Reward PointsNo points earned yet on current order. Log in to see how many reward points you have already earned Categories
LoginTestimonialsGREAT SERVICE
I only buy from MJM now. With prices that cannot be beat, quick shipping, and email notifications of when an order status changes this site is the... Customer Service The MJM Magic crew is great if not possibly the best in the business. Super fast service, great pricing, discounts, and no shipping. What more can... |


text:
- Most Watched
- Just In
Meet the SlothsCategory: infotainment show Hindi TV Channel Discovery Channel Please rate this show :2.8 Ratings | 0 Reviews
Serial Concept: In a sleepy corner of Costa Rica there is a very peculiar but extraordinary sanctuary. Run by Judy Avey-Arroyo for 20 years, this is the only sanctuary in the world devoted to saving orphaned and injured sloths, and is home to over 160 of them, some of whom have become an internet sensation. Watch Discovery Channel infotainment show Meet the Sloths videos online.
Post your comment (on this page)
Be the first one to post your comment! |


text:
Business & Information Systems Engineering
BISE (Business & Information Systems Engineering) is an international scholarly and double-blind peer-reviewed journal that publishes scientific research on the effective and efficient design and utilization of information systems by individuals, groups, enterprises, and society for the improvement of social welfare. Information systems are understood as socio-technical systems comprising tasks, people, and information technology. Research published in the journal examines relevant problems in the analysis, design, implementation, and management of information systems.
BISE is the English language successor of the journal WIRTSCHAFTSINFORMATIK, which has been the flagship journal of the German-language Information Systems community for more than 50 years. It is now one of the leading European journals in the field. BISE is sponsored by the Section "Information Systems" (Wirtschaftsinformatik, WKWI) of the German Association for Business Research (VHB) and the special interest group "Business Informatics" (GI-FB WI) of the Gesellschaft für Informatik e. V. (GI) with more than 1200 members. BISE is also an affiliated journal of the Association for Information Systems (AIS).
- 7 Volumes
- 40 Issues
- 358 Articles
- 6 Open Access
- 2009 - 2015 Available between
Latest Articles
Interview with Jonathan Grudin on "Computer-Supported Cooperative Work and Social Computing"
Prof. Dr. Michael Koch… (March 2015)
Marketing Automation
Dipl.-Kffr. Irina Heimbach… (March 2015)
CSCW and Social Computing
Prof. Dr. Michael Koch… (March 2015)
- Journal Title
- Business & Information Systems Engineering
- Coverage
- Volume 1 / 2009 - Volume 57 / 2015
- Print ISSN
- 2363-7005
- Online ISSN
- 1867-0202
- Publisher
- Springer Fachmedien Wiesbaden
- Additional Links
- Topics
- Industry Sectors
Continue reading...
To view the rest of this content please follow the download PDF link above.


text:
United States / $ (USD)
Judaica, Jewish Gifts, Tallits, Jewish Jewelry, Shofars & more
White Oval Magnet with Jerusalem Theme and English Text
Product ID: MGT-TM-52079
This white oval magnet features the word 'Jerusalem' in the center in large English letters that are surrounded by images of Jerusalem sites, a menorah, heart, the insignia of the holy city and other... Read more
Contact Our Judaica Experts 24/7 1-800-818-8394
For Phone Orders Please Mention: help-phonecode-updating
Live Chat Online
THIS ITEM QUALIFIES FOR FREE SHIPPING With an order of $59 and over
In accordance with our shipping policy
General Information
Temporarily out of stock
Similar Products
- $6 Metal Magnet with Jerusalem, Rainbow and Dove View Product
- $6 Blue Metal Magnet with Large Star of David and 'Israel' in White View Product
- $6 Ceramic Angelfish Magnet with Mosaic Pattern View Product
- $6 3D Hamsa Magnet with Judaica Symbols and Hebrew Text View Product
- $6 Metal Hamsa Magnet with Hebrew Text, Heart and Hebrew Text View Product
- $6 Jerusalem 3D Magnet with Western Wall and English Text View Product
- $6 Israel Magnet with English Text and Bright Decorations View Product
- $6 Rectangle 3D Magnet with Line of Camels and 'Israel' in Purple View Product
- $6 Metal Magnet with Ornamented Hamsa and Hebrew Text View Product
- $6 Round Metal Magnet with Jerusalem Depiction and English Text View Product
Recommended Products
- $28 Yair Emanuel Wooden Kiddush Cup Set with Jerusalem Vista View Product
- $65 Yair Emanuel Large Blue Menorah with a Tree Design and Birds in Lazer-Cut Metal View Product
- $6 Birth of a Girl Greeting Card with Rabbit Design View Product
- $60 Half Polished Half Natural Kudu Horn Shofar View Product
- $15 Men's Israel Defense Forces Army Green T-Shirt View Product
- $142 Sterling Silver Plated Kiddush Cup with Star of David, Lions and Tablets View Product
- $17 Yair Emanuel Large Wooden Dreidel with Jerusalem and Western Wall Design View Product
- $56 Adina Plastelina Mezuzah Case with Multicolored Mosaic Pattern and Shin View Product
- $6 Old City of Jerusalem Placemat View Product
- $26 Israel Defense Forces Black Hoodie with English and Hebrew Text View Product
Popular Searches that include this item:
Multiple Shipping Methods!
Choose among a variety of convenient shipping methods.
Learn more!
24/7 Customer Service
- Contact Our Judaica Experts 24/7 1-800-818-8394
- Live Chat
Judaica Products
- New Yair Emanuel
- New Judaica Brands
- New Candlesticks & Candles
- New Havdalah Sets and Candles
- New Kiddush Cups
- New Kippot
- New Mayim Achronim
- New Menorahs
- New Mezuzahs
- New Shofars
- New Sterling Silver
- New Synagogue Items
- New Tallit Items
- New Tefillin
- New Tzedakah Boxes
- New Tzitzit
- New Washing Cups
Jewish Occasions
- New Shabbat
- New Hanukkah
- New Passover
- New Purim
- New Rosh Hashanah
- New Sukkot
- New Wedding
- New Bar Mitzvah
- New Bat Mitzvah
- New Bris
- New Israeli Independence Day
From Israel
- New Body Care & Dead Sea
- New Military Surplus
- New Israeli Independence Day
- New Books
- New CDs
- New DVDs
- New Hebrew Learning
- New Israeli T-Shirts
- New Israeli Artists
- New Israeli Kosher Food
- New Israeli Cleaning Supplies
- New Israel Museum Products
- New Israeli Brands
- New Israel Coins & Medals Corp.
- New Megemeria by Yvel
Jewish Jewelry
- New Our Jewelry
- New Necklaces and Pendants
- New Bracelets
- New Rings
- New Earrings
- New Brooches
- New Accessories
- New Kabbalah Jewelry
- New IDF Jewelry
- New Name Jewelry
- New Choshen Jewelry
- New Magic Touch Jewelry
- New Adina Plastelina
- New Marina Jewelry
- New Ben Jewelry
- New Jerusalem Pearl Collection
- New Megemeria by Yvel
Jewish Home
- New Apparel
- New Blessings
- New Bookmarks
- New Children's Items
- New Decorative Plates
- New Figurines
- New Hamsa
- New Home Decor
- New Jewish Calendars
- New Jewish Pictures
- New Kitchen
- New Linens
- New Shot Glasses
- New Snow Globes
- New Stationery
- New Chabad
Featured Items
- New Popular Passover Items
- New New Arrivals
- New Artist of the Month-Megemeria
- New Souvenirs From Israel
- New Rockets into Roses
- New Ben Jewelry
- New Photographs by Duby Tal/Albatross
- About World of Judaica
- About Us
- Why Buy World of Judaica
- Contact us
- Customer Testimonials
- Coupons and Discounts
- Learn About Judaism
- Website Policies
- Privacy Policy
- Terms of Use
- Secure Shopping
- Return Policy
- Warranty
- Sitemap
- Newsletter Sign Up Now!
- United States / All prices in $ (USD)
- Change your country or language
- Change selected currency
© 2008-2015, World Of Judaica


text:
Want a free ringtone? Audiko.net! It's easy to download a free Bruno-Mars ringtones for your iPhone or mobile. Select your favorite trim from your favorite piece of art - Bruno-Mars, Lighters, Liquor-Store-Blues-ft, or any other track. You can obtain your tune both in the MP3 and m4a formats, supported by both mobile phones and iPhones. Just select a track, and choose free Bruno-Mars ringtones download option.
Download Bruno Mars Ringtones
Top free ringtones
Name | ||
Locked Out of Heaven | ||
Uptown Funk | ||
Just the Way You Are | ||
Treasure | ||
The Lazy Song | ||
Marry You | ||
When I Was Your Man | ||
Count on Me | ||
Grenade | ||
Up town Funk |


text:
Please note: the information on this page is provided for informational purposes only. As of 2013, Simmons Hanly Conroy is no longer accepting cases involving Depakote.
Depakote (divalproex sodium) is an anti-seizure medication manufactured by Abbot Laboratories. It is marketed under the brand names: Depakote, Depakote ER and Depakote sprinkles. The use of the epilepsy drug Depakote and similar dangerous drugs have been linked to an increased risk of birth defects and malformations, including cleft palate, spina bifida and deformed limbs and skulls.
Depakote Dangers
In a seven year study conducted at a Boston area hospital, Depakote was shown to cause major birth defects in women who took the drug while pregnant. Additionally, it has been linked to pancreatitis and hepatic failure.
Depakote can cause life-threatening problems. Dangerous side effects may include:
- Pancreatitis
- Liver failure
- Cleft palate
- Deformed arteries
- Heart defects in infants
- Malformed genitals in infants
Children who develop serious birth defects as a result of taking Depakote can face a lifetime of medical needs and special care. Our Depakote lawyers project may be able to help you demand compensation for the medical equipment, surgery and other costs associated with your child's care.
There has not yet been a Depakote recall. However, the FDA has Depakote listed as a pregnancy category D, which is a warning that means:
There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
Learn more about the symptoms and side effects associated with Depakote.
Client Testimonials
I appreciate all that the Simmons firm has done for me. I'm thrilled with the result they got for me and want to say thanks to everyone there.
- Cynthia


text:
Villa De Pai Guest House
Categories: Accommodation > Resort
Address: 87/1 Moo 3, Wiang Tai, Pai, Mae Hong Son 58130 Thailand See map
0 reply, 5,318 viewed
User reviews
There is no user review. You can give your opinion in the comment box below.
Share your thoughts on "Villa De Pai Guest House"
Sign in once and access every part of the website at your convenience!
Please log in to our Bangkokpost.com community to post your comments.
You can sign in to the community by clicking here.
If you weren't part of the community yet, please sign up here.
By being part of this community you will get all these privileges.


text:
Learn about the many advantages of a transferable service body versus the traditional, low-residual service body.
See the comparison »Steel security plus lots of tool or supply storage. Ladder rack and material tube standard. 1 ton trucks - Long bed only.
Take a Look »The work horse of the Durashell line. Long bed models only. 230 cubic feet of secure storage.
Learn More »


text:
Man arrested for allegedly causing hurt to hotel employee
Published on Jun 14, 2014 8:55 PM
SINGAPORE - A 31-year-old man was arrested on Friday night after he allegedly assaulted an employee of Conrad Centennial Singapore in front of the hotel's main entrance, and had to be pinned down by hotel staff when he tried to escape.
Police and the Singapore Civil Defence Force were alerted to the scuffle just before 8.30pm. The victim, a 32-year-old Singaporean woman who works as a duty manager at the hotel, was taken while still conscious to Singapore General Hospital after she complained of neck pains.
A hotel spokesman told The Straits Times that the man was not employee or guest of the hotel.
A witness to the incident, Mr Bryden Toh, said he was having dinner in a ballroom at the hotel, when he stepped out to make a phonecall.
To continue reading, log in if you are a subscriber
If you are not a subscriber, you can get instant, unlimited access here


text:
Who spiked the punch? Vodka or rum, mixed drinks or shots, get recipe ideas for your next party.
About StumbleDNA StumbleDNA
RayneElizabeth's Interests
From baby animals to wild creatures to exotic pets, discover cute pictures and more about animals.
We all need a little pampering sometimes. Explore makeup trends, hairstyles, skincare and more.
Discover funny pictures and more about cats, from cute kittens to fat cats. We promise you'll smile.
What's your style? From your shoes to your accessories, make a statement with your clothing.
Get ideas for fun and easy DIY arts and crafts perfect for kids, holidays and more. Do it yourself!
From slip knots to chain stitches, explore the art of crochet: patterns, how-to guides and more.
Learn more about man's best friend: big or small, mutts or purebreds, puppies or old-timers.
No more stick figures! Uncover your inner artist and the world of sketching, charcoals and pastels.
Do you think every day is Earth Day? Learn about ecology, pollution, sustainability, climate and more.
Are the hamsters at the pet store too tame for you? Learn about sugar gliders, bobcats, parrots and more.
Think you're the next fashion star? Explore the trends and designers heating up the runway shows.
Go fish! Whether they dwell in the ocean or in a tank, get photos and facts about our underwater friends.
Time to get your workout on! Up your fitness regime with tips on exercise, nutrition, diet and more.
Are you a foodie? Expand your culinary horizons with new recipes, cooking ideas and nutrition tips.
Stick the landing! Explore gymnastics and acrobatics: amazing videos, legendary Olympic teams and more.
Take care of yourself! Learn about physical and mental health, fitness, nutrition and more.
Home is where the heart is. Get tips and DIY ideas for keeping your home happy and beautiful.
There's no place like home! Get design and decorating ideas for every room in your house.
Do you prefer the aquarium to the zoo? Learn about the science of marine biology and ocean life.


text: Sale closed See all from Hotel Living 400 Thread Count Jacquard Window Pane Check Double Duvet Cover Set, White Hotel Living 400 Thread Count Jacquard Window Pane Check Double Duvet Cover Set, White ACHICA Loading Reserved. Please try again later. Sold Out In your basket The stunning Hotel Living Jacquard collection boasts beautiful quality and design, and the chic, versatile styling is sure to complement an array of interior decors. The Window Pane Check range features a subtle geometric check design, which meets somewhere between classic and contemporary for a sophisticated and stylish addition to any bedroom setting. Made from sumptuous, pure cotton, and boasting a beautifully high thread count, this luxurious bed linen promises to accommodate your comfort as well as your taste for a sublime night's sleep.Pillowcase dimensions: W75 x L50cmDuvet cover dimensions: W200 x L200cmMaterial: 100% CottonThread count: 400Care instructions: Machine washable at 40 degreesSet includes: 2 x Pillowcases, 1 x Duvet cover Product Code: MTR-5055268020807 Variant Code: : Delivery Returns Help You will be sent an email as soon as your order is placed. For more information please click here. We hope you will be thrilled with your purchases but in the unlikely event that you want to return something, you can find full return instructions on the back of your delivery note or click here. If you need assistance, please contact us here


text:
OSI-Approved Open Source (56)
- GNU General Public License version 2.0 (42)
- BSD License (6)
- GNU General Public License version 3.0 (6)
- GNU Library or Lesser General Public License version 2.0 (3)
- Artistic License (2)
- Common Public Attribution License 1.0 (1)
- GNU Library or Lesser General Public License version 3.0 (1)
- MIT License (1)
- Mozilla Public License 1.0 (1)
- Mozilla Public License 1.1 (1)
- Public Domain (4)
- Other License (3)
Home & Education Software
eFront - Refreshing eLearning eFront LMS is an easy to use, visually attractive, SCORM certified, Ajax powered, eLearning and talent management platform.
557 weekly downloads -
ILIAS LMS ILIAS is a web base learning management system (LMS, VLE). Features: Courses, SCORM 1.2 and 2004, mail, forum, chat, groups, podcast, file sharing, authoring, CMS, test, wiki, personal desktop, LOM, LDAP, role based access, see http://www.ilias.de/
310 weekly downloads -
ATutor (Learning Management System) Standards Compliant Learning Management System
251 weekly downloads -
Claroline Open Source Learning Management System
205 weekly downloads -
PhpGedView PhpGedView is a revolutionary genealogy program which allows you to view and edit your genealogy on your website. It has full privacy functions, can import from GEDCOM files, and supports multimedia. It also simplifies family collaboration.
166 weekly downloads -
formalms Forma is a Learning Management System (LMS), an e-learning application
188 weekly downloads -
refbase - Web Reference Database Online bibliographic manager for research groups. Zotero-compatible.
57 weekly downloads -
Chamilo Simple, fast and efficient Learning Management System
37 weekly downloads -
dcrteam Suite of diverse free tools under the platform win32 destined to help to increase the safety and ergonomics, of the users of internet of simple and comfortable way
100 weekly downloads -
Free Dean's Office for MOODLE Manage subscriptions to the Moodle course, contract with students, educational services, the trajectory of learning, academic groups, individual and group training, student record-books, learning processes, milestones, current and final grades, etc.
30 weekly downloads -
MediaWiki MediaWiki is the collaborative editing software that runs Wikipedia, the free encyclopedia, and other projects. MediaWiki is no longer distributed via SourceForge, for downloads and other information please visit www.mediawiki.org.
8 weekly downloads -
Glossword Glossword is a system to create and publish online multilingual dictionary, glossary, or encyclopedia. Suits for creating web sites also. WAMP [Windows, Apache, MySQL, PHP] package is available.
9 weekly downloads -
WackoWiki WackoWiki is a light and easy to install multilingual Wiki-engine.
10 weekly downloads -
General Knowledge Machine Project The volume of actual knowledge prevents people from applying it, because even the cleverest persons can not learn everything they need. Try to overturn this with idea of Just-In-Time Knowledge. Intelligent e-knowledge base engine provided.
2 weekly downloads -
www.travelsearchengine.org This was an UI course project. In this project we built an interface prototype of an online travel reservation system. This service was meant to revolutionize the travel idustry in several ways for occasional travelers as well as for large businesses.
2 weekly downloads -
Digrary Digrary is Open Source Digital Library System that enables services for creating electronic archives.
2 weekly downloads -
Short-term courses management This is a web-based program that helps to manage short-term teaching courses. It helps to avoid several types of human mistakes (like usage of room in several different lessons at the same time).
2 weekly downloads -
Structurized.info -- (E-books Catalogue) Structurized catalogue of all e-books available on the Inet. Bazed on rating system, maintained by users.
2 weekly downloads -
Adept Adept is a free multilanguage e-learning system. Users can choose, navigate, read courses on screen, do exercices and download related material. Authors can create courses online or import them from word processor files and quiz generation software such
1 weekly downloads -
DoceboLMS, e-learning platform and SCORM DodeboLMS is an e-learning platform for distance learning developed in italy and known as "Spaghettilearning", since the 2.0 version the name is changed in DoceboLMS. FOR DOWNLOAD, PLEASE REFER TO OUR WEBSITE
1 weekly downloads -
Hi, math! A simple on-line calculator for high mathematical problems Version 0.1 will be able to manage with matrixes
1 weekly downloads -
Mahara RADIUS Authentication Plugin This plugin enables single sign-on and uses a modified version of the RADIUS module.This RADIUS Plugin allows to work with all methods of RADIUS authentication, such as PAP, CHAP MD5, MS CHAP v.1, MS CHAP v.2. For Mahara 1.2.
1 weekly downloads -
Moodle RADIUS Authentication Plugin This plugin enables single sign-on and uses a modified version of the RADIUS module. This RADIUS Plugin allows to work with all methods of RADIUS authentication, such as PAP, CHAP MD5, MS CHAP v.1, MS CHAP v.2. For Moodle 1.8.
1 weekly downloads -
My-E-Lib This is little script, based on PHP language. It helps to organize, manage and share your digital library. Includes UDC navigation,
1 weekly downloads -
NetworX-Non-Profit, Social Community NetworX Non-Profit PHP-based, open source, downloadable, scalable free software that allows non-profits to achieve their goals by enabling them to collect donations for any charity at own branded website.
1 weekly downloads


text:
Take your filming to a new level of creativity, innovation and professionalism with our world-class highly versatile aerial crews and equipment.
Our range of helicopters, remote-controlled drones, stabilised camera systems, brackets and tracking vehicles, run by one of the most experienced teams in the industry, will ensure you get the best shots for your production.
More about usShot in the UK, Italy, South Africa, South Korea and Bangladesh, HFS used both helicopters equipped with the NSI SuperG and Cineflex Elite with Alexa, and drones with Red Epic
Read Full ArticleIn the skies over the UK, HFS capture Daredevil Tom Cruise in the "most dangerous airborne stunt ever"
Read Full ArticlePaddington Bear arrives, supported by HFS London Aerials for this very furry and funny romp.
Read Full ArticleLatest production with Legendary Films. Shot on location in Budapest, Hungary with both SuperG-2 on the helicopter and Drone units, using Alexa M and Red Dragon
Read Full ArticleThe New Jaguar XE Arrives by Helicopter and launched with the aid of The Red Arrows
Read Full ArticleJWT & Firecracker Films capture Phillipine based Super Yacht in all its glory
Read Full Article


text:
- Forum: iPhone
Another day, another stupid analyst survey. The carriers have done a great job of mucking up with 4G, let alone the difference between 4G LTE vs 4G (HSDPA/HSUPA) and that neither was the spec for 4G anyways. So its not surprising customers don't think they need it. If you are on CDMA then yes you really do want LTE, but you don't want the new data plans that are no where near as consumer friendly as they were on 3G (unlimited) data. Those days are long gone.


text:
Transform her bedroom or play area into a magical place. The simple, all-white canopy is intended as a backdrop for our array of garlands and clip-on adornments; use your imagination to create a custom look.
Item | Price | Delivery Surcharge |
Classic Tulle Canopy | $69 | $0 |


text:
Why register with the Steelers Fever Forums? • Intelligent and friendly discussions. • It's free and it's quick. Always. • Enter events in the forums calendar. • Very user friendly software. • Exclusive contests and giveaways. |
Donate to Steelers Fever, Click here |
Our 2014 Goal: $450.00 - To Date: $450.00 (100.00%) |
Home | Forums | Editorials | Shop | Tickets | Downloads | Contact | Not Just Fans. Hardcore Fans. |
Thread Tools |
A Son of Martha
Join Date: Oct 2008
Location: Mesa, Arizona
Posts: 7,976
Gender: Male
Member Number: 10438
Thanks: 0
Thanked 0 Times in 0 Posts
Steelers Report Card: Game 10 vs. Bengals
Steelers Report Card: Game 10 vs. Bengals
Gerry Dulac grades the Steelers' effort Sunday in their victory against Cincinnati: Monday, November 14, 2011 By Gerry Dulac, Pittsburgh Post-Gazette QUARTERBACKS B Ben Roethlisberger took another beating, but he passed for 245 yards and orchestrated an 81-yard TD drive with a hurry-up offense right after the Bengals tied the score at 17. Roethlisberger was 14 of 22 for 175 yards in the first half and was big on third down, converting 5 of 7 when the Steelers took a 14-0 lead. Even the interception wasn't his fault. And penalty negated a TD pass to Jerricho Cotchery. RUNNING BACKS C+ Rashard Mendenhall finished with only 44 yards on 16 carries, but he made one of the biggest plays with an off-balance 9-yard touchdown run that gave the Steelers the winning points. He also scored on a 2-yard run that gave the Steelers a 14-0 lead. The Steelers rushed for 105 yards on 30 carries, and that includes two reverse runs for 31 yards by WR Mike Wallace in the first half. WIDE RECEIVERS B Antonio Brown continues to be the team's most productive and go-to receiver. He finished with five catches for 86 yards. Heath Miller made a tough 18-yard catch to set up a TD and threw a big block on Mendenhall's scoring run. But he bobbled a pass that resulted in the lone interception and had an offensive interference penalty to negate a touchdown. Cotchery had one TD catch and could have had three. OFFENSIVE LINE C- It's never a good day when the quarterback is sacked five times and the running game averages 3.5 yards with 16- and 15-yard runs by a wide receiver. Three of the sacks came on the same series in the first half, stalling a drive and forcing the Steelers to settle for a field goal. G Chris Kemoeatu was responsible for two sacks, but he threw a big block on a counter play on Mendenhall's second TD. DEFENSIVE LINE C The Bengals did a nice job running the ball whenever Troy Polamalu wasn't tackling someone for a loss. They finished with 109 yards on 26 carries -- 57 by Cedric Benson -- and had 24 yards on three carries before William Gay ended their final drive with an interception. DE Brett Keisel had five tackles, a batted pass and tackle for loss. But NT Casey Hampton ran himself out of too many plays, allowing cutback runs. LINEBACKERS B The Steelers did not sack QB Andy Dalton, only the second game this season in which they didn't register a sack. But they got something better: an interception by ILB Lawrence Timmons on a tipped ball by Gay in the fourth quarter, one of two takeaways in the fourth quarter. And there were few gaffes, though backup ILB Larry Foote was late covering TE Jermaine Gresham on a 1-yard TD. DEFENSIVE BACKS A- Big plays by CB William Gay and two takeaways in the fourth quarter sealed the victory. Gay had a season-high four passes defensed -- including a deflection that was intercepted by Timmons -- and also intercepted Dalton with the Bengals threatening to tie the score in the final minutes. Polamalu was all over the field in the first half, but he failed to make a play on a 36-yard TD to rookie A.J. Green. SPECIAL TEAMS A- P Jeremy Kapinos was one of the unsung stars, averaging 50.4 yards on five punts on a gusty day. Four of the punts were into winds that gusted up to 40 mph, including a 55-yarder. His longest was 58 yards, the only one with the wind at his back. Shaun Suisham made his only field-goal try, from 39 yards, and that was into the wind, too. But there was little return yardage and a couple shaky coverage moments. COACHING B+ The Steelers accomplished three of their objectives: They started quick on the road with TDs on their first two drives; came up with two takeaways in the fourth quarter to end two scoring threats; and bounced back from a tough defeat. Even when the Bengals came back from 14 down to tie the score, offensive coordinator Bruce Arians went to a hurry-up offense that resulted in the winning TD drive. Gerry Dulac: firstname.lastname@example.com; twitter: @gerrydulac Read more: http://www.post-gazette.com/pg/11318...#ixzz1dgHlhEqz |
Assistant Coach
Join Date: Feb 2009
Posts: 1,158
Member Number: 13149
Thanks: 433
Thanked 227 Times in 152 Posts
Re: Steelers Report Card: Game 10 vs. Bengals
What a difference a good secondary coach makes.....I saw Foster getting stood up to many times on Running plays though...i know he's stronger than that right?
Head Coach
Join Date: Jan 2009
Posts: 1,657
Member Number: 11678
Thanks: 73
Thanked 75 Times in 49 Posts
My Mood:
Re: Steelers Report Card: Game 10 vs. Bengals
Oline played like shit. We made their Dline look like all pros. We had to go no huddle as Ben was getting killed when they could sub in and out. Im not sure if Foster is better than Legursky, or they both suck. but I'mnot a fan of legursky taking fosters spot either. Hard to imagine we contain the Ravens and let these clows tee off on Ben.
Look at the NE game with Brady. Masterful game plan. Thats what we need to do to manage blitzes etc. Coaching grade was to high. maybe a c+ at best. I like Kapinos better than Sepulvada, liked him last year and like him this year. Plus is he probably 1/3 the money. Special teams have stepped it up this year. Helps that we can at times kick it out of the endzone too. |
Assistant Coach
Join Date: Feb 2009
Posts: 1,158
Member Number: 13149
Thanks: 433
Thanked 227 Times in 152 Posts
Re: Steelers Report Card: Game 10 vs. Bengals
Team President
Join Date: Nov 2010
Location: Smoky Mountains, TN
Posts: 2,104
Gender: Male
Member Number: 17319
Thanks: 814
Thanked 367 Times in 206 Posts
Re: Steelers Report Card: Game 10 vs. Bengals
The o line has been playing pretty well since the Tennessee game, they played real well last week. As a whole the o line had a bad game, but I am confident that they will get it together next game as long as Starks is back.
Living Legend
Join Date: Apr 2010
Posts: 3,359
Member Number: 16173
Thanks: 99
Thanked 1,360 Times in 700 Posts
Re: Steelers Report Card: Game 10 vs. Bengals
Yeah Starks being LT has been huge. I believe we've only lost once since he's come back as starter.
Head Coach
Join Date: Oct 2006
Posts: 1,922
Member Number: 3516
Thanks: 1,034
Thanked 818 Times in 498 Posts
Re: Steelers Report Card: Game 10 vs. Bengals
No matter how you slice it Starks is our MVP!
Bookmarks |
Currently Active Users Viewing This Thread: 1 (0 members and 1 guests) | |
Thread Tools | |


text:
The latest news about biotechnologies, biomechanics
synthetic biology, genomics, biomediacl engineering...
Subscribe to our Biotechnology News feed
Glial cells send 'care packages' including protective proteins and genetic information to nerve cells.
Posted: Jul 16th, 2013
Read moreNew research provides a rare 'picture' of the activity taking place at the single molecular level: visual evidence of the mechanisms involved when a cell transports mRNA (or messenger RNA) to where a protein is needed to perform a cellular function.
Posted: Jul 15th, 2013
Read moreImagine millions of jigsaw puzzle pieces scattered across a football field, with too few people and too little time available to assemble the picture. Scientists in the new but fast-growing field of computational genomics are facing a similar dilemma.
Posted: Jul 15th, 2013
Read moreScientists have captured new details of the biochemical interactions necessary for cell division -- molecular images showing how the enzyme that unwinds the DNA double helix gets drawn to and wrapped around its target. The research may suggest ways for stopping cell division when it goes awry.
Posted: Jul 14th, 2013
Read moreTightly packed macromolecules enhance gene expression in artificial cellular system.
Posted: Jul 14th, 2013
Read moreBy employing next generation DNA sequencing of genomes isolated from single cells, great strides are being made in the monumental task of systematically bringing to light and filling in uncharted branches in the bacterial and archaeal tree of life.
Posted: Jul 14th, 2013
Read moreA new GBP10 million Innovation and Knowledge Centre (IKC), that will boost the UK's ability to translate the emerging field of synthetic biology into application and provide a bridge between academia and industry was announced yesterday.
Posted: Jul 12th, 2013
Read moreResearchers have developed a technique for the rapid and reliable distinction between strains that can cause chronic infections and those that cannot. Using infrared light and artificial intelligence, the scientists present a sophisticated method for the prediction of disease progression.
Posted: Jul 12th, 2013
Read moreCircular RNA molecules enable researchers to synthesize continuous protein chains from a single template.
Posted: Jul 12th, 2013
Read moreA novel therapeutic approach prevents dengue virus from reproducing in humans by targeting and silencing key regions of the dengue genome essential for viral replication.
Posted: Jul 11th, 2013
Read moreOnce all parts of the genome are complete, scientists can design new strains of the yeast Saccharomyces cerevisiae to make products including chemicals, vaccines and biofuels.
Posted: Jul 11th, 2013
Read moreResearchers at Memorial Sloan-Kettering Cancer Center, together with collaborators in Germany, have developed a new method for identifying the cell of origin of intracellular and secreted proteins within multicellular environments.
Posted: Jul 10th, 2013
Read moreMax Planck and Fraunhofer scientists team up to develop efficient biosynthetic processes for the production of pharmaceutical and industrial ingredients.
Posted: Jul 10th, 2013
Read morePhotosynthesis takes place in specialized membrane systems, made up of stacked disks linked together by unstacked planar leaflets. An LMU team has now identified a protein that tucks the membrane in at the edge of each stack.
Posted: Jul 10th, 2013
Read moreIn Bolivia, in the largest continuous salt desert in the world, researchers from the Polytechnic University of Catalonia have found a bacterium that stores large amounts of PHB, a prized polymer. This biodegradable plastic is used by the food and pharmaceutical industries, for example to produce nanospheres to transport antibiotics.
Posted: Jul 10th, 2013
Read moreResearchers have found a way to strongly adhere hydrogels to hydrophobic silicone substrates, an innovation that provides a valuable new tool for microscale biotechnology.
Posted: Jul 9th, 2013
Read more


text:
Travel & Tourism Logo Designs
We Take Your Travel & Tourism Logo as Personally as You Do.
- Professional in-house designers - original ideas, exceptional logos
- Personal interaction with your design team
- Dedicated to the small business community, because we're one too!
Travel & Tourism Logo Design
Travel logos express the sense of adventure associated with journeys to faraway lands. A travel agency logo needs to be associated with movement, but it also needs to embody the sense of rest and relaxation that many people seek when they voyage away from home. A professional logo design will embody both leisure and freedom of movement. When designing a logo for a travel agency, both the familiar and the exotic need to be on display for potential customers.
Travel agents and those who serve the needs of travelers are experienced professionals, and theirs is a serious business. That does not mean that their public image should be devoid of fun. There are different travel and tourism businesses for different market segments. By targeting a firm's core clientele, a professional logo designer will be able to implicitly communicate what services are being offered. This will maximize positive associations from the core client base, while separating the travel or tourist agency from those firms that offer other distinct services.
An upscale travel agent will have different logo requirements than an agent who tries to attract a more wholesale clientele. Neither line of business is superior to the other, but both need to effectively communicate what services they offer by way of their unique logo. Color, typeface, and images all come into play when designing the right logo for a travel-oriented business. Using a professional logo designer will narrow the options and focus attention on the most appropriate combination of elements.
Get a Great Logo Now
Our Silver Logo Package Offers Unlimited Revisions Plus Stationery Design!
only $345!
Browse Logos by Business Type
Does your current logo need work? Check out our before & after samples!
Got a Question? Get in touch


text:
View seniors Singles in Canyon
By clicking continue, I agree to receive transactional and promotional emails from Match.com. I understand that I am free to withdraw consent at any time.
By using our site, you agree to the Match.com Terms of Use.
The Golden State of California is place to find online singles from Match.com. Join Match.com to meet quality singles like you today! You're here to meet people and find a profile in Canyon, California Match.com helps you do that. Filling out a profile will allow us to find members who are right for you in Canyon, California, and make sure you're right for them. You'll also be able to start winking at members who strike your fancy. Not to mention, it's the only way other members can find you. So what have you got to lose, besides more nights cuddling with your pillow? Post your profile in Canyon, California today. A picture is worth a thousand clicks — Upload your personal photo to your free Canyon personals ad today!
Alameda, Alamo, Albany, Benicia, Berkeley, Blackhawk, Briones, Castro Valley, Concord, Crockett, Danville, Diablo, El Cerrito, El Sobrante, Emeryville, Hayward, Hercules, Hilltop Mall, Lafayette, Martinez, Moraga, Mount Eden, North Richmond, Oakland, Orinda, Pacheco, Piedmont, Pinole, Pleasant Hill, Point Richmond, Port Costa, Richmond, Rodeo, San Francisco, San Leandro, San Lorenzo, San Pablo, San Ramon, Tiburon, Walnut Creek view all states »
Asian , Black , Catholic , Christian , Divorced , Free Online Dating, Gay Singles, Gay Dating, Jewish , Lesbian Singles, Single Parents, view all communities »


text:
Afrixalus delicatus
Afrixalus delicatus Pickersgill, 1984
- kingdom Animalia
- phylum Chordata
- class Amphibia
- order Anura
- family Hyperoliidae Laurent, 1943
- genus Afrixalus Laurent, 1944
Original Published Description:
Common Names
Pickersgill's Banana Frog (English), Delicate Spiny Reed Frog (English), Delicate Leaf-folding Frog (English)
A. delicatus is distributed along the coastal plain of Mozambique (Pickersgill 1984; Poynton and Broadley 1987), and is also known to occur in southern Malawi, ranging northward along the East African coast to southern Somalia (Text from Minter et al., 2004, © SI/MAB Biodiversity Program).
This species is named for the Latin 'delicatus" meaning delicate or dainty.
Taxonomic Notes
This species is referred to as Afrixalus brachycnemis in Channing and Howell (2006).
Diagnostic Description
This is a small slender frog with a silvery or yellow dorsum. Small dark tipped spines cover the heads of the females and the heads and backs of males. A dark band with light spots runs along each side from the snout to the groin. The dorsal pattern is variable across the species range, but in the Eastern Arc and Coastal Forests there is usually a pair of dorsolateral stripes from the vent to a patch behind the eyes. The legs are pale with dark bands. Toe tips are yellow with expanded disks. In males the throat is yellow. Females have white throats (Text from Harper et al., 2010).
Snout-vent lengths of males are up to 25 mm and females are up to 27 mm (Harper et al., 2010).
This species is syntopic with A. s. spinifrons at many localities where the ranges of these two species overlap (M.P. pers. obs.). A. delicatus is also similar, morphologically, to A. aureus, and is sympatric with that species over part of its range. However, the latter seems to prefer drier habitat and does not usually utilize the same breeding sites (Pickersgill 1984; M.P. pers. obs.). Also, the advertisement call of A. aureus lacks a "zip" component and cannot be confused with A. delicates (Modified from Minter et al., 2004, © SI/MAB Biodiversity Program).
This species is referred to as Afrixalus brachycnemis in Channing and Howell (2006). A. delicatus and A. stuhlmanni are the two dwarf Afrixalus species that occur in the coastal lowland savannas. A. stuhlmanni has a similar dorsal pattern but lacks the patch behind the eyes (Text from Harper et al., 2010).
Habitat and Ecology
A mosaic of forest patches, evergreen thicket and secondary woody vegetation set in a grassy matrix. A. delicatus is found at an altitude of 300 m the habitat has an annual rainfall exceeding 1000 mm and with an abundance of surface water that collects in a variety of natural wetlands and artificial impoundments (Modified from Minter et al., 2004, © SI/MAB Biodiversity Program).
This species is usually found in near permanent waters within savanna, shrubland and grasslands at elevations up to 500 m (Harper et al., 2010).
A.delicatus is believed to feed largely on mosquitoes (Wager 1965) and other small insects. The predators of this species are unknown (Text from Minter et al., 2004, © SI/MAB Biodiversity Program).
Life History
The mating pair move a distance of 20-150 cm after amplexus at the call site so the female can lay the eggs. During oviposition these frogs construct nests. Eggs are laid on the leaf of either a Polygonum pulchrum or Ludwedegia stolonifer. Using their hind legs the frogs bring the leaf margins together by gluing (using the adhesive oviducal secretion) the opposing leaf faces (Backwell and Passmore, 1990).
Breeding takes place during September–February. Breeding sites include permanent bodies of water such as ponds, vleis and marshes, particularly those with emergent vegetation that includes Polygonum pulchrum and Ludwigia stolonifera used during oviposition (Text from Minter et al., 2004, © SI/MAB Biodiversity Program).
Males call from vegetation at the edges of permanent water. Eggs are laid on vegetation (Text from Harper et al., 2010).
Advertisement Call
Males congregate on emergent vegetation at their breeding sites in the evening and call, calling activity is more subdued after midnight or once most of the males have paired. In South Africa, calling males within a chorus form groups of about eight individuals (Backwell and Passmore 1991), with about 25% of males that are satellites (Backwell 1991). In Kenya, choruses consist of many hundreds of males (Text from Minter et al., 2004, © SI/MAB Biodiversity Program).
The call was described by Pickersgill (2007) as "a prolonged rattle."
IUCN Red List Category and Justification of Conservation Status
A. delicatus is considered to be of least concern occurs in a number of reserves (Text from Minter et al., 2004, © SI/MAB Biodiversity Program).
File | Size (kb) | Uploaded |
Harper_2010_1-143.pdf | 3764 | 2010-05-06T19:06:17Z |
Harper_2010_144-320.pdf | 4843.6 | 2010-05-06T19:06:33Z |


text:
ScripSmart searches inventory for discounted Lady Foot Locker Gift Cards from multiple sources throughout the day. Each of these companies operate secondary gift cards markets where consumers sell unwanted gift cards for less than face value.
The Lady Foot Locker Gift Card is great for: Christmas, Her Birthday, Shoes, Health & Beauty, RGCA Members, Girls, Mom, Women
By Value
By Discount
Card Type
Discount Range
By Seller
Great For Giving


text:
A short film produced for the WWF 'Life. Nature. You. Make the connection' 50th anniversary competition.
Shot on a cold yet beautiful October morning in Newquay, 58 year old British and European Champion, Jed Stone, talked to us about his life long connection with the ocean.
Cameras: Paul Hines & Richard Butterworth
Edited: Richard Butterworth
Produced: Harry Chambers
Loading more stuff…


text:
With the artist turning 90, there's been a lot of Kelly love evident in several gallery shows devoted to his work. MoMA joins the celebration with this presentation of paintings (each in the shape of an upside-down L) created as a color-study series in 1971 and named for the upstate town where Kelly keeps his studio.
"Ellsworth Kelly: Chatham Series"
Event phone: | 212-708-9400 |
Event website: | http://moma.org |


text:
Malaysia to table Cabinet paper on expert panel for MH370 crisis
Published on Apr 23, 2014 12:14 PM
PETALING JAYA (THE STAR/ASIA NEWS NETWORK) - The paper on the Panel of International Experts to look into the MH370 tragedy will be tabled by Acting Transport Minister Datuk Seri Hishammuddin Hussein in Cabinet on Wednesday.
"The panel will be placed under the Technical Committee chaired by my deputy Datuk Abd Aziz Kaprawi," Mr Hishammuddin said in a Twitter post.
He also said that the Asset Deployment Committee, chaired by Deputy Defence Minister Datuk Abdul Rahim Bakri, had already considered further assets that could be deployed to assist in the search for the missing Malaysia Airlines plane.
The Next of Kin Committee chaired by Deputy Foreign Minister Datuk Hamzah Zainuddin was already in Beijing to brief the families, he added.
To continue reading, log in if you are a subscriber
If you are not a subscriber, you can get instant, unlimited access here


text:
Scrabble word: DEADHEADING
In which Scrabble dictionary does DEADHEADING exist?
Definitions of DEADHEADING in dictionaries:
- verb - to travel without freight
There are 11 letters in DEADHEADING: A A D D D E E G H I N
All anagrams that could be made from letters of word DEADHEADING plus a wildcard: DEADHEADING?
Scrabble words that can be created with letters from word DEADHEADING
11 letter words
8 letter words
7 letter words
6 letter words
5 letter words
4 letter words
3 letter words
2 letter words
Images for DEADHEADING
Other Resources
SCRABBLE is the registered trademark of Hasbro and J.W. Spear & Sons Limited. Our scrabble word finder and scrabble cheat word builder is not associated with the Scrabble brand - we merely provide help for players of the official Scrabble game. All intellectual property rights to the game are owned by respective owners in the U.S.A and Canada and the rest of the world. Anagrammer.com is not affiliated with Scrabble. This site is an educational tool and resource for Scrabble & Words With Friends players.