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Ther Adv Med Oncol(2012) 4(3) 113 –125DOI: 10.1177/ 1758834012439738© The Author(s), 2012. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.navTherapeutic Advances in Medical Oncology Reviewhttp://tam.sagepub.com 113IntroductionThe importance of host factors in cancer aetiol-ogy and outcome has been highlighted recently [Goodwin et al. 2010]. Epidemiological and clinical studies have associated psychosocial factors such as chronic stress and depression with cancer progression and, to a lesser extent, cancer onset [Spiegel et al. 2007; Chida et al. 2008]. These effects are mediated in part through activation of the autonomic nervous system and the hypothalamic–pituitary–adrenal axis, causing the release of catecholamines, glucocorticoids and other stress hormones from the adrenal gland, brain and sympathetic nerve terminals [Entschladen et al. 2004; Antoni et al. 2006; Thaker et al. 2007; Armaiz-Pena et al. 2009; Lutgendorf et al. 2010]. In this review we focus on the sympathetic nervous system component of the physiological stress response, which results in release of epinephrine and norepinephrine. Both of these neurotransmitters have been shown in preclinical studies to impact several pathways necessary for tumour progression and metastasis through direct tumour effects and indirect effects on the tumour microenviron-ment [Entschladen et al. 2004; Antoni et al. 2006; Thaker et al. 2007; Armaiz-Pena et al. 2009; Goodwin et al. 2010; Lutgendorf et al. 2010]. Specifically, these studies have demonstrated that the protumour and prometastatic effects of epinephrine and norepinephrine are mediated primarily through the β-adrenergic receptor (β-AR) signalling pathway. This has led a num-ber of authors to hypothesize that the commonly prescribed class of β-AR antagonist drugs (β-blockers) may favourably impact cancer progression [Entschladen et al. 2004; Antoni et al. 2006; Thaker et al. 2007; Armaiz-Pena et al. 2009; Lutgendorf et al. 2010]. The purpose of this review is to present the epidemiological and clinical data relevant to the association between β-blockers and breast cancer progression within the context of current preclinical evidence [Pérez-Sayáns et al. 2010]. The effects of β-blockers on breast cancer incidence will not be discussed.Beta-adrenergic blocking drugs in breast cancer: a perspective reviewThomas I. Barron, Linda Sharp and Kala VisvanathanAbstract: The purpose of this review is to present the preclinical, epidemiological and clinical data relevant to the association between β-blockers and breast cancer progression. Preclinical studies have shown that β-adrenergic receptor (β-AR) signalling can inhibit multiple cellular processes involved in breast cancer progression and metastasis, including extracellular matrix invasion, expression of inflammatory and chemotactic cytokines, angiogenesis and tumour immune responses. This has led to the hypothesis that the commonly prescribed class of β-AR antagonist drugs (β-blockers) may favourably impact cancer progression. A number of recent pharmacoepidemiological studies have examined the association between β-blocker exposure and breast cancer progression. The results from these studies have suggested a potential role for targeting the β-AR pathway in breast cancer patients. Larger observational studies are, however, required to confirm these results. Questions regarding the type of β-blocker, predictive biomarkers or tumour characteristics, appropriate treatment paradigms and, most importantly, efficacy must also be answered in randomized clinical studies before β-blockers can be considered a therapeutic option for patients with breast cancer.Keywords: adrenergic beta-agonists, adrenergic beta-antagonists, adrenergic receptors, breast neoplasms, neoplasms, propranololCorrespondence to: Thomas I. Barron, PhD Department of Pharmacology & Therapeutics, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland firstname.lastname@example.com Sharp, PhD National Cancer Registry Ireland, Cork, IrelandKala Visvanathan, MD MHS Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA439738 TAM431758834012439738TI Barron, L SharpTherapeutic Advances in Medical Oncology2012
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Therapeutic Advances in Medical Oncology 4 (3)114 http://tam.sagepub.comPreclinical studiesβ-Adrenergic receptor expression in breast cancerβ-Adrenergic receptors are Gs-protein-coupled receptors that activate adenylate cyclase to elevate intracellular 3′,5′-cyclic adenosine monophos-phate (cAMP) and activate protein kinase A. There are three β-AR subtypes, β1-AR, β2-AR and β3-AR, each with specific physiological actions. The expression of β-ARs has been characterized in several breast cancer cell lines [Vandewalle et al. 1990; Badino et al. 1996; Slotkin et al. 2000; Sloan et al. 2010; Madden et al. 2011; Park et al. 2011; Shi et al. 2011] as well as in collections of human breast cancer tissue samples [Draoui et al. 1991; Powe et al. 2011; Shi et al. 2011] and in mammary tumours from rodents induced by administration of dimethylbenz(a)anthracene [Marchetti et al. 1991] (see Table 1). Studies have shown that these β-ARs are predominantly of the β2-adrenergic receptor (β2-AR) subtype [Draoui et al. 1991; Badino et al. 1996; Slotkin et al. 2000] and are functionally active, with pharmacological liga-tion resulting in significant cAMP production [Vandewalle et al. 1990; Badino et al. 1996; Slotkin et al. 2000; Sloan et al. 2010; Madden et al. 2011].Although β2-AR is expressed by both oestrogen receptor (ER)-positive and ER-negative breast cancer cell lines, the highest levels of expression have been observed in cell lines that are ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor receptor 2 (HER-2)-negative (triple-negative breast cancer [TNBC]) [Vandewalle et al. 1990; Madden et al. 2011]. This has led to suggestions that the β2-AR signalling may be of greatest significance in the pathogenesis and progression of TNBC [Melhem-Bertrandt et al. 2011]. Results from studies in human breast cancer tissue samples have not been as consistent as those of studies in cell lines [Draoui et al. 1991; Powe et al. 2011; Shi et al. 2011]. In a study by Draoui and colleagues, the authors reported only a weak correlation between β-AR and PR expres-sion and no correlation with the ER [Draoui et al. 1991]. However, in a recent study of breast tumour samples from 690 women [Powe et al. 2011], β2-AR expression was strongly correlated with ER and PR expression, 80% and 65% of tumours with high β2-AR expression co-expressing ER and PR respectively. There was no correlation between β2-AR and HER-2 expression in this study, although a correlation has been noted in another study of both clinical samples and breast cancer cell lines [Shi et al. 2011]. β-Blocker use by patients included in these breast tumour sample studies was not reported.The prognostic significance of β2-AR expression is also unclear. In the study by Powe and colleagues, patients with high levels of β2-AR expression had a nonsignificant increase in survival when compared with patients with low-level expression [Powe et al. 2011]. The authors suggest that this may be due to the observed association between β2-AR expression and small ER-positive tumours of low clinical stage and low proliferation. In unad-justed Kaplan–Meier analyses they also observed among ER-positive tumours a decrease in survival for tumours that co-expressed β2-AR, which may reflect interactions between the ER and β2-AR. However, further analyses are necessary before drawing such conclusions. A recently published abstract has also suggested that β-AR expression was not correlated with an observed association between β-blocker exposure and improved out-comes in women with breast cancer [Powe et al. 2010a]. It is, however, possible that the effects of β-AR signalling in breast cancer may be inde-pendent of β-AR expression by breast tumour cells. β2-AR signalling may impact breast cancer progression through its effects on tumour immune responses and the regulation of the tumour microenvironment.Blocking β-adrenergic receptor signalling in breast cancerPreclinical studies have shown that antagonism of β-AR signalling by a β-blocker can inhibit multi-ple cellular processes involved in breast cancer progression, including tumour cell proliferation, metastasis development, apoptosis, extracellular matrix invasion, matrix metalloprotease activa-tion, expression of inflammatory and chemotactic cytokines, angiogenesis and tumour immune responses (see Table 2).Tumour growthThere is evidence to suggest that β-AR signalling plays a role in the regulation of tumour growth in a number of cancers; however, the evidence relat-ing to breast tumour growth is conflicting. β-AR stimulation has been shown to both inhibit [Slotkin et al. 2000; Carie and Sebti, 2007] and promote breast tumour growth [Re et al. 1992; Cakir et al. 2002; Thaker et al. 2006; Shi et al. 2011], and more recent studies report that β-AR
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TI Barron, L Sharp et al.http://tam.sagepub.com 115Table 1. Overview of studies examining β-adrenergic receptor expression in breast cancer cell lines and tumour samples.StudyBreast cell typeER+PR+HER-2+β-ARβ1-ARβ2-ARComments/functional significanceMarchetti et al. [1991]Induced rodent mammary tumours---Yes--Influence of oestrogen levels on β-AR concentration assessed. Ovariectomy reduced β-AR expression and subsequent treatment with oestrogen caused a significant increase in β-AR levels.Vandewalle et al. [1990]MCF-7T47-DMDA-MB-231BT-20VHB-1YesYesNo NoYesYes-No No-No-No No-Low LowHighLow Low----------β-AR agonists stimulated cAMP production in a dose-dependent manner. Response was greatest in the triple-negative MDA-MB-231 cell line. The pathophysiological significance of this was not studied.Badino et al. [1996]CG-5Yes--YesYesYesThe ratio of β2-AR to β1-AR expression was 3:1. β-AR agonists stimulated cAMP production in a dose-dependent manner. The pathophysiological significance of this was not studied.Slotkin et al. [2000]MDA-MB-231NoNoNoHighNoHighβ-AR agonists reduced DNA synthesis and cell replication.Sloan et al. [2010]66cl4NoNoNoLow-Lowβ-AR agonists stimulated cAMP production. The pathophysiological significance of this was unclear as the effects of β-AR signalling on the development of tumour metastases were shown to be mediated through induction of tumour macrophage infiltration.Madden et al. [2011]MCF-7MDA-MB-361 MDA-MB-231 MDA-MB-231BRYes YesNo NoYes-NoNoNoYesNoNoLowLowHighHigh----Low LowHighHighβ-AR agonists stimulated cAMP production in proportion to β-AR expression levels. β-AR stimulation induced VEGF expression in the MDA-MB-231BR cell line but not others.Shi et al. [2011]MCF-7BT-474MDA-MB-435 MCF-7(HER-2)Human breast tumour samplesYesNo NoYes-YesYesNoYes-NoYesYesYes-LowHighHighHighYes-----Low LowHigh HighYesβ-AR expression was strongly correlated with HER-2 expression in cell lines and clinical samples. β-AR expression was upregulated in MCF-7(HER-2) cells overexpressing HER-2. Suggestion that β2-AR and HER-2 expression comprises a positive feedback loop in human breast cancer cells.Draoui et al. [1991]Human breast tumour samples---YesNoYesβ-AR normally coupled with G-protein. A slight correlation was shown between β-AR and PR, and no correlation between β-AR and ER.Powe et al. [2011]Human breast tumour samples---Yes-Yesβ-AR expression was negative in 2%, weak in 42% and strong in 55% of samples. β-AR expression was significantly associated with tumours of small size, low histological grade, early clinical stage, and ER and PR expression. High expression was associated with a nonsignificant increase in survival.ER, oestrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor 2; β-AR, β-adrenergic receptor; β1-AR, β1-adrenergic receptor; β2-AR, β2-adrenergic receptor, VEGF, vascular endothelial growth factor; cAMP, cyclic adenosine monophosphate.
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Therapeutic Advances in Medical Oncology 4 (3)116 http://tam.sagepub.comTable 2. Overview of preclinical studies examining the effects of β-adrenergic receptor signalling in breast cancer.StudyBreast cell typeModelTumour characteristicβ-AR agonist effectβ-AR antagonist effect (β-blockers)Re et al. [1992]CG-5In vitroTumour growthβ-AR signalling (pharmacological agonists) stimulated tumour growth.-Slotkin et al. [2000]MDA-MB-231In vitroTumour growthβ2-AR signalling (pharmacological agonists) inhibited tumour growth through a cAMP activated pathway.Inhibited by the β1/β2-AR nonselective antagonist propranolol. Propranolol itself had no effect on tumour growth.Drell et al. [2003]MDA-MB-468In vitroMigration and invasionβ-AR signalling (pharmacological agonists) stimulated tumour cell migration.Promigratory effects of β-AR signalling were completely inhibited by the β2-AR-selective antagonist ICI-118.551 and partially inhibited by the β1-AR-selective antagonist atenolol.Lang et al. [2004]MDA-MB-468In vitroMigration and invasionβ2-AR signalling (pharmacological agonists) stimulated tumour cell migration.Promigratory effects of β2-AR signalling were inhibited by the β1/β2-AR-nonselective antagonist propranolol.Melamed et al. [2005]MADB106In vivoMetastasisImmune responseβ-AR signalling (surgical stress induced) inhibited natural killer cell cytotoxicity against tumour cells and increased metastasis.Reduced natural killer cell activity and increased metastasis inhibited by the β1/β2-AR-nonselective antagonist nadolol. Effect of nadolol was greater in combination with the COX1/COX2 inhibitor indomethacin.Thaker et al. [2006]MDA-MB-231In vivoTumour growthAngiogenesisMetastasisβ2-AR signalling (pharmacological agonists and stress-induced) stimulated tumour growth, tumour angiogenesis and metastatic spread.-Carie and Sebti [2007]MDA-MB-231In vitroIn vivoTumour growthCell deathβ2-AR signalling (pharmacological agonists) inhibited tumour growth in vitro and induced in vivo tumour regression through cAMP activation, and subsequent inhibition of the RAF-1/MEK-1/ERK-1,2 pathway.Inhibited by β2-AR-selective antagonist ICI-118.551.Benish et al. [2008]MADB106In vivoMetastasisImmune responseβ-AR signalling (surgical stress induced) inhibited natural killer cell cytotoxicity against tumour cells and increased metastasis.Reduced natural killer cell activity and increased metastasis inhibited by the β1/β2-AR-nonselective antagonist propranolol. Effect of propranolol was greater in combination with the COX2 inhibitor etodolac.
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TI Barron, L Sharp et al.http://tam.sagepub.com 117StudyBreast cell typeModelTumour characteristicβ-AR agonist effectβ-AR antagonist effect (β-blockers)Avraham et al. [2010]MADB106In vivoMetastasisImmune responseβ-AR signalling (surgical stress induced) inhibited natural killer cell cytotoxicity against tumour cells and increased metastasis.Reduced natural killer cell activity and increased metastasis inhibited by the β1/β2-AR-nonselective antagonist nadolol in combination with the COX1/COX2 inhibitor indomethacin and immune stimulant poly I-C.Sloan et al. [2010]66cl4In vivoMetastasisAngiogenesisImmune responseβ2-AR signalling (pharmacological agonists and stress-induced) induced 30-fold increase in metastasis to distant tissues. Effects mediated by tumour macrophage infiltration and production of the pro-angiogenic and prometastatic factors VEGF and MMP-9.Tumour metastasis, macrophage infiltration and angiogenesis were Inhibited by the β1/β2-AR-nonselective antagonist propranolol. Propranolol had no effect on primary tumour growth.Shi et al. [2011]MCF-7In vitroTumour growthAngiogenesisMetastasisβ2-AR signalling (pharmacological agonists) stimulated the expression of HER-2 and induced tumour growth in a dose-dependent manner. β-AR signalling also upregulated production of the pro-angiogenic and prometastatic factors VEGF and IL-8.Expression of HER-2 was inhibited by the β2-AR-selective antagonist ICI-118.551.Madden et al. [2011]MCF-7 MDA-MB-361MDA-MB-231 MDA-MB-231BRIn vitroAngiogenesisβ2-AR signalling (pharmacological agonists) stimulated production of pro-angiogenic factors VEGF (MDA-MB-231BR) and IL-6 (MDA-MB-231BR and MDA--MB-231)Production of the pro-angiogenic factors VEGF and IL-6 inhibited by the β2-AR-selective antagonist ICI-118.551.Park et al. [2011]MDA-MB-231Angiogenesisβ2-AR signalling (pharmacological agonists) stimulated production of the pro-angiogenic factor VEGF via a HIF-1α-dependent pathway.Upregulation of VEGF and HIF-1α expression were inhibited by the β1/β2-AR-nonselective antagonist propranolol.β-AR, β-adrenergic receptor; β2-AR, β2-adrenergic receptor; VEGF, vascular endothelial growth factor; IL, interleukin; COX, cyclooxygenase; HIF, hypoxia-inducible factor ; Poly I-C, Polyinosinic:polycytidylic acid.Table 2. (Continued).
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Therapeutic Advances in Medical Oncology 4 (3)118 http://tam.sagepub.comsignalling has negligible effect on in vitro or in vivo breast tumour growth [Sloan et al. 2010; Madden et al. 2011]. The reasons for such heterogeneity are not entirely clear. Results from ovarian cancer models have demonstrated that the effect of β-AR signalling on tumour growth is associated with β2-AR expression by tumour cells [Thaker et al. 2006]. This does not appear to be the case for breast cancer, for which studies using cell lines with high β2-AR expression have produced oppos-ing results [Slotkin et al. 2000; Thaker et al. 2006; Carie and Sebti, 2007; Madden et al. 2011]. In one of these studies, the effect β-AR stimulation on tumour growth varied across β-AR agonist type. This has led to the suggestion that differ-ences between β-AR agonists may contribute to functional heterogeneity in breast cancer cell responses to β-AR stimulation [Madden et al. 2011]. It is also possible that the direct effects of β-AR signalling on the tumour microenvironment may explain the observed differences between studies conducted in vivo and in vitro [Sloan et al. 2010]. In ovarian cancer models, β-AR stimula-tion has been consistently shown to promote tumour growth [Thaker et al. 2006; Landen et al. 2007; Lee et al. 2009]. This effect, as noted, is associated with tumour cell β-AR expression, mediated through the β2-AR and inhibited by the β-blocker propranolol (β1/β2-AR nonselective) [Thaker et al. 2006; Landen et al. 2007; Lee et al. 2009]. Similar results have been observed in pan-creatic and oesophageal cancer [Liu et al. 2008; Zhang et al. 2009].Tumour metastasisSeveral in vivo breast cancer studies have shown that β-AR signalling is involved in the pathogen-esis of breast cancer metastases [Melamed et al. 2005; Benish et al. 2008; Avraham et al. 2010; Sloan et al. 2010]. In these studies either stress-induced or pharmacological β-AR stimulation resulted in up to a 30-fold increase in metastasis to distant sites, including the lymph nodes and lung. β-Blockers (propranolol, nadolol; β1/β2-AR-nonselective) inhibited these prometastatic effects by between 50% and 100%. Greater inhibition was also obtained by combining these β-blockers with prostaglandin synthesis inhibitors (cyclooxy-genase [COX] 1 and COX2 inhibitors, e.g. indo-methacin) and immune stimulants. [Melamed et al. 2005; Benish et al. 2008; Avraham et al. 2010]. The prometastatic effects of β-AR signal-ling have also been demonstrated in melanoma and ovarian, lung and prostate cancer [Palm et al. 2006; Thaker et al. 2006; Glasner et al. 2010]. β-AR signalling promotes the development of tumour metastases through the regulation of several key steps in the pathogenesis of metastasis. These include tumour vascularization, invasion, migration, survival in circulation and the evasion of tumour immune responses [Lutgendorf et al. 2010].Cell deathPreclinical studies have demonstrated conflicting effects of β-AR signalling in the regulation of tumour cell apoptosis and anoikis. Carie and colleagues demonstrated that the β2-AR agonist ARA-211 induced breast tumour cell apoptosis in vitro and tumour regression in vivo [Carie and Sebti, 2007]. However, Sastry and colleagues determined that signalling via the β2-AR reduces the sensitivity of prostate cancer cells to apoptosis [Sastry et al. 2007]. Sood and colleagues also showed that the β-AR agonists epinephrine and norepinephrine protected ovarian tumour cells from anoikis and that this effect was inhibited by the β1/β2-nonselective antagonist propranolol [Sood et al. 2010]. Two further studies have also shown that inhibition of β2-AR signalling by propranolol or a β2-adrenergic receptor- specific antagonist in combination with gemcit-abine induces apoptosis in pancreatic cancer cells [Zhang et al. 2009; Shan et al. 2011]. In these studies the β1-AR-selective antagonist metoprolol had the least effect on apoptotic rate [Zhang et al. 2009].Angiogenesisβ-AR signalling has been shown to increase the in vitro [Madden et al. 2011; Park et al. 2011; Shi et al. 2011] and in vivo [Thaker et al. 2006; Sloan et al. 2010] expression of vascular endothelial growth factor (VEGF) and interleukin (IL)-6, key pro-angiogenic factors, in a number of breast tumour models. This stimulation of VEGF expression by β-AR signalling is proportional to β-AR expression [Madden et al. 2011], dose-dependent [Park et al. 2011] and inhibited by propranolol [Park et al. 2011]. There have, how-ever, been discrepancies between the results from in vitro and in vivo studies of β-AR signalling and VEGF expression [Thaker et al. 2006; Madden et al. 2011]. It has been suggested that these dis-crepancies may be attributed to in vivo VEGF production by β-AR-expressing cells in the
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TI Barron, L Sharp et al.http://tam.sagepub.com 119tumour stroma (i.e. macrophages) [Thaker et al. 2006]. This suggestion has subsequently been confirmed [Sloan et al. 2010]. In vivo studies have associated β-AR-induced increases in VEGF pro-duction with significant increases in breast tumour vasculature [Thaker et al. 2006; Sloan et al. 2010]. These studies have focused on the role of β2-AR signalling in breast tumour angiogene-sis, but have not ruled out the possibility that other members of the β-AR family may also play a role. Studies in other tumour types have, how-ever, shown that the effects of adrenergic signal-ling are mediated primarily through the β2-AR [Liu et al. 2008; Zhang et al. 2010]. The stimula-tory effects of β-AR signalling on VEGF expres-sion have been observed in ovarian [Lutgendorf et al. 2003; Thaker et al. 2006; Lee et al. 2009], nasopharyngeal [Yang et al. 2006], melanoma [Yang et al. 2009], oesophageal [Liu et al. 2008], multiple myeloma [Yang et al. 2008], prostate [Park et al. 2011] and pancreatic [Guo et al. 2009; Zhang et al. 2010] tumour models. Also of inter-est has been the recent chance discovery that the nonselective β-blocker propranolol is an effective treatment for infantile haemangioma, a common benign tumour occurring in 5–10% of infants [Schiestl et al. 2011]. It has been suggested that the observed benefits of treatment are due in most part to the inhibition of VEGF production by propranolol [Storch and Hoeger, 2010].Migration and invasionIn vitro breast cancer models have shown that the β-AR agonist norepinephrine exerts both chemokinetic and chemoattractive effects on breast tumour cells [Drell et al. 2003; Lang et al. 2004]. In these studies, norepinephrine exposure positively influenced the number and direction of migrating tumour cells. Similar findings have been reported for several other tumour types, including ovarian, colon, prostate and pancreatic cancers [Masur et al. 2001; Lang et al. 2004; Sood et al. 2006; Zhang et al. 2010]. In vivo studies of these promigratory and pro-invasive effects have also demonstrated an association between norepi-nephrine exposure, increased invasiveness, nodal involvement and the development of metastasis [Palm et al. 2006; Sood et al. 2006]. It has been shown that these effects are mediated through the β-AR pathway, primarily the β2-AR, and are inhibited by nonselective β-blockers, for example propranolol [Masur et al. 2001; Drell et al. 2003; Lang et al. 2004; Palm et al. 2006; Sood et al. 2006; Zhang et al. 2010]. Similar inhibitory effects have not been uniformly observed with the use of β1-AR-selective antagonists such as atenolol [Masur et al. 2001; Drell et al. 2003; Lang et al. 2004; Zhang et al. 2010]. β-AR signal-ling regulates the migratory and invasive capacity of tumour cells through alterations in tumour gene expression and the upregulation of matrix metalloproteinase (MMP) expression (MMP-2, MMP-9) [Sood et al. 2006; Landen et al. 2007; Zhang et al. 2010]. Pharmacological blockade of these MMPs has been shown to inhibit the effects of β-AR signalling on tumour cell invasive potential [Sood et al. 2006].Immune responseβ-AR signalling plays an important role in the regulation of tumour-directed immune responses. Two studies have demonstrated, using in vivo breast tumour models, that β-AR agonists sup-press natural killer cell activity in a dose-dependent manner, resulting in a 10-fold increase in the number of tumour cells retained in the lungs and a similar rise in the number of consequent lung metastases [Melamed et al. 2005; Benish et al. 2008]. Further confirmation of these results was obtained in studies demonstrating that the perio-perative use of propranolol and a COX2 inhibitor regulates the immune response, reduces the risk of postoperative tumour metastasis and improves recurrence-free survival rates in mice undergoing primary tumour excision [Avraham et al. 2010; Glasner et al. 2010]. β-AR signalling also appears to regulate the prometastatic effects of the tumour immune response. Sloan and colleagues used an in vivo model of breast cancer to demonstrate that either stress-induced or pharmacological adrenergic stimulation resulted in a considerable increase in the development of metastases [Sloan et al. 2010]. This effect was mediated through β2-AR signalling, which promoted the infiltration of macrophages into the primary tumour paren-chyma and induced a prometastatic gene expres-sion signature. Macrophages were shown to be the intratumoral target of this β2-AR signalling, which resulted in the increased expression of macrophage-derived factors, including COX2, MMP-9 and VEGF, the last of which was associ-ated with a threefold increase in tumour blood vessel density. Treatment with the β-blocker propranolol inhibited macrophage infiltration, tumour spread to distant tissues and the vascu-larization of tumours.
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Therapeutic Advances in Medical Oncology 4 (3)120 http://tam.sagepub.comβ-Blockers in breast cancer: pharmacoepidemiological studiesSix recently published pharmacoepidemiological studies have examined the association between β-blocker exposure and breast cancer progres-sion. In the first of these studies, published in October 2010, Powe and colleagues reviewed medical records to identify female patients with stage I and II breast cancer presenting to the Nottingham City Hospital, UK, between 1987 and 1994 [Powe et al. 2010b]. These patients were then classified into one of three subgroups: women with a history of hypertension receiving a β-blocker for at least 1 year prior to diagnosis (n = 43, β1-AR-selective 74%, β1/β2-AR-non-selective 26%); women with a history of hyper-tension at the time of breast cancer diagnosis receiving other antihypertensive drug treatment for at least 1 year prior to diagnosis (n = 49); and normotensive women (n = 374) not on any anti-hypertensive drugs. Women receiving β-blocker treatment for less than 1 year were excluded from the study. The time to distant metastasis forma-tion and breast cancer-specific survival was com-pared between all three groups using multivariate analyses. These demonstrated a 57% reduced risk of metastasis development (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.20–0.93) and a 71% reduction in the risk of breast can-cer-specific mortality after 10 years (HR 0.29; 95% CI 0.12–0.72) after adjusting for tumour size, stage and grade in women taking any β-blocker compared with those who were not.In a subsequent study by Ganz and colleagues the authors examined associations between any β-blocker exposure and/or angiotensin convert-ing enzyme inhibitor (ACEi) exposure and breast cancer outcomes [Ganz et al. 2011]. The Life After Cancer Epidemiology (LACE) cohort was used to identify 1779 women enrolled from the Kaiser Permanente Northern California Cancer Registry with a diagnosis of early-stage invasive breast cancer between 1997 and 2000. β-Blocker and ACEi exposure in the year before and after breast cancer diagnosis was identified for each patient in this cohort from pharmacy dispensing records. They identified 407 women who filled at least one prescription for a β-blocker or an ACEi during this period. This number comprised 66 patients who filled a prescription for both, 137 who filled a prescription for an ACEi only and 204 who filled a prescription for a β-blocker only (β1-AR-selective 82%, β1/β2-AR-nonselective 18%). The time to breast cancer recurrence, breast cancer-specific mortality and overall mor-tality was compared between exposed and unex-posed groups using proportional hazards models adjusted for age, race, tumour stage, hormone receptor status, chemotherapy and hormonal therapy use, body mass index, hypertension and diabetes. In com-parison with unexposed women, women taking β-blockers had a nonsignificant 14% reduction in the risk of breast cancer recurrence (HR 0.86; 95% CI 0.57–1.32) and a nonsignificant 24% reduction in the risk of breast cancer-specific mortality (HR 0.76; 95% CI 0.44–1.33). There was, however, no reduction in all-cause mortality (HR 1.04; 95% CI 0.72–1.51). ACEi exposure was unexpectedly associated with a significant increase in breast cancer recurrence and cause-specific mortality.delayed-entry Cox Four further studies were published in 2011 [Barron et al. 2011; Melhem-Bertrandt et al. 2011; Sendur et al. 2011; Shah et al. 2011]. In the study by Melhem-Bertrandt and colleagues, the authors used the Breast Cancer Management System Database at The University of Texas MD Anderson Cancer Center to identify 102 women with invasive breast cancer, treated with neoadjuvant chemotherapy from January 1995 to May 2007 who also reported taking a β-blocker (β1-AR-selective 89%, β1/β2-AR non-selective 11%) and 1311 patients taking no β-blockers. There was no difference in the rate of pathological complete response between women taking and not taking β-blockers. Relapse-free survival and overall survival were also compared between the two groups. Women taking β-blockers had a 48% reduction in the risk of breast cancer recurrence (HR 0.52; 95% CI 0.31–0.88) and a nonsignificant 36% reduc-tion in the risk of death (HR 0.64; 95% CI 0.38–1.07) after adjusting for age, stage, race, body mass index, comorbidities and medication usage. In further subgroup analyses β-blocker use was associated with a 70% reduction in breast cancer recurrence (HR 0.30; 95% CI 0.10–0.87) among patients with TNBC (n = 377) and a nonsignificant 65% reduction in mortality (HR 0.35; 95% CI 0.12–1.00). β-Blocker use had no significant association with relapse-free survival and overall survival among women with ER-positive (n = 826) breast cancer. The study authors suggest that the relatively short follow-up time in their study (median follow-up 55 months) may have limited the ability to detect an association in this population.
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TI Barron, L Sharp et al.http://tam.sagepub.com 121In the study by Barron and colleagues, we used linked national cancer registry and prescription refill data from Ireland to identify 5801 women with a diagnosis of stage I–IV invasive breast can-cer between 2001 and 2006 [Barron et al. 2011]. From this population, women taking propranolol only (n = 70, β1/β2-nonselective), atenolol only (n = 525, β1-selective) or no β-blocker (n = 4738) at any time in the year prior to diagnosis were identified. Separate matched (ratio 1:2) analyses were conducted to examine associations between the use of propranolol or atenolol and the risk of local tumour invasion at diagnosis (T4 tumour), nodal or metastatic involvement at diagnosis (N2/N3/M1 tumour) and breast cancer-specific mor-tality. In comparison with nonusers, propranolol users were less likely to present with a T4 tumour (odds ratio [OR] 0.24; 95% CI 0.07–0.85) or N2/N3/M1 tumour (OR 0.20; 95% CI 0.04–0.88). Women taking propranolol at the time of diagno-sis (n = 47) had an 81% lower risk of breast cancer-specific mortality (HR 0.19; 95% CI 0.06–0.60) after adjusting for age, stage, grade and comorbidity score. No association with invasive tumour characteristics (T4 tumour: OR 1.31; 95% CI 0.91–1.88. N2/N3/M1 tumour: OR 1.10; 95% CI 0.72–1.71) or breast cancer-specific mortality (HR 1.08; 95% CI 0.84–1.40) was observed for patients taking the β1-selective antagonist atenolol.In the study by Shah and colleagues, the authors used the DIN-LINK primary care database in the UK to identify 3462 women with a primary diag-nosis of breast (n = 984), colorectal (n = 619), lung (n = 436), oesophagus (n = 159), ovarian (148), pancreas (n = 140), prostate (n = 759), renal (n = 124) or stomach (n = 93) cancer between 1997 and 2006, and at least two pre-scriptions for an antihypertensive agent in the year prior to diagnosis [Shah et al. 2011]. Patients with coronary heart disease, heart failure, stroke or arrhythmias before cancer diagnosis were excluded, as were patients with a contraindication for β-blocker or other antihypertensive therapy. The 1406 patients taking a β-blocker were com-pared with 2056 patients taking other antihyper-tensive therapy. The proportions of all patients taking selective and nonselective β-blockers were 83% and 17%, respectively. Information on selec-tive/nonselective β-blocker use by cancer subtype was not provided. In the breast cancer analysis, there was no difference in overall survival (HR 1.09; 95% CI 0.80–1.49) between patients receiv-ing any β-blocker (n = 434) and patients receiving other antihypertensive medications (n = 554) after adjusting for age, sex, year of diagnosis, smoking status, number of medications received in the year before diagnosis, socioeconomic status and national region. However, data on treatment received and prognostic tumour characteristics, such as stage, grade and receptor status, were not available. In addition, the use of patients receiving antihypertensives other than a β-blocker as a comparator group makes the interpretation of the results from this study difficult. This is because there is evidence to suggest that a number of these antihypertensive drugs may also influence breast cancer outcomes [Ganz et al. 2011].In the study by Sendur and colleagues, the authors report the results from an age-matched retrospec-tive analysis of breast cancer outcomes in users (n = 88) and nonusers (n = 456) of the β1-AR-selective antagonist metoprolol [Sendur et al. 2011]. There were no significant differences in 3-year disease-free or 5-year overall survival rates between metoprolol users and nonusers. This analysis was, however, not adjusted for relevant prognostic and confounding variables.Overall, the results from these pharmacoepide-miological studies suggest a potential role for tar-geting the β-AR pathway in breast cancer patients. There are, however, differences between their results that raise a number of important ques-tions. Firstly, preclinical data indicate that it is β2-AR signalling that plays the most prominent role in breast tumour regulation. Yet in the studies by Powe, Ganz and Melhem-Bertrandt and their colleagues the most commonly used β-blockers were β1-AR-selective antagonists (74–89%) [Powe et al. 2010b; Ganz et al. 2011; Melhem-Bertrandt et al. 2011]. It has been suggested that the observed associations with these agents may be due to the fact that many β1-AR-selective β-blockers have relatively large off-target β2-AR receptor affinity, and that even modest β2-AR antagonism may be sufficient to inhibit the effects of β2-AR signalling [Ganz and Cole, 2011]. However, this assumption is not strongly sup-ported by preclinical studies, which have shown relatively little effect for β1-AR antagonists, or the results from our study [Barron et al. 2011], in which no effect on breast cancer outcomes was observed for atenolol, a β1-AR-selective antago-nist with a β1:β2 adrenergic receptor affinity of 6:1 [Smith and Teitler, 1999]. It is difficult to draw definitive conclusions about the possible effects of β1-AR-selective agents from the studies by Powe,
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Therapeutic Advances in Medical Oncology 4 (3)122 http://tam.sagepub.comGanz and Melhem Bertrandt and their colleagues, as all of these studies included both β1-selective and β1/β2-nonselective antagonists in the same analyses. Understanding of the relative effects of β1-selective and β1/β2-nonselective antagonists therefore requires further clarification and future pharmacoepidemiological studies should, if possible, report their results stratified by β-AR subtype.The second question raised by the results from these studies regards the possible variation in the effect of β-blockers with respect to ER, PR and HER-2 status. Results from the study by Melhem-Bertrandt and colleagues suggest that the effects of β-blocker exposure are most evident in patients with TNBC [Melhem-Bertrandt et al. 2011]. A significant benefit from β-blocker exposure was not observed for ER-positive patients in their study. Unfortunately, the studies by Powe, Ganz and Shah and their colleagues and ourselves did not, or were unable to, distinguish between these different breast cancer subtypes and are thus unable to confirm this observation. The rationale for undertaking a subgroup analysis in TNBC patients was based upon the observation that TNBC patients have a higher prevalence of abdominal obesity and metabolic syndrome, both of which are linked to dysregulation of the sympa-thetic nervous system and potentially increased β-AR signalling [Melhem-Bertrandt et al. 2011]. Further work is required to clarify whether the clinical effects of β-blockers vary according to β-AR expression or ER, PR and HER-2 status.In addition to these remaining questions, future pharmacoepidemiological studies should address questions regarding associations between breast cancer outcomes and β-blocker dose or duration. Also of interest will be the timing of β-blocker exposure with respect to other anti-cancer treat-ments, in particular surgery; the presence of syn-ergies with other therapies, such as anti-angiogenic agents [Loges et al. 2009]; the possibility that β-blocker exposure is associated with site-specific inhibition of metastasis; and whether associations vary by degree of hypertension.β-Adrenergic receptor antagonists in breast cancer: clinical studiesThere are at least three phase II clinical studies currently assessing the safety and efficacy of β-blockers in breast, colorectal and ovarian cancers [ClinicalTrials.gov identifiers: NCT00502684, NCT00888797 and NCT01308944]. In the breast study, 460 women with stage I/II breast cancer undergoing surgery are being randomized in a double-blind fashion to receive either pro-pranolol (80 mg/day) and etodolac (nonsteroidal anti-inflammatory drug) or placebo from 2 days before to 3 days after surgery. In addition to labo-ratory studies and safety data, 5-year disease recurrence will be assessed. The planned colorec-tal cancer study follows a similar design to this. In the ovarian cancer study, 25 women with stage I–IV invasive epithelial ovarian cancer, primary peritoneal carcinoma or fallopian tube cancer will receive propranolol (80 mg/day) from 2 days before surgery and continue treatment for the duration of postoperative chemotherapy. The study's primary outcome will be safety, but pro-gression-free survival rates and biomarkers of response will also be assessed as secondary outcomes.ConclusionOverall, the results from preclinical and pharma-coepidemiological studies support the suggestion that β-blockers could provide a clinical benefit in breast cancer through inhibition of the prometa-static effects of β-AR signalling on tumour immune responses and the tumour microenvironment. To date, however, pharmacoepidemiological studies examining associations between β-blocker use and improved breast cancer outcomes have been limited in sample size. Larger observational stud-ies will enable subgroup analyses to be undertaken so that women most likely to benefit from the addition of a β-blocker to their breast cancer regi-men can be identified. This information can be used to better inform the design of randomized clinical studies to address questions regarding the type of β-blocker, predictive biomarkers or tumour characteristics, appropriate treatment paradigms and, most importantly, efficacy. The results from these randomized studies will be required before targeting of the β-AR signalling pathway can be considered a therapeutic option for patients with breast cancer.FundingDr TI Barron's position is supported by a post-doctoral fellowship from the Health Research Board Ireland.Conflict of interest statementThe authors declare no conflict of interest in preparing this article.
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TI Barron, L Sharp et al.http://tam.sagepub.com 123ReferencesAntoni, M.H., Lutgendorf, S.K., Cole, S.W., Dhabhar, F.S., Sephton, S.E., McDonald, P.G. et al. (2006) The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 6: 240–248.Armaiz-Pena, G.N., Lutgendorf, S.K., Cole, S.W. and Sood, A.K. (2009) Neuroendocrine modulation of cancer progression. Brain Behav Immun 23: 10–15.Avraham, R., Benish, M., Inbar, S., Bartal, I., Rosenne, E. and Ben-Eliyahu, S. (2010) Synergism between immunostimulation and prevention of surgery-induced immune suppression: an approach to reduce post-operative tumor progression. Brain Behav Immun 24: 952–958.Badino, G.R., Novelli, A., Girardi, C. and Di Carlo, F. (1996) Evidence for functional beta-adrenoceptor subtypes in CG-5 breast cancer cell. Pharmacol Res 33: 255–260.Barron, T.I., Connolly, R.M., Sharp, L., Bennett, K. and Visvanathan, K. (2011) Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol 29: 2635–2644.Benish, M., Bartal, I., Goldfarb, Y., Levi, B., Avraham, R., Raz, A. et al. (2008) Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann Surg Oncol 15: 2042–2052.Cakir, Y., Plummer, H.K. III, Tithof, P.K. and Schuller, H.M. (2002) Beta-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines. Int J Oncol 21: 153–157.Carie, A.E. and Sebti, S.M. (2007) A chemical biology approach identifies a beta-2 adrenergic receptor agonist that causes human tumor regression by blocking the Raf-1/Mek-1/Erk1/2 pathway. Oncogene 26: 3777–3788.Chida, Y., Hamer, M., Wardle, J. and Steptoe, A. (2008) Do stress-related psychosocial factors contribute to cancer incidence and survival? Nat Clin Pract Oncol 5: 466–475.Draoui, A., Vandewalle, B., Hornez, L., Revillion, F. and Lefebvre, J. (1991) Beta-adrenergic receptors in human breast cancer: identification, characterization and correlation with progesterone and estradiol receptors. Anticancer Res 11: 677–680.Drell, T.L. IV, Joseph, J., Lang, K., Niggemann, B., Zaenker, K.S. and Entschladen, F. (2003) Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat 80: 63–70.Entschladen, F., Drell, T.L. IV, Lang, K., Joseph, J. and Zaenker, K.S. (2004) Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters. Lancet Oncol 5: 254–258.Ganz, P.A. and Cole, S.W. (2011) Expanding our therapeutic options: beta blockers for breast cancer? J Clin Oncol 29: 2612–2616.Ganz, P.A., Habel, L.A., Weltzien, E.K., Caan, B.J. and Cole, S.W. (2011) Examining the influence of beta blockers and ACE inhibitors on the risk for breast cancer recurrence: results from the LACE cohort. Breast Cancer Res Treat 129: 549–556.Glasner, A., Avraham, R., Rosenne, E., Benish, M., Zmora, O., Shemer, S. et al. (2010) Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol 184: 2449–2457.Goodwin, P.J., Meyerhardt, J.A. and Hursting, S.D. (2010) Host factors and cancer outcome. J Clin Oncol 28: 4019–4021.Guo, K., Ma, Q., Wang, L., Hu, H., Li, J., Zhang, D. et al. (2009) Norepinephrine-induced invasion by pancreatic cancer cells is inhibited by propranolol. Oncol Rep 22: 825–830.Landen, C.N. Jr, Lin, Y.G., Armaiz Pena, G.N., Das, P.D., Arevalo, J.M., Kamat, A.A. et al. (2007) Neuroendocrine modulation of signal transducer and activator of transcription-3 in ovarian cancer. Cancer Res 67: 10389–10396.Lang, K., Drell, T.L. IV, Lindecke, A., Niggemann, B., Kaltschmidt, C., Zaenker, K.S. et al. (2004) Induction of a metastatogenic tumor cell type by neurotransmitters and its pharmacological inhibition by established drugs. Int J Cancer 112: 231–238.Lee, J.-W., Shahzad, M.M.K., Lin, Y.G., Armaiz-Pena, G., Mangala, L.S., Han, H.-D. et al. (2009) Surgical stress promotes tumor growth in ovarian carcinoma. Clin Cancer Res 15: 2695–2702.Liu, X., Wu, W.K.K., Yu, L., Sung, J.J.Y., Srivastava, G., Zhang, S.T. et al. (2008) Epinephrine stimulates esophageal squamous-cell carcinoma cell proliferation via beta-adrenoceptor-dependent transactivation of extracellular signal-regulated kinase/cyclooxygenase-2 pathway. J Cell Biochem 105: 53–60.Loges, S., Mazzone, M., Hohensinner, P. and Carmeliet, P. (2009) Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 15: 167–170.Lutgendorf, S.K., Cole, S., Costanzo, E., Bradley, S., Coffin, J., Jabbari, S. et al. (2003) Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res 9: 4514–4521.
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Therapeutic Advances in Medical Oncology 4 (3)124 http://tam.sagepub.comLutgendorf, S.K., Sood, A.K. and Antoni, M.H. (2010) Host factors and cancer progression: biobehavioral signaling pathways and interventions. J Clin Oncol 28: 4094–4099.Madden, K.S., Szpunar, M.J. and Brown, E.B. (2011) β-Adrenergic receptors (β-AR) regulate VEGF and IL-6 production by divergent pathways in high β-AR-expressing breast cancer cell lines. Breast Cancer Res Treat 130: 747–758.Marchetti, B., Spinola, P.G., Pelletier, G. and Labrie, F. (1991) A potential role for catecholamines in the development and progression of carcinogen-induced mammary tumors: hormonal control of beta-adrenergic receptors and correlation with tumor growth. J Steroid Biochem Mol Biol 38: 307–320.Masur, K., Niggemann, B., Zanker, K.S. and Entschladen, F. (2001) Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res 61: 2866–2869.Melamed, R., Rosenne, E., Shakhar, K., Schwartz, Y., Abudarham, N. and Ben-Eliyahu, S. (2005) Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: suppression by surgery and the prophylactic use of a beta-adrenergic antagonist and a prostaglandin synthesis inhibitor. Brain Behav Immun 19: 114–126.Melhem-Bertrandt, A., Chavez-Macgregor, M., Lei, X., Brown, E.N., Lee, R.T., Meric-Bernstam, F. et al. (2011) Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol 29: 2645–2652.Palm, D., Lang, K., Niggemann, B., Drell, T.L. IV, Masur, K., Zaenker, K.S. et al (2006) The norepinephrine-driven metastasis development of PC-3 human prostate cancer cells in BALB/c nude mice is inhibited by beta-blockers. Int J Cancer 118: 2744–2749.Park, S.Y., Kang, J.H., Jeong, K.J., Lee, J., Han, J.W., Choi, W.S. et al (2011) Norepinephrine induces VEGF expression and angiogenesis by a hypoxia-inducible factor-1α protein-dependent mechanism. Int J Cancer 128: 2306–2316.Pérez-Sayáns, M., Somoza-Martín, J.M., Barros-Angueira, F., Diz, P.G., Gándara Rey, J.M. and García-García, A. (2010) Beta-adrenergic receptors in cancer: therapeutic implications. Oncol Res 19: 45–54.Powe, D.G., Voss, M.J., Habashy, H.O., Zänker, K.S., Green, A.R., Ellis, I.O. et al. (2011) Alpha- and beta-adrenergic receptor (AR) protein expression is associated with poor clinical outcome in breast cancer: an immunohistochemical study. Breast Cancer Res Treat 130: 457–463.Powe, D.G., Voss, M.J., Habashy, K.S., Zänker, K.S., Green, A.R., Ellis, I.O. et al (2010a) Beta-blocker treatment is associated with a reduction in tumour metastasis and an improvement in specific survival in patients with breast cancer. EJC Suppl 8: 188–189.Powe, D.G., Voss, M.J., Zänker, K.S., Habashy, H.O., Green, A.R., Ellis, I.O. et al (2010b) Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget 1: 628–638.Re, G., Badino, P., Girardi, C. and Di Carlo, F., 1992. Effects of a beta 2-agonist (clenbuterol) on cultured human (CG-5) breast cancer cells. Pharmacol Res 26: 377–384.Sastry, K.S.R., Karpova, Y., Prokopovich, S., Smith, A.J., Essau, B., Gersappe, A. et al. (2007) Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation. J Biol Chem 282: 14094–14100.Schiestl, C., Neuhaus, K., Zoller, S., Subotic, U., Forster-Kuebler, I., Michels, R. et al. (2011) Efficacy and safety of propranolol as first-line treatment for infantile hemangiomas. Eur J Pediatr 170: 493–501.Sendur, M.A.N., Aksoy, S., Yaman, S., Arik, Z. and Altundag, K. (2012) Can all beta blockers improve the breast cancer survival? Breast 21(1): 107–108.Shah, S.M., Carey, I.M., Owen, C.G., Harris, T., Dewilde, S. and Cook, D.G. (2011) Does β-adrenoceptor blocker therapy improve cancer survival? Findings from a population-based retrospective cohort study. Br J Clin Pharmacol 72: 157–161.Shan, T., Ma, Q., Zhang, D., Guo, K., Liu, H., Wang, F. et al. (2011) β2-Adrenoceptor blocker synergizes with gemcitabine to inhibit the proliferation of pancreatic cancer cells via apoptosis induction. Eur J Pharmacol 665: 1–7.Shi, M., Liu, D., Duan, H., Qian, L., Wang, L., Niu, L. et al. (2011) The β2-adrenergic receptor and Her2 comprise a positive feedback loop in human breast cancer cells. Breast Cancer Res Treat 125: 351–362.Sloan, E.K., Priceman, S.J., Cox, B.F., Yu, S., Pimentel, M.A., Tangkanangnukul, V. et al. (2010) The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 70: 7042–7052.Slotkin, T.A., Zhang, J., Dancel, R., Garcia, S.J., Willis, C. and Seidler, F.J. (2000) Beta-adrenoceptor signaling and its control of cell replication in MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat 60: 153–166.Smith, C. and Teitler, M. (1999) Beta-blocker selectivity at cloned human beta 1- and beta
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TI Barron, L Sharp et al.http://tam.sagepub.com 1252-adrenergic receptors. Cardiovasc Drugs Ther 13: 123–126.Sood, A.K., Armaiz-Pena, G.N., Halder, J., Nick, A.M., Stone, R.L., Hu, W. et al. (2010) Adrenergic modulation of focal adhesion kinase protects human ovarian cancer cells from anoikis. J Clin Invest 120: 1515–1523.Sood, A.K., Bhatty, R., Kamat, A.A., Landen, C.N., Han, L., Thaker, P.H. et al. (2006) Stress hormone-mediated invasion of ovarian cancer cells. Clin. Cancer Res 12: 369–375.Spiegel, D., Butler, L.D., Giese-Davis, J., Koopman, C., Miller, E., DiMiceli, S. et al. (2007) Effects of supportive-expressive group therapy on survival of patients with metastatic breast cancer: a randomized prospective trial. Cancer 110: 1130–1138.Storch, C.H. and Hoeger, P.H. (2010) Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol 163: 269–274.Thaker, P.H., Han, L.Y., Kamat, A.A., Arevalo, J.M., Takahashi, R., Lu, C. et al. (2006) Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 12: 939–944.Thaker, P.H., Lutgendorf, S.K. and Sood, A.K. (2007) The neuroendocrine impact of chronic stress on cancer. Cell Cycle 6: 430–433.Vandewalle, B., Revillion, F. and Lefebvre, J. (1990) Functional beta-adrenergic receptors in breast cancer cells. J Cancer Res Clin Oncol 116: 303–306.Yang, E.V., Donovan, E.L., Benson, D.M. and Glaser, R. (2008) VEGF is differentially regulated in multiple myeloma-derived cell lines by norepinephrine. Brain Behav Immun 22: 318–323.Yang, E.V., Kim, S.J., Donovan, E.L., Chen, M., Gross, A.C., Webster Marketon, J.I. et al. (2009) Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun 23: 267–275.Yang, E.V., Sood, A.K., Chen, M., Li, Y., Eubank, T.D., Marsh, C.B., et al. (2006) Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res 66: 10357–10364.Zhang, D., Ma, Q., Shen, S. and Hu, H. (2009) Inhibition of pancreatic cancer cell proliferation by propranolol occurs through apoptosis induction: the study of beta-adrenoceptor antagonist's anticancer effect in pancreatic cancer cell. Pancreas 38: 94–100.Zhang, D., Ma, Q.-Y., Hu, H.-T. and Zhang, M. (2010) β2-Adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFκB and AP-1. Cancer Biol Ther 10: 19–29.Visit SAGE journals online http://tam.sagepub.comSAGE journals


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New details from two studies reveal troubling side effects from niacin, a drug that hundreds of thousands of Americans take for cholesterol problems and general heart health. Some prominent doctors say the drug now seems too risky for routine use.
Niacin is a type of B vitamin long sold over the counter and in higher prescription doses. Some people take it alone or with statin medicines such as Lipitor for cholesterol problems.
Niacin users' main complaint has been flushing, so drug companies have been testing extended-release and combining other medicines with it to minimize that problem. Introduced in the 1950s, the drug hadn't been rigorously tested until recent years when makers of prescription versions were seeking market approval.
Those details are published in this week's New England Journal of Medicine.
The larger study suggests that "for every 200 people that we treat with niacin, there is one excess death," plus higher rates of bleeding, infections and other problems -- "a completely unacceptable level" of harm, said Dr. Donald Lloyd-Jones of Northwestern University in Chicago. "Niacin should not be used routinely in clinical practice at all."
Heart specialists stress that patients never should stop taking any medicine without first talking with their doctors. Many have shied away from niacin since the initial results came out, but more than 700,000 prescriptions for various niacin drugs are written each month in the U.S. The top brand is Niaspan, long sold by Abbott Laboratories and now by AbbVie, which had nearly $900 million in sales in the U.S. alone last year, according to IMS Health, a health data firm.
The larger of the two studies tested Tredaptive -- a Merck & Co. combo of niacin and an anti-flushing medicine -- in nearly 26,000 people already taking a statin. Full results confirm there was a 9 percent increase in the risk of death for those taking the drug - a result of borderline statistical significance, meaning the difference could have occurred by chance alone, but still "of great concern," Lloyd-Jones wrote in a commentary in the medical journal.
The drug also brought higher rates of gastrointestinal and muscle problems, infections and bleeding. More diabetics on the drug lost control of their blood sugar, and there were more new cases of diabetes among niacin users.
The initial results in December 2012 led Merck to stop pursuing approval of Tredaptive in the U.S. and to tell doctors in dozens of countries where it was sold to stop prescribing it to new patients.
Prompted by that study, leaders of an earlier one that tested a different niacin drug, Niaspan, re-examined side effects among their 3,414 participants and detailed them in a letter in the medical journal.
Besides more gastrointestinal, blood-sugar and other complications, the new report details a higher rate of infections and a trend toward higher rates of serious bleeding.
The consistency of the results on studies testing multiple types of niacin "leaves little doubt that this drug provides little if any benefits and imposes serious side effects," said Yale University cardiologist Dr. Harlan Krumholz.
"It's an astonishing reversal of fortune" for niacin, one of the very earliest cholesterol treatments, he said. "This is a billion-dollar drug and it never really had the evidence to warrant that sort of blockbuster status."
The studies were on prescription niacin; risks and benefits of over-the-counter forms are unclear.
Lloyd-Jones said niacin still may be appropriate for some people with very high heart risks who cannot take statins, and for people with very high triglycerides that can't be controlled through other means.
Krumholz said patients should talk with doctors about other treatment options besides niacin.
"This drug can hurt you," he said.


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USDA officials learned late Friday afternoon, March 16, 2012, that fraudulent letters are being sent by FAX to individuals and businesses in at least four states. The letters purportedly come from a USDA procurement officer and seek personal information. These letters are false and in no case should a recipient respond with personal and financial information. The fraudulent letters …Read More »
Tag Archives: information
Fake USDA Faxes Being Received
Rumors Spread on Facebook Spark Harassment
The Beloit Police Department has been investigating information they recently received from the public concerning a maroon and silver colored van that has been seen at local daycare centers, schools, and other locations in the City of Beloit. Lots of "different" information concerning the investigation has made it to Facebook and the result says Mitchell County Attorney Mark Noah, an …Read More »
Peanut Butter Cup Burglars Strike
Reese Peanut Butter Cup Burglars strike the Blue Springs Methodist Church. The Gage County Sheriff's office is investigating a burglary of the Blue Springs Methodist Church that occurred between 1 p.m. and 10 a.m. on Monday. According to the Gage County Sheriff report someone threw a brick through a window of a door and entered the church. The burglars …Read More »
Blue Valley Telecommunications Warns Customers of Fraudulent Emails
An important reminder from Blue Valley Tele-Communications… There has been a recent wave of fraudulent emails to our customers, the purpose of which is to elicit personal information for criminal purposes. This is known as 'phishing' and is something of which you should be very wary since the emails often appear to be from legitimate sources. Here are some tips …Read More »
Southeast CC Offering Aviation Ground School On Beatrice Campus
A 12-week course that prepares students for the Federal Aviation Administration written exam will begin in January on Southeast Community College's Beatrice Campus. SCC's Continuing Education Division is offering Aviation Ground School Tuesday nights from Jan. 10 through March 27. The class will be held from 6-10 p.m. in Room 334 of the Kennedy Center on the Beatrice Campus, 4771 …Read More »
Several cars vandalized in Beatrice last weekend.
Beatrice authorities are seeking information regarding a series of vehicle vandalism incidents reported late Saturday or early Sunday morning last weekend. Most involved spray paint over license plates. Anyone with information is asked to contact authorities at (402) 223-4080.Read More »
State Main Street Coordinator Appearing in Washington
Mary Helmer, State Coordinator of the Kansas Main Street Association will be presenting a program to provide information to business owners who are interested in improving the façade of their business. The meeting will take place at 6:30 on Thursday at the First National Bank inWashington. The meeting will be hosted by the Washington Chamber of Commerce.Read More »
Hunter Education Course Comes to Marysville
A Hunter's Education Course will take place this Saturday and Sunday in Marysville. The course will teach new hunters the right and safe way to hunt. The program is being hosted by the Marysville Police Department. Anyone interested in participating in the course can register and pick up materials this week at the Marysville Police Department between 9 A.M. and …Read More »
Linn Student Arrested for Terroristic Threats
On Thursday October 6th Washington County officers were dispatched to Linn High School. After an investigation a juvenile was taken into custody on pending charges of Criminal Threat. The juvenile was transported to Juvenile Justice Authority in Junction City, KS. No other information is available.Read More »
River Valley Extension District Medicare Part D Enrollment Workshop Coming Soon
The River Valley Extension District is featuring a do it yourself Medicare Part D enrollment workshop Thursday, October 20 in Clay Center. Hour long sessions begin at 6:30 and 7:30 pm at the 4-H Fair Conference Center. Clay Center Extension office has details and registration information. Any of the River Valley Extension Offices have a Medicare prescription drug worksheet available, …Read More »


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Great Expectations (Unabridged with the original illustrations by Charles Green)This carefully crafted ebook: "Great Expectations (Unabridged with the original illustrations by Charles Green)" is formatted for your eReader with a functional and detailed table of contents. Great Expectations is a bildungsroman, or a coming-of-age novel, and it is a classic work of Victorian literature. It depicts the growth and personal development of an orphan named Pip. The novel was first
Get Financing Now: How to Navigate Through Bankers, Investors, and Alternative Sources for the Capital Your Business Needs"Every entrepreneur should read this book, ideally before they start their next business. The insights into finance and financial planning should help the entrepreneur not make many of the mistakes I did!" Jim Beach, Director of Education at The Entrepreneur School and author of School for Start-Ups "An exhaustive and invaluable resource for companies seeking funding at any stage of their life
$9.99This book contains cutting edge concepts and ideas regarding developing Higher Consciousness. It is a combination of the teachings of Yogic Masters connected to that of extra-terrestrials from the Andromedan, Sirian, Pleiadian and Essassani civilizations. The information is Self Empowering and crosses the line whereby self healing, healing others and energy transference can be achieved. Practical
Danny Kaye 138 Success Facts - Everything you need to know about Danny KayeNow available, Danny Kaye. This book is your ultimate resource for Danny Kaye. Here you will find the most up-to-date 138 Success Facts, Information, and much more.In easy to read chapters, with extensive references and links to get you to know all there is to know about Danny Kaye's Early life, Career and Personal life right away. A quick look inside: Cosmo Kramer - Physical moments, United
7 Things You Must Know About Studen LoansThe American Dream is only a dream when avoidance, stupidity, or laziness are allowed to dominate the decision making process in financing a college education. To avoid being labeled a dumb ass, parents and students must know the potential long-term risk, hazards, and cavernous money pits lying in wait before signing up for student loans. It begins here!
The Reluctant Warrior - The Journey BeginsJoel Richards leaves his family's West Virginia farm in 1863 to join the Union army where he becomes a highly-skilled, decorated cavalryman, After the war he returns home finding the farm in disrepair; his father alone and dying. Joel's family had been severely beaten by deserters causing the death of his mother and sister. Upon his fathers passing, he sells the farm and heads for Texas in search
The Revelation Of God And His WordReading the Bible is one of the most important disciplines for Christian growth, but for many believers Bible study can evoke an array of emotions-from awe to frustration to agony. The numerous translations, parables, types, and shadows add further dismay. Author and Bible teacher Charles Green says that studying the Scriptures doesn't't have to be intimidating. Green covers topics spanning the
Manufacturing Powerlessness in the Black Diaspora
Inner-City Youth and the New Global FrontierDespite the economic utopianism brought on by globalization, effective solutions to the persistent plight of urban blacks throughout the African diaspora continue to elude scholars, politicians, and community leaders. Charles Green brings a decade of research and original fieldwork in Africa, the Caribbean, and the United States to investigate the interface of the historic racism faced by these


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'Kids Are All Right' is fierce comic drama
|Annette Bening, left, and Julianne Moore star in 'The Kids are All Right. Focus Features
What an appropriate title writer-director Lisa Cholodenko chose for her family comic drama "The Kids Are All Right." The two kids of the film — teen siblings getting to know their biological dad — are great — smart, mature, high-minded, well-adjusted.
On the other hand, the three adults, played with fierce heart and a genuine sense of well-meaning inadequacy by Annette Bening, Julianne Moore and Mark Ruffalo, are a mess.
The scenario concocted by Cholodenko and co-writer Stuart Blumberg is a bit forced — repressed lesbian parents forced into contact with the carefree sperm donor who fathered their children. The mayhem that ensues strains credibility here and there.
Yet Cholodenko ("High Art," "Laurel Canyon") and her cast turn what could have been an utterly artificial story into a warm, funny, sharp-tongued and broiling examination of the volatility underlying even the happiest of families.
Southern California couple Nic (Bening) and Jules (Moore) live a seemingly ideal life with their kids, 18-year-old Joni (Mia Wasikowska) and 15-year-old Laser (Josh Hutcherson).
Nic's a doctor and the authoritarian in the family, while flighty Jules is starting a landscaping business. They complement each other nicely, and while the romance in their relationship has cooled, they are steady companions and doting if somewhat stifling parents.
To read the complete story see Thursday's Republican-American or our electronic edition at http://republicanamerican.ct.newsmemory.com.
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- Third try doesn't quite 'Eclipse' silly factor
- Rivers offers answers in Bantam
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- 'Kids Are All Right' is fierce comic drama
- Sweet story belies its 'Despicable' title
- Mildly magical 'Apprentice' family fare
- 'Inception' earns dreamy reception with $60.4M
- 'Salt' no thriller, but nicely seasoned fare
- For the love of the role


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National Public Radio interviews Truthdig Editor Robert Scheer and former White House advisor Ron Christie on the significance of the declassified National Intelligence Estimate.
Posted on Feb 8, 2016
A Progressive Journal of News and Opinion
Publisher Zuade Kaufman | Editor Robert Scheer
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I just put in a new 80gb HDD in my XBOX and I transferred over the contents of my old HDD but I screwed some stuff up. What I want to know is how can I make it its a completely clear HDD with just the default XBOX system files on, basically like its a brand new normal HDD only with more space. I'm using the X3 modchip.
Just Put In A New Hdd, Now I Want It Like New Again
Started by Dougtron , Jan 17 2006 01:23 AM
1 reply to this topic
Posted 17 January 2006 - 01:23 AM
Posted 17 January 2006 - 02:06 AM
Since it's chipped, just use an autoinstaller such as Slayer's.
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Taxpayers may choose to pay their property taxes quarterly by participating in an installment payment plan. To be eligible for the program, the taxpayers' estimated taxes must be in excess of $100.00. You may submit your application in the following manners:
- Search for your account(s) and click on the "Apply for Installment Plan" link . Complete the required fields and click "Submit". You will receive an email confirmation that you must click on "Confirm Installment Payment Plan" in order to finalize your application process.
- Complete the fillable pdf application and submit it by email to email@example.com, fax to 863-402-6697 or by mail to 540 S. Commerce Ave, Sebring, FL 33870. Application forms are available November 1st for the following year's tax and must be submitted by April 30th of the applying year.
- You may call 863-402-6685 to request an application be mailed to you or you may pick up an application at any office locations.
The installment Example & Calculator provides a sample of how the installment plan arrives at your quarterly payment amounts and provides you with an option to estimate your personal payment.
The plan requires that the first installment must be made no later than June 30th to receive a discount. Payments accepted after June 30th, but before July 30th, are not discounted, and will include a 5% penalty. Failure to make the first payment will automatically cancel the participant from the plan, and the taxpayer will be required to pay the taxes due, in full by March 31st.
Upon meeting the first installment deadline, the taxpayer is then obligated to participate in the program for the entire year. Discounts do not apply to delinquent payments. Any amount remaining unpaid on April 1st is treated as a delinquent tax bill.
The following payment schedule applies to the installment plan:
1st installment: 1/4 the total of estimate taxes discounted 6%.
Payment due by June 30th.
2nd installment: 1/4 the total estimated taxes discounted 4.5%.
Payment due by September 30th.
3rd installment: 1/4 the total estimated taxes plus 1/2 of any adjustment made for actual tax liability, discounted 3%.
Payment due by December 31st.
4th installment: 1/4 of the total estimated taxes plus the remaining 1/2 of any adjustment for actual tax liability. No discount applies.
Payment due by March 31st.
Taxpayers participating in the installment payment plan are automatically re-enrolled each year and do not have to fill out a new application. The first 2 installments are based upon the existing tax bill. Any changes to ownership, value, or exemption(s), will be reflected in the final 2 bills.
Method of Payment for Current Taxes:
- Personal or Company check, providing payment is received on or before May 31st.
- By telephone or online if paying by credit card.
- Wire transfer.
- ACH Upon Completion of the attached application, funds will be withdrawn from your designated account on the date specified on the application. The date(s) funds are withdrawn are determined by whether or not you are enrolled on the installment payment plan.


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Bert HagendoornTwitter Stats
@BertHagendoorn - Tracking since September 26, 2008
Consultant for creative agencies | positioning specialist | communication strategy | Dutch Digital Design | creative industry | blogger | speaker | moderator
Bert Hagendoorn Tweets
@BertHagendoorn has posted 138 tweets in the last 30 days, which translates to an average of 4.6 tweets per day.
Bert Hagendoorn Followers
@BertHagendoorn has 5,058 followers.
This account is #1,211,959 in the worldwide rank of the most popular Twitter users.
Bert Hagendoorn Following
@BertHagendoorn is following 2,375 Twitter accounts.
Last month this account followed 86 users.
Bert Hagendoorn Predictions & Milestones
@BertHagendoorn will hit 5,152 followers in the next 3 months, and 5,441 in one year.
You are on Bert Hagendoorn's Twitter stats page
We track these Twitter stats since September 26, 2008 . You can see how many followers Bert Hagendoorn lost or gained and what the prediction is for tomorrow or the next 15 days, together with all kinds of other stats like rank compared to all Twitter users, tweets etc.
Why don't you give it a try and compare Bert Hagendoorn to yourself ? Or if you are Bert Hagendoorn get even more feature rich & up-to-date stats with Premium & Pro Twitter Stats.
Twitter Counter is the #1 Twitter stats site powered by Twitter. It all started in June 12, 2008 and we grew rather rapidly because of our Twitter Counter badge. The button is a nice small image that shows your visitors how many followers you have on Twitter. Within a year the button was on many many blogs around the world and we displayed more than 100 million buttons in one month. We track follower stats for over 180 million users now.


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Parliament is reviewing legislation that would allow the federal privacy commissioner to apply to the federal court to levy fines on individuals and organisations for privacy breaches, reports The Australian. Privacy Commissioner Timothy Pilgrim said it means he could require companies to fix systems and pay for regular privacy audits. He believes "they will start to take their responsibilities around protecting information a lot more seriously once those powers are passed." One lawyer says companies that collect personal information as part of their business model may be nervous about the legislation, adding, those that can't provide "informed consent" risk breaching privacy principles. (Registration may be required to access this story.)
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text: Comments (84) + Add comment Comments (84) Featured « 1 2 » INMATEofARKHAM + 1155d ago As someone who has played lots and lots of Uncharted MP, and actually looked more forward to UC3 MP than its SP campaign, and found enough to enjoy even with all of its flaws I'm deeply worried by the mention of a melee booster... The melee has always been unbalanced/too powerful in Uncharted and I'm more than worried that this trend will now continue. This just reminds me of the blind firing Kal-7 issue... Hopefully, I'm wrong. Really, really hope that I am... but I won't be shocked if I end up being right. #31 Agree(1) | Disagree(3) | Report | Reply Conquerbeard + 1155d ago Hurray for more pre-order bonuses. Ugh. #32 Agree(1) | Disagree(0) | Report | Reply Munnkyman + 1155d ago O I can say is wow #33 Agree(1) | Disagree(0) | Report | Reply legend911 + 1155d ago I just hope it will be worth it, the story looks extremely intriguing but I can't say that Beyond Two Souls doesn't look good in itself. #34 Agree(0) | Disagree(1) | Report | Reply cedaridge + 1155d ago The Last of Us babe! I can't wait for this game. psn: cedar4Thunder / xbl: cedar4Thunder #35 Agree(2) | Disagree(0) | Report | Reply ShadowGhost + 1155d ago I remember getting down voted on one article regarding The Last of Us having multiplayer. I somehow knew ND was going to include it, regardless of how they concentrate more on the single player campaign. #36 Agree(1) | Disagree(0) | Report | Reply IWentBrokeForGaming + 1155d ago This game truely shows the graphical leap that PS3 Exclusives TRUELY have over 360 Exclusives... Naughty Dog are the main developers that TRUELY showed us and continue to show us what Next Gen gaming is supposed to look like! #37 Agree(1) | Disagree(0) | Report | Reply fgrtgjrtr 1155d ago | Spam TBONEJF + 1155d ago THE BLOOD AFFECT IS FREAKING AWESOME going to pre order now at gamestop reserve my copy can't wait till this comes out. NAUGHTY DOG HAVE OUT DONE THEMSELVES this time. #39 Agree(3) | Disagree(0) | Report | Reply Ethereal + 1155d ago SICK!!! Most anticipated, well this and Bioshock =) #40 Agree(2) | Disagree(0) | Report | Reply level 360 + 1155d ago Sure this will garner a Games of the Year nomination and hopefully the award. The trailer and game previous play demo videos are really impressive. Would like to know if it has a 3D option like the Uncharted Drake's Deception? #41 Agree(2) | Disagree(0) | Report | Reply th3n00bg4m3r + 1155d ago Sorry, The Last Of Us doesn't support 3D, but look at the bright side, they are using the "3D" space to make the game technically better than it already is. #41.1 Agree(0) | Disagree(0) | Report | Reply « 1 2 » Add comment You need to be registered to add comments. Register here or login Username Password Remember Rules & guidelines Login


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You asked and Nvidia listened
Good news, gamers. Nvidia has decided to slash $50 off the price of its upcoming Shield handheld gaming device , thus giving it a new MSRP of $299 (down from $349 previously). For those of you who already pre-ordered a Shield, you don't have to go pound sand. Nvidia says that you, too, will be charged the new price when the product ships.
"It's time for one more change. We've heard from thousands of gamers that if the price was $299, we'd have a home run. So we're changing the priceo Shield to $299," Nvdiia stated in a blog post .
Shield, if you somehow missed all the hoopla, is an open platform gaming handheld running Android. It has an Nvidia Tegra 4 quad-core mobile processor, 2GB of RAM, 5-inch 720p multi-touch display, stereo speakers, 16GB of internal storage, mini-HDMI output, micro-USB 2.0 port, microSD support, and a few other odds and ends.


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|right ascension
The position of a celestial object east of the vernal equinox along the celestial equator. Right ascension is measured in hours, minutes, and seconds from the vernal equinox (0 hours) to the point where a great circle drawn through the object and the north and south celestial poles intersects the celestial equator. Each hour corresponds to 15° of angular distance along the celestial equator for a total of 24 hours. See more at equatorial coordinate system.


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Offensive coordinator says Patriots offense is progressing
FOXBOROUGH -- Everything with the Patriots offense is about where Patriots offensive coordinator Bill O'Brien expected it to be at this point in the season.
The name of the game during O'Brien's 16-minute press conference this afternoon was progress as he said each offensive unit is coming along. Here are a few highlights:
On the offense's status at this point: "I think every year is different. I would say the difference in this year from last would be the offseason -- the players weren't here. But other than that, I would say training camp is going about as it would go at a normal pace for the situation that we're in this year. At this point, it's going well. We're trying to be very fundamentally strong in what we do. We're progressing. It's training camp; it's a grind. ..."
On Chad Ochocinco's progress: "I know from here being here. He's been very professional. He works really hard in the meeting room and on the field. He's a competitive guy. He takes a lot of pride in it and I would say that about the whole group of receivers right now. ... Ochocinco's fitting in. He's progressing on a daily basis and just like everybody else there's ups and downs at this point in training camp and he's just trying to be as consistent as he can be like everybody else out there."
On rookie running backs missing time due to injury: "I think any time you're not out on the field that's a tough adjustment. You have to try to keep up on your own with meetings and playbook things and not being out there, obviously you're not getting the reps. So they're working hard to come back as fast they can and they will and as soon as they're healthy, they'll be back out there."
On his relationship with Brady: "I'm going into my fifth year here. It's a good relationship, it's a professional relationship. It's a relationship where there's a lot of communication and it's all about football. .. It hink there's a lot of trust. You're talking about a guy that works really hard. ..."
On his duties since becoming offensive coordinator: "We have a really strong staff as a whole, obviously led by Bill. We have a really strong offensive staff that works very well together. We're all in it together. We each have different roles. I'm basically the guy that kind of collects the papers and puts it in the right stack. ..."


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Published: Sunday, June 26, 2011 at 3:30 a.m.
Last Modified: Wednesday, June 22, 2011 at 4:49 p.m.
James and Sheila Holland of Tuscaloosa announce the engagement of their daughter Andrea Javetta Holland of Bessemer to William Terrance Meade of Birmingham.
The wedding will be on July 9 at Brown Memorial Presbyterian Church in Tuscaloosa.
Miss Holland is the granddaughter of the late William R. Greene and the late Ellis Greene, of Tuscaloosa, and the late Ornie Holland and the late Aline Holland of Corinth, Miss.
She is a 1997 graduate of Central High School and earned a Bachelor of Science degree in business administration at The University of Alabama in 2001.She is employed by GlaxoSmithKline Pharmaceuticals.
Mr. Meade is the son of William "Jackie" Meade and Ollie Meade of Scottsboro.
He is the grandson of the late A. C. Nance and the late Margaret Nance of Chattanooga, Tenn, and the late Richard Meade and the late Ester Meade of Tuscumbia.
He is a 1999 graduate of Scottsboro High School and earned a Bachelor of Science degree in business administration in 2003 and a Master's degree in business administration in 2007, both at the University of Alabama. Meade was a four-year starter for the Alabama men's basketball team. He is employed by AmWins Brokerage of Birmingham.
Reader comments posted to this article may be published in our print edition. All rights reserved. This copyrighted material may not be re-published without permission. Links are encouraged.


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Pre-season guide to every NRL club, including the start of Ricky Stuart's reign at Canberra
- From: The Daily Telegraph
- October 29, 2013
RICKY Stuart is back home - and he means business.
Stuart's Raiders will return to the training field on Thursday — less than four weeks since the NRL grand final.
Canberra will be the second team back, following the Warriors' return to training on Monday.
The remaining 14 clubs will resume training throughout next month. All clubs will give their World Cup stars an extended break.
Former Canberra teammate Laurie Daley wasn't surprised the Raiders will be back training on Thursday.
"Because Canberra missed the finals this year, they have had some time off," said Daley, who played 244 first grade matches and won three premierships with the Raiders.
"Ricky is the new coach at Canberra and will want to get his teeth into the job.
"The players will be excited and I know Ricky will be looking forward to a new challenge.
"Canberra are among the first clubs back — so I reckon the players will return keen and motivated."
The Roosters have struggled to nominate a return date to training because 16 of their players are involved in the World Cup in England.
Gains: Ben Barba (Bulldogs), Martin Kennedy (Roosters)
Losses: Scott Prince (retired), Peter Wallace (Panthers), Corey Norman (Eels), Lama Tasi (Salford Red Devils), Delroy Berryman (Sea Eagles)
Best buy: Ben Barba
Biggest loss: Peter Wallace
Training return: November 6
Gains: Reni Maitua (Eels), Chase Stanley (Dragons), Pat O'Hanlon (Eels), Kayne Brennan (Dragons)
Losses: Ben Barba (Broncos), Dene Halatau (Wests Tigers), Steve Turner (retired), Martin Taupau (Wests Tigers), Danny Galea (Widnes Vikings), Kris Keating (Hull Kingston Rovers), Paul Carter (Titans)
Best buy: Chase Stanley Biggest loss: Dene Halatau
Training return: November 11
Gains: Lachlan Coote (Panthers), Cameron King (Dragons), Hezron Murgha (Northern Pride)
Losses: Matt Bowen (Wigan), Dallas Johnson (retired), Ashley Graham (retired), Jayden Hodges (Sea Eagles), Felise Kaufusi (Storm), Chris Grevsmuhl (Rabbitohs)
Best buy: Lachlan Coote
Biggest loss: Matt Bowen
Training return: November 11
Gains: Gareth Widdop (Storm), Sam Williams (Raiders), Joel Thompson (Raiders), Mike Cooper (Warrington), Dylan Farrell (Rabbitohs), Josh Ailaomai (Roosters), Matt Groat (Tigers), Peter Mata'utia (Knights)
Losses: Jamie Soward (Panthers), Michael Weyman (Hull Kingston Rovers), Matt Cooper (retired), Nathan Fien (retired), Chase Stanley (Bulldogs), Cameron King (Cowboys), Matt Prior (Sharks), Kayne Brennan (Bulldogs), Jackson Hastings (Roosters)
Best buy: Gareth Widdop
Biggest loss: Matt Cooper
Training return: November 18
Gains: Will Hopoate (return), Lee Mossop (Wigan), Nathan Peats (Rabbitohs), Corey Norman (Broncos), Justin Hunt (Rabbitohs), Brenden Santi (Tigers)
Losses: Reni Maitua (Bulldogs), Cheyse Blair (Sea Eagles), Jake Mullaney (Salford Red Devils), Pat O'Hanlon (Bulldogs)
Best buy: Will Hopoate
Biggest loss: Reni Maitua
Training return: November 7
Gains: Russell Packer (Warriors), Clint Newton (Panthers), Michael Dobson (Hull Kingston Rovers)
Losses: Danny Buderus (retired), Neville Costigan (Hull Kingston Rovers), Kevin Naiqama (Panthers), Peter Mata'utia (Dragons), Siuatonga Likiliki (Titans), Will Smith (Panthers)
Best buy: Russell Packer
Biggest loss: Neville Costigan
Training return: November 18
Gains: Peter Wallace (Broncos), Jamie Soward (London Broncos), Elijah Taylor (Warriors), Brent Kite (Sea Eagles), Kevin Naiqama (Knights), Tyrone Peachey (Sharks), Shaun Spence (Tigers), Will Smith (Knights)
Losses: Lachlan Coote (Cowboys), Luke Walsh (St Helens), Mose Masoe (St Helens), Clint Newton (Knights), Danny Galea (Widnes Vikings), Travis Robinson (Storm), Blake Austin (Tigers)
Best buy: Brent Kite
Biggest loss: Luke Walsh
Training return: November 11
Gains: Joel Reddy (Tigers), Chris Grevsmuhl (Cowboys)
Losses: Nathan Peats (Eels), Roy Asotasi (Warrington Wolves), Matt King (retired), Michael Crocker (retired), Andrew Everingham (rugby), Justin Hunt (Eels), Dylan Farrell (Dragons), Josh Starling (Sea Eagles), Christian Hazard (Titans)
Best buy: Joel Reddy
Biggest loss: Dylan Farrell
Training return: November, no set date.
Gains: Lagi Setu (Storm)
Losses: Blake Ferguson (released), Joel Thompson (Dragons), Shaun Berrigan (retired), Sam Williams (Dragons), Sandor Earl (ban pending), Michael Picker (retired), Jonathon Reuben (Roosters)
Best buy: Ricky Stuart
Biggest loss: Blake Ferguson
Training return: Thursday
Gains: Remi Casty (Catalan Dragons), Jackson Hastings (Dragons), Jonathon Reuben (Raiders)
Losses: Martin Kennedy (Broncos), Josh Ailaomai (Dragons)
Best buy: Jackson Hastings
Biggest loss: Marty Kennedy
Training return: November 4
Gains: Cheyse Blair (Eels), Josh Starling (Rabbitohs), Delroy Berryman (Broncos), Jayden Hodges (Cowboys), Tyson Andrew (Mackay Cutters)
Losses: Brent Kite (Panthers), George Rose (Storm), Joe Galuvao (retired)
Best buy: Cheyse Blair
Biggest loss: Brent Kite
Training return: November 18
Gains: Blake Ayshford (Wests Tigers), Matt Prior (Dragons)
Losses: Jayson Bukuya (Warriors), Jon Green (retired), Tyrone Peachey (Panthers), Ben Ross (retired), Mark Taufua (retired), Chad Townsend (Warriors)
Best buy: Blake Ayshford
Biggest loss: Jayson Bukuya
Training return: November 5
Gains: George Rose (Sea Eagles), Travis Robinson (Panthers), Cody Walker (Easts Tigers), Hymel Hunt (Titans)
Losses: Gareth Widdop (Dragons), Maurice Blair (Titans), Jason Ryles (retired), Brett Finch (retired), Junior Sa'u (Salford Red Devils), Lagi Setu (Raiders)
Best buy: Travis Robinson
Biggest loss: Gareth Widdop
Training return: November 7
Gains: Pat Richards (Wigan), Dene Halatau (Bulldogs), Cory Paterson (Hull Kingston Rovers), Martin Taupau (Bulldogs), Blake Austin (Panthers), Keith Lulia (Bradford)
Losses: Benji Marshall (rugby union), Blake Ayshford (Sharks), Lote Tuqiri (rugby union), Joel Reddy (Rabbitohs), Eddy Pettybourne (Wigan Warriors), Matt Groat (Dragons), Jacob Miller (Hull FC), Brenden Santi (Eels), Shaun Spence (Panthers)
Best buy: Pat Richards
Biggest loss: Benji Marshall
Training return: November 11
Gains: Maurice Blair (Storm), Siuatonga Likiliki (Knights), Paul Carter (Bulldogs), Christian Hazard (Rabbitohs)
Losses: Luke O'Dwyer (retired), Hymel Hunt (Storm) Best buy: Maurice Blair Biggest loss: Luke O'Dwyer
Training return: November 4
Gains: Sam Tomkins (Wigan), Jayson Bukuya (Sharks), Chad Townsend (Sharks)
Losses: Elijah Taylor (Panthers), Steve Rapira (Salford Red Devils), Russell Packer (Knights), Todd Lowrie (Brisbane) Best buy: Sam Tomkins Biggest loss: Todd Lowrie
Training return: MondayOriginally published as Pre-season guide to every NRL club
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text:
Tag "google news mobile"
Google News mobile website updated for Android smartphones
A new version of the Google News mobile website has arrived for Android and iOS devices. Rolling out over the next few days, the mobile experience gets a UI punch-up
Google News gets 'more natural and fluid' tablet experience
Tablet users who frequent Google News will soon find a new experience awaits them as Google has announced a new layout and features. Rolling out to U.S. readers over the
Google News Optimized for Android
Last week saw Google announcing that their mobile News site has been optimized for Android (and other WebKit-enabled browsers). This new version brings many of the same features found on


text:
Falling bokeh by EliseEnchantedWatch
©2011-2016 EliseEnchanted
a bit different from my usual work
I love the colours.
Wuoa .. simply .. *-*
Gorgeous, original color scheme
i sees u deleted the sand
Very nice color style !
Different is nice
Love the colors
Love the colors
Lovely shot, it's so creative
hm not sure what it's supposed to be (lol x;DD) but it looks cool! -gives cookie-
So cool looking and I really like the unusual combination of colors.
That's so cool!
cool! it's unusual and kind of mesmerizing...


text:
With 1.7 million freelancers, we'll match you with the perfect talent.
The client has made the following changes to the job.
Client prefers freelancers from:
You are still able to submit a proposal for this job.
The client prefers freelancers from
a different location.
I am a college student who performed a video interview for a news segment project. I do not want to re-shoot this interview for deadline purposes and it wasn't easy to get to this person in the first place, so I have no choice but seek some kind of post video editing in terms of color correction, obviously. I do not know what setting the camera was set to when this was recorded but it looked better through the viewfinder... I need this to look normal and possibly the audio set to television standard with BG noise reduction slightly.
Can your magic work for my project? the video can be viewed here:
[obscured] /JLwQOYg8Zqk
Please let me know its about 13 minutes of footage, asap.
Edward Washington
Sign in or Register to see more


text:
10 Comments
udin_grestz Artist from
sick idea, i got headache look it.+1 for you
nice work+1 check out my VZ design let me know what you think.
Awesome!! +1
hit mine =)
pinoy!! vote na u!! lol
nice +1
nice design!! cool +1 voted
TheWhiteRaven Human from
Im serious, If none of these humans votes for this, you and me are just gonna make 2. I would be proud to wear this.
mikesalesgarcia Artist from
thanks! i really appreciate it. =)
TheWhiteRaven Human from
I LOVE it.
honestly I don't care if this wins or not, I NEED THIS SHIRT!
RedRobotMonkey Artist from
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Shophouse The Social HostelSingapore, Singapore
Very poor. Impossible to sleep in the dorms as people turn the lights on and off and have loud conversations all through the night . There's a very annoying beeping that comes from their front door also which can be heard anywhere. All the doors are key codes but they don't tell you as everyone always props them open, so if you go to the toilet at night prepare to be locked out and sleep on the balcony! Good location though.
MEININGER Amsterdam City WestAmsterdam, Netherlands
No customer comment
Indraprastha Home StayUbud, Indonesia
Location was good and the room was nice and big but it's impossible to meet fellow travellers here as there is no common area. I'd stay again but not if I was travelling alone.
Tanaya Bed & BreakfastKuta, Indonesia
Stayed in tanaya for 6 nights, had a great stay. Staff were friendly, rooms were always cleaned very well, the whole place was very clean and maintained to a high standard. It's quiet at night to if you need to rest and close enough to kuta centre if you want to party. Breakfast was always great also, something different every morning. I would stay again : )


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Toy Industry Workers
According to the Toy Industry Association, sales of traditional toys totaled $22.09 billion in 2013, an increase of less than 1 percent from the previous year. Although there is always a demand for toys, this industry is definitely affected by downward trends in the economy. Employment outlooks, however, depend on factors such as the type of job done, the amount of automation introduced into the workplace, and the amount of production that is moved overseas.
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