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Sanli, Toran MSc*†; Liu, Caiqiong MSc*; Rashid, Ayesha MSc*†; Hopmans, Sarah N. MSc‡; Tsiani, Evangelia PhD§; Schultz, Carrie BSc#; Farrell, Thomas PhD∥#; Singh, Gurmit PhD‡; Wright, James MD#†; Tsakiridis, Theodoros MD, PhD*†#
*Translational Radiation Biology Laboratory, Juravinski Cancer Center, Departments of †Oncology, ‡Pathology - Molecular Medicine, and ∥Medical Physics, McMaster University, #Disivion of Radiation Oncology, Juravinski Cancer Center, Hamilton and §Department of Community Health Science, Brock University, St. Catharines, Ontario, Canada.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Theodoros Tsakiridis, MD, PhD, Radiation Oncology, Juravinski Cancer Center, 699 Concession Street, Hamilton, ON, Canada L8V 5C2. E-mail: email@example.com
Introduction: In this study, we investigated the effect of the 3-hydroxy-3-methylgutaryl-CoA reductase inhibitor lovastatin, as a sensitizer of lung cancer cells to ionizing radiation (IR).
Methods: A549 lung adenocarcinoma cells were treated with 0 to 50 μM lovastatin alone or in combination with 0 to 8 Gy IR and subjected to clonogenic survival and proliferation assays. To assess the mechanism of drug action, we examined the effects of lovastatin and IR on the epidermal growth factor (EGF) receptor and AMP-activated kinase (AMPK) pathways and on apoptotic markers and the cell cycle.
Results: Lovastatin inhibited basal clonogenic survival and proliferation of A549 cells and sensitized them to IR. This was reversed by mevalonate, the product of 3-hydroxy-3-methylgutaryl-CoA reductase. Lovastatin attenuated selectively EGF-induced phosphorylation of EGF receptor and Akt, and IR-induced Akt phosphorylation, in a mevalonate-sensitive fashion, without inhibition on extracellular signal-regulated kinase 1/2 phosphorylation by either stimulus. IR phosphorylated and activated the metabolic sensor and tumor suppressor AMPK, but lovastatin enhanced basal and IR-induced AMPK phosphorylation. The drug inhibited IR-induced expression of p53 and the cyclin-dependent kinase inhibitors p21cip1 and p27kip1, but caused a redistribution of cells from G1-S phase (control and radiated cells) and G2-M phase (radiated cells) of cell cycle into apoptosis. The latter was also evident by induction of nuclear fragmentation and cleavage of caspase 3 by lovastatin in both control and radiated cells.
Conclusions: We suggest that lovastatin inhibits survival and induces radiosensitization of lung cancer cells through induction of apoptosis, which may be mediated by a simultaneous inhibition of the Akt and activation of the AMPK signaling pathways.
Radiotherapy is a widely used therapy in all stages of non-small cell lung cancer (NSCLC). However, NSCLC demonstrates intrinsic radioresistance that leads to failure of even high-dose thoracic radiation.1 Therefore, there is an urgent need for rational development of effective radiation sensitizers for NSCLC, which are able to inhibit molecular pathways mediating radiation resistance.
Ionizing radiation (IR) elicits signal transduction leading to cell survival, apoptosis, and cell cycle regulation.2 IR-induced DNA double-strand breaks are potentially lethal DNA damages leading to activation of phosphatidylinositol 3-kinase (PI3k)-like family protein kinases such as DNA-protein kinase and ataxia telangiectasia mutated (ATM).3 ATM mediates phosphorylation of p53 leading to stabilization of this tumor suppressor and cell cycle arrest at the G1-S or the G2-M check points through induction of the cip/kip family cyclin-dependent kinase inhibitor (CDKI) p21cip1.4 p27kip1, another cip/kip family CDKI, functions independently of the p53-p21cip1 pathway and inhibits cyclin E-cyclin-dependent kinase 2 complex and cycle progression through the G1-S checkpoint.4
Recently, we reported that the energy sensor AMP-activated kinase (AMPK), an established effector of the tumor suppressor LKB1, is activated by IR in a variety of epithelial cancer cells.5 IR activates AMPK in LKB1-independent but ATM-dependent manner leading to induction of p53 and p21cip1, cell cycle arrest at the G2-M checkpoint, and modulation of the sensitivity of cells to IR. IR is also shown to regulate mediators of the signaling pathway of epidermal growth factor receptor (EGFR),6,7 a well-established activator of cancer cell proliferation. IR activates the downstream effector pathways of EGFR such as the PI3k—Akt—mammalian target of rapamycin (mTOR) and the Raf—mitogen-activated protein kinase-kinase (Mek1)—mitogen-activated protein kinase p42/44 (also known as extracellular signal-regulated kinase [Erk1/2]) pathways. These are known to mediate cell survival and radiation resistance, gene expression, and protein synthesis.8,9
Small GTP-binding proteins of the Ras family such as Ras, Rac, and Rho (A/B) mediate signal transduction downstream of EGFR to activate the PI3k-Akt-mTOR and the Raf-Mek-Erk1/2 pathways. Ras mutations are frequent in lung cancer, and they occur in both the H- and K-Ras isoforms and were shown to induce radiation resistance in vitro.10,11 For that, extensive work is focused on targeting Ras family members with inhibitors of prenylation, a posttranslational modification required for membrane targeting and function of Ras.12
Members of the statin family of 3-hydroxy-3-methylgutaryl-CoA (HMG-CoA) reductase inhibitors are widely used anticholesterol agents that inhibit the conversion of HMG-CoA to mevalonate, a rate-limiting step of the mevalonate—cholesterol biosynthesis pathway.13,14 This pathway is also vital for the production of farnesyl and geranylgeranyl moieties required for the posttranslational modification and function of Ras and Rho, respectively.13 For this reason, statins have been studied extensively as antitumor agents.
During the past 20 years, a large amount of studies have demonstrated the antiproliferative and proapoptotic effects of statins both in vitro and in animal models of cancer. Growth inhibition, cell cycle arrest, and induction of apoptosis in cancer cells have been demonstrated convincingly.15 The interest in these drugs was enhanced by epidemiological studies indicating that patients on statins may have lower risk for development of colorectal carcinoma16 and lung cancer.17 The Veterans Affairs Health Care System study17 showed that use of statins for more than 6 months could offer a 55% risk reduction on the incidence of lung cancer, indicating that these agents may have significant chemoprevention action. Further, in prostate cancer, statin use is suggested to decrease the risk for advanced and metastatic cancer in epidemiological studies,18 to slow disease progression after radical prostatectomy,19 and, importantly, to reduce disease recurrence in patients treated with curative radiotherapy.20,21
Lovastatin is probably the most widely studied statin in cancer. It has been shown to possess anticancer properties in vitro and in vivo.14 The antiproliferative action of lovastatin has been demonstrated in lung cancer cells,22 but its role as a potential IR sensitizer or adjunct to radiation has not been examined in lung cancer models. In this study, we examined the effects of lovastatin on clonogenic survival of lung cancer cells treated with or without IR and explored the effects of this drug on cell cycle, apoptosis, and signaling pathways involved in IR resistance.
Roswell Park Memorial Institute (RPMI) media, fetal bovine serum, trypsin, and antibiotic were purchased from Invitrogen (Burlington, ON). Antibodies against phospho-EGFR, phospho-Akt, phospho-Erk, p53, phospho-AMPK α-subunit, p21cip1, p27kip1, cleaved caspase 3, actin, and horseradish peroxidase-conjugated anti-rabbit secondary antibody were purchased from Cell Signal Technology (Mississauga, ON, Canada). Polyvinylidene difluoride membrane was purchased from Pall Corporation (Port Washington, NY). Lovastatin, mevalonate, and Hoechst 33258 were purchased from Sigma (Toronto, ON). A549 cells were from the American Type Culture Collection (Manassa, VA).
A549 cells were grown in Roswell Park Memorial Institute (RPMI) media containing 5 mM glucose, 10% (vol/vol) fetal bovine serum, and 1% (vol/vol) antibiotic-antimycotic at 37°C as described previously.23 Cells were treated with the indicated concentrations of lovastatin 24 hours before radiation.
A549 cells were subjected to clonogenic assays as described earlier.5 Briefly, 500 or 1000 cells were seeded into individual wells of a 6-well plate in triplicate and maintained at the indicated doses of lovastatin before radiation (2–8 Gy). After 7 days, cells were fixed and stained with methylene blue, and viable colonies (>50 cells) were counted. Results are expressed as cell survival fraction compared with untreated control. To evaluate radiation sensitization by lovastatin, data were fitted to the linear quadratic equation using Graphpad Prism version 5 software (La Jolla, CA) as described previously.24
Approximately 2500 cells were seeded into a 96-well plate and treated with the indicated concentrations of lovastatin before being exposed to 0, 2, or 8 Gy IR. Ninety-six hours later, the cells were washed with phosphate-buffered saline, distilled H2O was added to each well, and the plates were stored at −80°C until completely frozen. The plates were then thawed and stained with Hoechst working solution (20 μg/mL Hoechst 33258 in a Tris-Borate-EDTA buffer), and fluorescence was determined using the Cyto-Fluor Plate Reader (Applied Biosystems, Toronto, ON, Canada).
Twenty micrograms of protein was separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membrane as described earlier.23 The primary antibody was detected with horseradish peroxidase-conjugated anti-rabbit secondary antibody and enhanced chemiluminescent detection reagent.
The propidium iodine method was used as described previously.5 Cells were treated with lovastatin (10 μM) before treatment with 0 or 8 Gy of IR and incubated for the indicated times and were then subjected to flow cytometric cell cycle analysis using a FACScan flow cytometer (Beckton Dickinson, Mississauga, Canada).
Cells grown on glass coverslips for 24 hours were treated with lovastatin (10 μM) for the indicated times. Then the cells were stained with Hoechst 33258, and images were obtained as described previously.5 Quantitation of apoptotic cells (showing nuclear fragmentation) was performed by counting the average proportion of apoptotic cells in four high-power fields on each slide (100 cells counted in each quadrant of each slide). Values were normalized to the untreated control.
Statistical analyses was performed with unpaired T-test, using SPSS version 16.0 software (Somers, NY) and are presented as mean ± SEM of at least three separate experiments.
We initiated our studies with clonogenic survival assays. Lovastatin alone caused a dose-dependent inhibition of clonogenic survival in A549 cells (Figure 1A). The drug began inhibiting clonogenic survival at a dose of 5 μM (10% reduction in survival), inhibited the majority of clonogenic survival at 25 μM (95% reduction in survival), and completely abolished survival at 50 μM (Figure 1A).
Lovastatin sensitized A549 cells to IR (Figure 1B). Clonogenic assay values were fitted into a linear quadratic model. Both 5 and 10 μM of the drug showed significant radiosensitization of A549 cells to 2 to 8 Gy of IR. Almost complete inhibition of clonogenic survival was achieved with 10 μM lovastatin in combination with 8 Gy IR. In addition, we evaluated proliferation through DNA synthesis analysis using the Hoescht DNA staining method. Five micromolar of lovastatin inhibited basal cell proliferation (by 33%; compared with 0 Gy control) without affecting significantly the proliferation levels after IR (Figure 1C). However, at 10 μM, the drug inhibited dramatically cell proliferation in both control cells and those radiated with 2 or 8 Gy (by 63% and 90%, respectively).
We used mevalonate to examine the specificity of lovastatin for the mevalonate-cholesterol synthesis pathway (Figure 1D). Two gray of IR decreased clonogenic survival by 44% compared with control. Lovastatin alone (15 μM) inhibited survival by 75% and by 92% when combined with 2 Gy of IR. In these experiments, the higher concentration of 15 μM lovastatin was used to examine whether mevalonate is capable of reversing the effects of even high lovastatin doses. Mevalonate (100 μM) inhibited the lovastatin-induced decrease in cell survival in both nonradiated and radiated cells, suggesting that lovastatin mediates its cytotoxic action solely through inhibition of the mevalonate synthesis pathway.
To analyze the mechanism of action of lovastatin, we examined first its effects on EGF-induced EGFR and downstream effector phosphorylation. EGF induced phosphorylation of EGFR and the Akt and Erk1/2 kinases (Figure 2). However, lovastatin inhibited EGFR and Akt phosphorylation, in a dose-dependent fashion, without affecting phosphorylation of Erk1/2 (Figure 2).
Control and lovastatin-treated cells were subjected to increasing doses of IR and were analyzed by immunoblotting. IR induced a consistent Akt phosphorylation, even with the lower dose of 2 Gy, but Erk phosphorylation was seen only after 4 to 6 Gy (Figure 3A–C). Interestingly, lovastatin abolished the IR activation of Akt but did not affect significantly Erk1/2 phosphorylation by IR (Figure 3A–C). The inhibition of IR-induced Akt phosphorylation by lovastatin was completely reversed by addition of mevalonate (Figure 3D–E), consistent with clonogenic survival results (Figure 1D). IR also caused a dose-dependent phosphorylation of AMPK that was accompanied by activation of this kinase shown by the enhanced phosphorylation of its established substrate acetyl CoA carboxylase, as observed earlier5 (Figure 4A–C). Interestingly, lovastatin enhanced significantly both basal and radiation-induced AMPK phosphorylation and activity.
The Akt and AMPK pathways regulate cell cycle through modulation of p53 and CDKIs p27kip1 and p21cip1.25 Therefore, we examined whether lovastatin modulates the levels of these cell cycle inhibitors in control and IR-treated cells. We observed a significant increase in the expression of p53, p27kip1, and p21cip1 in response to IR (Figure 5A). However, lovastatin caused an early inhibition of the IR-induced expression of p53, p27kip1, and p21cip1, within 24 hours, and for that, we examined the levels of these three cell cycle regulators up to 96 hours after initiation of treatments. IR maintained enhanced p53, p27kip1, and p21cip1 levels up to 96 hours later (Figure 5A), but lovastatin inhibited this IR-induced expression, which was almost completely eliminated at 96 hours.
Lovastatin alone did not affect significantly the distribution of cells in the phases of the cell cycle in the first 24 hours (Figure 5B). However, lovastatin caused a progressive significant shift of cells into G0/G1 phase, after 24 hours, compared with control, and eventually a marked induction of apoptosis by 72 to 96 hours (24 hours: 2%; 96 hours: 89%). IR alone caused a significant arrest of cells in G2/M phase at 48 hours (control: 0%; IR: 31%). However, lovastatin attenuated IR-induced G2/M arrest and shifted cells into G0/G1 phase and apoptosis (IR G2-M: 31%; Lovastatin + IR G2-M: 12%; Figure 5C).
Finally, we examined the effects of lovastatin and IR on molecular and morphological markers of apoptosis. Cleaved caspase 3 levels, an established marker of apoptosis,26 was analyzed by immunoblotting. Lovastatin alone caused a significant increase in cleaved caspase 3 levels and further potentiated IR-induced expression of this protein at 12 hours (Figure 7A). IR induction of cleaved caspase 3 dissipated after 12 hours, but lovastatin enhanced cleaved caspase 3 levels for up to 48 hours later and decreased thereafter. We analyzed apoptotic events also with morphological analysis of cells treated with lovastatin for 0 to 72 hours. Consistent with induction of cleaved caspase 3 (Figure 6A) and the cell cycle results (Figure 5), lovastatin caused a time-dependent nuclear fragmentation and induction of apoptotic bodies (Figure 6B, C).
Lovastatin was shown to sensitize human cervix cancer cells to IR.27 Recently, another statin, simvastatin, was shown to inhibit small cell lung cancer growth in vitro and in vivo,28 and Bellini et al.29 showed that simvastatin inhibits the proliferation of A549 lung cancer cells. However, the potential benefit of combining statins with therapeutic doses of IR has not been examined in lung cancer models. To our knowledge, this is the first study to demonstrate that lovastatin acts as a radiation sensitizer in NSCLC cells.
We observed that lovastatin sensitized A549 lung cancer cells to therapeutic doses of IR of 2 to 8 Gy (Figure 1). This was mediated specifically through inhibition of the mevalonate pathway, as exogenous mevalonate completely reversed the decrease in lung cancer cell survival observed by lovastatin (Figure 1D). Fritz et al.27 examined the sensitivity of a number of cancer cell lines to lovastatin, but only a few of them showed sensitivity to lovastatin at high doses. HeLa cells required 20 to 50 μM of lovastatin to demonstrate radiosensitization.27 In this study, lung adenocarcinoma A549 cells showed higher sensitivity to the drug (at 5 and 10 μM), indicating that survival pathways in those cells may be more dependent on protein prenylation events.
Interestingly, in recent experiments investigating the effects of lovastatin in SK-MES lung cancer cells, a cell line of squamous cell carcinoma origin, we have observed an even greater sensitivity to the drug. These results are shown in Figure s1 (Supplemental Digital Content) and indicate a 20 to 50 times greater sensitivity of SK-MES cells to lovastatin compared with adenocarcinoma A549 cells. We are currently investigating in depth the molecular etiology of this higher sensitivity of SK-MES cells and its implications. However, overall, our results demonstrate that lung cancer cells show significant radiosensitization in response to lovastatin that should be explored further in preclinical in vivo and in clinical studies.
As other statins, beyond lovastatin, have shown antiproliferative effects in cancer cells,15 one wonders whether lung cancer cell radiosensitization is a phenomenon unique to lovastatin. For that, we began to explore the effects of other statins in A549 cells. In preliminary studies, we observed that simvastatin is also able to inhibit proliferation of A549 cells (as shown earlier29) and to sensitize lung cancer cells to IR. This indicates that radiosensitization is likely a common effect for this class of agents (Figure s2, Supplemental Digital Content).
Adenocarcinoma A549 cells have a genetic profile that offers a survival advantage including a K-Ras (Gly12-Ser) mutation.30 K-Ras activates the PI3k-Akt pathway31 and that is required for NSCLC tumorigenesis in K-Ras mutant mice.32 Because it inhibits posttranslational modification of Ras GTP-binding proteins, lovastatin is expected to abrogate oncogenic K-Ras and EGFR signaling. In this study, we observed that lovastatin selectively abrogated EGF-stimulated phosphorylation of EGFR and Akt but not Erk1/2. This discrepancy was observed also by Mantha et al.33 in SCC9 head and neck tumor cells and suggests that (1) persistent EGFR phosphorylation may not be required for Erk1/2 activation and (2) activation of Erk1/2 alone is not adequate to confer radiation resistance. Our observations suggest that in lung cancer cells, lovastatin is able to inhibit selectively the key prosurvival pathway of Akt. This alone could account for the antiproliferative and proapoptotic effects of the drug.
Similar to EGF-induced signals, lovastatin attenuated IR-activation of Akt, in a mevalonate-dependent fashion but did not affect IR-activation of Erk1/2 (Figure 3A–C). Similarly, Mistafa and Stenius34 found that statins primarily target the Akt pathway to sensitize pancreatic cancer cells to chemotherapeutic drugs, without effecting Erk. Studies in K-Ras mutant cells, including A549, have shown that in these cells, activation of the EGFR-PI3k-Akt pathway confers radioresistance35 and that inhibition of this axis by EGFR inhibitors sensitizes cells to IR.36 Further, Akt is an established mediator of radiation resistance in many cancer cells.37 The effect of lovastatin to inhibit IR activation of Akt illustrates a key property of this drug that luckily mediates its radiosensitization action.
A549 cells also carry a point mutation of the LKB1 gene (codon 37 [Q-Ter]) that generates a truncated LKB1 product.38 Therefore, these cells lack LKB1-regulated AMPK activation, an event that is shown to lead to aberrant activation of the Akt—mTOR pathway activating protein synthesis and survival.39 In this study, in agreement with earlier studies with statins,40 we observed that lovastatin alone activated AMPK. However, we observed that it also potentiated its activation by IR (Figure 4C). Recently, we observed that IR activates AMPK in LKB1 null A549 cells.5 Our observations in the same cells here suggest that lovastatin also activates AMPK in an LKB1-independent fashion. These observations are significant because AMPK is (1) shown to dephosphorylate and inhibit Akt through increased protein phosphatase 2A activity41 and (2) to inhibit the mTOR pathway by directly phosphorylating either its upstream regulator tuberous sclerosis 2 or its binding partner Raptor.39
Importantly, AMPK activation also mimics statin action because this kinase is known to inhibit HMG-CoA reductase.42 Therefore, AMPK activation by stimuli such as IR can work synergistically with lovastatin to augment the effects of inhibition of the mevalonate pathway. Taking these notions together with the discussion earlier, lovastatin seems to be a highly attractive agent with dual potential to enhance the activity of AMPK and inhibit the Akt pathway through a number of potential molecular steps.
IR regulates cell cycle through the induction of p53 and CDKIs, p21cip1 and p27kip1, expression to mediate mainly an arrest at the G2-M checkpoint.43 We hypothesized that lovastatin's antiproliferative effects may involve arrest of the cell cycle through enhanced expression of p53 and CDKIs. Although we did observe a potent induction of p53, p21cip1, and p27kip1 expression by IR alone, lovastatin inhibited IR induction of p53 and CDKI expression (Figure 5A). This may be due to either (1) effects of the drug on global gene transcription and translation or (2) a dependence of p53 and CDKI expression on specific events inhibited by lovastatin. Statins were shown to inhibit mTOR-dependent phosphorylation or deactivation of the translational repressor eukaryotic initiation factor 4E-binding protein, leading to suppression of initiation of cap-dependent mRNA translation.44 It should be stressed that we did not detect in our study any significant effects on the levels of any other proteins, including signaling molecules or actin, suggesting that a global effect on gene expression is unlikely. Conversely, Akt activity, which is inhibited by lovastatin, is required for the DNA damage–induced stabilization of p53,45 and this mechanism may be active in lovastatin-treated cells. A decrease in p21cip1 levels with statin treatment was observed by other investigators in A549 cells.22 Consistent with observations in HeLa cells,27 our work suggests that the mechanism of radiosensitization of A549 cells is independent of p53 and the CDKIs p21cip1 and p27kip1.
Lovastatin was shown to inhibit cell cycle progression at G0/G1 phase and promote apoptosis in thyroid cancer,46 breast cancer,47 glioblastoma,48 cervical cancer cells,27 and squamous cell carcinomas.49 In this study, we observed that lovastatin treatment shifted cells into G0/G1 phase with a markedly increased proportion of cells moving into apoptosis after 48 hours of treatment (Figure 5B). Prolonged treatment with lovastatin (96 hours) induced marked induction of apoptosis in nonradiated cells and caused a reversal of the G2-M checkpoint arrest induced by IR and a G0/G1 and apoptotic distribution (Figure 5B, C). It is possible that inhibition of the IR-induced G2-M arrest by lovastatin induced radiosensitization through prevention of DNA repair and induction of genomic instability.
Consistent with the cell cycle analysis results, we observed that lovastatin alone induced cleaved caspase 3, a significant contributor to protein degradation. Although IR caused a reversible induction of this marker that was not detectable after 24 hours, lovastatin enhanced and prolonged the IR-induced cleaved caspase 3 formation for up to 72 hours (Figure 6A). Furthermore, morphological analysis verified a progressive formation of apoptotic bodies with continued incubation with lovastatin (Figure 6B, C). Overall, our results are consistent with other studies,22,50 suggesting apoptosis as major mechanism of the cytotoxic action of lovastatin and suggests that this is also a predominant mode of action of the drug when combined with radiation in lung cancer cells.
A number of clinical studies explored the potential of lovastatin to achieve tumoricidal doses in human patients. Typical doses of lovastatin aiming to control cholesterol levels in humans are approximately 1 mg/kg/d and are shown to yield serum concentrations in the range of 0.15 to 0.3 μM.51 Early phase dose-escalation studies have explored a number of regiments, and in a study of 7 consecutive days treatment, in 4-week cycles, doses up to 25 mg/kg/d were tolerated without severe myopathy.51 Ubiquinone is used to address myopathy. Under these conditions, maximum tolerated doses were not reached, and systemic drug concentrations reached 0.1 to 3.92 μM.51 In a study with end-stage head and neck and cervix cancers patients,52 a regiment of 7.5 mg/kg/d for 21 consecutive days in 4-week cycles was defined as maximum tolerated doses in patients with good renal function. Although no objective responses were seen in this study, where lovastatin was used as a single agent, the authors still reported a 23% rate of stable disease at 3 months,52 which is indeed encouraging in patients with end-stage disease.
The aforementioned studies suggest that it is possible to achieve safely tumoricidal and radiosensitizing doses of lovastatin in cancer patients. Our work indicates that some lung cancer tumors may exhibit sensitivity to lovastatin even in the high nanomolar range (Figure s1, Supplemental Digital Content and discussion earlier) making it even more plausible that lovastatin will sensitize tumors to IR in human patients. Overall, these data indicate that this drug deserves further investigation with in vivo preclinical and clinical studies. Although, other statins may also be able to radiosensitize lung tumor cells (Figure s2, Supplemental Digital Content and discussion above), lovastatin remains the best studied agent in this class, in both the preclinical and the clinical setting and, therefore, is the most favorable candidate for further development.
Figure 7 illustrates our model of the action of lovastatin in lung cancer cells. Our work suggests that lovastatin is a promising agent with significant antitumor properties as a single agent and a radiation sensitizer. Lovastatin seems to function mainly through induction of apoptosis. This effect may be mediated by a unique simultaneous inhibition of the prosurvival Akt and activation of the tumor suppressor AMPK pathways. This work presents compelling evidence that support further investigation of lovastatin as a radiation sensitizer in vivo. Work in animal models of lung cancer will expedite the development of this drug to the clinical setting in early phase studies in combination with radiotherapy.
Supported by funds from the Juravinski Cancer Center Foundation. We appreciate the support by Dr. William K. Evans (CEO, Juravinski Cancer Center), in the pursuit of this study.
This article has been cited 1 time(s).
Lovastatin; Lung cancer; A549 cells; Radiation sensitizer; Apoptosis; Akt; AMPK; Erk; EGFR; Cell cycle; Cleaved caspase 3
© 2011International Association for the Study of Lung Cancer
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Delicate pink, purple, & yellow butterflies send a simply worded "thank you" to your loved ones and guests on this gentle butterflies thank you card design. You can make this into a flat or folded butterfly thank you card, and we can make the back/inside blank for your handwritten notes or we can include a printed message for wee ones who are too little to write notes yet. See more ideas & personalize this design for your own gratitude on the product page here: Pastel Butterfly Thank You Cards.
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April 2, 2015
Soft Blue Butterfly Kisses Thank You Card
Send a personal note of thanks with this sweet & soft blue butterfly kisses thank you card! The design features a water colored style blue border, accented with soft butterfly graphics along the bottom right corner. The simple flowing script of "Thank…
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I have a ScoreView that keeps track of the current score, but I am having trouble getting it to re-render when a model attribute changes. Here is what the view looks like:
var ScoreView = Backbone.View.extend({
initialize: function() {
_.bindAll(this, 'render');
this.model.bind("change", function() {
if (this.hasChanged("score")) {
alert("score has changed");
render: function() {
alert("drawing new score");
return this.model.get("score");
When the score changes, the view does not re-render. I do get the alert, "score has changed", when the score changes. When I print out the contents of "this.render", the console says that the function is undefined. I think that the code thinks that the "this" in this context is the model, but I want the context to be the view. How would I fix this?


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CITATIONS: Social Security Act Secs. 206, 206(a), 1631(d), 208, 1106, 1107, and 1631(d)(2) CFR No. 4 Sec. 404.1740 and CFR No. 16 Sec. 416.1540 Regulations No. 4 Sec. 404.1740, Regulations No. 16 Sec. 416.1540, and Regulations No. 10, Sec. 410.687
To ensure that claimants receive competent services from their representatives and to improve the efficiency of the Social Security Administration's (SSA) administrative process, SSA formulated the Rules of Conduct and Standards of Responsibility for Representatives. (20 CFR 404.1740 and 20 CFR 416.1540). These rules establish affirmative duties and describe prohibited actions for representatives. We may suspend or disqualify a representative from practicing before us if the representative violates these rules.
A representative must:
Act with reasonable promptness in obtaining and submitting, as soon as practicable, to SSA or the disability determination services (DDS), information and evidence that the claimant (or the representative) wants the decision-maker to consider when ruling on the claimant's claim.
Assist the claimant in complying, as soon as practicable, with SSA's or DDS' requests for information or evidence at any stage of the administrative decision-making process in his or her claim. In disability and blindness claims, this includes assisting the claimant to acquire and provide evidence about the claimant's:
daily activities,
work experience and efforts,
workers' compensation, and
other disability or non-disability related information
Conduct his or her dealings in a manner that furthers the efficient, fair, and orderly conduct of the administrative decision-making process. This includes both of the following:
Provide competent representation to a claimant
Providing competent representation means that a representative knows the significant issue(s) in a claim and has a working knowledge of the applicable provisions of the Social Security Act, the Regulations, and the Social Security Rulings. In addition, the representative should also know how to obtain and submit evidence regarding the claim; and
Act with reasonable diligence and promptness
Acting with reasonable diligence and promptness means that the representative provides prompt and responsive answers to requests and communications from SSA or DDS pertaining to the processing of a pending claim.
Conduct business with us electronically at the times and in the manner we prescribe on matters for which the representative requests direct fee payment.
On September 12, 2011, we published a final rule requiring that certain representatives conduct business with us electronically using our online services (76 FR 56107). We said that we would publish a notice in the Federal Register announcing each new electronic service requirement.
On January 31, 2012, we filed a Notification of Implementation of Requirement announcing that representatives who are eligible for and request direct fee payment on a case must file certain medical appeals electronically beginning on March 16, 2012 (77 FR 4653).
We initially provided an educational period to encourage representatives to work with iAppeals and to become more familiar with the process. Now that this initial educational period has expired, we are providing instructions on how to refer potential sanctions situations to the Office of General Counsel (OGC).
Accept and process all paper appeals (SSA-561, Request for Reconsideration, and HA-501, Request for Hearing by Administrative Law Judge, along with paper SSA-3441s, Disability Report - Appeal). Do not return paper appeals to the representatives and do not re-contact the representatives to ask them to re-submit their already-filed paper appeals forms in an electronic format. Do not require submission of the SSA-1696 (Appointment of Representative) or the SSA-1695 (Identifying Information for Possible Direct Payment of Authorized Fees) prior to, or in conjunction with the appeals submission. Instead, for referral of violations for possible imposition of sanctions, see GN 03970.017F in this section.
We are not mandating that representatives use direct deposit.
This new requirement does not affect direct payment of fees. Continue to pay fees directly to an eligible representative on cases where the representative has requested direct payment, even for paper appeals.
A representative must not:
In any manner or by any means threaten, coerce, intimidate, deceive, or knowingly mislead a claimant, or prospective claimant or beneficiary, regarding benefits or other rights under the Social Security Act.
Knowingly charge, collect, or retain, or make any arrangement to charge, collect, or retain, from any source, directly or indirectly, any fee for representational services in violation of applicable law or regulation.
Knowingly make or present, or participate in the making or the presentation of, false or misleading oral or written statements, assertions, or representations about a material fact or law concerning a matter within SSA's jurisdiction.
Through his or her own actions or omissions and without good cause, unreasonably delay or cause to be delayed, the processing of a claim at any stage of the administrative decision-making process. Unreasonable delay is delay that is not justifiable, or delay that is preventable with reasonable care.
Divulge, without the claimant's consent, except as authorized by regulations prescribed by SSA or as provided by Federal law, any information SSA or the DDS furnishes or discloses about a claim or prospective claim.
Attempt to influence, directly or indirectly, the outcome of a decision, determination, or other administrative action by offering or granting a loan, gift, entertainment, or anything of value to a presiding official, SSA or DDS employee, or witness who is or may be expected to be involved in the administrative decision-making process, except as reimbursement for legitimately incurred expenses or lawful compensation for the services of an expert witness retained on a non-contingency basis to provide evidence.
Engage in actions or behavior prejudicial to the fair and orderly conduct of administrative proceedings, including, but not limited to:
repeated absences from, or persistent tardiness at, scheduled proceedings without good cause;
willful behavior which has the effect of improperly disrupting proceedings or obstructing the adjudicative process; and
threatening or intimidating language, gestures, or actions directed at a presiding official, witness, or SSA or DDS employee that results in a disruption of the orderly presentation and reception of evidence.
Violate any section of the Act for which the law prescribes a criminal or civil monetary penalty.
Refuse to comply with any of our rules or regulations.
Suggest, assist, or direct another individual to violate our rules or regulations.
Advise any claimant or beneficiary not to comply with any of our rules or regulations.
Fail to comply with our decision about sanctions.
Knowingly assist someone who is suspended or disqualified to provide representational services or exercise the authority of a representative as described in 20 CFR 404.1710 and 20 CFR 414.1510.
NOTE: The sanctions described in the introduction are not exclusive. Aside from suspension or disqualification, a representative who engages in conduct that violates a provision of the Act may also be subject to incarceration, fines, and civil monetary penalties. See information on violations of the Social Security Act in GN 04105.000, Violations of the Social Security Act.
A total unauthorized fee collection is when the representative collects his or her fee directly from the claimant, any auxiliary beneficiary, another individual (whether related or unrelated to the claimant or auxiliary beneficiaries), or through an erroneous SSA fee payment, without prior SSA authorization. (Payments to representatives by third-party entities are an exception to the SSA general authorization requirement. See information on representative's fees not subject to Social Security Administrations authorization in GN 03920.010 and 20 CFR 404.1720(e) for other exceptions). For processing instructions, see information on referrals of suspected fee violations, possible fee violations, and non-fee violations in GN 03970.017.
A partial unauthorized fee collection occurs when SSA authorizes a fee based on a fee agreement or fee petition, but the representative collects an amount in excess of the fee SSA authorized. The amount over the authorized fee is a partial unauthorized fee collection. For processing instructions, see information on referrals of suspected fee violations, possible fee violations, and non-fee violations in GN 03970.017.
NOTE: Occasionally, SSA pays a representative in error. Such a direct payment error may result in an unauthorized fee collection if the representative does not return the erroneous fee on receipt or following an SSA request (see GN 03970.010D.3. in this section). This unauthorized fee collection could be partial or total as described in GN 03970.010D.1.a. and GN 0970.010D.1.b. in this section. For example, the Processing Center (PC) or Field Office (FO) directly pays the representative more than the fee amount that SSA authorized (and the representative does not return the excess payment). This often is in the form of a duplicate payment and it can be any amount in excess of the authorized fee. For processing instructions, see information on referrals of suspected fee violations, possible fee violations, and non-fee violations in GN 03970.017.
Non-fee violations are unrelated to charging and collecting a fee. A representative commits a non-fee violation when he or she fails to comply with the affirmative duties in GN 03970.010B (in this section), or if he or she violates any of the prohibited actions in GN 03970.010C (in this section), in the Rules of Conduct, except for the fee rule in GN 03970.010C.2. (in this section) to knowingly charging, collecting, or retaining a fee in violation of law or regulation. For example, ignoring a request to submit certain evidence or obstructing the administrative process; deliberate and consistent tardiness or inexcusable delay for hearings; disruptive, coercive, or threatening behavior to SSA staff or claimants; conspiring to submit or knowingly submitting false documents; disclosing the claimant's or auxiliary's private information without his or her prior consent; or failing to conduct business with us electronically when SSA requires it, are all non-fee violations. Some non-fee violations may also be criminal violations.
Non-violations are actions in conflict with our fee-charging rules, generally done because of lack of knowledge and without intent to violate our rules. In these cases, the representative often acts to correct the issue before SSA intervenes or upon notification. For example, SSA sends a representative an unauthorized fee check by mistake, but the representative repays the fee immediately after he or she learns that the check was a mistake and before SSA takes further action.
Non-violations usually occur when the representative is not at fault, or the questionable fee is not an actual violation of our rules.
A representative petitions for and SSA authorizes a fee of $1,950. Withheld past-due benefits are only $1,640. Through error, SSA pays the representative directly the full fee of $1,950. The representative is not in violation of any Social Security regulations because the representative has not collected a fee in excess of what SSA authorized.
The representative correctly identifies herself as a non-attorney ineligible to receive direct fee payment. She submits neither an SSA-1695, nor an SSA-1699 (Request for Appointed Representatives Direct Payment Information). SSA authorizes a fee and directly pays the amount to the representative in error. Because the representative did not do anything to secure a direct fee payment and SSA's payment was in error, the representative has not violated SSA's rules. Refer to Office of General Council those situations where a non-attorney actually took affirmative steps to secure a direct fee payment by wrongly claiming attorney or eligible for direct payment non-attorney (EDPNA) status, per GN 03970.017.
Susie B., a representative employed by a non-profit group petitions, for a fee in a title XVI (SSI) claim. The organization's bylaws however, prohibit the representative from petitioning SSA for a fee. Since the representative did not waive her right to charge and collect a fee and since SSA has no authority to enforce a non-profit organization's rules (SSA only governs the authorization and payment of fees), the representative may file a fee petition and receive an authorized fee without violating SSA rules.
While the following examples do not cover every situation, they provide a general idea of the types of situations that may indicate that a representative has failed to meet his or her affirmative duties or has engaged in prohibited conduct. This conduct may lead to a representative's suspension or disqualification and possibly criminal prosecution.
Before the hearing John Rep, the appointed representative, submits the wrong evidence. He is ill informed about the process, and unfamiliar with Social Security laws. At the hearing, the representative is unfamiliar with the issue(s) or the applicable Social Security laws and regulations or with the facts of the case. During the course of the hearing, it becomes evident that the representative is unprepared to ask questions, argues the wrong issue, or cites the wrong title or rule. By failing to provide the claimant with competent representation, the representative has failed to perform his affirmative duties, as described in GN 03970.010B (in this section).
Jane Jones, a representative of a claimant for title XVI benefits advises the claimant that she will charge the claimant 25 percent of retroactive benefits if SSA allows the claim, but nothing if we deny the claim. The representative tells the claimant that she does not want all the "red tape" involved with direct payment of her fee from SSA and persuades the claimant to bring her first installment check to the representative's office for settlement of the fee. The representative never submits a fee agreement or fee petition to SSA and further tells the claimant that, "anyway, SSA routinely authorizes representative fees of 25 percent of retroactive benefits." SSA allows the case on reconsideration, which results in the reopening of a prior denied claim and an award of retroactive benefits. The claimant pays the representative, per their agreement, 25 percent of her retroactive benefits–$8,500. By knowingly charging, collecting, and retaining a fee without SSA's authorization, the representative has engaged in prohibited conduct as described in GN 03970.010C (in this section).
NOTE: SSA permits representatives to collect a fee from a claimant prior to receiving authorization from SSA as long as they hold the money in a trust or escrow account and do not withdraw the money until they receive SSA's authorization. See information on representative's fee – trust or escrow accounts in GN 03920.025.
Joe Abel, a claimant, has a private insurance policy that pays him benefits when he is unable to work. The insurance company informs Mr. Abel that the terms of the policy require him to file for title II disability insurance benefits (DIB). The claimant receives assurance that the insurance company provides, at no charge, a representative to represent him before SSA. The claimant agrees to this representation. Later, SSA awards the claimant DIB. Tom Cain, the representative informs SSA that he is waiving his fee in this representation. Following the terms of the policy, the claimant notifies the insurance company about the award of benefits. The insurance company then pays the representative $6,000 for representation of the claimant before SSA and deducts the same amount from the claimant's insurance policy benefits. By knowingly circumventing our rules, which require that when a third party pays a representative's fee, the claimant and any auxiliary beneficiaries must be free of liability directly or indirectly, the representative engaged in prohibited conduct as described in GN 03970.010C (in this section). See 20 CFR 404.1720(e) and 20 CFR 416.1520(e).
Pat Slick, the appointed representative, informs the claimant that she will not receive a fee unless SSA allows the case and the case results in past-due benefits. The representative also advises the claimant that SSA must authorize her fee unless an entity or government agency is paying for the fee from its funds. To avoid delay in payment and "red tape" the representative suggests that the claimant's uncle write a check from his company's account to pay the fee and the claimant can later reimburse the uncle. The representative waives her fee from SSA. The representative receives a check from the uncle's company for her requested fee. When the representative collects the indirect payment, she has knowingly circumvented our rules and engages in prohibited conduct described in GN 03970.010C (in this section). See 20 CFR 404.1720(e) and 20CFR 416.1520(e).
Jim Cool, a representative, receives a properly authorized direct payment of $1,800 from withheld past-due benefits for his services representing a disability claimant before the Office of Disability Adjudication and Review (ODAR). Inadvertently, SSA certifies duplicate payment of the fee to the United States Treasury. The representative receives the second check of $1,800 and deposits the check into his account. The FO or PC notifies the representative of the duplicate fee payment, provides copies of the United States Treasury checks involved, and seeks refund. The representative ignores the notices from the FO or PC to refund the duplicate payment or declines to repay. This conduct violates the rules in GN 03970.010C (in this section), as the representative is now knowingly retaining a fee in excess of the amount SSA authorized.
Joe Harper, a claimant, signs a fee contract with Mr. Sawyer, a representative for representational services before SSA. This fee contract states that the "minimum" fee is $1,000. The fee contract does not state that SSA must authorize the fee. Later, the representative sends SSA a fee petition requesting $1,000 for representing the claimant. SSA authorizes a fee for $700. The representative then seeks an additional $300 from the claimant. This is a fee violation because the representative is charging, and possibly collecting, a fee that is $300 more than the fee SSA authorized. Furthermore, the representative misled the claimant concerning the minimum fee. In a fee petition matter, SSA never determines a fee based upon a specific sum agreed between the representative and the claimant, and the representative never told the claimant that SSA has to authorize the fee. See GN 03970.010C (in this section).
Bob Sid, a representative, requires that prospective clients agree to and implement the following conditions before appointing him as their representative:
Establish a bank account in the client's name that permits the representative to sign, or requires the representative to co-sign, checks against the funds in that account, or allows the representative to make electronic withdrawals; and
Request that SSA direct deposits the client's Social Security or Supplemental Security Income benefit or both into the account.
After SSA deposits the claimant's past-due benefits into the account, the representative writes a check, or requires the claimant to co-sign a check against the funds, or the representative accesses the funds to collect his fee for representative services. Any such arrangement circumvents the direct payment provisions of the Social Security Act and the Social Security Disability Applicants' Access to Professional Representation Act of 2010. By gaining such control of the claimant's Social Security benefits, the representative may violate the provisions in sections 207 and 1631(d)(1) of the Act that prohibit the transfer or assignment of the right of any person to any future payment (benefits) under our titles. (For information on assignment of benefits, see GN 02410.001D.2.) In addition, if a fee is collected from the claimant without SSA's prior authorization, then the representative is charging and collecting an unauthorized fee and may be violating our regulations in 20 CFR 404.1720, CFR 20 404.1740(c)(2), and CFR 416.1540(c)(2).
The attorney or EDPNA routinely requests direct payment of fees on cases that he or she submits paper appeal requests on medically denied initial claims or reconsiderations. By failing to file these appeals electronically, the attorney or EDPNA is violating the affirmative duty to conduct business with us electronically when we require it.
The attorney or EDPNA routinely suggests that the claimant submit a paper request for reconsideration or hearing and then after the fact, routinely submits the SSA-1696 indicating his or her choice of direct fee payment along with the SSA-1695. By routinely encouraging the claimant to file these appeals in paper and subsequently submitting the SSA-1696 and SSA-1695, the attorney or EDPNA is circumventing the affirmative duty to conduct business with us electronically.
NOTE: As long as a representative submits any part of the appeal electronically, we will consider that he or she is complying with the requirement to use iAppeals. When a representative continually fails to comply, however, and repeatedly submits appeals entirely on paper, at the same time requesting direct fee payment, we may document and refer the representative to OGC for an investigation that could lead to his or her suspension or disqualification.
While the following examples do not cover every situation, they provide a general idea of the types of situations that may indicate that a representative has engaged in prohibited conduct. Some actions that violate the Rules of Conduct Prohibited Actions may also violate laws that have criminal penalties. For example, a fee violation or a representative's knowing and willful action to deceive, mislead, or threaten a claimant or beneficiary could violate not only SSA's Rules of Conduct and Standards of Responsibility for Representatives, but also could constitute a criminal violation. We may find an individual guilty of a criminal violation and also suspend or disqualify him or her from being a claimants' representative.
Trudy Jones, a mother files on behalf of her 2-year old son, alleging the deceased number holder (NH) is the child's father. She is unable to establish the child's relationship to the NH or provide proof that the NH supported the child before his death, so SSA denies her claim at the initial level. The mother appoints a representative to appeal the unfavorable determination. The representative submits additional evidence in the form of four affidavits of persons alleging knowledge, which attest to the NH's paternity of the child. The child is awarded benefits as a surviving child. SSA later learns that a legal wife and two children are entitled to benefits on the earnings record of the deceased. During the adverse claim proceedings, the legal wife challenges the validity of the illegitimate child's paternity. An investigation reveals that the affiants only had casual acquaintance with the deceased. The representative initiated conversation with all four affiants in a bar and ultimately persuaded each to prepare and sign the affidavits in return for $50 each. In this instance, the representative engaged in prohibited conduct as described in GN 03970.010C (in this section), which could subject the representative to suspension or disqualification from practicing before SSA and possibly criminal penalties, including a fine and incarceration.
Becky T., the claimant, approaches H. P. Finn, a representative, to inquire about filing a claim for title XVI benefits and about representation in this claim. After explaining all options, the representative asks the claimant if she wishes to file for benefits at SSA, and if she would like the representative to represent her in her claim. The claimant shakes her head uncertainly and replies that she would like to think about it. She promises to call back. After the claimant leaves, the representative applies online on the claimant's behalf, clicking to sign the application as if the representative were actually the claimant. By impersonating the claimant, the representative engaged in prohibited conduct that could subject him to suspension or disqualification and possible criminal penalties, including a fine and incarceration.
Jules Smith, a busy representative shares an office with Tim Nemo, an independent insurance agent. The insurance agent proposes to pay the representative a finder's fee for the name, address, and monthly benefit amount of each of his or her clients found entitled because of disability. The insurance agent intends to use these beneficiaries as prospective customers for a medical insurance plan he hopes to sell, as a supplement to coverage provided by State and Federal programs. The representative agrees and provides the agent a list of such people without first obtaining consent from his clients. By divulging information that he obtained from SSA, without the claimant's written consent, the representative engaged in prohibited conduct as described in GN 03970.010C (in this section). This conduct could subject the representative to suspension or disqualification and possibly criminal penalties, including a fine and incarceration.


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MDW Chaplains show off new office
November 6, 2013
By Mr. Cory Hancock (JFHQNCRMDW)
The Joint Force Headquarters-National Capital Region/U.S. Army Military District of Washington Chaplains Office hosted an open house and lunch to showcase their new office at Fort Lesley J. McNair, Nov, 4.
"Awesome facility! I am very impressed by the Chaplains new location," said Stan Trader, Plans and Operations J/G1. "Kudos to everyone involved in designing and making this a first class office."
The Chaplains office moved from Building 45 to the recently remodeled Building 48 Annex. Visitors to the new location were treated to tour and lunch.
"This event was important in three ways," said Chaplain (Lt. Col.) Mitch Butterworth, MDW deputy command chaplain. "Number one, it helped orientate the staff and directorates to the location of the new office. Number two; it was a morale and team building activity for staff and directorates; and number three, the open house provided an outlet for everyone to decompress and interface with other staff and directorates."
"Thanks to the Chaplain staff for putting together a great Open House," said Trader. "Not only was the food fantastic, but the welcoming and friendly atmosphere that is always projected by their staff is a blessing."
According to Butterworth, the new office is spacious, comfortable, modern, and functional. "I think that service members, civilians, and their families will appreciate the space, comfort, and warm environment should they need to seek out a Chaplain for assistance," said Butterworth.


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GM and Chrysler are already shutting down assembly lines and dropping some of their poorest-selling models. Say goodbye to Dodge Aspen, Durango, PT Cruiser, Saturn, Hummer, some Pontiac models ... and who knows how many others by the time all this is over.
A lot of good people, people who've done their jobs and followed the rules, many of whom have been pillars of their church and community, are going to get hurt. Like the kind of small-town car dealers who are the bulwark of every good cause in their community. While the highbinders may float away on their golden parachutes, everybody else could feel the pinch.
But Americans have gone through much worse and not only survived but triumphed. Better a definite crisis now that leads to a new start than unending entropy.
Creative destruction, the economist Joseph Schumpeter called the essence of capitalism. While it's the destruction that may be most evident at the moment, the creativity is already showing. Saturn dealers, for example, are tying to find a way to preserve Saturn as an independent, freestanding, international company.
Why let these huge moribund corporations divest themselves of this or that branch piecemeal as they founder? Are they likely to do any better at shutting down their unprofitable branches than they did adding them?
Why not do the job for them? It needs to be done quickly, clearly, legally -- in bankruptcy court.
Yes, it would be painful. Drastic surgery usually is. But afterward these overextended outfits could start to recuperate.
Congress' approach to date can be summed up simply enough: Send good billions after bad, getting only paper promises and vacuous assurances in return. That's not good enough. These corporate leviathans are a money hole. The only thing sure about the next bailout is that still another will be demanded.
But the administration may only temporize, and wind up adopting the Japanese model willy-nilly. This country, too, can lose the next decade. East and West can meet -- in failure.
Let's give the American auto industry a new beginning. And end this form of corporate welfare as, unfortunately, we're coming to know it.
Pulitzer Prize-winning Paul Greenberg, one of the most respected and honored commentators in America, is the editorial page editor of the Arkansas Democrat-Gazette.
McCain: Let's face it, Trump's rhetoric is turning Muslims all over the world against us | Allahpundit


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Taste of Ocala winners
Published: Monday, April 20, 2009 at 3:26 p.m.
Last Modified: Monday, April 20, 2009 at 3:26 p.m.
These are the announced contest winners from Taste of Ocala 2009:
Judges Award for Food & Booth Presentation
- 1st Place CTAE (Community Technical & Adult Education)
- 2nd Place Brick City Catering
- 3rd Place Hilton Ocala
Peoples Choice Awards
- Casual Dining
- 1st Place Horse & Hounds Restaurant & Pub
- 2nd Place Barbazons Sports Bar & Grill
- 3rd Place Mojo Grill
- Catering
- 1st Place Brick City Catering
- 2nd Place CTAE (Community Technical & Adult Education)
- 3rd Place Hilton Ocala
- Quick Service
- 1st Place Back Yard Burgers
- 2nd Place Dukes Original Cheesesteaks
- 3rd Place Wing Zone
- Specialties & Desserts
- 1st Place Brusters Real Ice Cream
- 2nd Place Melting Pot
- 3rd Place CJs Bakery & Sweets
- Beverages
- 1st Place Smoothie King
- 2nd Place Bernie Little Distributing LLC
- 3rd Place Silver Springs Bottled Water Co.
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My Glamorous Research Assistant is holding a 'vintage tea party' themed party this weekend, so naturally she looked at the mountain of organising, styling, designing, catering and collating that would be needed and deduced immediately that I was best put in charge of … the music. And nothing else.
Puppet to Ansible
I've just completed the move of the configuration management for my very small home network from an obsolete Puppet 2.x setup to Ansible. Total time = approximately half a day. Showstoppers - none.
Parsing a Twitter Archive
I just signed up to Pinboard because I wanted a permanent resource to capture all the links I've posted and retweeted on Twitter. While Pinboard integrates well in terms of capturing links from your ongoing feed, it will only work backwards to the previous 3200 tweets due to Twitter's API limit. So the first thing I wanted was to do was process my long term Twitter archive to get everything from the previous four years. You'd think other people would want this too, so something must exist to do it, right? Wrong.
It's Complicated
A curmudgeon's guide to Hand. Cannot. Erase. by Steven Wilson
An interesting thing happened when I added Steven Wilson's forthcoming album Hand. Cannot. Erase. to my Amazon wishlist. Suddenly, my Amazon recommendations filled up with the most appalling shite, presumably on the basis that "other people who want Hand. Cannot. Erase. also have absolutely no taste in music". A solo album from a member of a decidedly middle-ranking, way past best-before neo-prog act - srsly? What bothered me more was the worry that all the other fans of Wilson' oeuvre were actually displaying consistent taste, whereas this was an outlier for me.
Computational Pragmatics
Everyone should attend at least one truly memorable lecture in their university career: the one so well-presented or eye-opening in its content that it stayed with you for the remainder of your career. Mine was the last lecture of our Computer Science C235h module at UWA, in which the lecturer immediately grabbed our attention by announcing that there would be no notes as what he was about to say would 'upset' certain members of the rest of the department wedded to the accepted wisdom of software engineering practice. In fact, he said, this lecture might be subtitled 'What they don't tell you in Software Engineering'.
Plum Umbrella by Saul Leiter
"Plum Umbrella, c. 1957" by Saul Leiter. An early adherent of colour film, Leiter's work in the medium was mostly neglected during his working career, finding few commercial outlets at the time. The rich body of images he amassed around NYC in the late 50s and early sixties was only rediscovered and promoted in his latter years.
In this shot, Leiter employs one of his favourite devices, closed framing: the titular object blocks our view of the majority of the figures underneath. Between the umbrella in the foreground, which is out of focus, and the large expanse of pavement in the background below, the middle ground forms only a minor part of the overall image and yet holds the key details we need to make sense of it.
The Basics of Baking
Having some time on my hands lately (in which to grow and flourish in exactly the way that potted plants tend not to in office environments), I did some baking. I baked a chocolate loaf, some Aberffraw (shortbread) biscuits, an apple cake and some soda bread, and they all turned out decently, to varying degrees of yumminess. But this was entirely thanks to following the recipes; had I not done so, I wouldn't have had the first clue what I was doing or where to start - rather reminiscent of several pieces of software I've installed and configured under Googled recipes. I don't actually understand how any of this stuff works; I just know to follow a recipe.
Astra Head Unit Replacement
I know it's not a glamorous vehicle and it will never set anyone's pulse racing, but I quite like my Vauxhall Astra. For a start, it has an engine, four wheels and a roof, all of which appear to be of adequate construction, and that's always been a key consideration for me as a discerning car-shopper with absolutely no knowledge or interest in cars whatsoever. However, the one component that lets it down, as with so many popular makes, is the factory-fitted stereo.
Entertainment U Say?
This is the story of a time when I had poor taste. (In music, I mean. Clothing, I've never had much taste in.) But I wasn't alone. It was the Eighties. And my poor taste wasn't as poor as everyone else's poor taste.
Must Be True, I Saw It on Telly
This week, Prime Minister David Cameron attempted to justify a fresh push on the Communications Bill to the Joint National Security Strategy committee by referring to the use of mobile data in "crime dramas" on television. (He also later urged the media to "think before they act" in relation to the Snowden revelations, presumably as opposed to "thinking while watching acting" or, to put it more precisely, "not really thinking at all".)


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Herald of the Titans earnt before the release of Cataclysm. Had someone ask me when I got it recently, and I said WOTLK and he told me the achievement wasn't possible to get back then, cried a little bit inside. However I earnt it after the Cataclysm system patch with the introduction of Holy Power and the like so I don't consider it a proper one, but at least I earnt it back then without leveling an alt for it.
A Tribute to Insanity (10man) - earnt in early ICC days so again not proper but over 75% of the people I did this with have since quit and being on an underpopulated server very few people got this ever.
Champion of Ulduar - basically The Undying but in Ulduar. Got all the bosses for this in Ulduar days except Mimiron for which I had to wait til early ICC again, because we kept running Ulduar for it and different people each week purposely ran into Mimiron's one shot abilities thinking it was funny. Great guild I was in, in terms of attitudes and people. Don't think more than 4 or 5 guilds got this on the server and all the others except mine were primarily 25man guilds and we weren't, so they got the 25man one too (and then almost all of them promptly quit, I have NEVER seen anyone wear Champ of Uld on my server except me and 1 person wearing Conqueror).


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text: > see full product details Please select the size of the product. Pour la Victoire fuchsia satin 'Floral' jeweled bow pumps overview details reduced price $29.97 sale $20.98 bluefly price $99.00 retail value $170.00, you save 88% color : We're sorry. This style is sold out. We're sorry. This style is sold out. David Giordano gives us a taste of Parisian style with his eclectic range of Pour La Victoire shoes and accessories. Color: Fuchsia Semi-lustrous satin upper Pointed toe Jewel encrusted bow adorns toe Lightly padded footbed Leather lined Leather sole 4" satin covered heel All measurements are approximate Fabric / Leather; Imported; style#317409402


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HIGH SCHOOL FOOTBALL: Bobcats' offense gains statewide attention
CHS rewrites record books with 84-point outburst
SAN ANGELO, Texas - What: District 2-5A football opener
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A Thai inspired squash soup that is great as a first course or even as a main course in larger batches. Warm and fragrant, it is perfect for any time of year and is great paired with a nice, light tasting, hoppy beer (Victory Prima Pils, DAB, Flying Fish Farmhouse Summer Ale ).
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Whole, uncrushed grapes are fermented in a sealed vat containing a layer of carbon dioxide. This results in fruity, soft and distinct red wines. These wines have little tannin and are immediately drinkable. This is the method used throughout France's Beaujolais region.
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This is a well established vending route. The business services long standing customers in both New Jersey and Pennsylvania. The business operates 4-5 days per week and offers snack and beverages services to their customers. The sales are pretty consistent throught the year! The Seller will be available for Traning and Transition after the sale. This is an excellent opportunity for you to be your own boss, call today about this great opportunity!
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Solid opportunity to own this highly successful Vending company with dozens locations in the Northern New Jersey. The company supplies corporate refreshment services in New Jersey with well over one hundred modern vending machines in various commercial and corporate locations. From school systems to office building, this thirty five year old company...
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Jan. 4, 1964—Mary Sullivan, 19, the last of the 11 victims, found murdered in her apartment in the Beacon Hill section of Boston.
1965—Albert DeSalvo, a factory worker being held on unrelated charges, confesses to the Strangler's 11 killings and two others. He never is charged with them.
1973—DeSalvo killed in prison by another inmate.
July 1999—Boston police reopen the Strangler case, hoping to use DNA technology to analyze evidence from the crimes.
Sept. 14, 2000—The DeSalvo and Sullivan families sue local and state authorities in Massachusetts to force investigators to turn over crime scene evidence they say will prove DeSalvo's innocence.
Oct. 14, 2000—Sullivan's remains exhumed for DNA testing.
Oct. 20, 2000—Massachusetts Attorney General Thomas Reilly says his office will do new DNA tests on evidence from Sullivan's slaying.
Oct. 26, 2001—DeSalvo's body exhumed for DNA testing.
Dec. 6, 2001—Forensic scientists announce that DNA evidence taken from Sullivan's body does not match DeSalvo's DNA.
Dec. 24, 2001—Judge says state doesn't need to share forensic evidence with the DeSalvo and Sullivan families because the investigation into the killings remains open.
July 11, 2013—Suffolk District Attorney Daniel Conley says advances in DNA technology have allowed investigators to link DeSalvo to Sullivan's killing.


text: Simon is embarking on his third consecutive EuroBasket after making a debut in 2011. At that tournament Croatia might have failed miserably, but the lefty combo-guard grabbed the chance he was given, and has become a regular member and a key contributor for Croatia ever since. With a long-ago developed scoring habit, the 30-year-old Simon is no stranger to being among Croatia's top scorers at the end of the night. He is not the most athletic of players, but he keeps defences honest with his sweet three-point touch, and the ability to penetrate, while being a great ball handler with a knack to find an open man. Such versatility, combined with his size, allows coaches to comfortably use him at both guard positions, but also exploit mismatches at small forward. In other words, when the game is on the line, Simon is likely to be on the floor.


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I saw
Type: Posts; User: OneSloRngr
I saw
Wow, my kind of build. Wouldnt even talk you down from 5k, glws :thumbup:
I had a 1991 Brougham, its was underpowered but sounded cool. Pretty much just glided on the highway. Super comfortable, reliable and cheap to buy.
Wow glws :thumbup:
Youre in danbury? Plenty a decent shops that'll do it for decent price, it should only take an hour total removing / installing the knuckle plus however long it takes to press the bearing out and in....
I know these cars are known to last a long time and are most shuttles to nyc...
Does it run? Just not drive?
Flipped it
Its a vf engineering kit.
Did you rear end someone? Dont understand why theres a black bumper and no grille with the rare wingswest brow and the smoked e-codes.
Beautiful car man, she deserves a good home
The op also posted this masterpiece a while back
Well, we'll see what happens maybe ill by this from you in a few months. I know how you feel, the reason why i cant buy it today is because ive been through 5 cars this year haha.
Price is deff not the issue. Dunno how much longer youre gonna have this but unfortunately im not looking to buy a car till tax return season. GLWS tho :thumbup:
5k and you still have this? Id buy this in a heartbeat if ibwasnt so bad with money.
Aw man sweet ass truck! Id offer my miata if it werent such a ****box GLWS :thumbup:
Dude. Its amazing, dont sell it cause i cant afford to buy it.
Having driven both, charger 11/10 times. I found the sonata hard to get comfortable in and really disliked the the electric assist steering. The charger on the other hand was much more comfortable,...
How is it not a future classic? It's already a classic.
So i just got a 96 1.8 in a trade for my old jetta, ive been waiting to make a thread about it so i figured i'd ask here. Anyone have a spare right front knuckle? Po was a moron, left the ipper...


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Everything tagged
Latest from The Spokesman-Review
Gear Junkie: Standouts at Utah Outdoor Retailer Show
Aug. 19, 2012 in Outdoors on Page C11 More than 1,000 brands and tens of thousands of attendees gathered last week for the twice-annual Outdoor Retailer trade show in Salt Lake City. I was on site for four …
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July 5, 2009 in Outdoors on Page C9 Swooping nylon and linked poles, zippered doors, screened windows and stakes in the dirt holding it down – the humble formula for a tent has long prevailed as an ultimate …
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April 19, 2009 in Outdoors on Page C11 There is a soft place in my heart for REI tents. As a developing backpacker in the early '90s, I bought an REI tent on sale for about $150 and …


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"I really liked everything about the card. My only wish is that I was able to write a message on the back - especially since it's a pool party and wanted to add additional info about rain location etc."
"I ordered these invites for our daughters first birthday and was thrilled with how they came out. This is the second time I have used Tiny Prints and the results are outstanding. The quality of the paper and the clarity of the image are brilliant and everybody loved both the birth announcement and invite. Thank you Tiny Prints, I happily recommend you to my family and friends and will continue to do so. Regards Casey Butterworth"
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Latest Activity: Played Papa's Freezeria (Aug 10, 2014 11:56pm)
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Odd topic for a vodka.
Ron English recently painted the X-Ray Guernica mural in Rome.
At least five police officers have been shot, and an untold number of other people have been injured, in what is reported at the time of this blog post as an "a very active shooter situation" either at or near a Planned Parenthood in Colorado Springs, Colorado.
Vtech is a ubiquitous Hong Kong-based electronic toy company whose kiddy tablets and other devices are designed to work with its cloud service, which requires parents to set up accounts for their kids. 4.8 million of those accounts just breached, leaking a huge amount of potentially compromising information, from kids' birthdays and home addresses to […]
If you're a woman on the Internet, harassment comes with the territory. There have been jerky dudes since time immemorial, after all. But with the advent of America's militarized cops, sociopathic misogynists have a new, deadly force-multiplier in their war on women.
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These knitted gloves are here to save the day (and your hands) with an ultra-comfy, double-layer that will allow you to stay warm and use your phone. Now you can take photos on the fly, text, Tinder, and more without letting freezing temperatures get in your way. Plus they work with all touchscreens, so no […]
Odd topic for a vodka.
Any relation to Ron Mexico?
Shouldn't it be a vision by Pablo Picasso and an x-ray vision by Rob English?
hmmm …. right after the atomic flash ….
I wish I "got" art appreciation. Everytime I read or have people explain to me what is actually depicted in that piece (or any picasso, or almost any cubist/surreal art), I just can't see it. To me, it doesn't look anything at all like what other people commonly agree it is. Sure, it looks pretty damn cool, but it's frustrating not being able to interpret any meaning whatsoever, especially when it seems like everyone else can interpret the same things. (bitch moan groan etc)
I hear you, Bob. Sometimes it's best to just look without trying to think about any kind of meaning or purpose. Appreciate it in the same way you would appreciate a nice photo of the Horsehead Nebula
For me, the key to grok-ing Cubism/Modernism/etc. was spending enough time with the originals to let them speak. Park your eyes in front of the real deal, and then just let it reveal whatever it chooses. Akin to "studying" your lover's face…learning what's there and what isn't there over time, and how to appreciate it. My breakthrough was Duchamp's Nude Descending… — it took a couple of hours (interrupted by a few brain-palate-clearing walks), but when I finally decoded the abstraction and saw all four dimensions (space and time), I was hooked.
Fortunate enough to have seen the original Guernica at MOMA, maybe 35 years ago. Wow — just wow. It's still the most powerful abstraction of war I've ever witnessed.
Hope you don't give up. Check out Picasso's Mother and Child (non-abstract) and imagine re-mixing its elements to convey changes in viewpoint and time while never leaving the single frame. Or, watch the "bullet time" parts of The Matrix; pretty much the same technique in newer clothes.
bobhughes, I minored in art history and talk pretty confidently about visual art, but you've captured exactly how I feel about music.
It might help to know that when a German asked Picasso who created a painting about the Germans and Italians bombing the Basque Country, Picasso replied, "You did."
Curses. We just got back from Rome today – I'd like to have seen this, it looks pretty impressive. And even bigger than the original. Anyone know where it is? The student area?
It's in Testaccio. Looks pretty cool…but the slaughterhouse turned into a modern art museum right beside it (MACRO) outcools it by far.
Um, is no one bothered by the idea of this furious depiction of a Basque town bombarded by the fascists during the Spanish Civil War being co-opted by a colossal vodka corporation for our viewing pleasure?
What's next? Absolut Kim Phuc Napalm Attack? Sheesh!
So is art appreciation correlated to culture & refinement in general, or is it more of an academic endeavor that has to be developed with experience and knowledge, or is it a talent that some people will never really succeed at no matter the effort they put into it?
morganmae I'm a hobby musician, but I don't have any formal music education, so there's probably alot of things I'm not doing right or taking into account when I compose my own pieces. My music appreciation and analysis is patchy, even though I regularly listen to music spread across 70-80% of all genres, and have probably spent alot more time listening to music than I have with any other recreational activity. I also have perfect pitch.
But, I'm an engineer, so the vast majority of my creative streaks are "left-brain" (metaphorically speaking)
S2, I actually saw Guernica myself in Madrid some 15 years ago. Back then I was a kid and I hadn't seen much art, but also I didn't have much appreciation for art appreciation (heh) since not only I didn't get it, I also decided that most people who supposedly did were just following each other to arrive at the same analyses as the original one which someone had pulled outta their ass and published. I'd guess that feeling was due to envy, but didn't realize it. My spanish teacher was going over the various components, telling us what they were & what they meant, but my friends and I were just giggling in disbelief and quietly saying stuff like "I would've never guessed that was a lightbulb", "That's totally not a horse", etc… I've gotten better since then, so I'm guessing alot of it comes with practice and experience, but I wonder if it takes a certain mindset, or talent even, to ever really be good at it?
I checked out Mother and Child in your link, and I was able to visualize it the way you suggested, but I didn't have any kind of realization or anything… I just saw a mother holding a baby, and couldn't really infer anything deeper.
Comments are closed.


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2005 Kia Rio • 60,000 miles
The first time I start my car it will idle for awhile (like 10 minutes) before it sputters out and dies. From there on out every time you start it it will almost immediatly try and sputter and die. If you rev the gas pedal it will stay running until u take your foot off of the gas. It almost sounds to me like its getting starved for gas after a brief time. I was going to change the fuel filter but after much searching and researching there is none to be found. I also thought it might be the fuel pump but I can here it coming on when I turn the key over. Before this issue when I would start the car cold it would not want to eccelerate untill I reved on the gas for a bit. Seems like that was possibly the beginning of the same problem. Any ideas?
April 29, 2012.
April 29, 2012.
The first thing we need to check is have the computer scanned for codes. If there are any codes please post the exact code numbers not code descriptions. The code will have a P followed by a four digit number. Also just because you can hear the fuel pump running doesnt mean that the pump is delivering the correct fuel pressure.
There were a ton of codes on the car but since someof them had been there for a long time I cleared them in hopes that only the ones causing the current issue would come back right away. Unfotunatly now I cant keep the car running long enough for them to come back on. I cant remember the exact codes but I can remember roughly what they said. 1 was something regarding the fuel being lean. Another one said something about cyliner 3 misfire (i think).
Then lets start by checking fuel pressure that cause a lean code and a no start if the fuel pressure was too low.
IS there anyway to do that without a fuel pressure gauge? Also the car does start everytime it will just quickly die out withing 5-10 seconds without pressure to the gas pedal.
No you cant check fuel pressure without a fuel pressure gauge. They rent fuel pressure gauges at auto zone you can also check fuel pressure without the car running.
I have rented a fuel pressure tester from a auto store but It does not seem like any of the connectors fit. Im not sure If I am connecting to the right thing but I think I am. Any idea on the location of this or If a standard test kit would have the correct adapter? There are two lines I was trying to connect it too. They both had ports that came off with caps that unscrew. One cap had a "H" and one had a "L".
May 2, 2012.
May 2, 2012.
The line that goes to fuel rail where the injectors plug in should be the pressure side. The return line should be to the rear of the fuel rail. Also usually the pressure line is always bigger then the return line.
May 2, 2012.
May 2, 2012.
Hallo my name is fabrizio I have a problem !!!!! my hummer h3 of 2006 cold engine vibration, heat better, but it accelerates well and the engine makes a clanking noise I replaced ...
3 answers • 2006 Hummer H3 • 47,000 miles
1992 Lexus ES 300 My lexus does not have a fuel pressure test port. How do I check the fuel pressure?
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Engine Performance problem 1998 Ford Taurus 6 cyl Front Wheel Drive Automatic 110000 miles At cold start the fuel pressure was 10 lbs (key on, no engine running). After starting ...
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Engine Performance problem 2005 BMW X5 6 cyl All Wheel Drive Automatic 40000 miles how much fuel pressure should build up on the fuel line when you turn the switch on for a 3.0i ...
1 answer • 2005 BMW X5


text: Once you're behind the wheel of your new car you can rely on our Jeep service center to help maintain the quality of your vehicle. Our Mechanicsburg used car dealership is located at 6039 Carlisle Pike Mechanicsburg, PA and is easily accessible from all over the area. We look forward to working with you at Brenner Chrysler Jeep!