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1082 Current Drug Targets, 2011, 12, 1082-1093 1389-4501/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. Biology of Cox-2: An Application in Cancer Therapeutics Zakir Khan*,1,5, Noor Khan2, Ram P. Tiwari3, Nand K. Sah4, GBKS Prasad5 and Prakash S. Bisen5 1INSERM U-955, Team No. 10, Institut Mondor de Recherche Biomédicale, Université Paris Est, 94010 Créteil, Paris, France 2Division of Plant-Microbe Interactions, National Botanical Research Institute, Rana Pratap Marg, Lucknow, 226 001, India 3Research and Development Centre, Diagnova, RFCL Limited, New Delhi-110020, India 4Department of Botany/Biotechnology, TNB College, T.M. Bhagalpur University, Bhagalpur-812007, India 5School of Studies in Biotechnology, Jiwaji University, Gwalior-474011, India Abstract: Cyclooxygenase-2 (Cox-2) is an inducible enzyme involved in the conversion of arachidonic acid to prostaglandin and other eicosanoids. Molecular pathology studies have revealed that Cox-2 is over-expressed in cancer and stroma cells during tumor progression, and anti-cancer chemo-radiotherapies induce expression of Cox-2 in cancer cells. Elevated tumor Cox-2 is associated with increased angiogenesis, tumor invasion and promotion of tumor cell resistance to apoptosis. Several experimental and clinical studies have established potent anti-cancer activity of NSAID (Non-steroidal anti-inflammatory drugs) and other Cox-2 inhibitors such as celecoxib. Much attention is being focused on Cox-2 inhibitors as a beneficial target for cancer chemotherapy. The mode of action of Cox-2 and its inhibitors remains unclear. Further clinical application needs to be investigated for comprehending Cox-2 biological functions and establishing it as an effective target in cancer therapy. Keywords: Cyclooxygenase-2 (Cox-2), apoptosis, angiogenesis, cancer, prostaglandin, chemotherapy, radiotherapy, celecoxib. INTRODUCTION is the key enzyme in prostaglandin (PG), prostacyclin and thromboxane synthesis from arachidonic acid [1, 2]. Two Cox isoforms have been described so far. Cox-1 is cons-titutively expressed in nearly all cells where as Cox-2 is an inducible gene which is expressed only under influence of certain oncoproteins, growth factors, cytokines and tumor promoters but not detectable in most normal tissues [1-6] and recently the relationship between Cox-2 and cancer has been projected [1, 5-7]. It has been well established that Cox-2 promotes overall growth of tumor and gets up-regulated in a high percentage of common cancers [8-11] where it is associated with neoplastic transformation, cell growth, angiogenesis, invasiveness and metastasis [8, 12-15]. It has been reported that conventional cancer therapies increase level of Cox-2 in cancer cells which leads to resist-ance [16-18] and down-regulation of Cox-2 with modern approaches significantly inducing sensitivity of cancer cells to these therapies [5, 10, 19, 20]. Molecular studies have demonstrated induction of apoptosis and angiogenesis by Cox-2 inhibition, two highly promising cancer therapeutic targets [19-24]. Cyclooxygenase (Cox), known as prostaglandin synthase do not affect Cox-1, but selectively block only Cox-2. The Cox-2 inhibitor is now in the market as a form of celecoxib The Cox-2 inhibitors represent a new class of drugs that *Address correspondence to this author at the INSERM, U955, Team no. 10, Institut Mondor de Recherche Biomédicale, Faculté de Médecine, Hôpital Henri-Mondor, 8, rue du Général Sarrail 94010 Créteil Cedex, Paris, France; Tel: (+33) 01 49 81 37 10; Fax: (+33) 01 49 81 36 42; E-mail: firstname.lastname@example.com (CelebrexM). It is widely accepted that Cox-2 inhibitors will be of great value to people with arthritis and variety of pain conditions. Recently Cox-2 inhibitors and their derivatives in combination with chemotherapy or radiation therapy are rapidly emerging as a new generation of therapeutic drug for the treatment of cancer [25, 26]. However, the mechanisms underlying its antitumor effects are not fully understood, and more thorough preclinical trials are needed to determine if Cox-2 inhibition represents a useful approach for prevention and treatment of cancer. This review article is focused on the molecular and clinical aspects of Cox-2 in tumor progression and treatment. MOLECULAR CANCER BIOLOGY OF COX-2 Cox-2 and its Inhibitors: Mechanism of Action arachidonic acid. First step of PGs biosynthesis is the hydrolysis of phospholipids to produce free arachidonic acid which is catalyzed by phospholypase-A2 [23, 27, 28]. The next step is catalyzed by Cox-2 in which molecular oxygen inserts into arachidonic acid in order to synthesize an un-stable product PGG2 [29], and then after peroxidase activity of Cox-2 converts PGG2 to PGH2 that is the precursor for all other prostanoids. The production of individual prostanoids is catalyzed by different specific synthases which may vary in their expression between different types of cells (Fig. 1). Analogs of arachidonic acid, NSAID and other Cox-2 spe-cific inhibitors act as primary substrate for enzyme. There-fore, it competes for binding to the active site more promptly than arachidonic acid due to multiple favorable interactions and thus inhibits PGs synthesis [30]. Cox-2 is rate-limiting enzyme of PGs biosynthesis from
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Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1083 Cox-2 Inhibitors Act beyond Cox-2 ive inhibitors may illustrate anti-proliferative activity in Cox-2-independent manner [29, 31]. As for example celecoxib inhibit the growth of various cancer cell lines that are Cox-2 deficient and also inhibit the growth of Cox-2 deficient colon cancer xenografts in nude mice [32, 33]. The underlying mechanisms are not well investigated. However, several molecular targets have been studied which may be involved in Cox-2-independent mechanisms. 15-lipoxyge-nase-1 is verified as one of the target enzyme which gets up-regulated by Cox-2 inhibitors (NS398 and sulindac sulfone) and is devoid of Cox-2 inhibitory activity [34]. The pro- duct of 15-lipoxygenase-1 enzyme is 13-S-HODE, which has both growth inhibitory and pro-apoptotic activities. Thompson et al. (2000) demonstrated that the anti-cancer activity of Cox-2 inhibitors may be attributed to the phosphodiesterase-2 and -5 [35]. It has also been reported that a product of Cox-2, PGI2 activates PPAR-gamma [36] which in turn down-regulates NF-kB transcriptional activity and activator protein (AP-1) [37-39]. This pathway may signal growth inhibitory effects in cancer cells. The relation between Cox-2 inhibitors and classical cell cycle regulatory molecules has also been established [40]. Precisely, treat-ment of cancer cells by celecoxib reduces the level of p21 and p27 proteins, which decrease CDKs kinase activity. This reduction in kinase activity modulates the mechanisms of their down-stream targets such as pRB, E2F, ultimately causing cell cycle arrest [21, 40, 41]. Additional studies delineating the molecular mechanisms by which Cox-2 and Evidence from the data also suggested that Cox-2 select-its inhibitors provide important therapeutic implications are required. Pathways of Cox-2 Up-Regulation in Cancer Cells adverse stimuli such as inflammation and physiological imbalances. It is evident that Cox-2 gets up-regulated in cancer cells and is likely to be a consequence of multiple effects. Cox-2 expression can be regulated at several levels including transcriptional, post-transcriptional, translational and post-translational levels [3, 42]. The Cox-2 promoters have several putative regulatory regions that bind trans-criptional factors viz. CRE (c-AMP response element), NF-kB and NL-IL6 [43, 44]. These regulatory sites respond differentially to various stimuli. The NF-IL6 and NF-kB are required in response to tumor necrosis factor (TNF) in which MAPK (mitogen activated protein kinase) and c-jun signal-ing pathways are involved [45-48]. Lipopolysaccharide-mediated Cox-2 induction involves p38, MAPK and C-ζ (PKC-ζ) signal transduction pathways in which NF-IL6 and CRE have been identified as being critical [47, 49-51]. Ceramide and platelet derived growth factor induces Cox-2 expression via CRE-mediated activation of either Ras/Raf-1/MEK/MAPK or Ras/MEKK-1/JNK pathways (Fig. 2) [43, 52]. Reportedly CBP, AP constituents (c-fos and pc-jun), EGFR and p53 are associated positively with Cox-2 while the PPAR-gamma are negatively correlated [20, 37, 52]. However, it is suggested that down-regulation of PPAR-gamma and induction of the CBP transcription co-activator can augment NF-kB and AP-1 transcriptional activities In most tissues, Cox-2 expression is largely responsive to Fig. (1). Biosynthesis of Prostaglandins by cyclooxygenase pathway in vascular smooth muscle cells (VSMC). Membrane phospholipids are converted to arachidonic acid by phospholipase-A2 action. Cox-2 over-expresses in tumor tissues in response to specific oncogenic stimuli where its oxygenase activity metabolises arachidonic acid into PGG2, which is thereafter converted to PGH2 by the peroxidase activity of Cox-2. Several other eicosanoids are further synthesized from PGH2 by tissue specific isomerase. Phospholipase-A2 Arachidonic Acid Celecoxib Cyclooxigenase-2 (Cox-2) PG-D2 Mast Cell Brain Airways PG-E2 Brain Kidney Platelets VSMC PG-F2a Uterus Airways Eye VSMC PG-A2 Platelets Macrophages Kidney Kidney Platelets VSMC Brain Prostacyclin Endothelium Membrane Phospholipids Via Prostaglandin-G2 Sites: Tumors, Macrophages, Others Stimuli: Oncoproteins, Tumor promoters, Cytokines Growth Factors
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1084 Current Drug Targets, 2011, Vol. 12, No. 7 Khan et al. leading to up-regulation of Cox-2 in cancer cells [37, 53]. Recently Cox-2 has been identified as a new down-stream target of p53. Wild type p53 can induce Cox-2 expression via Ras/Raf/ERK pathway [54]. revealed that Cox-2 is one of the most consistently up-regulated gene induced by NFAT, justified by presence of NFAT binding sites on Cox-2 promoter [55, 56]. In addition, several post-transcriptional factors also play an important role in the regulation of Cox-2 in cancer cells. Translation of immediate early Cox-2 gene is strictly controlled by mRNA splicing [3, 42]. Aberrant methylation of CpG island and subsequent silencing of the Cox-2 promoter have also been observed in colorectal and gastric tumors [57]. Further studies are needed to elucidate mechanisms of Cox-2 gene In breast and colon cancer, gene expression profiling regulation, which will help in designing effective cancer therapy based on Cox-2. Cox-2 in Cancer Progression biological pathways leading to cancer [8, 10, 13-15, 58]. Over-expression of Cox-2 has been reported in majority of human cancers including colon, breast, lung, head and neck, cervical, prostate, pancreas and bladder. Existing evidences suggest that Cox-2 is elevated at early stage of tumor progression [59-61]. In general Cox-2 gets up-regulated throughout the tumorigenic process, from premalignant to malignant condition in human beings. In carcinomas, Cox-2 over-expression is often greater in well and moderately differentiated tumors as compared to poorly differentiated Cox-2 is likely to be a key player in a number of Fig. (2). Proposed signal pathways of Cox-2 gene regulation. Receptor Tyrosine Kinase TNF-alpha Lypopolysaccharide (LPS) Cox-2 Expression NF-kB NF-IL6 CRE Basal Transcriptional Assembly Modulate Cox-2 gene transcription PKC- ζ GRB SOS RAS RAF MEKKS MEK1/2 MKK4, 7 MKK3 MAPK/ ERK JNK p38 PKC
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Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1085 ones [62]. Induced level of Cox-2 supports overall growth of tumor and provides resistance against therapies. Cox-2 interferes in several vital processes, as for example, it inhibits apoptosis, promotes tumor specific angiogenesis and induces proangiogenic factors such as VEGF, inducible nitrogen oxide synthase protein IL-6, IL-8 and TIE-2 [23, 63-70]. involved in carcinogenesis. The malignant tumor cells constitute the bulk of the cellular mass in the vast majority of human cancers [71, 72]. Thus, the tumor cell production of Cox-2 would be predicted to have a great impact on local PGs production. It is well established that an increased level of PGs contributes in tumor cell progression. Enhanced PGs synthesis can directly stimulate mitogenesis which can induce oncogenesis in osteoblasts, fibroblast and mammary epithelial cells [73-75]. Certain PGs such as PGE2 have been shown to promote both cancer cell growth and motility [76]. Cox-2 expression and consequent PGs production by tumor endothelium, infiltrating macrophages and other accessory cells in tumors resulted in paracrine growth stimulatory effects. However, PGs do not act as mitogens for all cell types and in fact are known to depress proliferation of some cells particularly involved in immune system [77]. Over-production of PGs, locally disrupts immune surveillance by down-regulating T and B cell proliferation [78, 79], cyto-toxic activity of natural killer cells [80], antigen processing and cytokine synthesis such as IL-12 and TNF-alpha [79-81]. However, immune suppression by PGs may contribute in tumorigenesis. Metabolites derived from Cox-2 are reported to be tase has been established [82]. PGE2 is shown to stimulate In breast cancer, a correlation between Cox-2 and aroma-aromatase transcription, leading to supraphysiological local estrogen levels which subsequently release growth factors and enhance proliferation [82, 83]. In all cases of human breast cancer, cytochrome p450 aromatase enzyme and Cox-2 were co-expressed [82, 84]. Thus there is a possibility that estrogen over-production mediated by PGs may be an organ specific consequence of Cox-2 up-regulation in breast cancer. Another important Cox-2 metabolite which contri-butes to carcinogenesis is PGH2. By enzymatic and non-enzymatic reaction, PGH2 isomerizes into a potent mutagen malondialdehyde which can induce frame shift and base substitution mutations in target genes [77]. In addition, per-oxidase activity of Cox-2 can also activate other mutagens by oxidation of heterocyclic and aromatic amines [85]. Thus mitogens derived from Cox-2 can induce DNA damages, thereby contributing to carcinogenesis. which largely relies on angiogenesis. Ischemia (low nutrition supply) can induce tumor cell apoptosis, speeding up necrosis and cell extinction. Many researches verified relationship between Cox-2 and angiogenesis [8, 14, 23, 63]. Cox-2 derived PGE2 can promote angiogenesis and helps in tumor growth and metastasis [64, 67, 86]. Over-expression of Cox-2 can induce secretion of several angiogenic factors such as VEGF, TGF-1 and bFGF [87, 88]. These factors specially stimulate vascular tube formation and support tumor growth due to sufficient nutrition supply. Anti-angiogenic activity of Cox-2 inhibitors is an important mechanism by which they suppress tumor growth. Celecoxib inhibits angiogenesis by complete inhibition of angiogenic factors in tumor cells [8]. In an important study, Darmond et al. (2001) demonstrated that inhibition of Cox-2 in Overall growth of tumor depends on nutrition supply Fig. (3). Role of PGE2 and other down-stream mediators of Cox-2 in tumor development. Primary signal of PGE2 in (1) an autocrine or paracrine (2) manner to tumor cell, promotes cell proliferation and survival. Another paracrine signaling pathway involves in production of PGE2 by tumor cells, which in turn acts in an autocrine/paracrine fashion to promote synthesis of angiogenic growth factors such as VEGF by tumor cell. These factors act in a paracrine fashion (3, 4) to promote proliferation, migration and tube formation. PGE2 also increase invasiveness by EGFR-P13K-Akt pathway. Tumor Cancer Cell 3 4 Proangiogenic Proliferation, migration Invasiveness Factor (VEGF) and tube formation 2 PGE2 1 EGFR PGE2 P13K Akt Arachidonic Acid
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1086 Current Drug Targets, 2011, Vol. 12, No. 7 Khan et al. endothelial cells by NSAID suppresses Alpha-V-beta-3-dependent activation of cdc42 and Rac resulting in inhibition of spreading and migration of endothelial cells and sup-pression of angiogenesis [89]. PGE2 can increase invasive-ness and motility that is predominantly mediated by EGFR-phosphotidylenositol-3-kinase-Akt pathway [86, 90, 91]. In brief the mechanisms of Cox-2 inhibition resisting the growth of cancer might prevent angiogenesis and weaken invasiveness which further enhances its potential in anti-cancer therapy (Fig. 3). investigated [24, 92]. Over-expression of Cox-2 and its end point metabolite, PGE2, protected cells against apoptosis and majority of Cox-2 inhibitors enhance apoptotic cell death [20, 23, 24, 76, 93, 94]. Till date mechanism of apoptosis inhibition by Cox-2 is poorly understood. Cox-2 products have influence on both extrinsic (receptor mediated) and intrinsic (mitochondrial mediated) apoptotic pathways [93, 95, 96]. Many researches have demonstrated that Cox-2 directly or indirectly changes the ratio of pro-apoptotic and anti-apoptotic proteins toward anti-apoptosis. Over-expres-sion of Cox-2 reduced the levels of bax and bclxl (pro-apoptotic) [71] and induced the levels of bcl2 and survivin (anti-apoptotic) proteins [67, 76, 95-97]. Survivin is one of the key anti-apoptotic proteins which is over-expressed in most of the human cancers [98, 99] and provides resistance to conventional cancer therapies including chemotherapy and radiotherapy [100, 101]. Cox-2 stabilizes survivin due to ubiquitination levels which provide resistance to apoptosis [102]. Above findings suggested that Cox-2 inhibiting apop-tosis might be through the regulation of proteins that are predominantly involved in mitochondrial-mediated apop-tosis. PGE2 appears to have an inhibitory effect on Fas-me-diated apoptosis also [23, 93]. PGE2 over-production repress-ses expression of DR-4 and DR-5 receptors consequently inhibiting recruitment of the intracellular adaptor molecules for Fas-associated death domain and thus attenuating caspase activation [103, 104]. It is interesting to note that inhibition of Cox-2 by a Cox-2 inhibitor sulindac sulfide restored expression of DR-4,5 and augmented Fas-mediated cell death [84]. Correlation between apoptosis and Cox-2 has also been understood. However, a possibility is that wild type of p53 in cancer cells decreases Cox-2 expression while mutation in p53 gene contributes in Cox-2 induction consequently result-ing in anti-apoptosis [105]. In an important study, Han et al. (2002) demonstrated that oxidative and genotoxic effects induced expression of Cox-2 in p53-dependent manner and inhibition of Cox-2 potentiates DNA damage/p53-mediated apoptosis [54]. Interaction between Cox-2 and apoptotic protein may represent additional mechanisms by which Cox-2 expression interferes with tumor growth (Fig. 4). Role of p53 in Cox-2-mediated apoptosis is poorly CLINICAL CANCER THERAPEUTICS OF COX-2 Pioneer Studies Associating Cox-2 with Cancer Several in vivo studies have been conducted to evaluate the role of Cox-2 in tumorigenesis. In a frontline research, Oshima et al. (1996) engineered an Apc716 Cox-2 null mice and got up to 86% reduction in intestinal adenoma, thus providing for the first time definitive evidence of the role of Cox-2 in tumorigenesis [106]. Many of the same molecular and biochemical changes underlying human colon cancer were observed in the azoxymethane (AOM)-induced rat colon cancer model, in which Cox-2 down-regulation effectively prevented development of colon tumors by 93% and inhibited tumor initiation by approximately 80% [106, 107]. Similar trend was observed in 7,12-dimethyl-benz(a) anthracene (DMBA)-treated animal model, which is well suited for breast cancer studies [108, 109]. A significant correlation between Cox-2 and HER-2 expression was reported in mammary tumors expressing HER-2/neu gene in mice and consistently these findings have also been estab-lished in human breast cancer [110-112]. Interestingly, epidemiological researches also suggest a reduction in the risk of cancer development and cancer-related deaths by administration of Cox-2 inhibitors [113, 114]. Cox-2 Inhibitors in Cancer Prevention and Treatment progression, researches conducted using a variety of Cox-2 specific inhibitors demonstrate a decrease in cancer incidence in many animal models [106, 109, 115]. Celecoxib (CelebrexTM) is a well known Cox-2 inhibitor, approved by the U.S. Food and Drug Administration (FDA) for the treatment of arthritis. Since many prior studies suggested potential of Cox-2 inhibitors in cancer prevention, the National Cancer Institute (NCI) conducted many laboratory studies and clinical trials for the validation of Cox-2 inhibitors in the prevention and treatment of a variety of cancers including bladder, breast, cervical, colorectal, oeso-phageal, head and neck, lung, and prostate cancers at differ-ent research organizations. As of now NCI continues to test celecoxib in more than 50 clinical trials for the prevention and treatment of cancer. On the confirmation of Cox-2 involvement in cancer Adenoma Prevention with Celecoxib (APC) Trial Polyps Trials conducted on more than 3500 patients demonstrated the successful use of celecoxib [116, 117]. It is important to note that celecoxib was more effective against advance stage lesions and in patients at a greater risk for colorectal cancer. Despite reducing the adenoma recurrence in a dose-dependent manner, the cardiovascular risk posed on administration of celecoxib (400 mg/day) drew the attention. Furthermore, an adverse dose-response effect was observed, with higher toxicity in patients receiving higher dose. However, ongoing clinical trials (NCT00005094) with altered dose and time schedules of celecoxibs may provide better results with reduced side effects. In Adenoma and Colorectal Sporadic Adenomatous Cox-2 Clinical Studies in Breast Cancer 2. Several preclinical studies on breast tumor mice model showed involvement of Cox-2 and its metabolites at many key points throughout tumorigenesis, including premalignant hyperproliferation, transformation, tumor viability, growth, invasion and metastatic spread [118, 119]. Breast tumor is well reported for over-expression of Cox- capecitabine are considered an active treatment strategy for breast tumor [120, 121]. A pilot study was conducted to Conventional therapeutic drugs such as trastuzumab and
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Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1087 determine if the addition of celecoxib is useful in improving the response rate of breast cancers to neoadjuvant cytotoxic treatment [122]. It was followed by a phase-II study of celecoxib and trastuzumab in patients with HER-2/neu-over-expressing metastatic breast cancer which had progressed while receiving trastuzumab [123]. In this trial, an improved response rate of 20% was recorded as compared to trastuzu-mab alone. One more phase-II trial of celecoxib in combi-nation with capecitabine was conducted on advanced meta-static breast cancer patients [124]. This combination was found to be very effective with a response rate of 20-30%. Interestingly lower toxicity was observed in combination as compared to capecitabine alone. Currently this trial is moving in its further stage with larger series of patients. Additionally, in both the mentioned trials, the Cox-2 level was significantly higher in tumors that showed a clinical response to the addition of celecoxib as compared to non-responders whereas this was not observed in patients treated with chemotherapy alone. Moreover, both regimens were well tolerated and there were no clinical signs and symptoms of cardiac failure. Importantly, as we described above, Cox-2 and aromitase expressed in a significantly positive manner in human breast cancer, suggest the involvement of autocrine and paracrine mechanisms in hormone-dependent breast cancer develop-ment via growth stimulation from local estrogen biosynthesis Endocrine therapy is another treatment for breast cancer. [82-84, 125]. Induced vascularization and estrogen synthesis adversely affect the endocrine therapy and this portrays Cox-2 blocking as an important remedy to combine with hormone therapy. A successful preclinical study was conducted to test the potential of celecoxib and exemestane combination on DMBA rat model [108, 109]. Then after a CAAN (Celecoxib anti-aromatase neoadjuvant) trial was conducted to investi-gate the efficacy combining aromatase inhibitors with Cox-2 inhibitor in postmenopausal hormone sensitive breast cancer patients [126, 127]. The preliminary results of these trials show that celecoxib and anti-aromatase combination therapy works well in breast cancer. Cox-2 in Head and Neck Cancer 2 as a therapeutic target in head and neck cancer prevention and treatment. Pathological studies indicate a higher expression of Cox-2 in head and neck cancer tissues [128, 129]. Treatment of head and neck cancer cell lines with celecoxib induced cell death in vitro and suppressed the in vivo tumor growth in animal model [130]. NCI and other Cancer Research Centers across the world have started clinical trials of celecoxib alone and in combination with other drugs to treat head and neck cancer. It is well known that celecoxib suppresses tumor growth by reducing blood supply. However, NCI started a phase-I/II trial in year 2008 (NCT00357617) to determine, if celecoxib could be useful in Several studies have been undertaken to investigate Cox- Fig. (4). Schematic representation of Cox-2 apoptotic targets. Elevated Cox-2 level has influence on both mitochondrial and receptor-mediated apoptosis. Cox-2 over expression induces apoptotic resistance in cancer cells by increasing anti-apoptotic and suppressing pro-apoptotic proteins involved in both apoptotic pathways. In mitochondrial pathway Cox-2 showed negative effect on bcl-xl and Bax (pro-apoptotic) and positive effect on bcl2 and survivin (anti-apoptotic) and in receptor mediated pathway Cox-2 over expression constrains formation of death domain complex by decreasing DR-4 and DR-5 receptor proteins. It is hypothesized that anti-cancer therapies can induce Cox-2 expression in p53-dependent manner, which in turn attenuate p53-mediated apoptosis by regulating pro and anti-apoptotic proteins. Fas Ligand Death Receptor Complex Fas Receptor Bcl2 Procasp-8 Bclxl Bax Cyt-c Survivin Casp-8 P53 Apaf1 Casp-3, 6 Procasp-3,6 Procasp-9 Casp-9 APOPTOSOME Apoptosis Radiation Anti-cancer drugs Cox-2 NUCLEUS Degradation of chromosomal DNA Mitochondria
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1088 Current Drug Targets, 2011, Vol. 12, No. 7 Khan et al. reducing the amount of normal tissues that need to be removed by surgery. The results of this ongoing trial could be useful for doctors in learning more about the cancer and predict how well patients will respond to treatment with celecoxib. NCI had also conducted a phase-II trial in order to check the molecular effects of short-term celecoxib treatment on head and neck squamous cell carcinoma (HNSCC) (NCT00596219). This study aims to measure how celecoxib affects those chemicals, which can be found in the tumor, blood and urine of patients with head and neck cancer. Cox-2 inhibitors are also testing in combination with other key therapeutic targets of head and neck cancer. A clinical trial is going on at Winship Cancer Institute of Emory University to test the feasibility and efficacy of Cox-2 inhibitor (celecoxib), EGFR inhibitor (ZD1839) and Tyrosine Kinase Inhibitor (OSI-774) in Early Stage (Stage I/II) of HNSCC (NCT00400374). Preliminary reports of these trials showed chemopreventive effect of Cox-2 inhibition in head and cancer. Upcoming data may help in the treatment of head and neck cancer in clinical settings. and cell lines of neuroblastoma also. Inhibition of Cox-2 by celecoxib significantly induced apoptosis of neuroblastoma cell lines and suppressed in vivo tumor growth [7, 131]. Furthermore, use of NSAID was found to be effective in treating paediatric neuroblastoma [7]. All together, these findings suggest that Cox-2 inhibitors may be a novel adjuvant therapy for neuroblastoma. Cox-2 was found highly up-regulated in primary tumors Cox-2 in Lung Cancer expression of Cox-2 [132, 133]. The level of Cox-2 in both types of non-small cell lung carcinomas (NSCLC: adenocar-cinomas and squamous cell carcinomas) was significantly higher than in normal lung tissues. In vitro cell studies have demonstrated that over-expression of Cox-2 stabilizes anti-apoptotic genes and induces invasiveness in NSCLC (Dohadwala M et al. 2001, Krysan K et al. 2004) leading to resistance of NSCLC against chemotherapy and radiotherapy [134, 135]. Preclinical studies on NSCLC animal models have shown that treatment with either NSAID or celecoxib reduced tumor growth by acting on multiple tumor-progres-sion targets such as angiogenesis, tumor invasion, resistance to apoptosis, and suppression of antitumor immunity via Lung cancer tissues were also identified with high both Cox-2-dependent and-independent pathways [136]. In sync with preclinical studies, epidemiological evidence has shown a decreased incidence of lung cancer in patients who used cox-2 inhibitor. Based on these observations, many clinical studies have been initiated to evaluate the effect of celecoxib in combination with chemotherapy and radio-therapy [137, 138]. Phase I/II, III/IV clinical trials in colla-boration with NCI and University of California are in prog-ress to test celecoxib on NSCLC patients (NCT00104767, NCT00055978). A combination trial of celecoxib, paclitaxel and carboplatin is being conducted by Bimodality Lung Oncology Team (BLOT). correlation with EGFR. Preclinical studies have demons-trated successful use of Cox-2 inhibitors with EGFR inhi-bition [138]. Ongoing clinical trials are also evaluating the combination of celecoxib with epidermal growth factor receptor inhibitors (ZD1839) of NSCLC (NCT00068653). Initial trends of these clinical studies have shown that cele-coxib can be safely administered alone and in combination with other chemoradiotherapeutic agents in NSCLC patients. In NSCLC, Cox-2 has shown a significant positive Cox-2 Clinical Studies in Other Cancers 2 was significantly associated with poor prognosis and shorter patient's survival in cervical, prostate, skin and bladder cancers [139-141]. In addition, high levels of Cox-2 have also been found in gastric, liver, pancreatic and biliary tumors [142]. Cox-2 inhibitors are already in clinical trials for the prevention of skin cancers and for the treatment of cervical and prostate cancer (Table 1). Like various mentioned cancers, high expression of Cox- different cancers, celecoxib was promisingly shown to reduce tumorigenesis alone and in combination with other conventional chemoradiotherapies. It is interesting to note that celecoxib is effective in the advanced stages of cancer. Overall clinical successes of trials are stepping stones to progress. Further studies are warranted to clarify if Cox-2-inhibition has an impact in clinical settings. In the above preclinical and clinical studies regarding Future Prospects unknown variables and might be much more complex than Role of Cox-2 in tumor progression still has many Table 1. Clinical Trials of Celecoxib in Skin, Cervical and Prostate Cancer Prevention Trial Phase Number of Patients Participants Skin II 36 Basal cell nevus syndrome [142] Skin II, III 240 Actinic keratoses [142] Skin II, III 240 No elevated risk [142] Treatment Trial Cervical I, II 62 Radiation, 5-FU, cisplatin, NCT00023660 Cervical II/III 130 Intraepithelial neoplasia, placebo, NCT00081263 Prostate I 60–70 Surgery, NCT00022399 Prostate II, III 85 Recurrent, placebo, NCT00136487
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Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1089 currently believed. It is a key challenge to researchers and scientists across the world for better understanding of argument as regarding their mode of action throughout the body and, therefore, an improved strategy based on Cox-2 needs to be designed for treating cancer. Since it is well established that most of the tumors produce high levels of Cox-2, investigations are being directed towards elucidating the role of Cox-2 inhibitors in preventing cancer. An anti-cancer effect of Cox-2 inhibitors is widely accepted but its utilization is controversial due to side effects including cardiovascular risk [143]. It is important to note that only high dose (400 mg/d) of celecoxib showed this side effect in colon cancer trial. Researchers may investigate giving lower doses of celecoxib or different dose regimens to determine if this causes less cardiovascular risk. Still it is unclear whether cardiovascular side effects are a class effect or all Cox-2 inhibitors exhibit the same behavioral pattern. More resear-ches in this direction will assist in the development of novel drugs with lesser side effects once the mechanisms through which Cox-2 inhibitors reduce tumor progression are understood. Many clinical trials from phase-I to IV are still in progress with most of the cancers to test celecoxib alone and in combination with other chemoradiotherapeutic agents in different doses and time schedules. The preliminary results are very exciting to carry on further study with celecoxib with fewer side effects. It is interesting to mention that Cox-2 inhibitors have shown good results in personal medication according to the status of Cox-2 expression. For example, celecoxib used in combination with ZD1839 (EGFR inhibitor), which is an excellent therapeutic target in head and neck and lung cancer (NCT00068653). Many more studies are needed to test the feasibility and efficacy of celecoxib with other specific tumor marker inhibitors in particular cancer. As it is reported that Cox-2 inhibitors have capacity to reduce tumorigenesis even without involving Cox-2 [33, 131]. Now researchers are being initiated in order to unravel other targets for Cox-2 inhibitors in cancers. This will aid in the construction of innovative derivatives of Cox-2 inhibitors to enhance effectiveness with reduce side effects in cancer cure. CONCLUSION over-expression is found in many cancers including head and neck, lung, colon and breast. Cox-2 generated biomarkers such as PGs or other down-stream mediators have an important role in regulating cell proliferation and survival. Elevated level of Cox-2 gives anti-apoptotic and angiogenic signals thus resisting cancer cells to conventional cancer therapies. 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Cyclooxygenase-2 (COX-2) mRNA Expression Levels in Normal Lung Tissues and Non-small Cell Lung Cancers. Jpn J Cancer Res 1999; 90: 1338-43. [133] Mascaux C, Martin B, Verdebout JM, Ninane V, Sculier JP. COX-2 expression during early lung squamous cell carcinoma oncogenesis. Eur Respir J 2005; 26: 198-203. [134] Qadri SS, Wang JH, Redmond KC, O' Donnell AF, Aherne T, Redmond HP. The role of COX-2 inhibitors in lung cancer. Ann Thorac Surg 2002; 74: 1648-52. [135] Park SY, Kim YM, Pyo H. Gefitinib radiosensitizes non-small cell lung cancer cells through inhibition of ataxia telangiectasia mutated Molecular Cancer 2010, 9: 222, DOI:10.1186/1476-4598-9-222. [136] Sandler AB, Dubinett SM. COX-2 inhibition and lung cancer. Semin Oncol 2004; 31: 45-52. [137] Liao Z, Komaki R, Milas L, Yuan C, Kies M, Chang JY, et al. A Phase I Clinical Trial of Thoracic Radiotherapy and Concurrent Celecoxib for Patients with Unfavorable Performance Status Inoperable/Unresectable Non–Small Cell Lung Cancer. Clin Cancer Res 2005; 11; 3342-8. [138] Chen L, He Y, Huang H, Liao H, Wei W. Selective COX-2 inhibitor celecoxib combined with EGFR-TKI ZD1839 on non-small cell lung cancer cell lines: in vitro toxicity and mechanism study. Med Oncol 2008; 25, 161-71. [139] Higashi Y, Kanekura T, Kanzaki T. Enhanced expression of cyclooxygenase (COX)-2 in human skin epidermal cancer cells: evidence for growth suppression by inhibiting COX-2 expression. Int J Cancer 2000; 86: 667-71. [119] [120] [121] as a Prognostic Factor in
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Biology of Cox-2 Current Drug Targets, 2011, Vol. 12, No. 7 1093 [140] Kulkarni S, Rader JS, Zhang F, Liapis H, Koki AT, Masferrer JL, et al. Cyclooxygenase-2 Is Overexpressed in Human Cervical Cancer. Clin Cancer Res 2001; 7: 429-34. Wülfing C, Eltze E, von Struensee D, Wülfing P, Hertle L, Piechota H. Cyclooxygenase-2 Expression in Bladder Cancer: Correlation with Poor Outcome after Chemotherapy. Eur Urol 2004; 45, 46-52. [141] [142] Michalowski J. COX-2 Inhibitors: Cancer Trials Test New Uses for Pain Drug. J Natl Cancer Inst 2002; 94: 248-49. Solomon SD, McMurray JJV, Pfeffer MA, Wittes J, Fowler R, Finn P, et al. Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention for the Adenoma Prevention with Celecoxib (APC) Study Investigators. N Engl J Med 2005; 352:1071-80. [143] Received: June 17, 2010 Revised: October 26, 2010 Accepted: November 01, 2010 PMID: 21443470


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Tobi and the Jelly Bean Tree by imaginismWatch
©2009-2016 imaginism
Here's a very special and rare little rodent named "Tobi." He's on a search for some fruit from the almost extinct Jelly Bean Tree.
Please help the re-population of the species by planting a jelly bean today!
Watercolor and Gauche on watercolor paper mounted on board.
Print available here --> [link]
Original painting available here --> [link]
Please help the re-population of the species by planting a jelly bean today!
Watercolor and Gauche on watercolor paper mounted on board.
Print available here --> [link]
Original painting available here --> [link]
Awwwww, my gosh! This is so cute!
Wonderful character!
Wonderful character!
so cute!
I loved it! Brought a smile to my face!
i love this painting, feeling so GOOD
Totally dig it!
Funny and well done.
Love this!! want this Tobi soooo much!
One of my very favourites of all time it's so cute!
I like
All your works are incredible!!! Bravo!!!!!!!!
It's so tender and sweet ^o^
i love this! i looked up "watercolor tree" hoping to get some japanese looking cool watercolor stuff and i found this....im much happier with this i find! haha i love the concept and the painting is adorable and dramatic. it would make for a good childrens story.
Tobi! Cute!
How cute is /he/!
I don't know how you do it, but you get like two or three animals, mesh them together and come out with thtese adorible little things!!!
Your work is AMAZING! This almost got me eye teary lol so cute! Im planting a jelly bean as soon as i get a bag lol
it reminds me the tales about the fox and the grapes XD
sweet & amazing
Wonderfully unique, highly adorable, and thoroughly enjoyable. ^^
Great job!
Great job!
resembles a tapir!
I like the emphasis on the lone red jellybean
I like the emphasis on the lone red jellybean
the poor little thing! Wonderful work
I like how you created a frame here. However, I think it would be better if Tobi was looking up directly at the jelly bean. It appears as if he is looking towards the right.
The detail on his trunk is amazing.
The detail on his trunk is amazing.
shame on me I never faved this I was just browsing through my favs realizing that it's missed. It's such a great painting, awesome colour scheme and of course an insanely cute character. and the jelly bean..the jelly bean. well, it's time to fav it!
Rly cute rodent I like the way You use watercolours. Do You have any tutorials?
That's just one of the cutest animals ever! *giggles*
Aw! The composition of this one is really great--it makes a sweet, powerful little artwork. I'm definitely planting a jellybean now! xD
i love it. its one of the best of my favs.
He is just amazingly sweet! *huggles him*
I wish jelly bean trees exsisted ^__^
this little guy is adorable
this little guy is adorable
He's adorable! He reminds me of some kind of ice age mammal, though I'm no expert on that so I'll just leave it there. A Jelly Bean Tree? I want one! Yummy jelly beans all the time!^_^ Amazing work!
Your ideas make me happy!
so cute
the weirdest and cutest thing I've seen for ages! love it!
very interesting specie you did there and i would like to see one in our reality X3
how excelent "(^_^)"
hi hi:] so so so rginal and sweet
Aww, he looks so hungry!
Great imagination as always!
Great imagination as always!
so cute! <3
I'm sending him a bag of jelly beans
Nicely done
You do a nice job in a surreal way of showing the human condition.
You do a nice job in a surreal way of showing the human condition.
Hes Adorable ^^
great illustration!
Greetings from Peru
great illustration!
Greetings from Peru
Wonderful work with watercolors. I love your style to draw
ouuuuu i love him! : D
Your painting style amazes me!! I only hope to someday be just half as good!! very very lovely picture! and as for Tobi I hope to meet a real one some day he is just darling
That's such a cute concept!
and the colors look very nice!
and the colors look very nice!
i so want to help him out
GREAT! Instant favorite.
I love him <3

subset: commoncrawl


text:
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RainRain (1999) Episode 7-A- Maisy Cartoon Episode Guide by Dave Koch
This page has been viewed 6 times this month, and 498 times total.
- Maisy Cartoon Episode Guide
- King Rollo Films Ltd., Polygram Filmed Entertainment, Universal Pictures Visual Programming
- Distributed by: Nickelodeon Network
- Cartoon Characters: Maisy, Charley, Cyril, Eddie, Tallulah.
- Originally Released in 1999.
- Color
- Running Time: 5 minutes.
- United Kingdom
Cartoon Summary:
It's raining and Charley has forgotten his umbrella, something which Maisy finds is easily done.
Submit Additional Information:
Do you have anything to add to this page? Have we made any mistakes... or do you ahve any additional information about Rain? If so, we would love to hear from you. Please send us a quick note with your additions or corrections to this page, and we will make the corrections as soon as possible!Report Errors / Submit Additional Information
Cartoon Comments:
Do you love Rain, or do you think it is the worst cartoon ever? Let us know what you think! Surely you have an opinion... so share what you think. Take a minute and post your own comments about this cartoon here.


text:
Freeman Facial Clay Mask - Mint & Lemon
143 reviews
88% would repurchase
Package Quality: 4.3
Price: $$
Package Quality: 4.3
Price: $$
Not tested on animals
INGREDIENTSWater (Aqua), Kaolin, Bentonite, Titanium Dioxide, Propylene Glycol, Magnesium Aluminium Silicate, Citrus Medica Limonum (Lemon) Fruit Extract (Lemon), Mentha Piperita (Peppermint) Leaf Extract (Peppermint), Tocopherol (Natural Vitamin E), Capric/Caprylic Triglyceride, Montmorillionite, Disodium EDTA, Sodium Polyacrylate, Diazolidinyl Urea, Methylparaben, Propylparaben, Methylchloroisothiazolinone, Methylisothiazolinone, Fragrance (Parfum), Yellow 5 Lake, Blue 1 Lake (CI 42090)
Age: 19-24
Skin: Dry, Fair-Medium, Not Sure
Hair: Black, Other, Other
Eyes: Brown
OMG I love this mask!! I bought it because they don't sell the Queen Helene mint julep mask in Canada or so I think. We have a target now but they don't carry it either (maybe in the future), so I tired maybe finding something similar and I saw all the good reviews here so I gave it a shot. Normally nothing that most people like work for me skincare wise. So I wasn't expecting much. I was really shocked how well it worked. My skin looks brighter and softer. I mainly was looking for something to help with black and white heads. Not really sure if it does help but my face does feel cleaner. I've only used it notice since i got it yesterday but I wanted to write a review right away because my face looks so dewy, bright and glowly after one use. I had trouble in that area, my face always looked so dull for so time now but I was more concerned with my white heads. I read some reviews that it helped with acne too. I'm really happy to read that, I was breaking out for a while but my acne was clearing up, I hope this mask helps with the remaining healing process because they are competely gone, just going away. I recommend this mask if your face isn't looking up to pare than it use too. I'm really loving it so far.
Age: 19-24
Skin: Sensitive, Tan, Not Sure
Hair: Black, Other, Other
Eyes: Black
When I saw this I had to get it. ! Unfortunately I can't find it anywhere anymore. I got it from ulta but never saw it again. I have a lot left but if anyone knows please leave a comment ! Besides amazon... So this mask is amazing. I Lov lemon because it makes me look glowy lighter and brighter. Also I'm hoping the lemon might take away blemishes. I felt cleaner. Not sure if it helped with blackheads pores and acne but I have the mint julet masque for that... Def would but again if I can find it otherwise I might have to resort to scrubbing lemons on my face or use the juice which takes more effort id rather have a already made mask!
Age: 19-24
Skin: Combination, Fair-Medium, Not Sure
Hair: Black, Other, Medium
Eyes: Brown
I LOVE THIS THING. I think it's waaayyy better then Queen Helene's mint julep mask! I used to use it as a full face mask, but now I'm just to lazy. xD
Now, I use it as a spot treatment! Once I feel a pimple coming or I have a pimple, I apply the mask on the pimple and the area around it and let it dry. Then I rinse it off and wash my face or that area with my Cetaphil cleanser. I do this before I go to bed. When I wake up, the pimples have either stopped growing, isn't irritated or it shrunk.
Age: 19-24
Skin: Very Oily, Dark, Not Sure
Hair: Brown, Other, Other
Eyes: Brown
Excellent. I purchased this product before being exposed to another much more expansive mask (Skinceuticals Clay Mask) and can truthfully say I still enjoy using it. I see a marked difference in the clarity of my skin the next morning and if I have a breakout at the time it is reduced, The trick for me with masks is to use them only once a week otherwise my face becomes aggravated. I love the mint/lemon mask because it is cost effective, does not overdry my skin, smells good, and spreads well. I definitely prefer it over Queen Helene's.
Age: 30-35
Skin: Combination, Medium, Not Sure
Hair: Black, Wavy, Fine
Eyes: Brown
After the terrible experience with Freeman Gogi Berry mask....i kinda scare with this one, since it contain mint and lemon which it can be irritating. But surprisingly im happy with it...i only use it once a week, after washing my face and toner. The scent is ok for me, normally i will apply it for 15-20 minutes even its not completely dry, my skin will get itchy if i wait longer.
The result is amazing, the face getting smoother and brighter after use, i will continue using this mask. My only problem is Freeman product is hard to find in Malaysia, onle Caring pharmacy carried it...Right now im just looking Freeman mask that moisturizing skin.
Age: 30-35
Skin: Acne-prone, Fair, Cool
Hair: Blond, Straight, Fine
Eyes: Blue
I've bought two of the little .5 fl oz packets because there isn't a store that carries the larger tube (near me) that this is also supposed to be available in. the scent doesn't really bother me and I'm very sensitive to things like that. I love how this makes my skin feel after I rinse it off. I usually try to do 3 masks a week and when I do I notice a huge difference in my skin. I've had acne since puberty and as I've gotten older it's gotten a little better. I really wish I could find the tube of this because I think that it would be an even better deal money wise. That being said I can usually get about 7-9 masks from the packet. I do notice a little stinging if I've done a scrub before the mask but it's not too bad.
Age: 25-29
Skin: Combination, Fair, Cool
Hair: Blond, Wavy, Coarse
Eyes: Blue
All I can say is... WOW.
After reading all the positive reviews here, I dashed off to purchase this mask and I am so pleased I did!
After cleansing and exfoliating first, I applied an even layer all over my face (avoiding the eye contour) and let it sit on my face for about 30 minutes. After this time it had turned hard (could barely move my face, haha) so I rinsed it off with luke-warm water and my skin looked AMAZING. It was almost as though I was wearing make-up - seriously.
It was glowing, smooth, all the usual T-Zone oil was gone, I had a rosy glow and my skin just looked radiant and healthy!! Possibly the best my skin has ever looked without make-up in my 27 years of life. I had no blemishes, but the few post-blemish red marks I did have look less red and obvious which is an added bonus! I am hoping this matte look sticks around for awhile! I really recommend this for oily or combo skin like mine. If you have dry skin I would stay away as it really did strip all the oil - great if you have too much (like I do) but would be too drying on already dry skin I'd imagine. Will definitely be using this once a week from now on. LOVE.
Age: 19-24
Skin: Sensitive, Fair, Not Sure
Hair: Brown, Straight, Medium
Eyes: Green
Age: 19-24
Skin: Combination, Tan, Not Sure
Hair: Brunette, Other, Other
Eyes: Hazel
Freeman continues to amaze me!! I just went crazy this week on freeman masks! I had the older version of avocado and oatmeal and that worked wonders growing up, Recently I noticed the change in their packaging and decided to try them out, Bought 4 this week and today was the last one which is the mint and lemon! I can honestly say this works, My face feels so soft and my pores look great, I have blackheads on my nose and more pores in my cheek area and those are all smaller now!!! So happy, It looks like my face is evened out now too! This is a must grab! I purchased for 3.77 @ Wallyworld
Age: 18 & Under
Skin: Combination, Fair-Medium, Not Sure
Hair: Brunette, Other, Other
Eyes: Hazel
I had tried this mask for the first time last night, and it was amazing! I loved it! I bought the travel size but I am definitely going today to buy the tube. I have an oily T-Zone and a few blackheads on my nose, well let me tell you, right after I washed the mask off, my nose looked amazing! They do visibly reduce the size of pores. As for the breaking out I've read in reviews, I'll update in a few days to see. When I first put it on it did sting a bit but it's not too bad. It's just showing it works! Love love love this product, going to try more!
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You never need to clip coupons. Whenever you order $75 or more of Volvo XC90 Thermostat parts, we will ship your order free UPS Ground. Never worry about when our web store is open. It always is. Saving big money on Volvo XC90 Thermostat parts can almost become a game on our website. Our knowledgeable staff is ready to help you find the auto parts you need for your vehicle. Please feel free to email our customer service department with any questions or comments you may have about your Volvo XC90 Thermostat parts order. Don't let other sites fool you, AutohausAZ has the best quality and best price on Volvo XC90 Thermostat parts.
Bret H. - Hudson, ME: Thank you for getting the part to me so fast. My car is running great and I am sure I will use you in the future. Have a great day.


text:
My husband and I found this hotel to be comfortable and quiet. The desk staff were very friendly and they even let us check in a little early since we arrived in town an hour early.
The room was spacious enough, the bed was very comfortable and even though our room faced the main road, we didn't hear any noise at night. The room has a microwave and little refrigerator which we used.
The hotel has free parking.
The only problems we found with our room is: no ventilation fan in the bathroom, and the bathroom door doesn't close completely - it seems to be too large for the door frame. But we would stay in this hotel again because we enjoy the Marriott hotel chain.
Downtown is about 1-1/2 to 2 miles away and only takes a couple of minutes to drive there. Downton Charleston has a number of parking lots and you can park along most streets, so that wasn't a problem.
- Official Description (provided by the hotel):
- Discover Courtyard Charleston Waterfront, located just minutes from the heart of downtown Charleston, SC. Unique among hotels in Charleston, guests can experience stunning views of the Ashley River while enjoying our hot breakfast options, unwinding on our beautiful terrace, swimming in the outdoor waterfront pool, relaxing by our fire pit or whirlpool, or resting in their spacious guest room. Our stunning hotel is a short drive from the city's top destinations including; the shopping on King Street, the downtown market, historic plantations, and military parks. This unique hotel offers a 24 hour fitness center and a business center. Join us each morning in The Ashley River Cafe for a delicious breakfast buffet. If you're looking for something quick, our waterfront Charleston hotel offers a 24-hour market with snacks, beverages, soups, sandwiches and salads. Our Charleston, SC meeting space is ideal for intimate rehearsal dinners, meetings, and social events. Experience true luxury accommodations at the top waterfront hotel in Charleston, Courtyard Charleston Waterfront. An unforgettable retreat. ... more less
- Reservation Options:
- TripAdvisor is proud to partner with Booking.com, Expedia, Travelocity, Orbitz, Marriott, TripOnline SA, Odigeo, Hotwire and Hotels.com so you can book your Courtyard by Marriott Charleston Waterfront reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
- Also Known As:
- Courtyard By Marriott Charleston Waterfront Hotel Charleston
- Courtyard Charleston Waterfront
- Charleston Courtyard
- Charleston Marriott


text:
Chocolate Banana Muffins
Oh Nigella, you're so witty and entertaining and lovely and your recipes are divine. You really are a domestic goddess. Even my husband is infatuated with you. For my birthday, I was lucky to receive a copy of Nigella Lawson's Kitchen: Recipes From the Heart of the Home and I'm in love with this cookbook. I don't say this lightly. I have a lot of cookbooks. And while I like many of them, I only love a few. Here's what I read when I first flipped open the book, haphazardly, to page 38 (Nigella's Chicken Teriyaki recipe):
(For the full effect, read with a British accent)
I know the world is full of good parents who never give their children food with salt or sugar, and this recipe (among others) proves conclusively that I am not one of them. Oh, and on top of these dietary failings, the following also contains alcohol.
Now tell me, aren't you smitten too? So now that I've brought you all up to speed on my fondness for Nigella, let me tell you that I just made her chocolate banana muffins and oh my they are something else. I've never had a muffin so yummy and moist.
3 very ripe bananas
2 large eggs
1/2 cup vegetable oil
1/2 cup light brown sugar
1 3/4 cup flour
3 tbsp coco powder
1 tsp baking soda
In a large bowl, mash bananas. Beat in oil and eggs, followed by sugar. In a another medium bowl, sift together flour, coco powder and baking soda. Mix flour mixture into the banana mixture. Spoon batter into muffin tins (makes 12 muffins). Bake at 400 for 15-20 minutes. Enjoy!
Sounds like I would like her too : )
I always get good cookbook recommendations from you!
Yum! Those looks fantastic. I love bananas in all sorts of baking- they add such a wonderful sweetness.
grace permalink
i could listen to nigella talk for hours on end–the only thing more magical than her voice is her cooking. great muffin selection!


text:
In the Centre of it All
In the heart of downtown's business and entertainment districts, the Sheraton Centre Toronto Hotel is connected to PATH, a 16-mile underground network of shops and services. We are steps from the Eaton Centre shopping mall and Toronto's convention centre.
A New Kind of Classic
Experience a fresh kind of classic. A 2.5-acre waterfall garden atrium highlights our new lobby. Newly renovated ballrooms and meeting spaces total more than 120,000 square feet. Savour some of the city's best burgers and comfort food at BnB.
Refreshed Comfort and Style
Each of our 1,372 modern guest rooms offer the plush comfort of our Sheraton Sweet Sleeper® Bed. Sheraton Club Rooms offer another level of service with an array of upgraded amenities and access to the stylish 43rd-floor Sheraton Club Lounge.
Sheraton Club Lounge
The Club Lounge, accessible to Sheraton Club guests, offers complimentary breakfast, evening hors d'oeuvres and a variety of beverages. It's the perfect environment to meet with your team, connect with friends, or relax in front of a 42" Plasma HDTV. More >
Please note:
- Important Notice Regarding Customer Payment Cards
- Highway Lane Restrictions: Jun. 25, 2014 – Dec. 31, 2016
10,000 Starpoints for a free night. Redeem
Check in: 3:00 PM Check out: 12:00 PM


text:
Cephas Atheos
Apparently, this user prefers to keep an air of mystery about them.
- Melbourne, Australia
- CephasAtheos.wordpress.com
- Member for 3 years, 3 months
- 1 profile view
- Last seen Oct 24 '12 at 5:41
Communities (4)
Top Network Posts
We respect a laser-like focus on one topic.
Keeping a low profile.
This user hasn't posted... yet.


text:
Gamernode writes: "Metal Gear Solid 4 (MGS4) is a highly detailed game truly best viewed as a whole. While it's necessary to nitpick the convoluted story and over-dramatic voice acting in order to progress the medium, doing so for too long may significantly and unnecessarily detract from the overall, and in this case, highly polished product.
On the "making of" disc included with the limited edition version only available at GameStop and with the Gun Metal PS3, series creator Hideo Kojima says, "There are certain things you need to pass on in life but the theme of this game is 'sense,' or that which you can't pass on. A person's will and way of life is symbolized by Snake continuing to fight despite his old age, and also myself retuning to direct the game."
Regardless, right now it's one of the best-looking, engaging, and emotionally driven experiences, with the gameplay to match, on the PS3 or any console." 10/10


text:
So, Murphy, you're going to be a little busy next week, just letting you know. Invest in some Red Bull .
Whatever do you mean, Lord Will?
Well Murphy, we're building this new thing called a "website," and you'll be uploading and/or correcting a number of articles next week. As in all of next week. All day. No stopping.
DAVE'S face gets slightly ashen.
Y...yes sir.
And thus, an explanation as to why Dave "The Murph" Murphy (who ever-so-often changes his first name, depending on the mood) will be a wee behind the furious blogging pace set by his Maximum PC peers. You see, not only is Dave talking in the third person, but he's also busy updating and fixing the very content you're reading right now. In addition to reviewing products for Katherine's June feature. In addition to that, reviewing products for his normal beats -- cooling, cases, storage, rocking out , et cetera.
Speaking of, Dave is actually looking at webcams right now for said feature. And three out of three MPC editors (and one PC Gamer intern emeritus ) agree: Logitech's QuickCam Orbit MP is damn hilarious.
And for some odd reason, the fancy spellcheck app on Dave's computer isn't working right now. Accordingly, he is quite upset.


text:
A Unique Villa in Athens with Sea View & Jacuzzi
From $135 / night
Description from the manager
Description from the manager
Bedrooms: 3/
Bathrooms: 3/
Sleeps: 8/
Type: House
Ideally located, a unique two-floor villa in a very peaceful neighborhood in Voula, with an amazing sea view over Saronic Gulf. It was fully renovated in 2010, modern decorated with very expensive materials. It is furnished and fully equipped. It is a detached house. There are three bedrooms, 2 bathrooms and one WC. The kitchen is fully equipped with oven,microwave, dishwasher, fridge with freezer and automatic ice maker, cutlery, dishes and pans, kettle, espresso coffee maker, toaster. There is jacuzzi in the main bathroom. There is also a vacuum cleaner and a laundry machine. Numerous of big closets will make your stay more comfortable. Bed ...Read more
About the manager
About the manager
George Kanellopoulos
George Kanellopoulos
- Response rate : n/a
- Response time: n/a
- Calendar updated: 3 days ago
Overall rating:
Additional Location Information
Voula is a southern suburb of Athens. It is located approximately, 20 km South of Athens center, SW of the Eleftherios Venizelos International Airport, NW of Cape Sounio and South of the Hymettus mountain. Poseidonos Avenue (GR-91) links Voula with the center of Athens. The Northern part is linked with Athens by the Terminal station of Athens Tram. An organized beach lies to the West and one of the largest Athens hospitals, "Asklipieio", lies to the North. Voula and especially the district "Panorama� of Voula, where the apartment is located, is a wealthy, chic and upmarket district. Voula lies next to Glyfada which is a fashionable meeting area and as one of the capital's leading shopping areas, it includes a number of high-end boutiques from young adult to casual fashion to prestigious haute couture from Greek and international designers.
More About This Location
Waterfront, Beach or lakeside relaxation
Getting There
Nearest airport, 13 miles
Nearest ferry port, 8 miles
Car is recommended


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Competency Hearing Ordered for Accused White House Shooter
A federal magistrate judge scheduled a hearing to determine whether an Idaho man accused of shooting at the White House in an attempt to assassinate President Barack Obama is mentally competent to stand trial.
U.S. Magistrate Judge John Facciola in Washington today ordered the hearing for Dec. 16 after prosecutors said a November mental health exam that found Oscar Ramiro Ortega-Hernandez to be competent wasn't thorough.
"There are issues the government is aware of that were not addressed in the 50-minute screening," George Varghese, an assistant U.S. attorney, argued during a brief hearing today.
Facciola said witnesses at the hearing may include the doctor who examined Ortega-Hernandez and one of his defense lawyers.
Prosecutors on Nov. 28 asked U.S. Magistrate Judge Alan Kay in Washington to order a full psychiatric or psychological screening "given the serious nature of the criminal charges" and the "likelihood that mental health issues may arise in the course of these proceedings."
Lawyers for Ortega-Hernandez urged the court to reject the government's request for another examination, arguing that their client has "exhibited no signs of any mental impairment" and is "actively" assisting in his defense.
In court papers, they accused prosecutors of "misconstruing" the competency inquiry as a prelude to an insanity defense, which hasn't been raised.
'Entirely Improper'
"Our concern is that the government is trying to stick its nose into the defense camp, which is entirely improper at this stage," David Bos, an assistant public defender, told Facciola.
Ortega-Hernandez, 21, is accused of firing a semi-automatic rifle at the White House on Nov. 11 in an attempt to kill Obama. He was arrested at a hotel near Indiana, Pennsylvania, on Nov. 16 after a task force of federal and local law enforcement officers searched for him.
Prosecutors said in court filings that Ortega-Hernandez drove to Washington with an assault rifle and other weapons after telling people in his home state of Idaho that he "needed" to assassinate the president.
Ortega-Hernandez fired shots from a street less than 800 yards from the White House just after 9 p.m. in Washington, prosecutors said. Obama already had departed for a nine-day trip to Hawaii and Asia.
The attempted assassination charge carries a maximum penalty of life in prison.
The case is U.S. v. Ortega-Hernandez, 11-00883, U.S. District Court, District of Columbia (Washington).


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Tuesday, October 21, 2008
Space Flight For Sale
How Virgin Galactic and Scaled Composites are rewriting the rules of space travel
Beyond the technical marvels is the simple fact that this feat was accomplished by private industry, not some budget-gulping government monolith. Rutan created Scaled Composites in 1982 with a small group of young, skilled engineers, and continues to wow the aerospace world from his small corner out in the Mojave Desert of California. Investor Paul Allen provided initial money to get Rutan's mind-boggling designs off the computer and into the sky, but it was all government-free.
Virgin's Branson was following Rutan's progress and, after the SpaceShipOne success, formed a new aerospace company with him that would offer space tourism by licensing the spacecraft designs created by Rutan at Scaled. The latest result of that venture is the first manned, commercial, space tourism launch vehicle, WhiteKnightTwo, and the orbital craft it will launch, SpaceShipTwo. The former was unveiled with great media hype in Mojave this past July.
The WhiteKnightTwo launch vehicle is impressive in its size and beauty. True to other Rutan innovations, this vehicle presents bold new concepts. Its gangly twin-boom tail design can carry a mix of passengers and commercial payloads in side-by-side fuselages. It's constructed 100% of carbon composites and features ultra-efficient jet engines. The craft's wingspan is about equal to that of a WWII B-29 bomber and its all-composite wing spar is so innovative that much about it is secret.
Branson (left) teamed with Rutan (right) to form a new aerospace company that will offer space tourism to "ordinary" people. The two pose aboard VMS Eve, which features Galactic Girl as its nose art, a homage to Evette Branson, Sir Richard's mother.
When Lina goes into space in about 18 months, if all goes right, she'll be inside the six-seat SpaceShipTwo—a larger version of SpaceShipOne. She'll be carried to an altitude of about 50,000 feet, under the wing of the launch vehicle, WhiteKightTwo. SpaceShipTwo will drop from the mother ship and ignite its hybrid rocket engines, propelling it to 350,000 feet in 90 seconds at Mach 3.
"Then there will be silence," says Will Whitehorn, president of Virgin Galactic. "A pure silence never experienced before." Passengers will enjoy weightlessness and will be able to leave their seats and float around the cabin, with its carefully designed observation windows and inclined seats. From her lofty perch, Lina will be able to see the curvature of the Earth and view our planet as few have.
The craft will begin its reentry into Earth's atmosphere with its unique feathering device and will convert back into a winged shape for landing. It will glide, unpowered, to a landing at either Mojave or Virgin Galactic's new spaceport in New Mexico. The future promises longer and higher orbital flights and even space hotels and resorts for overnight stays.
Page 2 of 4
Labels: Features, Journeys, People and Places, Travel


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Why would anyone want to live in Downtown Dallas? Ten years ago that was a good question, but what a difference a decade can make! Highrise condos, lofts and apartments have been built throughout downtown, bringing more full-time residents to the district. With those residents have come restaurants, shops, nightlife and even a downtown grocery store.
Search by Building View All Downtown Condos For Sale View All Downtown Condos For Lease
Below are the condo buildings located in downtown. If you would like to see all Dallas condo buildings, and sort by amenities, height, pet policy and more visit our Interactive Building Directory.
The Downtown Dallas Arts District has changed dramatically. New additions include the Winspear Opera House, Wyly Theater and two parks all located near the Meyerson Symphony Center, Nasher Sculpture Center and Dallas Museum of Art. Now you can live within easy walking distance of these world-class venues with buildings like One Arts and Museum Tower.
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Listing information last updated on February 14th, 2016 at 10:45am PST.


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|Vitapharm-Com SRL,IM
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|14-25 Business Days
|Approx. Sep,2017
Quantity Form Manufacturer Price Order
60 Capsules Vitapharm-Com SRL,IM 24.00 Item is Sold Out Notify Me
- silymarin
Hepatovit is a combined preparation that include microelements, amino acids and vitamins in the form of natural extracts. The drug exerts the following effects:
- Bile-expelling
- Pain relieving
- Improves peristalsis of the bile ducts and intestines
- Antimicrobial
- Anti-inflammatory
- Anti-sclerotic
The preparation is indicated in the following conditions as subsidiary treatment:
- Hepatitis
- Cholecystitis
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The drug should not be used if:
- An allergy to honey, farina or any components of the preparation
It is important to tell your doctor or pharmacist what medicines you are already taking, including those bought without a prescription and herbal medicines, before you start treatment with Hepatovit. Similarly, check with your doctor or pharmacist before taking any new medication while taking this one, to ensure that the combination is safe.
DO NOT SHARE Hepatovit with others. DO NOT USE THIS MEDICINE for other health conditions. KEEP THIS PRODUCT, as well as syringes and needles, if needed during treatment, out of the reach of children. Do not reuse needles, syringes, or other materials.
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