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Although mitochondrial respiration is decreased in most cancer cells, the role of this decrease in carcinogenesis and cancer progression is still unclear. To better understand this phenomenon, instead of further inhibiting mitochondrial function, we induced mitochondrial biogenesis in transformed cells by activating the peroxisome proliferator‐activated receptors (PPARs)/peroxisome proliferator‐activated receptor gamma co‐activator 1α (PGC‐1α) pathways. This was achieved by treating the cells with bezafibrate, a PPARs panagonist that also enhances PGC‐1α expression. We confirmed that bezafibrate treatment led to increased mitochondrial proteins and enzyme functions. We found that cells with increased mitochondrial biogenesis had decreased growth rates in glucose‐containing medium. In addition, they became less invasive, which was directly linked to the reduced lactate levels. Surprisingly, even though bezafibrate‐treated cells had higher levels of mitochondrial markers, total respiration was not significantly altered. However, respiratory coupling, and ATP levels were. Our data show that by increasing the efficiency of the mitochondrial oxidative phosphorylation system, cancer progression is hampered by decreases in cell proliferation and invasiveness.
Several lines of evidence support the concept that cancer can be considered a metabolic disorder. In 1920s, Otto Warburg found that cancer cells down‐regulate their oxidative phosphorylation (OXPHOS) machinery, producing energy predominantly from glycolysis, followed by lactic acid accumulation in the cytosol, irrespective of oxygen concentration in the environment (Warburg et al., 1926). It is now widely accepted that OXPHOS is decreased in most cancer cells (Formentini et al., 2010). This bioenergetic signature has been used in early cancer diagnosis and developed as a marker for tumor progression (Cuezva et al., 2002). Concomitantly, cancer cells have an elevated glycolytic metabolism as their main approach to obtain ATP. Recently, Vender Heiden et al. showed that fast‐proliferating cells also employed an alternative glycolytic pathway to support the anabolic metabolism (Vander Heiden et al., 2010). Changes in the nuclear DNA are likely the underlying cause of the OXPHOS deficiency in many cancers (Selak et al., 2005; Zhou et al., 2003); however, the common decrease in OXPHOS function in cancer cells has been associated, in some cases, with mutations in the mitochondrial DNA (mtDNA) (Chatterjee et al., 2006; Park et al., 2009).
The dependence on glycolysis and inefficient OXPHOS function allows for the production of large amounts of metabolic intermediates that serve as precursors for the biosynthesis of the three major classes of macromolecules (nucleic acids, lipids, and proteins) in fast‐proliferating tumor cells (Deberardinis et al., 2008). Despite this large body of evidence, the role of decreased OXPHOS in cancer progression is not well‐defined. Wallace and colleagues had reported mtDNA mutations that inhibited OXPHOS increased ROS production and facilitated tumorigenesis in prostate cancer, which also suggested potentially similar etiology of other solid tumors (Petros et al., 2005). Lopez‐Rios et al. further dissected the inverse correlation between bioenergetic capacity of mitochondria and the aerobic glycolytic flux in carcinomas (Lopez‐Rios et al., 2007).
Metastasis is usually associated with poor prognosis and accounts for over 90% cancer‐related deaths (Mehlen and Puisieux, 2006). Lactate acidosis resulted from high glycolytic flow reduces extracellular pH, which induces angiogenesis and facilitates cancer cell invasion (Gatenby et al., 2006; Gatenby and Gillies, 2004). Avadhani and colleagues found that cells with mtDNA depletion had increased invasiveness, which was associated with a mitochondria‐to‐nucleus signal that upregulated the expression of cathepsin‐L (Biswas et al., 2005). Van Waveren et al. found that mtDNA depletion also promoted invasion by altering expression of members of the matrix metalloproteinases (MMPs) and tissue inhibitors of the MMP (TIMP) family, as well as other invasion related genes (van Waveren et al., 2006). However, most cancer cells do not have a depletion of mtDNA, even though OXPHOS function is markedly reduced.
Most experimental paradigms exploring the role of OXPHOS in cancer were achieved by reduction of OXPHOS function, either through genetic or pharmacological manipulations, followed by phenotypic analysis of cancer cells behavior. Although an effective approach, cancer cells are already impaired in OXPHOS function, and thereby potentially adapted to a more glycolytic status. Therefore, we decided to take the opposite approach, in which instead of inhibiting, we boosted OXPHOS function in cancer cells (143B, HeLa, and MDA‐MB‐231) and analyzed changes in their phenotypes. To do so, we took advantage of others and our recent experience with PPARs agonists that were able to increase OXPHOS components and function (Bonnefont et al., 2009, 2008, [Link]). We found that cells with increased mitochondrial biogenesis had decreased glycolytic growth. In addition, they became less invasive due to reduction in lactate production. Furthermore, even though bezafibrate‐treated cells had higher mitochondrial load, total respiration was not significantly affected, while respiratory coupling, mitochondrial membrane potential and hence ATP levels were increased. Our study provides independent support for the concept that robust OXPHOS inhibits cancer progression.
Three human cancer cell lines including HeLa (cervical carcinoma), 143B (osteosarcoma), and MDA‐MB‐231(breast cancer) were used in this study. Cells were grown in high glucose Dulbecco's modified Eagle's medium (DMEM, Gibco Cat.# 11965) supplemented with 1 mM pyruvate, 50 μg/ml uridine, 10% fetal bovine serum (FBS), and 0.2% gentamycin. Bezafibrate, dissolved in DMSO, was supplemented at a concentration of 400 μM. Controls were supplemented with the equal volume of DMSO (vehicle). Cells were grown for 3 days in the supplemented media.
Total protein was prepared from cultured cells and quantified using Bradford method. Equal amount of proteins were loaded either on a 10%, 12%, or 4%~20% gradient SDS‐PAGE gel. After electrophoresis, the proteins were transferred onto nitrocellulose membrane (BioRad) and blotted with antibodies against mitochondrial or nuclear proteins. The primary antibodies used were against Total OXPHOS Antibody Cocktail (MitoSciences Cat.# MS604), Tim23 (BD Biosciences Cat.# 611222), Human‐TFAM (Novus Biologicals Cat.# NB600‐1462), LC 3B (Cell Signaling Cat.# 2775), Tubulin (Sigma, Cat.# T‐9026).
Total DNA was extracted from cultured cells using Necleon™ BACC2 Genomic DNA Extraction Kit (GE Healthcare). Quantitative real‐time PCR experiments were performed in the presence of fluorescent dye (SYBR Green, Fermantas) with 7300 Real‐Time PCR System (Applied Biosystems). MtDNA copy numbers were normalized against genomic DNA level of β‐Actin. All results were obtained from 3 batches of cultured cells, and are expressed as means ± SEM. Primers used: mtDNA forward primer: 5′‐TCACCCTATTAACCACTCA, mtDNA reverse primer: 5′‐AGACAGATACTGCGACATA, gDNA forward primer for β‐Actin: 5′‐TCACCCACACTGTGCCCATCTACGA, gDNA reverse primer for β‐Actin: 5′‐CAGCGGAACCGCTCATTGCCAATGG. Human‐PPARGC1A: (Qiagen, #QT00095578). cDNA forward primer β‐Actin: 5′‐TGACAGGATGCAGAAGGAGAT, cDNA reverse primer β‐Actin: 5′‐GCGCTCAGGAGGAGCAAT.
Cells were counted and re‐plated in 24‐well plates at 5×10^3~10^4 cells/well. For growth curve in galactose medium, cells were plated in regular glucose medium and changed to galactose medium (No glucose DMEM medium (Gibco Cat.# 11966) supplemented with 25 mM l‐galactose, 1 mM pyruvate, 50 μg/ml uridine, 10% dialyzed FBS, and 0.2% gentamycin.). Cells were counted in triplicate using a Beckman Coulter Z1 Dual Cell and Particle Counter (Beckman Coulter, Inc., Brea, CA) and medium containing DMSO or bezafibrate were changed every day for up to 7 days.
Controls and cells treated with bezafibrate were plated in 1 ml low glucose medium in 24‐well plates at 105 cells/well. The concentrations of glucose and lactate in the medium were measured after 24 h with an YSI 2300 TSAT Plus Glucose & Lactate Analyzer (YSI Life Sciences, Yellow Springs, OH). Cells were counted and both glucose consumption and lactic acid production were normalized according to the cell number in each well.
Cell invasion assay was performed using a QCM ECMatrix Cell Invasion kit (Millipore, Cat.# ECM555). Serum‐free medium in the lower chamber was used as negative controls. In an additional set of wells, 25 mM HEPES was supplemented in the medium to stabilize pH. Invaded cells were quantified according to the manufacturer's instructions in quadruplicate.
Cells treated with bezafibrate or DMSO for 3 days were grown to confluence then washed thoroughly and switched to serum‐free medium that just covered the flask. After 24 h, the conditioned medium was collected. Equal volume was mixed with 2× sample buffer (125 mM Tris HCl, 20% Glycerol, 4% SDS, 0.005% Bromophenol Blue, pH 6.8) and loaded onto Novex 10% Zymogram (Gelatin) Gel (Invitrogen, Cat.# EC61755BOX). Run the gel in 4 °C at 125 V for 90 min, develop and stain the gel according to manufacturer's instructions.
Mitochondrial enzyme complex activities were measured spectrophotometrically in cell homogenates using a DU‐640 spectrophotometer (Beckman Instruments Inc., Fullerton, CA) as described elsewhere (Barrientos et al., 1998). The activity of citrate synthase was determined by following the formation of DTNB‐CoA, which is coupled with citrate formation catalyzed by citrated synthase (CS), at 412 nm. The activity of Complex IV (COX) was determined by following cytochrome c oxidation at 550 nm (Barrientos et al., 1998). Assays were performed at 30 °C for CS and at 37 °C for COX.
Total CPT activity was measured using Carnitine hydrochloride, l‐[N‐Methyl‐14C] as substrate. Briefly, 50 μl cell homogenate was mixed with 200 μl reaction mixture (75 mM Tris, 1.5 mM CoA, 0.625 mM DTT, 0.25 mM Palmityl‐carnitine, and 3.2 mM LCarnitine) and incubated at 37 °C. The reaction was stopped by adding 1 ml 1 M HCl and 1 ml 1‐Butanol to the mixture, at 0 min, 5 min, and 10 min. The radioactivity was measured in 250 μl of the organic phase using a scintillation counter and used to calculate the rate of LCarnitine incorporation into Palmityl‐Lcarnitine, which was normalized against protein concentration and corresponded to the total CPT activity of the sample.
Intracellular ATP levels were measured with the CellTiter‐Glo Luminescent Cell Viability Assay kit (Promega, Cat.#G7571) according to manufacturer's instructions. Briefly, cells were plated in 96‐well plate in sextuple and cultured for 24 h to reach 80%~90% confluence. Cells were lysed in the same plate with the reagent included in the assay kit for 15 min at room temperature with gentle agitation. The mixture was transferred to an opaque‐walled 96‐well plate, and luminescence produced from ATP‐mediated chemical reaction was recorded by the luminescence module of the Wallac Victor2 1420 multilabel counter (PerkinElmer Life Sciences). Readouts were normalized to total protein in each well. The result showed was the average of sextuple samples ± SD from one representative experiment out of at least three independent analyses.
For flow analyses 105 cells were aliquoted and washed once with modified Ringer's buffer (127 mM NaCl, 5.5 mM KCl, 2 mM MgSO4, 2 mM CaCl2, 0.5 mM KH2PO4, 20 mM HEPES, 10 mM Glucose, 1% FBS, pH 7.4). The cell pellet was resuspended in 1 ml of 75 nM TMRE dye diluted in modified Ringer's buffer and incubated for 20 min at 37 °C in the dark. The staining medium was aspirated after a 5 min centrifugation at 600 g and the pellet was resuspended in 0.5 ml of 7.5 nM TMRE dye diluted in modified Ringer's buffer for equilibration. In a duplicate group, 2 μM of CCCP was also added to the final reaction. Samples were immediately analyzed at Absorbance/Emmisions = 549/573 nm on LSR Fortessa (BD Biosciences). The result showed was the relative CCCP‐sensitive (endogenous minus CCCP‐resistant) TMRE fluorescence.
Celluar hydrogen peroxide concentration was measured using Amplex® Red Hydrogen Peroxide/Peroxidase Assay Kit from Invitrogen (Cat.# A22188). Briefly, in a 96‐well plate, 20 μl of ~1.5 × 104 control or bezafibrate‐treated cells were added to 100 μl of Krebs–Ringer phosphate buffer (145 mM NaCl, 5.7 mM sodium phosphate, 4.86 mM KCl, 0.54 mM CaCl2, 1.22 mM MgSO4, 5.5 mM glucose, pH 7.35) containing 50 μM Amplex® Red reagent and 0.1 U/mL HRP. The fluorescence was followed at Absorbance/Emissions = 535/590 nm for 1 h on BioTek Synergy H1 Hybrid Reader.
Cells in exponential growing phase were plated in 96‐well cell culture plate supplied in XF96 FluxPaks (Seahorse Bioscience Inc.) and cultured overnight to reach ~90% confluence. Oxygen consumption rate (OCR) was measured with a Seahorse XF96 analyzer according to manufacturer's instructions. After the measurement, cell numbers in each well of the culture plate were quantified using the Sulforhodamine B method described elsewhere (Vichai and Kirtikara, 2006). OCR was then normalized against cell number in each well. Result showed was one representative from at least three independent experiments.
Cells in exponential growing phase were collected and respiration rate of intact cells was measured at 37 °C with Oroboros high resolution respirometer Oxygraph‐2k (Oroboros Instruments GmbH, Austria). Besides the endogenous respiration, oligomycin‐resistent respiration in the presence of 15 nM oligomycin and uncoupled respiration with 1 μM CCCP were also recorded. Data was analyzed with DatLab 4 software (Oroboros Instruments, Austria).
Data were analyzed using a two‐tailed, unpaired Student t test. Differences were considered significant when p < 0.05 (), 0.001 < p < 0.01 (), p < 0.001().
Mitochondrial proliferation and thus an increase in oxidative phosphorylation (OXPHOS) components has been induced via administration of bezafibrate, a PPAR panagonist that also stimulates PGC‐1α expression, both in vitro and in vivo (Bastin et al., 2008, 2008, [Link]). It was reported that for fibroblasts, 400 μM bezafibrate promoted the highest increase in OXPHOS enzyme activities in 72 h without being toxic to cells (Bastin et al., 2008). Therefore, we used a standard 400 μM bezafibrate dose in the experiments described below. Control cells were treated with the same volume of the vehicle (DMSO) only. We confirmed the increased expression of PGC‐1α upon bezafibrate treatment (Figure 1A) as well as an increase in OXPHOS markers (Figure 1B). Treatment with bezafibrate did not have a noticeable effect on the morphology or the distribution of mitochondria in the cell (Figure 1C and data not shown). In addition to OXPHOS components, the levels of Tim23 and TFAM, two mitochondrial markers of inner membrane and matrix respectively, were increased in all the cell lines (Figure 1D). Accordingly, the levels of mtDNA, measured as ratios to the nuclear DNA, were also increased in the cancer cell lines (Figure 1E).
Bezafibrate induces PGC‐1α and OXPHOS components in cultured cells. A, Real‐time PCR determination of PGC‐1α transcript levels from cDNAs from 143B and HeLa cells. B, Western blot showing the steady‐state ...
The activities of mitochondrial enzymes were also increased after bezafibrate treatment. We measured the activities of a Krebs cycle enzyme (citrate synthase, CS), fat acid catabolism (carnitine palmitoyl transferases, CPT‐I and CPT‐II) and oxidative phosphorylation (cytochrome oxidase, COX), all of which were significantly increased in bezafibrate‐treated cells (Figure 2A–C).
Bezafibrate improves oxidative phosphorylation in cultured cells. A and B, Citrate synthase (CS) and Cytochrome c oxidase (COX) activity in bezafibrate‐ and DSMO‐treated cells (n = 3 and bars represent SD). C, carnitine ...
Based on the above evidence showing that bezafibrate upregulated OXPHOS components in cancer cells, we then investigated the energy status of the cells. We found that bezafibrate‐treated cells had higher ATP levels (Figure 3A). However, despite the increase in mitochondrial components and ATP levels we found that bezafibrate treatment did not affect total cell respiration, measured as oxygen consumption in a Seahorse XF96 analyzer and an Oroboros O‐2k high resolution respirometer (Figure 3B and data not shown). This apparent discrepancy was clarified by measuring CCCP‐uncoupled respiration in Oroboros O‐2k, which showed that mitochondria from bezafibrate‐treated cells were better coupled than in control cells (Figure 3C). In other words, even with the same level of electron transport and oxygen consumption, a stronger proton electrochemical gradient could be generated, more efficiently driving ATP synthesis through complex V. To confirm a critical prediction of this hypothesis we also measured the mitochondrial membrane potential (ΔΨm) in these cells by the uptake and retention of TMRE using FACS analysis. In agreement with the tighter coupling hypothesis, bezafibrate‐treated HeLa cells showed a significant increase in CCCP‐sensitive ΔΨm, while there was also a trend for increases in 143B and MDA‐MB‐231 cells (Figure 3D). Although the relationship between ΔΨm and levels of ROS is controversial (MacLellan et al., 2005), we found a decrease in the rate of H2O2 in bezafibrate‐treated cells, as determined by Amplex Red (Figure 3E).
Bezafibrate treatment increases cellular ATP levels by enhancing respiration coupling. A, Cellular ATP levels of bezafibrate‐ and DMSO‐treated cells (n = 6 and bars represent SD). B, Endogenous respiration in different ...
We next investigated how this shift toward oxidative metabolism influenced cell growth. Cells were grown in either glucose medium or in galactose medium. Galactose is metabolized very slowly through glycolysis and generates much less ATP compared to glucose, thus requiring a more robust OXPHOS and in general does not support pure glycolytic growth (Marroquin et al., 2007; Robinson et al., 1992). In our hands, 143B and HeLa cells did not survive for a long period of time in galactose medium most likely because they primarily rely on glycolysis. However, cells with increased mitochondrial metabolism were able to survive longer in medium containing galactose as the carbon source (Figure 4A,C). MDA‐MB‐231 cells were able to grow very slowly in galactose medium, and still, bezafibrate‐treated cells tended to grow better than control cells over time (Figure 4E). On the other hand, all bezafibrate‐treated cells grew significantly slower in rich glucose medium (Figure 4B, D, F). These experiments were repeated in high and low glucose media and consistently, bezafibrate‐treated cells had reduced growth rates when compared to control‐treated cells (not shown). These results further confirm that bezafibrate treatment has induced transitions in cancer cells' metabolic patterns and demonstrate that this metabolic change influences the cell growth phenotype.
Ratios of cell growth in high glucose medium and galactose medium. Growth of A, 143B, B, HeLa, and C, MDA‐MB‐231 cells in high glucose and galactose medium. Data is expressed as the ratio of the number of bezafibrate‐treated cells ...
The reduction in glycolytic growth indicated a shift in the metabolic status of cells treated with bezafibrate. The increased glucose utilization, a feature of cancer cells metabolism and the basis of the Warburg effect (Warburg et al., 1927), was reduced in bezafibrate‐treated cells (Figure 5A). Accordingly, these cells also showed a reduction in lactate secretion (the end product of glycolysis) (Figure 5B). When cells were analyzed for their invasive phenotype in an extracellular matrix (ECM) assay we observed a significant decrease in invasiveness in the bezafibrate‐treated cells (Figure 5C). However, this decrease in the invasion phenotype was not associated with decreased levels of active MMP‐2 or MMP‐9 (Figure 5D). To investigate the role of pH in the invasion phenotype, we supplemented the assay medium with 25 mM HEPES at pH 7.4 to stabilize the pH during the assay. HEPES buffered the medium, which led to a marked decreased invasion of cells through the ECM. This effect of the neutral pH was blunted in bezafibrate‐treated cells, which produced less lactate (Figure 5C).
Bezafibrate treatment decreases glycolytic flux and cell invasion. A, Glucose consumption of bezafibrate‐ and DMSO‐treated cells in 24 h (n = 6 and bars represent SD). B, Lactate concentration in medium of bezafibrate‐ ...
We also investigated the effect of a metabolic shift in apoptosis induced by either staurosporin or TNFα in HeLa, 143B and MDA‐MB‐231 cells. We did not find a significant difference between treated and control cells, although there was a trend for the bezafibrate‐treated cells to be more sensitive to stimuli inducing apoptosis (Supplementary Figure S1 and data not shown).
As resistance to apoptosis is important for transformed cells to survive nutrient and oxygen depletion at early stages of tumorigenesis, enhanced autophagy is also essential to maintain cell self‐turnover, restrict necrosis and inflammation. Therefore, we analyzed the influence of increased OXPHOS on autophagy. For glucose‐starvation‐induced autophagy, we observed lower levels of the macroautophagy marker LC3B‐II in bezafibrate‐treated cells (Supplementary Figure S2). This is probably because these cells consume glucose slower than control cells, and thus sense less stress due to glucose deprivation. However, we were not able to find a consistent change of LC3B‐II levels in treated cells when they underwent serum‐starvation‐induced autophagy (Supplementary Figure S2). In summary, we did not find major effects of bezafibrate on apoptosis or autophagy.
The metabolic shift in cancer cells has received much attention in the last decade. Extensive investigations have tried to tether genomic changes to metabolic phenotypes as well as target metabolism for cancer therapy. We reported here that activation of oxidative phosphorylation function in cancer cells impair carcinogenesis at multiple levels. With increased mitochondrial load, we found decreases in glycolytic flux and reduced growth of cancer cells. We also found decreased invasion which was directly associated with a reduction in extracellular acidosis (Figure 6). Bezafibrate treatment did increase cellular ATP levels, as well as respiratory coupling and CCCP‐sensitive mitochondrial membrane potential (ΔΨm), but it is not clear how or if these changes contribute to tumorigenesis and cancer progression (Figure 6). Increased ΔΨm has been associated with increased ROS production (Samudio et al., 2009). However, we found that the rate of H2O2 production was actually reduced in bezafibrate‐treated cells. We do not know the reason for this decrease, but PGC‐1α is also known to increase antioxidant defenses (St‐Pierre et al., 2006). It is difficult to predict whether this decrease would have a negative role in tumorigenesis, but ROS has been described as a signaling molecule promoting growth (Rigoulet et al., 2011). D'Errico and colleagues reported that overexpression of PGC‐1α in intestinal cells was associated with decreased tumorigenesis (D'Errico et al., 2011), which is in agreement with our findings. However, they found an increase in ROS, which contrasts with our and other models (St‐Pierre et al., 2006). Therefore, it is possible that increased mitochondrial biogenesis may have model/cell‐specific effects on ROS production.
Model describing the effect of bezafibrate treatment on carcinogenesis. This model summarizes our data, showing how PPARs agonists act through the PPARs/PGC‐1α pathway to impair carcinogenesis.
Our lab has previously showed that low mitochondrial membrane potential (ΔΨm) and lack of OXPHOS decreased the susceptibility of osteosarcoma cells to apoptosis triggered by certain inducers (e.g. staurosporin) (Dey and Moraes, 2000). Other work also suggested a close and direct relationship between decrease in ΔΨm and induction of autophagy (Li et al., 2007; Paglin et al., 2005; Zhang et al., 2009). Surprisingly, the increased ΔΨm resulting from bezafibrate treatment did not show major changes in caspase‐dependent cancer cell death induced by staurosporin or TNFα or autophagy triggered by serum starvation. It is still possible that apoptosis induced in vivo could be potentiated by increased mitochondrial biogenesis, as described (D'Errico et al., 2011).
PPAR is a small nuclear receptor family which has three members: PPARα, PPARβ/δ, and PPARγ. Fibrates are PPAR ligands, and bezafibrate is a pan‐PPARs agonist that has been administered in patients to treat hyperlipidemia with a good safety profile for over 30 years. Tenenbaum et al. showed its effect in reducing the incidence of myocardial infarction (MI) in patients with metabolic syndrome (Tenenbaum et al., 2005). Many other clinical studies have also revealed beneficial effects of bezafibrate on glucose and insulin metabolism (Jonkers et al., 2002; Kim et al., 2003). In our hands, bezafibrate dramatically boosted fatty acid beta‐oxidation. Bezafibrate also increased the activities of OXPHOS complexes in cells with related enzyme defects and activated the PPAR/PGC‐1α pathway (Bastin et al., 2008, 2009, 2008, [Link]). Our data showed that an increase in mitochondrial biogenesis was not accompanied by a stoichiometric increase of all mitochondrial components. That may not be surprising as the effect of PPARs and PGC‐1α/β on promoters of genes coding for mitochondrial proteins is unlikely to be identical. This may also explain why respiration was not increased, as one or more limiting factors could restrict the flow of electrons.
It is becoming clear that the understanding the bioenergetics of cancer cells is important to unravel tumors behavior and to develop new targets for therapy (Ferreira, 2010). Schulz and colleagues have found that overexpression of frataxin induces mitochondria biogenesis and inhibits cell growth, supporting our findings (Schulz et al., 2006). PPAR/PGC‐1 is an emerging pathway associated with tumorigenesis. Ban et al. found that PPAR gamma agonist troglitazone inhibited colon cancer cell growth via inactivation of NF‐κB by suppressing GSK‐3β activity (Ban et al., 2010). Recently, Giguere and colleagues reported that miR‐378 mediated metabolic shift in breast cancer cells by inhibiting the PGC‐1β/ERRγ transcriptional pathway (Eichner et al., 2010). MiR‐378/378 were implied in adipocyte gene expression and lipogenesis (Gerin et al., 2010), while mi‐R378 was reported to also promote tumor progression and angiogenesis both in vitro and in vivo (Lee et al., 2007). Activation of PPARγ has been identified as an approach for inducing differentiation and inhibiting proliferation in a variety of cancers. Moreover, activation of PPARγ by specific ligands was shown to induce apoptosis and potentiate current anti‐tumor treatment (Lee et al., 2006).
Diverse metabolic pathways have been implicated in tumorigenesis. New evidence suggests that classical oncogenic pathways such as the PI3‐kinase/mTOR, the p53 and the myc pathways are centrally involved in the reprogramming of glucose and glutamine metabolism to fuel cancer cell growth (Amornphimoltham et al., 2008; Okuyama et al., 2010). PPARs represent a group of transcription factors that are central to control of metabolism in a wide variety of tissues. The new advances in the understanding of tumor metabolism have provided clues for several novel targets for anti‐tumor treatment. Xu et al. reported that inhibition of glycolysis was a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance (Xu et al., 2005). One of the best‐known hexokinase inhibitors, 2‐deoxyglucose (2‐DG), has entered phase I/II clinical trial for the treatment of advanced prostate cancer (Clinical trial: NCT00633087).
In summary, our work showed that increased OXPHOS in cancer cell impairs tumorigenic phenotypes including cell growth, cell invasion and survival. This study supports the concept that decreased mitochondrial metabolism contributes to tumorigenesis and cancer progression.
The following are the Supplementary data related to this article:
Supplementary data
Supplementary data
We thank Dr. Brian Kim and Dr. Douglas Crawford (University of Miami) for assistance with cell respiration measurements, and the Flow Cytometry Core Facility at the UM Sylvester Comprehensive Cancer Center for assistance with membrane potential determinations. We thank Actavis Pharmaceuticals for the generous gift of bezafibrate. This work was supported by NIH grants CA085700, AG036871 and EY010804. It was also supported by the James & Esther King Biomedical Research Program.
Supplementary data associated with this article can be found in the online version, at doi:10.1016/j.molonc.2011.07.008.
Wang Xiao and Moraes Carlos T., (2011), Increases in mitochondrial biogenesis impair carcinogenesis at multiple levels, Molecular Oncology, 5, doi: 10.1016/j.molonc.2011.07.008.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Rental Bonds
When you rent a place to live, you will usually be asked to pay a rental bond.
In Queensland, this bond money is held by the Residential Tenancies Authority (RTA) until you move out.
The rules about the payment and refund of your rental bond are set out in the Residential Tenancies and Rooming Accommodation Act 2008.
When you move out if you do not leave the premises clean, are behind in the rent, or have damaged the premises, your lessor or provider may be entitled to claim money from the bond.
Information supplied courtesy of the Tenants Union of Queensland Inc
Further information and advice for Queensland tenants can be sourced from www.tenantsqld.org.au

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Tuscaloosa County Board of Elections 2501 7th Street Tuscaloosa AL 35401 13.3 miles from Elrod 205-464-8415
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A board of elections is a government body tasked with overseeing elections at the local, county, state and federal levels. However, they're usually organized at the county level. They may also be responsible for school board elections. A board of elections works closely with the local board of registrars or county registrar of voters. These organizations work to ensure that elections are orderly and voting results are accurate.
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text: In Sonobe, a tiny town 50 minutes from Kyoto by train. Staying with Fiona and Pia in their little (though large by Japanese standards) comfy apartment, worrying that I could crash through a wall at any moment – classic gaijin smash. Being blown away by the richly coloured autumn foliage, and again when we awoke one day to a blanket of white covering the town. I'm so pleased I had this place as a base to explore Kyoto and other cities from, and with such super hospitality. Thanks, friends!


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Inner Glass Seal, Right; 87-95 Jeep Wrangler YJ
This replacement inner glass seal from Omix-ADA fits the right full steel door on 87-95 Jeep Wrangler (YJ).
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A church where Love is preached and taught according to the Holy Scriptures and manifested in the lives of all the disciples by offering support, fellowship, friendship and the Love of Christ to those around us.
Jr and his wife Diann we married on July 4, 1969. Shortly after they were wed Jr was called to preach. He was appointed as a pastor in 1974. Jr has pastored at 9 different Methosdist churches in his career. He came to OBC in June 1994 as a part-time local pastor. In September 2007, the congregation voted for him to become a full-time local pastor. The Plunkets have 3 children and 6 grandchildren.
Old Brashiers Chapel United Methodist Church
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Allied Telesis AT GS900/8-Switch-unmanaged-8 x 10/100/1000-desktop-AT-GS900/8-50Item#: 612429 | Model#: AT-GS900/8-50
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Allied Telesis AT GS900/8 - switch - 8 ports Product Details
The AT-GS900 Series switches require minimal configuration and can be installed in minutes for use in network racks or on desktops. The 10/100/1000TX copper ports on the AT-GS900 Series are fully auto-negotiating, allowing the switches to connect to all other 10Mbps Ethernet, 100Mbps Fast Ethernet, or 1000Mbps Gigabit Ethernet devices. Equipped with MDI/MDIX ports for easy connection to other hubs and switches, the ATGS900 Series offers a natural migration path from legacy networks and a cost-effective introduction to Gigabit Ethernet. Finally, easy to read front panel LEDs show ongoing switch status and simplify troubleshooting.
The AT-GS900/8 8 port 10/100/1000T Unmanaged Switch is ideal for bandwidth-demanding desktop and small workgroup applications where local device management is not required. It is simple to install with no configuration necessary.
Device Type: Switch - 8 ports - unmanaged
Enclosure Type: Desktop
Interfaces: Gigabit Ethernet
Ports: 8 x 10/100/1000
MAC Address Table Size: 4K entries
Features: Flow control, auto-negotiation, VLAN support, auto-uplink (auto MDI/MDI-X), half duplex mode, full duplex mode
Compliant Standards: IEEE 802.3, IEEE 802.3u, IEEE 802.3z, IEEE 802.3ab, IEEE 802.3x
Built-in Devices: LED panel
Expansion / Connectivity
Interfaces: 8 x 1000Base-T - RJ-45
Power Device: Internal power supply
Voltage Required: AC 120/230 V ( 50/60 Hz )
Power Consumption Operational: 15 Watt
Rack Mounting Kit: Included
Compliant Standards: FCC Class A certified, TUV, C-Tick, EN 60950, UL 1950, VCCI Class A ITE, EN55024, EN55022 Class A
Localization: Europe
Dimensions & Weight
Width: 9.8 in
Depth: 4.5 in
Height: 1.5 in
Weight: 2 lbs
Manufacturer Warranty
Service & Support: Limited lifetime warranty
Service & Support Details: Limited warranty - lifetime
Environmental Parameters
Min Operating Temperature: 32 °F
Max Operating Temperature: 104 °F
Humidity Range Operating: 5 - 90%
Additional Resources: Product Manuals
Recommended Items
Related ItemsPrevious
Manufactured by: Allied Telesyn
Warranty provided by: Allied Telesyn
UPC No: 767035177991
Mfg Part No: AT-GS900/8-50
Box Size:
( Length:13, Width:8, Depth:3)
Shipping Weight: 3.5000 pound(s)
Click here for full warranty and support information
- Allied Telesyn logos are registered trademarks of Allied Telesyn. All others trademarks and copyrights mentioned herein are the property of their respective owners.


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The Partners
Coventry Cathedral
During the night of 14th November 1940, Coventry's Cathedral was destroyed and hundreds of civilians killed during hours of aerial bombardment by the Luftwaffe. Next morning across the nation, many voices were calling in their grief and anger for revenge. The Provost of Coventry Cathedral, Dick Howard, responded differently, and in a Christmas broadcast called instead for reconciliation: He said "When all this is over we must reach out to our enemies and together build a kinder more Christ-Child-like world." Provost Howard's response sowed the seeds for the Cathedral's ministry of peace and reconciliation, which continues to this day through The Cross of Nails, our network of over 170 partners around the world working to reconcile communities.
Coventry City Council
Coventry City Council delivers hundreds of services to the city's residents, from education and roads to licensing and parks. The lively, multicultural city lies at the heart of the UK, within an hour of London and with easy transport links to the whole of the UK. It is rich in culture and diversity – combining world famous history with technology and innovation.
The city has a population of almost 320,000 and two leading universities that bring a vibrant student life. It was recently named as one of the top 10 cities in the country for jobs growth, patents granted and business growth over the past decade and one of only four cities outside the south east where people earn above the national average wage. The future is looking bright for Coventry and its residents – and the Council is proud to be at the heart of it all.
Coventry University
Coventry University is currently the highest placed modern university in both the Guardian and Times and Sunday Times league tables, ranking 15th and 42nd respectively – the highest ever rankings for a post-1992 institution.
Coventry University is a proud partner in Coventry's legacy as a City of Peace and Reconciliation. Working together with local government, faith and community partners to promote and continue the city's work as a voice for peace in the modern world. The Centre for Trust, Peace and Social Relations conducts research that has a real impact on improving the lives of ordinary people living in difficult circumstances. Working locally, nationally and internationally helps create safe, secure and connected communities, inspired by the city's past and invested in its future.
Coventry and Warwickshire Champions
Coventry and Warwickshire Champions unite businesses, organisations and individuals across the area in a powerful network to help develop and promote Coventry and Warwickshire and raise its profile. Champions are proactive advocates for the area who want to help influence how the area is perceived and portrayed, and make sure the area is talked about in the right places and by the right people.
Coventry and Warwickshire Champions are proud, positive and passionate about their place. They recognise the difference they can make by championing the place professionally, publicly and with pride.


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June 8, 2010
4:20 PM Eastern
Read NetRightDaily.com.
Good Tuesday Afternoon -
3 GOP Senators are on the fence over EPA regulations. The big vote is on Thursday. The GOP votes to watch are Scott Brown and the two usual suspects, Susan Collins and Olympia Snow. Get the story.
The EPA's reckless endangerment. Form ALG President Bill Wilson, "The EPA's alarmist decision greatly understates the impact of restricting and reducing carbon emissions — which means limiting energy use — on global population sustainability and economic growth. The American people (and everyone else) depend upon petroleum, gasoline, diesel, coal, and natural gas to do just about everything, including getting to work, delivering goods and services, heating their homes in the summer and cooling them in the winter, and providing hot water."
Cartoon of the day, "So sorry, Mr. Gore".
VIDEO: Oil on Obama's hands. After 45 days, the Obama administration announces it will contain the BP oil spill. Is this administration willfully negligent, or woefully incompetent?
ObamaCare nails its first "villain". "Nancy Pelosi called insurance companies "villains" last year, and in that sense, ObamaCare scores its first success today. The Virginia firm nHealth announced that it will close its doors by the end of the year, thanks to the costs associated with insuring people under the mandates imposed by Congress."
CREW asks HHS IG to inspect panel's conflict of interest.
ObamaCare Watch: The more we learn, the worse it gets. "This week, we learned that the Obama administration is orchestrating a $125 million propaganda campaign to sell the recently enacted health-care law to the public. That effort will be funded by labor unions and other groups from the Democratic political orbit. It comes on top of the misleading government mailer sent to the nation's seniors, at the expense of taxpayers, touting the supposed benefits of ObamaCare for the elderly. On Tuesday, the president himself will join the fray again to make the sales pitch, this time promoting the colossal waste of taxpayer money associated with $250 per senior bribes to be issued this summer and fall."
Thomas Sowell: Random thoughts on the passing scene. "We have now reached the truly dangerous point where we cannot even be warned about the lethal, fanatical, and suicidal hatred of our Islamic extremist enemies in our midst, because to do so here would be politically incorrect – and in some European countries, would be a violation of laws against inciting hostility to groups."


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Northern Region
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Straight from the CTO, Jeff Sacks delivers today's insight on tomorrow's technology services in the CTO's Corner. Select one of the tabs above to select an episode, watch, and enjoy.
Jeffrey D. Sacks, Chief Technology Officer, has over 25 years of experience leading technology services for federal clients. He has a wide array of experiences in strategic planning, business development, and project delivery.


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mimi9899 replied to Chi Le's topic in k-dramas & movies
mimi9899 changed their profile photo
mimi9899 replied to Chi Le's topic in k-dramas & moviesI dont like the way Sorim behaves like this. This is the way she puts angry at HG because of lying her or for what? I like this drama from the begining but i really dont like a girl like this. DISAPPOINTED
mimi9899 replied to Chi Le's topic in k-dramas & moviesMonday, pls come faster More bts pics: http://naver.me/FDZ0fcno Today Hyunwoo IG was updated with this picture, his fans suppose that he probably gave us a hint about next kiss scene in TLAHL. But there are total 6 new photos updated till now so i dont know he uploaded them by himself or his IG got hacking. I wish we could have another kiss like this :))
mimi9899 replied to Chi Le's topic in k-dramas & moviesCollection of songs Sorim sang in drama Video [fanmade] HG x SR moments (Cr to the owner)
mimi9899 replied to Chi Le's topic in k-dramas & moviesI also really like Hyunwoo and HG as well. About 2 bassists, i think its a little unreal since CP is really famous and has a busy schedule, they even doesnt have enough time to practice sometimes. Meanwhile, HG now will be CP and Mush&Co producer, do you think he could produce well after being tired with CP busy activities? And im not sure now he wants to do this or not. I really hope CY would change his point of view to know about how important he is in CP and in company, how much other members and HG care about him, hope he would understand why HG wanted him to replace HG. I know HG bass ability is suitable with other CP members' ability now and they like him being in their group but thats not enough for them to be famous and can stay long in this industry. They also need good songs and a well producing. So lets CP members the chance to keep up (or almost at least) with CY, lets them accept each other and be in good term of relationship and lets them can play live. HG, i hope he will be producer for CP and M&Co. CEO Yoo said before when she knew HG likes SR that Love can make the better music #Saranghae Saranghae Hangyeol hangyeol gyeol... Omg thank god. Preview ep 13 http://tv.naver.com/v/1638567 There is an article said: CP's dirty substance - acting band (GG translates ). Maybe the truth about CP is shown up :((
mimi9899 replied to Chi Le's topic in k-dramas & moviesOmggggg how i hate seeing HG, SR always have to feel guilty to CY. Love HG's choices from the begining until now. The choice not become a fake bassist, the choice become a producer to prevent Choi from kicking his friends out, the choice write a song for Yuna to prevent Choi from kicking Sorim, and now, his choice is reveal himself for saving Crude Play performance. He wants to replace CY in the show today? No. he is pushed. He will replace CY position from now on? Im sure he will not. He just saves today's performance only. Im wondering CY has no choice in every his problems? Other people told him what to do, he accepted it then blames them. Others dont like him, he blames them. Others do better than him, he is envious Choi told him before that Mush&Co need another song to put their fame up but he objected. So Im wondering again, has he ever been thinking for Mush&co?
mimi9899 replied to Chi Le's topic in k-dramas & moviesOmg i like this thought Feel so excited now. (I like the way HG looks at Sorim... so so in love. He looks at other girl but why does my heart get flustered?? =))) )
mimi9899 replied to Chi Le's topic in k-dramas & moviesost part 7. I really like it bonus
mimi9899 replied to Chi Le's topic in k-dramas & moviesLike many of you, i also like HG father a lot. I love hearing their conversation :)) And what about this? HG new song? PD maybe gives us a hint, but who will sing? Sorim? In this ep, i like HG attitude the most. He trusts what SR says. He told her what she would have to hear from others no matter who she is. He confidently asked CY not to interfere in their relationship... About CY, What is this? Ya Mush&Co is a band. But that band is not a THING that you can own. They are 3 people. If he thinks thats his band then he should impove his music production, support them, sometime should even listen to other people for the good sake of that band... but all he does is being envious with HG ("why does it have to be HG?" ...) and only caring about his personal feeling for Sorim... I agree with what mr Choi says in preview ep 12. He should be back his original place. Yup, some scenes i feel so chessy as well in this ep. I think there are some small problems in editing or direction. - Why does CY need to touch SR hand so long? - When HG got into the room in hopital, 1: SR should hug him right away then cried. Or 2: HG should hug her at first. Awh PD lets them look distanced and awkward in many seconds Anyway, look forward to the new ost this afternoon and ep 12 tonight
mimi9899 replied to Chi Le's topic in k-dramas & moviesI just watch raw but in the preview part for ep12 is Hong Seoyoung singing. That is her song released today. They released 2 her songs today. One is "starry night" (ost 6) and another is the song she practiced (i dont remember which ep) and couldnt catch high note then Ceo played piano for her. It sounds really gud.
mimi9899 replied to Chi Le's topic in k-dramas & moviesEp11 <3
mimi9899 replied to Chi Le's topic in k-dramas & moviesIn this case, i think ceo and CY will talk about another thing, like "you wanna make Crude Play Ver2...?" But CEO tells CY go back to his original place. That means his current place is not suitable for him. So i think they will change the song like some of you here guessed
mimi9899 replied to Chi Le's topic in k-dramas & moviesNaver link is the TLAHL official channel on naver. But they limit region. Not every country can watch. tvN youtube channel hasnt updated yet. Thats why someone downloaded it from official naver channel and uploaded it on youtube for whom cant watch it on naver. Still photos. See more in this link: http://m.post.naver.com/viewer/postView.nhn?volumeNo=7306792&memberNo=3669297
mimi9899 replied to Chi Le's topic in k-dramas & movieshttp://m.tv.naver.com/v/1625091/list/124592 Kiss scene making. Hearing CY said they popo. So it could be written in the script that its just a popo. Well im ok with it. Just look forward some more deeper as their relationship is longer and stronger
mimi9899 replied to Chi Le's topic in k-dramas & moviesYa so beautiful. You make me remember this moment, Sorim looked so beautiful and HG couldnt say anything :)) (I wanna upload many Sorim gifs but dont know why i cant see anything after uploading them on here )


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The sports and physical activities team, in partnership with Tower Hamlets BMX Club, is running cycling sessions in Mile End Park where young people aged 5-16 can learn how to do basic BMX tricks.
Sessions will take place on Tuesday, May 26, to Friday, May 29 at the BMX Track in Mile End Park, Burdett Road at:
- 12.45pm for 11- to 16-year-olds
- 2.15pm girls' only session for 11-year-olds and over
Spaces are limited and places must be booked in advance.
To book a place email@example.com or call 020 7364 2433.
To find out more about sporting opportunities in the borough visit www.towerhamlets.gov.uk/sports


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Uub is the incarnation of Kid Buu. He is human and is originally from a tropical island. He is the eldest of five siblings. His name, Uub, is Buu spelled backwards. This is due to the fact that he was born to be the positive incarnation of the evil Kid Buu.
At the age of ten Uub decides to enter the 28th World Martial Arts Tournament, in hopes of being able to win the prize money for his family. As per request by Goku, Mr. Buu changes the matchups so that he is able to fight Uub in the first round.As Uub begins his fight with Goku, he at first seems very reluctant to fight. Although, this quickly changes after Goku begins to insult his parents. Uub's power level then increases to a level that would be able to succesfully inflict damage on Goku. After the match, Goku apologizes and offers to take Uub in as his student. Uub, at first, is reluctant to take Goku up on his offer due to the fact that the reason he entered the tournament was to help out his family with the prize money. Although, Goku then explains that he will simply just have Hercule give Uub all the money he needs in order to support his village. After hearing this, Uub agrees and he and Goku fly off to his village to train. This marks the end of Dragon Ball Z. At the beginning of Dragon Ball GT, Uub is now a teen and is seen fighting with Goku on top of Kami's Lookout. His clothing now resembles that of Goku's at the end of Dragon Ball Z and his appearance has changed. He has gained ample amounts of muscle and no longer looks malnourished. At the conclusion of their fight Goku states that Uub's training is now complete. After saving Pan and witnessing Goku's supposed death at the hands of Baby, Uub decides to continue the fight his master could not finish. Although, Uub proved to be no match for Baby, and soon found himself on the receiving end of Baby's Revenge Death Ball. Before Uub could be destroyed, he was saved by Mr. Buu. The two of them then decided to fuse together in order to increase their strength. Together they are able to match the power level of Baby, though they are turned into chocolate shortly after.
Though Uub was assumed to be dead, it turns out it was not the case. He was able to succesfully stop Golden Great Ape Baby Vegeta from attacking Goku, by attacking him by the insides. He was then spit out by Baby to stop the pain. Majuub later fights in the 31st World Martial Arts Tournament, throwing the match in the final round facing Mr. Satan.
During the Super 17 Saga, Majuub is seen fighting against clusters of dead enemies as well as Super 17. Later Majuub contributes during the fight against Omega Shenron and is rather successful in being able to hold him off.


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Click here to print the obituary below
Jill (Grissinger) Montgomery
Jill (Grissinger) Montgomery, 66, passed away peacefully Wednesday October 23rd. She was born on April 16th, 1947 to Robert and June (Barnes) Grissinger of Homerville, Ohio. She graduated from Black River High School in 1965. She worked at the Greene County Court House as a Law Librarian for many years and also at the Warren County Court House. Jill had an infectious smile and laugh; she loved to garden, read, dance, and especially loved being Mimi to her grandchildren. She is survived by her children Jason LeSourd of Xenia, Ohio, Sarah Auckland (David) of Sammamish, WA, her grandchildren Nolan, Beckett and Tessa, partner Berney Swaab of Issaquah, WA, her brother Lynn Grissinger and sister Merrybeth Richter. Jill was preceded in death by her parents, her brother Jack Grissinger and sister Linda Jo Mann. Celebration of Life will be held November 1st from 4-8pm at Tibbetts Creek Manor in Issaquah. In lieu of flowers donations may be made to Evergreen Hospice Care in Kirkland, WA.


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Paul Revere Lantern Bookmark
Find your page every time with this beautiful bookmark engraved with a lantern.
- Shown in maple. Available in maple or cherry
- Engraved design of a lantern with Paul Revere quote and signature
- Lacquer finish
- Measurements: 6" x 2" inches (length x width)
The White Mountain Bookmark is made in Antrim, New Hampshire by the artisans at Cogworks.


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More Cat Care Information:
March is National Nutrition Month in the United States, a time for us all to take a closer look at the foods we eat on a daily basis and how we can improve our overall diet. As a cat owner, it's also your responsibility to make sure that your feline is receiving optimal nutrition, and this month is the perfect time to start. If your feline has become a bit tubby over the winter or doesn't seem to have the same spunk that he used to, you may need to examine what he's eating on a regular basis. Keep the following tips in mind to improve your furry friend's quality of life and increase his longevity.
1. Food labels. The next time you're at the pet store and examining the ingredients in your feline's food, keep in mind that cats are carnivores and shouldn't be eating the corn, grain and carb-filled foods that are very common. Look into products that are made with mostly natural ingredients and are free of preservatives and fillers. Going for an even split between a nutritious dry food and a tasty wet food can help your cat receive well-rounded nutrition.
2. Treats. The occasional treat is alright for your furry friend, but you should really search for a product that will add to his overall nutrition instead of just giving him junk food. If you can't find healthy cat treats at your local pet store, consider looking up all-natural pet stores and holistic vets. These locales will give you great advice to find natural cat treats that can improve animal wellness and prevent any weight gain.
3. Multiple cats. If one of your felines is in need of weight loss more than others, it can be difficult to feed one feline a specific diet while keeping the other one at bay. According to CatChannel.com, while you could decide to place the food in a separate area of the house or on a counter top where the other feline can't get it, it may be better just to separate the cats during mealtime. This will prevent your tubby kitty from dipping into extra food and it can help you be diligent about his diet.
Pet nutrition is one of the most important aspects of cat wellness, so use National Nutrition Month as your motivation to improve your feline's overall well-being.


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Archive for
Lang smoker cookers
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grease drain
mine is already clogged. any suggestions on how to clean it?
clog drain
open the valve as far as it will go then run a stiff wire up the pipe.
Wood River BBQ Team
Re: grease drain
mine is already clogged. any suggestions on how to clean it?
dsarphie: In the event I have this problem, which I haven't yet and to help me avoid it, what do you think caused it to clog in the first place?
I wonder if you closed the drain and poured in boiling hot water and after a few seconds opened the drain if that would help unclog it or maybe a wire bristle bottle cleaner?
I don't know and am just guessing.
The valve it always kept wide open. It was that crust that builds up on the drip pan. while I steam clean before and after each cook, I scrap the pan and grease channel after every couple of cooks. Some it built up in the drain and clogged it. I got a metal rod and ran it down the drain to unclog it, then shot the hose down the drain. It worked. I have the firebox going so it dried out any moisture.
I have a friend with an 84 and a 108 for his restaurants. He told me that he does basically the same thing, except wire hangar and a pressure washer.
That reminded me of a guy that I met at a competition who was cooking on a Jambo Pit. He told me that he takes his pit to a car wash once a month to clean it out with a pressure washer. That's not feasible for me, nor necessary, but this experience has shown me that I need to expand the scope of my cleaning routine.
medic smoker
you can buy a water hose nozzle that just screws on to the end of a garden hose, that turns a normal garden hose into a high pressure stream of water. They are cheap, seems like something that might suit needs for cleaning out the drain plug.
So what is the correct way to use this valve? Is it supposed to be open all the time? When do you close it? Also how do you dispose of your oily water?
would seem since it's only a foot long, open it up and spray water from a hose down it. unless the grease is made of concrete, it will break up in a few seconds.
I leave mine open all the time. Only time I'd close it is during travel. Otherwise there's a bucket hanging.
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Somaluxe Intensive Hydration Moisturizer Review, PhotosMonday, April 14, 2014
(Please note the brand has changed its name from Somatique to Somaluxe)
The first thing I noticed about this cream was the smell -- delicious! It's a really wonderful, chocolate-y smell, and I think I detect a slight undertone of orange. It really reminds me of chocolate pudding mix and I love it. There's no added fragrance to this by the way; I think the chocolate scent comes from the cocoa butter in the formula, and the orange undertone from the orange hydrosol (the first ingredient). It's not overly-strong either, so unless you really dislike chocolate scents, it shouldn't be much of an issue if you're scent-sensitive (scentsitive?)
The texture is on the thinner side but not watery. I use this at night because I find it takes a while to completely soak into the skin, and can be a little bit sticky. It doesn't pill up though, and works well with my current serum. In the morning after leaving it on overnight, my skin is so soft! I have combination/oily skin, but this winter has been rough (to say the least), and this moisturizer has kept it protected from the ravages of the polar vortex.
I haven't noticed any significant changes with regards to reversing free radical damage or fighting wrinkles, but those haven't really shown up on my skin (yet!) I do see more even texture in my skin, along with the aforementioned softness.
Now... this is the caveat. The ingredients in this moisturizer are quite awesome, but I'm worried they won't deliver their full potential due to the jar packaging. Unfortunately, antioxidants break down when exposed to air or light. An opaque container with a pump would be the ideal packaging for this type of moisturizer, and I can't 100% recommend Somatique Intense Hydration Moisturizer because of this. You could possibly transfer it to your own pump container to minimize the damage, but at $44 USD, it's not really worth it.
I would definitely recommend this moisturizer if its packaging limited contact with air and light to ensure its ingredients are stable. The scent, texture, and moisture benefits are all great, but the stars should be the antioxidants and vitamins, and unfortunately, skin probably won't benefit much from them. I really hope Somatique considers changing the packaging to reflect this flaw, as this is definitely a promising moisturizer with great ingredients.
What do you think? What kind of packaging do you prefer moisturizers have?
Ingredients: Orange Hydrosol, Organic Aloe Vera Juice, Organic Sunflower, Glyceryl Stearate, Organic Vegetable Glycerin, Organic Coconut, Cocoa Butter, Matrixyl 3000, Hyaluronic Acid, Vitamin C, MSM, Cetyl Alcohol, Potassium Stearate, Organic Beeswax, Vanilla and Rose Absolutes, Organic Jojoba, Tamanu Oil, Organic Borage Oil, Organic Flax Seed, Organic Evening Primrose Oil, Organic Oregon Grape, Organic Rose Hip, Vitamin B5, Organic Arnica, Organic Lavender, Organic Calendula, Organic Chamomile, Grapeseed Oil, Macadamia Nut, Noni, Raspberry, Sodium Carbomer, Phenoxyethanol, Ethyl Hexyl Glycerin.
*Product provided for review. No monetary compensation given. All opinions are my own.
7 comments
I have so many face moisturizers, it's crazy. But I do have dry skin so they're all necessary and worth it.ReplyDeleteReplies
I have about 50,000 samples of them. Always searching for the best one!Delete
Yes I too agree that packaging should be good. However it seems a good product. Nice post dear :-)ReplyDelete
Thanks! It is a very good moisturizer even if you don't get the full benefit of the antioxidants!Delete
Wow I never thought of it that way! I have some really high-end stuff that is in a jar. So glad Lancome comes in an opaque pump. Great review :)ReplyDeleteReplies
Thanks! I think a lot of companies just put moisturizers in jars because it's convenient for both them and the consumer.. but unfortunately it's just not the best for some ingredients!Delete
I had no idea that packaging made that much of a difference, but that does make sense!ReplyDelete


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Panasonic NNSD261MBPQ Silver Ecohikari Microwave
Item is currently out of stock
Free Delivery
Product Overview
Product Overview
A Panasonic microwave oven in Silver with a 950W power output, 23 litre capacity, in a compact size in order to fit into any small kitchen, simple to operate and will reheat and cook food to perfection. The acrylic lining also means that the interior is easy to clean and simple to maintain.
- Type: Freestanding
- Capacity (Litres): 23
- Colour / Finish: White
- Type of Controls: Buttons
- Turntable Size (mm): 285
- Microwave Power (Watts): 950
- Height: 279mm, Width: 488mm, Depth: 395mm


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After dinner, the boys and I made some pumpkin spice rice crispy treats. I have to admit, I was skeptical, but they were really good.
We followed the recipe for original rice crispy treats:
Original Rice Crispy Treats
3 Tbs of butter
3 Tbs of butter
10 oz of marshmallows*
6 cups of crisped rice cereal
*Obviously, here we used pumpkin spice flavored marshmallows.
Prepare a 9x13 dish. In a large pot over medium heat, melt the butter, being careful not to burn it.
Once the butter is melted, add the marshmallows.
Stir the butter/marshmallow mixture continuously until all marshmallows are melted. Remove from heat and stir in the crisped rice cereal and combine well.
Once all cereal is coated well with the marshmallow mixture, pour into the prepared baking dish. I would recommend putting butter on your hands and using your hands to press this down into the dish. Using butter will keep the mixture from sticking to your hands. Remember hot marshmallow can and will burn if it sticks to you.
Gabe was a little impatient, and didn't want to wait on the treats to cool. So, he grabbed the pot and scraped out what he could. I see he got it all over his school shirt in the process. I don't know why I even buy him white. UGH!
To add a little extra flavor punch, I drizzled some caramel ice cream sauce across the top of these, and the boys snatched them up as soon as I took the picture. I imagine drizzling some chocolate across the top would be good as well, but Garrett isn't quite sold on the awesomeness that is chocolate. I know! Crazy, right??
I'm sure most of us have made the basic rice crispy treats a few times in our lives. They are so simple to make, and so yummy. If you're looking for something quick that you can make with your kiddos, this is it. In fact, my boys did all of the work themselves except pressing the hot mixture into the dish. I didn't want them to get burned, so I did that. Try doing what we did and change things up a bit. We've made these treats with the fruity or cocoa flavored crisped rice, corn flakes, etc. I think next time I may try using some caramels and chocolate - ooooh or maybe even some peanut butter. Yummm! I'll let you know how those turn out.
I hope you have fun, and enjoy!


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All prices are in All prices are in USD
Patchouli helps to ground and calm. For skin, this oil is a great anti-inflammatory and anti-fungal and also helps to relive itching. We have heard great feedback from those suffering with eczema and dermatitis after using this soap. We added a ribbon of bamboo charcoal to help detoxify and deodorize. Vegan and nut free.


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It's nearly here – Black Friday. the official firing of the retail starting gun in the race through the holiday season to get great gifts at the best prices.
For retailers how they do on Black Friday and Cyber Monday are a prediction of what they can generally expect in the 4th quarter of their year.
It's a big deal.
Retailers like Best Buy, who last year promised, but didn't deliver on a lot of goods (canceling orders made a lot of folks pretty peeved…) may see a dip in sales but it's doubtful as consumer memories are short when you throw up a 46″ HDTV for $197 for a Doorbuster deal!
But is Black Friday a boon for consumers who want the best deals possible on clothing, electronics, toys and holiday gift items?
There are fantastic deals available during Black Friday both in-stores and online. However, consumers will often find that in both locations, the hottest deals are snapped up before they can get to them and 'Sold Out' will be an issue when promotions like free gift cards are in the mix.
They will also find that many stores will offer similar deals off and on throughout the holiday season leading up to Christmas, but it may be in the form of limited time only sales with coupons in your local paper, or promotions for online-only deals.
Online Black Friday deals will happen everywhere, and often, like the case with evo's Biggest Sale, be combined with Outlet prices for outstanding savings on big ticket items like ski boots and The North Face jackets.
Then there's the up and coming Cyber Monday, right on the heels of Black Friday.
It's a gamble whether or not the deals will be better on Cyber Monday. My advice is that if you really want the item on Black Friday and it looks like you may not be able to get it at the price you're happy with later, buy it when you see it. Particularly if that item has a size or color selection that may not be available later.
One note on refurbished electronics items sold during Black Friday. If you find a Black Friday deal on a refurb, make sure you're purchasing it from a reputible retailer such as Newegg, Apple, TigerDirect or Amazon. Make sure it has a warranty with terms you're comfortable with, and a good return policy under that warranty. That goes for deals sold off of Ebay too!
2012 Black Friday online expect to see deals on iPod Touch 4th and 5th generations, Apple iPads (refurbished and new), clothing and outerwear deeply discounted, gift card promotions, cheap laptops, buy-one-get-one toy and DVD s, and lots of flash sale deals at crazy-low prices from places like WhiskeyMilitia , TheClymb, and Zulily.
The good news – deals are out there!
The bad news – they just keep coming, and you have to decide which deals are the best deals for you.
If you're looking for online Black Friday deals, check out the Savvy Sleuth's 2012 Black Friday Deal Sheet which will be posted at 12:01am on Friday, 11/23.


text: Based out of Chicago, as a singer/songwriter, Owen is back performing for the Midwest people he loved performing for back in college at Indiana University. After performing on Celebrity Cruises as a solo entertainer (Guitarist/Vocalist) for 3 years, touring North and South America, as well as the Mediterranean, Baltic and Holy land, and simultaneously working on featured musical arrangements with show bands, orchestras and a cappella groups. He started singing at a very early age...try 3! In fact, he used to make up songs when his mom, a professional singer/actress, was taking him to kindergarten. Owen was a charter member of the Children's Chorus of Washington, which provided the opportunity to sing at Carnegie Hall, The Kennedy Center, and an Italian tour. He attended Blake High School's performing arts signature program in Silver Spring, Maryland, and then went on to Indiana University's prestigious Jacobs School of Music where he received a BS in Vocal Performance and Theatre. At Indiana, Owen sang with two widely acclaimed groups: The Singing Hoosiers, America's premier show choir; and the renowned a cappella group Straight No Chaser. Both groups toured the United States extensively, as well as a tour throughout Greece. He also was musical director and performed the role of Tommy in the musical "Tommy," and was featured in the musical, "Urinetown." In 2005, Owen formed his own band, True Story, and the 7-piece pop/R & B group produced its debut original CD in 2008. After graduation, Owen formed a new a cappella group called The Dockers, and embarked on his first of many tours with Celebrity Cruises. [+]


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― White Bird in a Blizzard (2014) "I just want to be free to do what I want."
R.M. Drake poetry
Voy pecado musa y con el Corazon a voces
I like this quote. There are some people you can love forever but not be close to. You can long for the good old days.....and remember with a smile. I do.
100 Inspirational Quotes For Girls On Strength And Confidence
Most days are those tomorrow's where I'm not with you... But I smile because everyday you are with me in my heart!
Love Best collections of tumblr images/pictures with sayings and quotes about love, life, happiness, trust, truth, sweet, relationship, friendship, inspirational http://www.picsandquote.com/
Happy Birthday to a wonderful co-worker and even better friend xoxo
My rule of life: #1 "If you want something you never had, you have to do something you've never done.":


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KYOSHO.DEGerman Official Kyosho webshop
You still can find some vintage wheels or tires from Kyosho. Really.
W-5078 tires
W-5021 Chromed OT-67 wheels wide
W-5022 Chromed Wheels narrow (can be combined with Pargu's Half Alu wheels or even with classic white Kyosho OT-67 wheels)
Of course, they are vintage stuff, so they flake easily. Not to be compared with Pargu's Aluminium wheels (well, his wheels are too heavy to race though) :D


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9mm EX Drivers — Allows for a comfortable fit and a deep and full sounding bass performance all in a small package. In-Line Volume control — Allows you to control your volume without having to take out your player from where you are carrying it. Cord adjuster — Allows you to conviently control the length of the cord. Three sizes of ear buds — You can pick the size that right for you for comfort and performance.
Sony's MDR-W08L vertical in-the-ear headphones get you ready to rock! Featuring a super-light in-the-ear design Sony Acoustic Turbo Circuitry a High Power Neodymium Magnet and an L-Shaped Mini Plug these headphones combine quality sound with a comfortable fit. This product also admits outside sound for added safety when you are listening on the go.
The Skullcandy Lowrider Headphone in Black & Gold packs a monster 40mm power driver in a super small lowrider chassis. With smooth styling, 90 degree swivel DJ style speakers, and a unique fold-up headband for ultra portability, the Lowrider will roll all over the competition.
Hi-Fi Streo Adapter
Stero Mini-Plug Adapter
RCA-to-Phono Plug Adapter
Listen to all of your favorite audio anywhere around the house, office or on the go without messy, limited range cords! These dynamic wireless headphones plug into any stero, dvd, mp3 or personal audio player for listening enjoyment virtually anywhere. Great for the computer or television. Headphones automatically lock onto the transmitter's signal. Includes an adjustable headband and all of the accessories you need to get high-quality sound without disrupting others.
Precision-cut metal housings encapsulate a sound coming from deep within the TiTAN ear buds that resembles an army of unstoppable warrior giants marching in lockstep to the beat of your music to purge the earth of dinosaurs, woolly mammoths, saber-tooth tigers, yetis, and Klingons. Features; 11mm Power Drivers Nylon Mesh Carry Case 3 Silicone Gel Sizes Specs; Speaker Diameter: 11mm Magnet Type: NdFeB Frequency Response: 20-20k Hz Impedance: 16 ohms Max Input Power: 100mW Cable Type: Aluminum Braided, Nylon Braided Cable Length: 1.3m Plug Type: 3.5mm Gold Plated
This new collection of affordable a dn stylish headphones provides a wide variety to consumers, particularly young sound lovers. There are six models each for men and women.
Dynamic element design for deep bass performance; Comfort zone setting on temporal pad for comfortable, secure fit; Multi-pivoting earplates and adjustable headband for added comfort; Collapsible for maximum portability when listening on the go; Includes convenient carrying case; Includes 1/8″ and 1/4″ stereo plugs for home and portable use; Straight, dual entry 4 foot cord; Frequency response: 15-25,000 Hz.
This new collection of affordable a dn stylish headphones provides a wide variety to consumers, particularly young sound lovers. There are six models each for men and women.
A musical all-rounder, the PX 100-II Supra-Aural Mini Headphones let you enjoy your personal favorites at any time on your portable player. Their dynamic, open ear cup design allows for a natural sound reproduction with a strong bass.
These robust, steel-reinforced headphones can also be folded easily, thanks to their unique fold and flip design. Once folded, you can simply place them into their convenient soft carrying case. Optimized for MP3, iPod, iPhone and portable media players Frequency response 15 – 27000 Hz Sound pressure level (SPL) 114 dB Impedance 32 Ohms THD, total harmonic distortion < 0.1 % (1 kHz, 100 dB SPL) Connector 3.5 mm straight plug Cable length 1.2 m (3.93 ft.) single-sided cable In the box – PX 100-II headphones Carrying case Manufacturer's 2-year warranty
Features sophisticted curves, modern stainless stell accents and the finest sound quality. Complements devices like Apple iPhone and iPod.
Sennheiser MX 980 High Fidelity Metal Crafted Earbuds with Balanced and Precise Sound Reproduction


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If you want to experience thrilling and amazing moments from a big war, please land on The Leon Wars at this time. You will become a talented ruler, and your task is to occupy a large territory. What would you do to attain this aim? Go with us and uncover all now! Before starting, the sole request that players should do is to create an army. They are permitted to create 3 armies at first. Tap on New Army button and train some available heroes. Remember to read each hero's function and price carefully before training. After that, send all to the war in order to annihilate the enemies. Attempt the best to capture more churches, mines, villages, etc. and steal more iron and gold. Thanks to these valuable things, the heroes' fighting ability will be upgraded at the best rate. Continue fighting until attaining about 70% territory to win this game. Good luck to you!
The mouse is to interact with this game.
The arrow keys are to scroll the screen.
Spacebar is to deselect the heroes.
Game Stats185 views
Game Tags
army, heroes, iron, leon, wars


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A glowing smile charms irritable librarians, stern highway-patrol officers, and reactionary judges with their big, fancy ideas about driving through the library. Rev up your smile with this Groupon.
Choose Between Two Options
- $129 for an in-office Zoom! teeth-whitening treatment (a $299 value)
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Aesthetic Dental Studio of Rhode Island
Dr. Candida Castillo and the team at Aesthetic Dental Studio of Rhode Island offer general and cosmetic dentistry services with a specialty in smile makeovers for special occasions. They whiten smiles for weddings and install natural looking porcelain crowns for driving-school graduations, in addition to filling cavities and performing regular cleanings. They also offer sedation dentistry for anxious patients and 360-degree x-rays for better dental diagnosis.


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Determining one's entitlement to alimony (known also as spousal support or spousal maintenance) can be a complicated matter. Alimony is defined by https://en.wikipedia.org/wiki/Alimony as "a legal obligation on a person to provide financial support to his or her spouse before or after marital separation or divorce". Traditionally alimony was paid by the husband to his wife, but since the 1970's this is no longer necessarily the case. Alimony has nothing to do with gender, and everything to do with earnings.
Click here to learn more about alimony. http://www.divorceandseparationlaws.com/Divorce_Attorney_fichiers/alimony_laws_USA.htm
Source: divorceandseparationlaws.com


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A lot of variety. Fresh. European standard. Friendly and quick service. Unique. Food is great and they also they make excellent cappuccinos.
11 - 20 of 70 reviews
A lot of variety. Fresh. European standard. Friendly and quick service. Unique. Food is great and they also they make excellent cappuccinos.
before visiting Québec I did extensive research of the city's gastronomy, and I found this jewel and thought... MUST VISIT! so one day we just took a walk and headed there and... the pictures are real! an amazing exposition of a wiiide variety of cakes,...More
If you are in search of a cafe with pastries or breads for every desire and taste, this is your place. When you first walk in, you will confront huge glass cases filled with fancy chocolates and even fancier desserts. As you move further in,...More
We were here twice, breakfast and lunch. There are a few others on the same street, breads/croissants/dessert/coffee, this one has be most variety. Not the best coffee but enormous selection of desserts and breads. Reasonably priced too. Get the croissants and desserts, all yummy. Not...More
Got croissants, a white miche and kouign amanns. For the drive back home. Everything was excellent. The Kouign Amanns had chocolate in them, which was a bit too sweet, not sure if the plain were sold out or if they dont make plain.
We visited this wonderful bakery up the street from our Hotel, Hotel Pur, to get sandwiches for our picnic to the Montmorency Falls. We had the Genoa salami and cheese with a delicious homemade mustard and mayonnaise. We were not disappointed! We also picked up...More
If you're looking for something fun, unique and delicious this is the place. Don't let the long lines scare you, as it's well worth the wait. Their specialty is the eclair ( obviously) as the whole top shelf of the display case is filled with...More
I will be back for a pastry/dessert! I needed a croissant to keep me from being too hungry before dinner, so stopped in here. Lots of people were in line for gelato. The desserts looked great.
Great food. Crunchy baguettes. Wide range of pastries, cakes and chocolates. Extremely busy. Have to line up. Staff friendly and helpful.
Great bread and sandwiches. A huge selection of tarts, cakes, and pastries. They do fabulous éclairs - I've tried most of them and they are delicious!