text:
Journal of Oncology
Volume 2011 (2011), Article ID 950140, 9 pages
Hypermethylation of CCND2 May Reflect a Smoking-Induced Precancerous Change in the Lung
1Division of Nuclear Medicine, Department of Radiology, Box 357115, School of Medicine, University of Washington, Seattle, WA 98195-7115, USA
2Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA 98195-7230, USA
3Department of Pathology, School of Medicine, University of Washington, Seattle, WA 98195-6100, USA
4Department of Radiation Oncology, School of Medicine, University of Washington, Seattle, WA 98195-9441, USA
Received 12 November 2010; Revised 12 January 2011; Accepted 26 January 2011
Academic Editor: Venkateshwar Keshamouni
Copyright © 2011 Alexander Salskov et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
It remains unknown whether tobacco smoke induces DNA hypermethylation as an early event in carcinogenesis or as a late event, specific to overt cancer tissue. Using MethyLight assays, we analyzed 316 lung tissue samples from 151 cancer-free subjects (121 ever-smokers and 30 never-smokers) for hypermethylation of 19 genes previously observed to be hypermethylated in nonsmall cell lung cancers. Only APC (39%), CCND2 (21%), CDH1 (7%), and RARB (4%) were hypermethylated in >2% of these cancer-free subjects. CCND2 was hypermethylated more frequently in ever-smokers (26%) than in never-smokers (3%). CCND2 hypermethylation was also associated with increased age and upper lobe sample location. APC was frequently hypermethylated in both ever-smokers (41%) and never-smokers (30%). BVES, CDH13, CDKN2A (p16), CDKN2B, DAPK1, IGFBP3, IGSF4, KCNH5, KCNH8, MGMT, OPCML, PCSK6, RASSF1, RUNX, and TMS1 were rarely hypermethylated (<2%) in all subjects. Hypermethylation of CCND2 may reflect a smoking-induced precancerous change in the lung.
1. Introduction
Lung cancer causes more deaths in the United States each year than breast, colon, pancreatic, and prostate cancer combined, approximately 157,300 deaths estimated in 2010 [1]. Cigarette smoking is the most significant risk factor for developing lung cancer and contributes to 80–90% of these deaths [2, 3].
Over the past four to five decades, significant progress has been made to elucidate the carcinogenic mechanisms of tobacco smoking. Using animal models, it has been shown that among over 60 established carcinogens in cigarette smoke, 20 can cause lung tumors [4]. It has been proposed that these carcinogens, when metabolized, form DNA-adducts which may directly cause genetic alterations if not repaired. When these genetic alterations affect tumor suppressor genes or tumor oncogenes, they can promote cell proliferation and malignant transformation [5]. Studies in lung cancer patients clearly suggest that cigarette smoking can lead to acquisition of genetic mutations in p53 and ras oncogene [6, 7]. In addition, cigarette smoke is proposed to cause immunosuppression, which provides an environment for tumor progression [8, 9].
Recently, DNA hypermethylation has been recognized as an alternative, epigenetic mechanism for gene silencing in lung cancer, in addition to genetic mutation. Several environmental exposures are thought to cause aberrant DNA methylation, including dietary factors, chemotherapeutic agents, and heavy metals [10]. Tobacco smoke exposure has been associated with increased expression of DNA methyltransferases [11–14]. Consistent with this observation, lung cancers arising in heavy smokers show increased hypermethylation of various genes, especially CDKN2A (p16) and RASSF1, compared with lighter smokers or nonsmokers [15–27].
However, these results do not reveal whether DNA hypermethylation occurs early or late in carcinogenesis. Early changes in carcinogenesis (especially those related to smoking) are hypothesized to occur somewhat diffusely in the lung and may therefore be detectable in noncancerous lung tissue, as well as in any cancers which arise [28–30]. For example, frequent hypermethylation of CDKN2A, RASSF1, CDH13, and other genes has been observed in sputum samples from cancer-free smokers, suggesting that they may be hypermethylated early [31–34]. In contrast, late changes in carcinogenesis are thought to arise mainly in overtly malignant tissues.
We recently analyzed matched cancerous and noncancerous lung tissues from patients with nonsmall cell lung cancer (NSCLC). We observed that in the 27 genes tested, most DNA methylation changes were tumor-specific and therefore might be considered late changes in carcinogenesis [35]. However, in these NSCLC patients, a small number of genes, including CCND2, APC, CDH1, and RARB (Table 1), were also hypermethylated in a portion of noncancerous lung tissues, suggesting that one or more of these genes might become hypermethylated as an early precancerous change. We hypothesized that early changes in DNA methylation, if present, might be associated with exposure to cigarette smoke. Furthermore, because smoking-related lung tumors and emphysema are known to disproportionately affect the upper lobes of the lungs [36, 37], we hypothesized that methylation changes related to smoking would similarly be more frequent in the upper lobes, compared with the lower lobes.
2. Materials and Methods
2.1. Subject Enrollment
All procedures were conducted in accordance with institutional review board and human subjects committee approval. Subjects were retrospectively enrolled who had undergone lung surgeries (lung volume reduction, lung transplant, wedge biopsy, or lobectomy) for nonmalignant diseases including emphysema, chronic bronchitis, bronchiectasis, granulomatous disease, various infectious diseases, and cystic or pulmonary fibrosis, at the University of Washington Medical Center (UWMC) between July 1st 1995 and July 1st 2005. All specimens were reviewed by an expert pathologist (CDJ) to confirm that they represented noncancerous lung tissue. All clinical data were gathered from subjects' UWMC medical records, including smoking history and primary pulmonary diagnosis. Subjects were excluded for the following reasons: previous diagnosis of lung cancer, insufficient lung tissue for methylation analysis, or unknown pack years of smoking. In total, 372 nonmalignant lung tissue samples from 159 subjects were identified for DNA methylation analysis.
2.2. DNA Isolation from Paraffin Blocks
From each block, six 20-μm sections were cut and deparaffined by xylene extraction. Proteinase K was used to digest the resulting tissue pellets overnight, at 48°C. Genomic DNA was then isolated by phenol/chloroform extraction and ethanol precipitation. Finally, DNA was purified using a QIAamp DNA minicolumn (Qiagen) according to the manufacturer's instructions.
2.3. Sodium Bisulfite Conversion
As previously described in detail [42], in vitro fully methylated DNA (methylated DNA control) and human sperm DNA (unmethylated DNA control) were converted with clinical samples. Briefly, ~1 μg DNA was modified by 5 mol/L sodium bisulfite, desulfonated with NaOH, and then purified and resuspended in 80 μL elution buffer (EB; 10 mmol/L Tris-HCl, pH 8.0).
2.4. DNA Methylation (MethyLight) Assay
All primers and probes for MethyLight assays were designed specifically for bisulfite-converted fully methylated DNA. Their sequences have been reported previously [35]. Amplification of bisulfite converted beta-actin (ACTB) DNA was used to normalize for the quantity of input DNA. Samples negative for ACTB were excluded from methylation analysis. Of 372 identified samples, 56 (15%) were excluded because they were negative for ACTB. The percentage of samples excluded after bisulfite conversion was similar in smokers (15%) and nonsmokers (16%). A plasmid containing bisulfite converted ACTB gene of known concentration was diluted and used as a standard curve for quantification. The assay for a given set of samples was only considered valid if the converted unmethylated human sperm DNA was not amplified, whereas the converted fully methylated DNA was amplified. For each locus, the percentage methylated reference (PMR) was calculated by dividing the gene/reference ratio of a sample by the gene/reference ratio of fully methylated DNA control [43]. Genes were considered to be positive for any hypermethylation at PMR >0%.
2.5. Statistical Methods
For comparisons between groups, to provide independent observations, we randomly selected one tissue block per subject to represent each subject's hypermethylation profile. To evaluate potential differences in gene methylation by site of the lung, paired upper, and lower lobe tissue samples from within subjects were compared using McNemar's Test. To assess the univariate and multivariate relationships between gene methylation and independent variables (smoking, age, gender, lobe of lung, pack years, and years since quitting), we included all available tissue samples from each subject and employed generalized estimating equations (GEE). This method enables the analysis of data with repeated measurements (multiple tissue samples per subject from different lobes) and accounts for within-subject correlations. In selecting a model, a logit link was used and we assumed an exchangeable working correlation structure to account for intrasubject correlation. Parameter estimates were exponentiated to provide odds ratios (OR) and 95% confidence intervals (CI). A 2-sided 0.05 test level determined statistical significance for all analyses. All analyses were conducted using SAS version 9.1 (SAS Institute Inc., Cary, NC).
3. Results
3.1. Study Population and Tissue Samples
We retrospectively enrolled 151 subjects who contributed a total of 316 available pathology blocks (Table 2). At the time of their surgery, 121 subjects were current or former smokers (ever-smokers), while 30 reported no smoking history (never-smokers). Among the never-smokers, none had any history of cancer, either prior to or after the surgery that yielded the tissue used in this study. Of the ever-smokers, 10 had a history of prior cancer other than lung (1 breast, 2 cervical, 2 colon, 2 prostate, 1 testicular, and 2 uterine) and all were cancer free at surgery. Four of the ever-smokers developed a cancer subsequent to the surgery that yielded the cancer-free lung tissue (1 bladder, 1 colon, and 2 NSCLCs, one at 2 years after, one at 5 years after). The clinical data show that never-smokers and ever-smokers who had undergone lung surgery comprised two distinct populations. Ever-smokers were significantly older than never-smokers (61 years versus 44 years). Further, of ever-smokers who contributed specimens from lung surgery, 71% had a diagnosis of emphysema, compared to only 10% of never-smokers.
We analyzed a total of 316 available pathology blocks from these 151 subjects, including 177 upper lobe samples, 105 lower lobe samples, 30 middle lobe or lingula samples, and 4 whose lobe of origin was unclear. Multiple blocks were available for 98 (81%) of ever-smokers and 13 (43%) of never-smokers; from the 121 ever-smokers, 269 samples were tested, while from the 30 never-smokers, 47 samples were tested. Sample sites varied substantially in ever-smokers and never-smokers as 50% of ever-smokers, compared to 17% of never-smokers, contributed only samples from the upper lobes. This difference arose because many ever-smokers in our sample underwent lung volume reduction surgery for emphysema, which predominantly affects the upper lung zones when induced by smoking.
3.2. Gene Hypermethylation and Smoking Status
Considering one random tissue block per subject, only APC (39%), CCND2 (21%), CDH1 (7%), and RARB (4%) were hypermethylated in more than 2% of subjects (Figure 1). All 15 remaining genes (BVES, CDH13, CDKN2A (p16), CDKN2B, DAPK1, IGFBP3, IGSF4, KCNH5, KCNH8, MGMT, OPCML, PCSK6, RASSF1, RUNX, and TMS1) were hypermethylated in less than 2% of subjects. CCND2 was hypermethylated significantly more frequently in ever-smokers compared to never-smokers (26% versus 3%, ). APC was hypermethylated somewhat more frequently in ever-smokers (41% versus 30%), but this did not achieve statistical significance ().
3.3. Correlation of APC and CCND2 Gene Hypermethlation
APC and CCND2 were often hypermethylated in the same samples; 179 (57%) samples were negative for both genes, 16 (5%) were positive for hypermethylation of CCND2, but not APC, 68 (22%) were positive for hypermethylation of APC but not CCND2, and 53 (17%) samples were positive for both genes. CCND2 hypermethylation was significantly correlated with APC hypermethylation in all subjects (OR = 7.3, 95% CI = 3.9–13.8) and in smokers only (OR = 7.4, 95% CI = 3.9–14.0). In nonsmokers, 31 (66%) samples were negative for both genes, 14 (30%) were positive for APC only, and 2 (4%) samples were positive for both APC and CCND2.
3.4. Gene Hypermethylation and Clinical and Demographic Factors
In univariate GEE analyses of all specimens (Table 3), CCND2 hypermethylation was significantly associated with a positive smoking history, increasing age, and sample origin from the upper versus lower lobe of the lung. APC hypermethylation was significantly less frequent among females and moderately more frequent in upper lobes compared to lower lobes but was not significantly associated with a positive smoking history. In a multivariate model simultaneously assessing smoking history, age, gender, and location of the sample (upper versus lower lobe) in all subjects, hypermethylation of CCND2 remained significantly associated with increased age (OR = 1.7, 95% CI = 1.2–2.4 for each 10 years of age) and upper lobe location (OR = 2.0, 95% CI = 1.0–3.8). CCND2 hypermethylation was somewhat associated with a positive smoking history (OR = 2.8, 95% CI = 0.6–12.1) but this did not achieve statistical significance.
3.5. Gene Hypermethylation and Duration of Smoke Exposure
Within the subset of 269 samples from 121 ever-smokers (Table 4), APC hypermethylation was not related to pack-years of cigarette smoking or years since quitting smoking. In univariate GEE analysis, CCND2 hypermethylation was significantly associated with greater pack years but was not related to years since quitting. However, in a multivariate GEE analysis simultaneously assessing pack years, years since quitting, age, gender, and location of the sample (upper versus lower lobe), CCND2 hypermethylation was no longer associated with pack years (OR = 1.0, 95% CI = 0.9–1.2 per 10 pack years).
3.6. Gene Hypermethylation in Upper- and Lower-Lobe Samples
Smoking-related lung tumors and emphysema are known to disproportionately affect the upper lobes of the lungs. Thus, if hypermethylation of a gene is associated with smoking, we might expect to find more hypermethylation in upper lobe samples compared to lower lobe samples, among ever-smokers.
Examining all 269 samples from ever-smokers (Table 4), in univariate GEE analysis, both APC (OR = 2.0, 95% CI = 1.1–3.5) and CCND2 (OR = 1.9, 95% CI = 1.0–3.5) hypermethylation were more common in upper compared to lower lobes. In multivariate analysis including pack-years, years since quitting, age, gender, and upper versus lower lobe, APC hypermethylation remained significantly associated with upper-lobe sample location (OR = 2.1, 95% CI = 1.1–4.0), while CCND2's positive association with upper lobes was reduced to slightly below the level of statistical significance (OR = 1.7, 95% CI = 0.9–3.4).
Among the 121 ever-smokers in our cohort, 30 had both upper and lower lobe samples available, and were included in within-subjects, pairwise comparisons. For APC, 12 of 30 pairs had discordant hypermethylation status (1 positive and 1 negative), of which 8 of 12 displayed APC hypermethylation in an upper lobe but not a lower lobe sample (). For CCND2, only 7 of 30 pairs had discordant hypermethylation status, of which only 3 of 7 were hypermethylated in the upper but not the lower lobe (). Thus, too few subjects had discordant hypermethylation in upper and lower lobe samples to yield statistically meaningful results in within-subjects comparisons.
4. Discussion
DNA hypermethylation is an important event in lung carcinogenesis. However, it is currently unknown whether changes in DNA methylation are early events, occurring in previously normal lung tissue or whether they are late changes that occur only in overt tumor cells [30]. To attempt to answer these questions, we tested DNA hypermethylation in lung tissues from subjects without cancer—both smokers and nonsmokers—using a panel of 19 genes which we had previously found to be hypermethylated in some nonsmall cell lung cancers [35, 44]. This unique study design allowed us, for the first time, to characterize the DNA hypermethylation profile of nonsmokers' lung tissues and to compare this profile to that of smoke-exposed lung.
Importantly, we observed that CCND2, which is known to be frequently hypermethylated in lung cancer tissue [35, 44–47], was hypermethylated more frequently in ever-smokers (26%) than in never-smokers (3%). Also, as predicted, in ever-smokers, CCND2 was hypermethylated more frequently in samples from the upper lobes, which are known to suffer far more negative effects from cigarette smoke, such as lung cancer and emphysema [36, 37]. These findings support the conclusion that CCND2 reflects an early, precancerous change in the lung, caused by cigarette smoke.
CCND2 encodes cyclin D2, a protein involved in cell cycle progression that is thought to act as a regulator of cyclin dependent kinase 4 and cyclin dependent kinase 6 in the transition from G1 to S-phase [39]. CCND2 hypermethylation appears to be common in many cancers. In breast cancer, where it has been studied most extensively, CCND2 hypermethylation is detected frequently, though it appears to be rarely detected in normal breast tissue [48–54]. Interestingly, while CCND2 hypermethylation (and therefore low CCND2 protein expression) has been associated with poor prognosis in epithelial ovarian cell cancer [55] and recurrence of hepatocellular carcinoma [56], increased CCND2 expression has been associated with poor prognosis in diffuse large B-cell lymphoma [57].
In the lung, CCND2 hypermethylation has been found in 40–56% of NSCLCs [35, 44, 45, 47]. In noncancerous lung tissue, whereas Virmani et al. found CCND2 hypermethylation in 0 of 18 samples [45], our previous investigation found CCND2 hypermethylation in 24% of noncancerous lung tissues from patients with NSCLC [35]. This closely matches the rate observed in the present study, in cancer-free ever-smokers (26%). Possibly, our group observed a higher rate of CCND2 hypermethylation in both cancerous and cancer-free lung tissues because we used MethyLight assays instead of methylation-specific PCR (MSP), which was used by Virmani et al. Thus, we may have detected low levels of hypermethylated genes in cancer-free tissues which were not detected by MSP. Discrepancies may also be due to the somewhat different primers and probes used in analyses, which indicate different sequence regions investigated. In addition, Kubo et al. did not observe any CCND2 hypermethylation in 30 matched noncancerous lung tissues but it should be noted that in this study, 70% of subjects were nonsmokers who would not be expected to have significant rates of CCND2 hypermethylation [46].
Combined, these results reveal a progression in the rate of CCND2 hypermethylation in the lung, corresponding with the risk for developing lung cancer. While CCND2 hypermethylation was very infrequent (3%) in our current study's low-risk group of 30 never-smokers, it was more frequent in a high-risk group of ever-smokers (24–26% in our current and previous studies), and most frequent in overt NSCLC tissue (40–56%). This risk-stratified progression in lung tissues suggests that CCND2 hypermethylation may truly reflect an early precancerous change in the lung, en route to overt cancer, which may be due to the effects of smoking.
Still, our findings regarding CCND2 should be regarded as preliminary at this time, for several reasons. In multivariate analysis, the effect of smoking status on CCND2 hypermethylation was reduced to trend-level significance after taking into account the effects of sample location (upper versus lower lobe) and subject age. This likely occurred because in our sample, the majority of smokers underwent lung surgery for emphysema and represented a significantly older group, more likely to contribute samples from upper lobes (where emphysema is most prominent). In contrast, nonsmokers were younger and underwent lung resection for a variety of diseases. With such significant correlation of these factors, multivariate analysis may not have reliably separated each factor's relative contribution to gene hypermethylation. Thus, observed differences in the rate of CCND2 hypermethylation could be attributable to any of these factors or others that differed between ever and never-smokers. Emphysema, for example, made CCND2 hypermethylation more likely although significant rates of CCND2 hypermethylation were also found in smokers with other diagnoses. While CCND2 hypermethylation could be part of the unique pathophysiology of emphysema, it more likely arose because emphysema reflects severe smoking-induced lung damage. The effect of age on CCND2 hypermethylation has not been studied previously in noncancerous lung, although several genes have been reported to undergo increased rates of hypermethylation with age, in various body tissues, including CDH1 and DAPK1 in the lung [58]. In noncancerous breast epithelium [59] and in peripheral blood samples from cancer-free subjects [60], advanced age was not observed to correlate with CCND2 hypermethylation. Thus, the relationship between age and CCND2 hypermethylation remains unknown at this time. In weighing the relative contributions of age, sample location, and emphysema status on CCND2 hypermethylation, it is worth noting that smoking history was by far the strongest single predictor of CCND2 hypermethylation in univariate analysis (OR = 6.9, 95% CI = 1.6–29.8). One limitation of the present study was that despite our overall large number of 151 subjects, only 30 were never-smokers. This occurred because never-smokers far less frequently undergo lung resections which produce tissue. This may have been part of the reason why in multivariate analysis, we observed only trend-level significance for smoking's effect on CCND2 hypermethylation. We were able to improve our statistical power somewhat by using generalized estimating equations (GEE) for our univariate and multivariate analyses, allowing us to enter multiple tissue blocks per subject when available (multiple observations), without biasing the results. However, future studies should seek to verify the low rate of CCND2 hypermethylation we observed in never-smokers. An additional limitation of our study design was that all subjects had an underlying non-cancer pulmonary diagnosis that necessitated lung surgery. Thus, while observed gene hypermethylation was unrelated to cancer, it cannot definitely be said to represent healthy lung. Finally, due to our study design, we only provide indirect evidence of interaction between smoking and CCND2 hypermethylation. Future studies utilizing animal models may be useful to elucidate the potential causal relationship between smoking and CCND2 hypermethylation.
In our current and previous studies, CDKN2A (p16) was hypermethylated in 26% of cancer tissues [44] but was rarely hypermethylated in noncancerous lung tissues, regardless of smoking status [35]. However, CDKN2A hypermethylation has previously been characterized as an early event in lung carcinogenesis [28–30], and hypermethylation of CDKN2A has been commonly detected in sputum samples from heavy smokers without lung cancer [32, 61]. Overall, a very wide range of hypermethylation rates for CDKN2A has been reported in the literature, for noncancerous lung tissues. Along with other researchers who observed low rates of CDKN2A hypermethylation in noncancerous lung tissues, our results suggest that CDKN2A hypermethylation may actually represent a later change in carcinogenesis [62–66]. However, the surprisingly large discrepancies between studies may be related to differences in assay methodology (including PCR primers and specific CpG islands) or patient populations.
5. Conclusions
CCND2 hypermethylation likely represents an early, smoking-induced, precancerous change in the lung; it is very infrequent in the lung tissue of never-smokers, more frequent among smokers, and most frequent in overt NSCLC tissue. This conclusion should be verified in future investigations. In addition, this study supports the conclusions of our previous investigation, that although they are hypermethylated in many NSCLC tumor tissues, RASSF1, DAPK1, BVES, CDH13, MGMT, KCNH5, and to some extent CDH1 and RARB, are rarely hypermethylated in the cancer-free lung, even after significant tobacco exposure [35]. These genes may therefore yield clues to understanding the later stages of carcinogenesis. In addition, if hypermethylation of CCND2 or other genes represents an early precancerous change, it is possible that drugs aimed at reversing DNA methylation could be used to prevent smoking-related carcinogenesis.
Conflict of Interests
None Declared.
This study was supported by NIH/National Cancer Institute Grants nos. R01 CA115559, R01 CA107264, and R01 CA80907.
- Cancer Facts & Figures, American Cancer Society, Atlanta, Ga, USA, 2010.
- CDC, "The 2004 United States surgeon general's report: the health consequences of smoking," New South Wales Public Health Bulletin, vol. 15, no. 5-6, p. 107, 2004. View at Google Scholar
- CDC, "Annual smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 1997–2001," Morbidity and Mortality Weekly Report, vol. 54, no. 25, pp. 625–628, 2005. View at Google Scholar
- S. S. Hecht, "Tobacco smoke carcinogens and lung cancer," Journal of the National Cancer Institute, vol. 91, no. 14, pp. 1194–1210, 1999. View at Google Scholar · View at Scopus
- K. Straif, R. Baan, Y. Grosse et al., "Carcinogenicity of polycyclic aromatic hydrocarbons," The Lancet Oncology, vol. 6, no. 12, pp. 931–932, 2005. View at Publisher · View at Google Scholar · View at Scopus
- J. A. Ross and S. Nesnow, "Polycyclic aromatic hydrocarbons: correlations between DNA adducts and ras oncogene mutations," Mutation Research, vol. 424, no. 1-2, pp. 155–166, 1999. View at Publisher · View at Google Scholar · View at Scopus
- D. Yu, J. A. Berlin, T. M. Penning, and J. Field, "Reactive oxygen species generated by PAH o-quinones cause change-in-function mutations in p53," Chemical Research in Toxicology, vol. 15, no. 6, pp. 832–842, 2002. View at Publisher · View at Google Scholar · View at Scopus
- A. A. Frazer-Abel, S. Baksh, S. P. Fosmire et al., "Nicotine activates nuclear factor of activated T cells c2 (NFATc2) and prevents cell cycle entry in T cells," Journal of Pharmacology and Experimental Therapeutics, vol. 311, no. 2, pp. 758–769, 2004. View at Publisher · View at Google Scholar · View at Scopus
- R. Kalra, S. P. Singh, S. M. Savage, G. L. Finch, and M. L. Sopori, "Effects of cigarette smoke on immune response: chronic exposure to cigarette smoke impairs antigen-mediated signaling in T cells and depletes IP3-sensitive stores," Journal of Pharmacology and Experimental Therapeutics, vol. 293, no. 1, pp. 166–171, 2000. View at Google Scholar · View at Scopus
- L. E. Moore, W. Y. Huang, J. Chung, and R. B. Hayes, "Epidemiologic considerations to assess altered DNA methylation from environmental exposures in cancer," Annals of the New York Academy of Sciences, vol. 983, pp. 181–196, 2003. View at Google Scholar · View at Scopus
- R. K. Lin, H. S. Hsu, J. W. Chang, C. Y. Chen, J. T. Chen, and Y. C. Wang, "Alteration of DNA methyltransferases contributes to CpG methylation and poor prognosis in lung cancer," Lung Cancer, vol. 55, no. 2, pp. 205–213, 2007. View at Publisher · View at Google Scholar · View at Scopus
- Y. M. Kwon, J. H. Park, H. Kim et al., "Different susceptibility of increased DNMT1 expression by exposure to tobacco smoke according to histology in primary non-small cell lung cancer," Journal of Cancer Research and Clinical Oncology, vol. 133, no. 4, pp. 219–226, 2007. View at Publisher · View at Google Scholar · View at Scopus
- H. Liu, Y. Zhou, S. E. Boggs, S. A. Belinsky, and J. Liu, "Cigarette smoke induces demethylation of prometastatic oncogene synuclein-gamma in lung cancer cells by downregulation of DNMT3B," Oncogene, vol. 26, no. 40, pp. 5900–5910, 2007. View at Publisher · View at Google Scholar · View at Scopus
- S. A. Belinsky, D. M. Klinge, C. A. Stidley et al., "Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer," Cancer Research, vol. 63, no. 21, pp. 7089–7093, 2003. View at Google Scholar · View at Scopus
- H. Kim, MI. K. Young, S. K. Jin et al., "Tumor-specific methylation in bronchial lavage for the early detection of non-small-cell lung cancer," Journal of Clinical Oncology, vol. 22, no. 12, pp. 2363–2370, 2004. View at Publisher · View at Google Scholar · View at Scopus
- S. Toyooka, R. Maruyama, K. O. Toyooka et al., "Smoke exposure, histologic type and geography-related differences in the methylation profiles of non-small cell lung cancer," International Journal of Cancer, vol. 103, no. 2, pp. 153–160, 2003. View at Publisher · View at Google Scholar · View at Scopus
- S. Toyooka, M. Suzuki, T. Tsuda et al., "Dose effect of smoking on aberrant methylation in non-small cell lung cancers," International Journal of Cancer, vol. 110, no. 3, pp. 462–464, 2004. View at Publisher · View at Google Scholar · View at Scopus
- Y. S. Hong, M. S. Roh, N. Y. Kim et al., "Hypermethylation of p16 in Korean non-small cell lung cancer patients," Journal of Korean Medical Science, vol. 22, pp. S32–S37, 2007. View at Google Scholar · View at Scopus
- Y. Liu, Q. Lan, J. M. Siegfried, J. D. Luketich, and P. Keohavong, "Aberrant promoter methylation of p16 and MGMT genes in lung tumors from smoking and never-smoking lung cancer patients," Neoplasia, vol. 8, no. 1, pp. 46–51, 2006. View at Publisher · View at Google Scholar · View at Scopus
- K. Kondo, Y. Takahashi, Y. Hirose et al., "The reduced expression and aberrant methylation of p16 in chromate workers with lung cancer," Lung Cancer, vol. 53, no. 3, pp. 295–302, 2006. View at Publisher · View at Google Scholar · View at Scopus
- R. Dammann, M. Strunnikova, U. Schagdarsurengin et al., "CpG island methylation and expression of tumour-associated genes in lung carcinoma," European Journal of Cancer, vol. 41, no. 8, pp. 1223–1236, 2005. View at Publisher · View at Google Scholar · View at Scopus
- O. Furonaka, Y. Takeshima, H. Awaya, H. Ishida, N. Kohno, and K. Inai, "Aberrant methylation of p14, p15 and p16 genes and location of the primary site in pulmonary squamous cell carcinoma," Pathology International, vol. 54, no. 8, pp. 549–555, 2004. View at Publisher · View at Google Scholar · View at Scopus
- Y. Tomizawa, H. Iijima, T. Nomoto et al., "Clinicopathological significance of aberrant methylation of RARβ2 at 3p24, RASSF1A at 3p21.3, and FHIT at 3p14.2 in patients with non-small cell lung cancer," Lung Cancer, vol. 46, no. 3, pp. 305–312, 2004. View at Publisher · View at Google Scholar · View at Scopus
- M. Suzuki, H. Shigematsu, D. S. Shames et al., "Methylation and gene silencing of the ras-related GTPase gene in lung and breast cancers," Annals of Surgical Oncology, vol. 14, no. 4, pp. 1397–1404, 2007. View at Publisher · View at Google Scholar · View at Scopus
- S. Kikuchi, D. Yamada, T. Fukami et al., "Hypermethylation of the TSLC1/IGSF4 promoter is associated with tobacco smoking and a poor prognosis in primary nonsmall cell lung carcinoma," Cancer, vol. 106, no. 8, pp. 1751–1758, 2006. View at Publisher · View at Google Scholar · View at Scopus
- K. K. Divine, L. C. Pulling, P. G. Marron-Terada et al., "Multiplicity of abnormal promoter methylation in lung adenocarcinomas from smokers and never smokers," International Journal of Cancer, vol. 114, no. 3, pp. 400–405, 2005. View at Publisher · View at Google Scholar · View at Scopus
- T. Vaissière, R. J. Hung, D. Zaridze et al., "Quantitative analysis of DNA methylation profiles in lung cancer identifies aberrant DNA methylation of specific genes and its association with gender and cancer risk factors," Cancer Research, vol. 69, no. 1, pp. 243–252, 2009. View at Publisher · View at Google Scholar · View at Scopus
- M. Kersting, C. Friedl, A. Kraus, M. Behn, W. Pankow, and M. Schuermann, "Differential frequencies of p16(INK4a) promoter hypermethylation, p53 mutation, and K-ras mutation in exfoliative material mark the development of lung cancer in symptomatic chronic smokers," Journal of Clinical Oncology, vol. 18, no. 18, pp. 3221–3229, 2000. View at Google Scholar · View at Scopus
- S. A. Belinsky, K. J. Nikula, W. A. Palmisano et al., "Aberrant methylation of p16 is an early event in lung cancer and a potential biomarker for early diagnosis," Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 20, pp. 11891–11896, 1998. View at Google Scholar · View at Scopus
- K. M. Kerr, J. S. Galler, J. A. Hagen, P. W. Laird, and I. A. Laird-Offringa, "The role of DNA methylation in the development and progression of lung adenocarcinoma," Disease Markers, vol. 23, no. 1-2, pp. 5–30, 2007. View at Google Scholar · View at Scopus
- S. Zöchbauer-Müller, S. Lam, S. Toyooka et al., "Aberrant methylation of multiple genes in the upper aerodigestive tract epithelium of heavy smokers," International Journal of Cancer, vol. 107, no. 4, pp. 612–616, 2003. View at Publisher · View at Google Scholar · View at Scopus
- R. Cirincione, C. Lintas, D. Conte et al., "Methylation profile in tumor and sputum samples of lung cancer patients detected by spiral computed tomography: a nested case-control study," International Journal of Cancer, vol. 118, no. 5, pp. 1248–1253, 2006. View at Publisher · View at Google Scholar · View at Scopus
- E. Georgiou, R. Valeri, G. Tzimagiorgis et al., "Aberrant p16 promoter methylation among Greek lung cancer patients and smokers: correlation with smoking," European Journal of Cancer Prevention, vol. 16, no. 5, pp. 396–402, 2007. View at Publisher · View at Google Scholar · View at Scopus
- S. A. Belinsky, W. A. Palmisano, F. D. Gilliland et al., "Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers," Cancer Research, vol. 62, no. 8, pp. 2370–2377, 2002. View at Google Scholar · View at Scopus
- Q. Feng, S. E. Hawes, J. E. Stern et al., "DNA methylation in tumor and matched normal tissues from non-small cell lung cancer patients," Cancer Epidemiology Biomarkers and Prevention, vol. 17, no. 3, pp. 645–654, 2008. View at Publisher · View at Google Scholar · View at Scopus
- J. M. Lee and A. Bernstein, "p53 Mutations increase resistance to ionizing radiation," Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 12, pp. 5742–5746, 1993. View at Google Scholar · View at Scopus
- T. E. Byers, J. E. Vena, and T. F. Rzepka, "Predilection of lung cancer for the upper lobes: an epidemiologic inquiry," Journal of the National Cancer Institute, vol. 72, no. 6, pp. 1271–1275, 1984. View at Google Scholar · View at Scopus
- C. A. Hanson and J. R. Miller, "Non-traditional roles for the Adenomatous Polyposis Coli (APC) tumor suppressor protein," Gene, vol. 361, no. 1-2, pp. 1–12, 2005. View at Publisher · View at Google Scholar · View at Scopus
- C. J. Sherr, "D-type cyclins," Trends in Biochemical Sciences, vol. 20, no. 5, pp. 187–190, 1995. View at Publisher · View at Google Scholar · View at Scopus
- A. Jeanes, C. J. Gottardi, and A. S. Yap, "Cadherins and cancer: how does cadherin dysfunction promote tumor progression?" Oncogene, vol. 27, no. 55, pp. 6920–6929, 2008. View at Publisher · View at Google Scholar · View at Scopus
- S. Alvarez, P. Germain, R. Alvarez, F. Rodríguez-Barrios, H. Gronemeyer, and A. R. de Lera, "Structure, function and modulation of retinoic acid receptor beta, a tumor suppressor," International Journal of Biochemistry and Cell Biology, vol. 39, no. 7-8, pp. 1406–1415, 2007. View at Publisher · View at Google Scholar · View at Scopus
- D. J. Weisenberger, M. Campan, T. I. Long et al., "Analysis of repetitive element DNA methylation by MethyLight," Nucleic Acids Research, vol. 33, no. 21, pp. 6823–6836, 2005. View at Publisher · View at Google Scholar · View at Scopus
- C. A. Eads, R. V. Lord, K. Wickramasinghe et al., "Epigenetic patterns in the progression of esophageal adenocarcinoma," Cancer Research, vol. 61, no. 8, pp. 3410–3418, 2001. View at Google Scholar · View at Scopus
- S. E. Hawes, J. E. Stern, Q. Feng et al., "DNA hypermethylation of tumors from non-small cell lung cancer (NSCLC) patients is associated with gender and histologic type," Lung Cancer, vol. 69, no. 2, pp. 172–179, 2010. View at Publisher · View at Google Scholar · View at Scopus
- A. Virmani, A. Rathi, S. Heda et al., "Aberrant methylation of the cyclin D2 promoter in primary small cell, nonsmall cell lung and breast cancers," International Journal of Cancer, vol. 107, no. 3, pp. 341–345, 2003. View at Publisher · View at Google Scholar · View at Scopus
- T. Kubo, H. Yamamoto, K. Ichimura et al., "DNA methylation in small lung adenocarcinoma with bronchioloalveolar carcinoma components," Lung Cancer, vol. 65, no. 3, pp. 328–332, 2009. View at Publisher · View at Google Scholar · View at Scopus
- M. Castro, L. Grau, P. Puerta et al., "Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in lung cancer," Journal of Translational Medicine, vol. 8, article 86, 2010. View at Publisher · View at Google Scholar
- C. Jeronimo, P. Monteiro, R. Henrique et al., "Quantitative hypermethylation of a small panel of genes augments the diagnostic accuracy in fine-needle aspirate washings of breast lesions," Breast Cancer Research and Treatment, vol. 109, no. 1, pp. 27–34, 2008. View at Publisher · View at Google Scholar · View at Scopus
- C. M. Lewis, L. R. Cler, D. W. Bu et al., "Promoter hypermethylation in benign breast epithelium in relation to predicted breast cancer risk," Clinical Cancer Research, vol. 11, no. 1, pp. 166–172, 2005. View at Google Scholar · View at Scopus
- A. Lee, Y. Kim, K. Han, S. K. Chang, M. J. Hae, and I. S. Sang, "Detection of tumor markers including carcinoembryonic antigen, APC, and cyclin D2 in fine-needle aspiration fluid of breast," Archives of Pathology and Laboratory Medicine, vol. 128, no. 11, pp. 1251–1256, 2004. View at Google Scholar · View at Scopus
- R. T. Pu, L. E. Laitala, P. M. Alli, M. J. Fackler, S. Sukumar, and D. P. Clark, "Methylation profiling of benign and malignant breast lesions and its application to cytopathology," Modern Pathology, vol. 16, no. 11, pp. 1095–1101, 2003. View at Publisher · View at Google Scholar · View at Scopus
- U. Lehmann, F. Länger, H. Feist, S. Glöckner, B. Hasemeier, and H. Kreipe, "Quantitative assessment of promoter hypermethylation during breast cancer development," American Journal of Pathology, vol. 160, no. 2, pp. 605–612, 2002. View at Google Scholar · View at Scopus
- E. Evron, C. B. Umbricht, D. Korz et al., "Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation," Cancer Research, vol. 61, no. 6, pp. 2782–2787, 2001. View at Google Scholar · View at Scopus
- E. Evron, W. C. Dooley, C. B. Umbricht et al., "Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR," The Lancet, vol. 357, no. 9265, pp. 1335–1336, 2001. View at Publisher · View at Google Scholar · View at Scopus
- M. Sakuma, J. I. Akahira, K. Ito et al., "Promoter methylation status of the Cyclin D2 gene is associated with poor prognosis in human epithelial ovarian cancer," Cancer Science, vol. 98, no. 3, pp. 380–386, 2007. View at Publisher · View at Google Scholar · View at Scopus
- M. Tsutsui, N. Iizuka, T. Moribe et al., "Methylated cyclin D2 gene circulating in the blood as a prognosis predictor of hepatocellular carcinoma," Clinica Chimica Acta, vol. 411, no. 7-8, pp. 516–520, 2010. View at Publisher · View at Google Scholar · View at Scopus
- I. S. Lossos, D. K. Czerwinski, A. A. Alizadeh et al., "Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes," The New England Journal of Medicine, vol. 350, no. 18, pp. 1828–1837, 2004. View at Publisher · View at Google Scholar · View at Scopus
- T. Waki, G. Tamura, M. Sato, and T. Motoyama, "Age-related methylation of tumor suppressor and tumor-related genes: an analysis of autopsy samples," Oncogene, vol. 22, no. 26, pp. 4128–4133, 2003. View at Publisher · View at Google Scholar · View at Scopus
- D. M. Euhus, D. Bu, S. Milchgrub et al., "DNA methylation in benign breast epithelium in relation to age and breast cancer risk," Cancer Epidemiology Biomarkers and Prevention, vol. 17, no. 5, pp. 1051–1059, 2008. View at Publisher · View at Google Scholar · View at Scopus
- M. Brait, J. G. Ford, S. Papaiahgari et al., "Association between lifestyle factors and CpG island methylation in a cancer-free population," Cancer Epidemiology Biomarkers and Prevention, vol. 18, no. 11, pp. 2984–2991, 2009. View at Publisher · View at Google Scholar · View at Scopus
- S. A. Belinsky, K. C. Liechty, F. D. Gentry et al., "Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high-risk cohort," Cancer Research, vol. 66, no. 6, pp. 3338–3344, 2006. View at Publisher · View at Google Scholar · View at Scopus
- S. Zöchbauer-Müller, K. M. Fong, A. K. Virmani, J. Geradts, A. F. Gazdar, and J. D. Minna, "Aberrant promoter methylation of multiple genes in non-small cell lung cancers," Cancer Research, vol. 61, no. 1, pp. 249–255, 2001. View at Google Scholar · View at Scopus
- J. D. F. Licchesi, W. H. Westra, C. M. Hooker, and J. G. Herman, "Promoter hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung," Clinical Cancer Research, vol. 14, no. 9, pp. 2570–2578, 2008. View at Publisher · View at Google Scholar · View at Scopus
- W. Yue, S. Dacic, Q. Sun et al., "Frequent inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation," Clinical Cancer Research, vol. 13, no. 15, pp. 4336–4344, 2007. View at Publisher · View at Google Scholar · View at Scopus
- M. Esteller, M. Sanchez-Cespedes, R. Resell, D. Sidransky, S. B. Baylin, and J. G. Herman, "Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients," Cancer Research, vol. 59, no. 1, pp. 67–70, 1999. View at Google Scholar · View at Scopus
- N. Yanagawa, G. Tamura, H. Oizumi, N. Takahashi, Y. Shimazaki, and T. Motoyama, "Promoter hypermethylation of tumor suppressor and tumor-related genes in non-small cell lung cancers," Cancer Science, vol. 94, no. 7, pp. 589–592, 2003. View at Publisher · View at Google Scholar · View at Scopus


text:
You can get everything in life you want if you will just help enough other people get what they want.
~ Zig Ziglar
The world would be a much better place if more people lived by this philosophy. So much can be gained by helping other people. I've seen it on both sides and there's almost nothing more powerful than helping others get what they want.
Help someone out today. Give someone advice, share a business lead with someone, send someone a pick-me-up note if you know they're down, hand a homeless person $10, just do something that has no direct benefit to yourself but means a great deal to another person. It will make your, and their, day.

subset: commoncrawl


text:
Original Sin - Update #21, Live Streams, Reddit and A New Quest
Just 4 days to go for the Original Sin Kickstarter and to reach the next stretch goal ($650K needed, currently at $578K). This update brings us information on Gragt's preview, we reported about earlier today, an upcoming live stream with PCGames.de, an upcoming Reddit section and a video on what reaching the stretch goals would mean.
And finally a rather large quest will be added to the game in which the red imps of the Codex and the army of The Watch are heading towards a conflict.
We want to thank both the RPGWatch and the RPGCodex for the fundraisers they've been holding to back Divinity: Original Sin. To show our gratitude, we came up with a bit of extra lore that we'll happily include should both communities agree.
We probably shouldn't refer to the little red guys as imps, but the troll-position is already taken in Divinity: Original Sin.
The Curious Tale Of Commander Myrthos And The Little Red Riding Imps
You'll find many a curious place in Rivellon, but none - Zixzax the Imp Historian will tell you - is quite as curious as the Shelter Plane At The End of Time. Fabulous indeed, would be the heroes who come to inhabit this enigmatic abode, and just as fabulous (as they'd soon find out) are the critters that live there!
No one - and when we say 'no one' we mean 'not even Bellegar' - knows where these red, diminutive demon imps come from, but even though they live at the very edge of the cosmos, a hunter haunts their path ...
Myrthos he is called, and rumour has it he is not alone. Does he stalk them because they wronged his kin? Have they broken a sacred oath? Are the forces of the very Divines at work? We can only guess, but the fact of the matter is that a sinister feud is slumbering beneath the surface of an already troubled realm.
Myrthos and his guild obey the mighty Watch. The Red Riding Imps swear by the ancient Codex. Between the two of them there is no common ground; by every oath imaginable they are sworn enemies that seek one another's destruction.
You decide the outcome...
Information aboutOriginal Sin
SP/MP: Single + MP
Setting: Fantasy
Genre: RPG
Platform: PC
Release: Released


text:
Last year was a terrible year for Nvidia. The company had a ton of inventory going into the fourth quarter, just as the demand for its graphics chips evaporated. Today, the company's executives talked about how they plan to get their momentum back.
In 2008, Nvidia let Advanced Micro Devices get ahead in the graphics chip race. Nvidia's partners also ran into reliability problems attaching its graphics chips to laptop system boards. And then the economic crisis hit, just as Nvidia was carrying more than a billion dollars in inventory.
The company's long-term comeback plan is to trust in the engineers' ability to deliver outstanding graphics chips. Another generation of high-end graphics chips is due soon, but Jen-Hsun Huang, chief executive of the Santa Clara, Calif., company declined to say when. He also declined to comment on current quarterly sales. That leaves some doubt in the near term.
The Nvidia plan includes a push into new markets. David White, the company's chief financial officer, said the company hopes to regain its historical gross margins above 40 percent (currently, it's at about 32 percent to 34 percent) by selling a richer mix of high-end chips. Those include Tegra mobile chips, Tesla and Quadro heavy-duty computing products, and the new Ion chipset for netbooks. But it's going to take time, perhaps a year or two, before those product lines all kick into high gear. And Ion remains tied up in a lawsuit with Intel, a fact Huang acknowledged has definitely hurt its sales.
In the meantime, it's going to be a very tough road, especially if there is no near-term recovery, says JoAnne Feeney, analyst at FTN Equity Capital Markets. That has led to a wait-and-see attitude about the prospect of a turnaround at Nvidia, whose stock is trading around $11 a share, down from $19 a share a year ago.
Nvidia and other computer companies are hoping to see a spur in demand in the fall, when new operating systems debut from both Apple and Microsoft.
Regaining footing will be difficult. White acknowledged that the downturn has changed the way consumers think, leading to a permanent shift toward low-priced products such as netbooks, or small laptops meant to cruise the web. That means lower average selling prices for Nvidia's mainstay chips. More consumers will likely settle for computers with low-cost Intel chip sets, which combine low-end graphics with other chip functions. Nvidia will also have to make sure it has a smooth transition to a new manufacturing process.
But Huang believes that the downturn has also accelerated a fundamental shift in computing, away from the costly serial processing of the Intel central processing unit, or CPU, and toward Nvidia's graphics processing unit, or GPU. While Intel CPUs consist of a hefty processor that handles big tasks one at a time, Nvidia's GPUs have a lot of little processors that handle small tasks in parallel. Huang believes GPU computing, or the use of graphics chips to perform parallel processing tasks even in non-graphics applications, is the future.
That's why he believes Apple is spending more money on Nvidia graphics chips than it is on processors in some of its newest laptops. Other computer makers will logically follow Apple's path, or find that their machines fail to satisfy consumers, Huang said.
Nvidia is also trying to get software developers to make more programs that exploit GPU computing, from the smallest of consumer applications to the heaviest of supercomputers. He says the resulting wave means that graphics processors will always be in demand, even if Intel and Advanced Micro Devices launch their hybrid chips that combine both a CPU and a GPU. Today, numerous analysts asked Huang what he would do when that happens, but Huang stuck to his answer that such hybrid chips will never dominate the market, much the way that a single car model never dominates the entire car market.
Huang says GPU computing has hit the tipping point, since more than 120 million graphics chips have hit the market with the capability. (AMD has its own version of GPU computing as well. If it catches on, Nvidia won't be alone). This is the way the computer industry will get its sex appeal back, Huang said.
"The GPU has volume sales," he said. "It is the best way to bring parallel computing to the world."


text:
Propose Day 2016 SMS Status for Boyfriend and Girlfriend Free information has been available here. You can also get latest collection of Propose Day 2016 WhatsApp Status, Poems, Facebook Status, Love Shayari, Gift Ideas, Quotes, Essay, Wishes, Sayings, Thoughts and HD Wallpapers.
Propose Day 2016 SMS Status for Boyfriend and Girlfriend Free
In this whole world U R just somebody,
& for somebody U R the whole world….
That stupid somebody is me.???
I love u so somebody…
Happy Propose Day this somebody..
If Roses were Black & violets were brown,
My love for "U" would never be found .!!
But "Roses" R red & violets are blue…
All I want to say Just is..!!!
I LOVE "U" So Happy Propose Day..
Hum Harr pal tumhare bare mein hi sochtey hain
k pyar ka iqraar tumhaare taraf se ho …
Q k hamhare equarar se, Hum inqaar se darte hain…
plzzz … Dont Mind …
At This Propose Day …
I Am Opening,
An Emotional Bank Account,
That is Only For You Sweetheart,
So .. Deposit Your All Love In It,
& You Will Get The Interest Be My Valentine.
Happy Propose Day Dear Sweety
I never saw In My Life…
so sweet a face…
As That I stood before….
My heart has left..
It is dwelling place….
& can return no more Be with me forever..
For my part,,
I consider that it will be found,
Much better by all parties,
To leave The past to history,
Especially as I propose,
To write that history myself.
I Love You..
Take her back to the 1st restaurant where,
'U' dined & surprise her with the ring…
'U' can arrange for the waiter to present
It to her with the dessert….
Have Very Happy Valentines Day.. ??
We Hope that information on Propose Day 2016 SMS Status for Boyfriend and Girlfriend, Life Partner Lover BF GF, Husband, Wife, Friends will be useful to all. Don't forget to share this post in social websites like Facebook, Google+, Twitter & more other social networking websites.


text:
Of course, Peter Jackson had done just that not too long ago but this is not another retelling of the classic King Kong tale of "'twas beauty killed the beast." Kong: Skull Island is set in 1973. The story follows scientist Bill Randa (John Goodman) and his mission to get Congressional funding for his plan to map a newly discovered island ... before the Russians find it. Randa has been at this for years and finally gets what he wants, including a military escort. His plan is to drop seismic charges on the island to test out his colleague's "Hollow Earth" theory. After flying through a perpetual storm that encircles the island, they find a pristine and lush landscape never before seen. But their presence, and the seismic charges, seem to have stirred up something else never before seen – a giant ape, which swats the military choppers out of the sky like gnats, killing many of commander Packard's (Samuel L. Jackson) men, leading him to seek revenge on the beast while the civilians, including tracker James Conrad (Tom Hiddleston) and photographer Mason Weaver (Brie Larson), think the sensible thing to do is get to their rendezvous point and get off the island as quickly as possible. During all the mayhem, it comes to light that there may be another reason for this mission to the island.
If you're thinking you don't need to see another King Kong story, just put that thought out of your head. This is not that story, nor is it that Kong which is much, much smaller than this Kong. Kong: Skull Island takes the concept of the original but gives it a totally new spin, and crafts a terrific and logical story (which is where Godzilla came up short) to keep you hanging on the edge of your seat. The film spends just enough time to let you get to know the main and supporting characters, including many of Packard's men (one of whom is played by Toby Kebbell, who himself has played in ape in the Planet of the Apes movies). These are characters you actually care about, and then as things go from bad to worse, it's interesting to see someone you think is a hero evolve into a villain.
And that villainous behavior is one thing that always bugs me about these types of movies where humans invade a place they don't belong, the native species defend themselves and then the humans feel like they have to kill the things that killed their people. No! But this issue is addressed when Kong is seen as the enemy after defending himself, and Conrad rightly points that out. A round of applause to the writers for that.
Besides the script, which nicely balances plot with action, the cast is perfection, even in the smaller roles. Goodman, Hiddleston, Larson and Jackson are real pros, bringing the same seriousness to these roles as they would any standard drama. There's nothing over-the-top about them or their characters, they make you feel like they are ordinary people in one huge, extraordinary circumstance. The script fleshes them out just enough that you feel like you know them and you are on this journey with them as well. Save for Kebbell, most of Packard's men are unfamiliar faces, but each actor makes you care about their fate as well (and this movie is not shy about killing anyone off, pushing the limits of the PG-13 rating). And then John C. Reilly pops up midway through the movie to bring some much needed, but not out of place, humor to the dire situation and instantly becoming the most likable character in the film, especially when we learn of his backstory. For a big, special effects-filled, giant monster extravaganza, this cast elevates the material above what you might expect.
Director Jordan Vogt-Roberts does a great job of keeping the story flowing, allowing the pauses in action to let us all take a breath, get our wits about us, and let the characters continue to come up with a solution to aid in their survival. Even with a two-hour running time, the film never lags or gets boring. The effects are also outstanding, from the harrowing flying through the storm scene to the first encounter with Kong and the introduction of the other horrific beasties that inhabit the island (including a nightmare-inducing giant spider). Nothing looks cartoony, like the "Fantastic Beasts" of another recent movie filled with CGI creatures. The movie lives or dies on Kong, and he is a fully living, breathing creature with soulful eyes (and the rendering of digital eyes has come a long way since the dead-eyed characters of The Polar Express). Everything about Kong is realistic right down to the hair gently moving in the breeze. It is a truly remarkable achievement. The action scenes are also shot very well, putting the viewer right in the middle of the fray, maybe even causing you to hang on to your arm rests as the choppers are being swatted out of the sky. This is brought to life even more if you take in the movie in IMAX 3D, which really adds quite a lot of depth to the film, helping to immerse you in the action, not making the 3D simply an afterthought.
Kong: Skull Island probably could have been a huge summer event movie, so I'm not sure why Warner Brothers decided to give it an early spring release, but it may eventually see greater financial success in this slot. And the studios certainly have plans for more to come. Be sure to sit through the end credits for a fantastic tease of what the future holds! From start to finish, Kong: Skull Island scores on every level. Don't miss it!


text:
Death notices for May 29, 2011
Gazette staff
Sunday, May 29, 2011
Beatrice B. Fuller, 97, formerly of Lake Geneva, died Friday at Winchester House in Libertyville, Ill. Services will be at 10 a.m. Wednesday at Roselawn Memorial Gardens Chapel in Delavan Township. Visitation will be 5 to 8 p.m. Tuesday at Steinke Funeral Home, Lake Geneva.
Larry D. Stefanovich, 73, Lake Geneva, died Thursday at Aurora Memorial Hospital, Burlington. No services have been scheduled. Steinke Funeral Home & Cremation Services, Lake Geneva, is assisting the family.
Mary Treder, 96, Delavan, died Friday at Vintage on the Ponds, Delavan. Arrangements are pending with Monroe Funeral Home, Delavan.
Last updated: 3:48 pm Wednesday, December 19, 2012


text:
I've downloaded the file to my PC, copied it to my SD card and followed all other instructions for installing this rom. I've installed many roms. This one is just not installing for some reason. TWRP goes through the process of flashing, but nothing flashes. It just says the flash was successful, but it obviously wasn't. I tried this from my internal storage and my external SD with the same results. I checked the file I downloaded and it looks like everything is there on my PC and phone.
I'll try downloading again. Any other suggestions?
I am unable to turn my Wireless on at all, and I get an error message that my Carrier Network does not provide time and date information. My time is incorrect and I have to manually set it.
I have a brand new SGS3 as of yesterday afternoon. I have CWM Touch installed for my Recovery (I will flash TWRP to the phone when I decide to use Kuban)...
I wiped Data/Factory Reset
I wiped Dalvik.
I wiped Cache for the hell of it.
I flashed the ROM only.
I wiped all three again, just in case.
I rebooted.
System comes up just fine and I begin the setup process.
First error: Time Date error for Carrier.
Get into the system, and begin my file updates/etc. I am unable to turn Wireless on at all. I hit the switch on-screen and the status changes to "Turning Wireless On" but the switch stays in "Off" mode, and it eventually just goes back to Off and "Turn Wireless On"
I rebooted into Recovery, and selected Fix Permissions. This ran for about 30 seconds, and then completed.
I get the same issue after reboot.
Under "Settings", I do not have the option to Install openrecoveryscript. If I click Flash ROMs though, I get asked about the OpenRecoveryScript, and then I can select Find one for me or I already have one...
I have flashed TWRP to the phone, and will reboot now.
bleh...i didnt realize there was a settings button on the app itself... I meant click the menu button at the lower left corner of your phone (opposite of the back button) and it should open a diferent menu with the install openrecoveryscript shown.
Edit: hmmm since i havent flashed this yet, thats about as far as i can help. Besides checking if it was a bad download, you're gonna have to wait till someone who had a sucessful flash or OP chimes in.
|wicked sensations att i747 d2att
|Thread Tools
|Search this Thread
|Display Modes
Linear Mode


text:
As someone in the process of moving, and having the house shown at often surprising times, I am so with The Cutter Rambles on this one. On prospective buyers who come over. Any time.
Pretty pictures of casual shrimp today, thanks to The Pumpernickel Collection.
Sometimes I feel this way, Wet Dog – I miss stopping too.
Even as the weather turns unseasonably warm, nothing melts my heart more than little hockey kids. Stimeyland takes us on the road for his little mite's very special hockey extravaganza.
And to take us out today, that most DC of spring traditions. Go out and do what Feast After Famine did – take in some beautiful cherry blossoms! Have a glorious weekend!


text:
Opening Friday
Evil Dead *** - This remake of the 1981 horror classic about five teens besieged by evil forces in the woods is not your typical do-over cash-in. The creators of the original film - Sam Raimi, Bruce Campbell and Rob G. Tapert - served as producers and oversaw the making of the film. It marks the feature debut of Uruguayan filmmaker Fede Alvarez, who certainly loves the gory stuff. Barf bags may be required.Rated R. 91 minutes. Review on Page 10. Cinemark, El Con, Foothills, Marketplace, Oasis, Park Place.
Jurassic Park 3D - "See it the way it was meant to be seen!" blare the TV ads for this 3-D upgrade of Steven Spielberg's dinosaur classic. Rated PG-13. 126 minutes. Related story on Page 14. Desert Sky, El Con, Foothills, Marketplace, Park Place, Spectrum, Uptown.
Ginger and Rosa *** 1/2- It's 1962 in London and two longtime friends grow apart as they grow up under the shadow of a possible nuclear war. Rated PG-13. 89 minutes. Review on Page 13. El Con, Loft, Marketplace.
Lore *** - A German girl and her four younger siblings are left to face the consequences of their parents' actions after their SS officer father and mother, a staunch Nazi believer, are interred by the Allies at the end of World War II. Not rated. 109 minutes. Review on Page 12. Loft.
The Sorcerer and the White Snake - Jet Li stars as the sorcerer in this fantasy film based on a Chinese legend about an herbalist who falls in love with a thousand-year-old White Snake disguised as a woman. Rated PG -13. 99 minutes. Not reviewed. Loft.
Continuing Friday
Admission ** 1/2 - Tina Fey is a Princeton University admissions officer who runs into an old classmate (Paul Rudd) with a gifted kid - the same boy she put up for adoption years earlier. What are the chances? No, seriously: What are the chances? Rated PG-13. 107 minutes. El Con, Foothills, Marketplace, Oasis, Park Place, Spectrum, Uptown.
Amour ** 1/2 - Michael Haneke's heart-breaking portrait of an elderly Parisian couple stars French New Wave icons Jean-Louis Trintignant and Emmanuelle Riva. PG-13. 125 minutes. Crossroads.
Argo **** - Director Ben Affleck continues to stretch as a filmmaker with this riveting, fact-based story about an attempt to rescue six Americans during the Iran hostage crisis in 1979. It won the Oscar for best picture. Rated R. 120 minutes. Crossroads, Gateway, Oracle View.
The Call ** - Halle Berry is a 911 operator drawn into a dangerous situation when she receives a distress call about a missing girl. Rated R. 95 minutes. Not reviewed. El Con, Foothills, Marketplace, Oasis, Park Place, Spectrum, Uptown.
The Croods *** - A gorgeous kids' cartoon with heart and wit, if not exactly a firm grasp of paleontology. Rated PG. 93 minutes. Cinemark, Desert Sky, El Con, Foothills, Marketplace, Oasis, Park Place, Spectrum.
Dead Man Down * - Noomi Rapace reunites with her "Girl with the Dragon Tattoo" director Niels Arden Oplev playing a woman who plots revenge by seducing the partner (Colin Farrell) of a mob boss who did her wrong. Rated R. 110 minutes. Gateway.
Django Unchained ** - With the help of his mentor, a slave-turned-bounty hunter sets out to rescue his wife from a brutal Mississippi plantation owner. Rated R. 165 minutes. Crossroads, Oracle View.
Emperor ** 1/2 - Tommy Lee Jones is Gen. Douglas MacArthur and Matthew Fox is Gen. Bonner Fellers in this World War II drama about Japan's surrender and the fate of Emperor Hirohito. Rated PG-13. 105 minutes. Gateway.
The Gatekeepers *** 1/2 - Dror Moreh's Oscar-nominated documentary finds six former heads of Israel's counterterrorism agency speaking with striking candor, and with no little regret, about the decisions that backfired, the iron-fisted policies that brought about more violence, more bloodshed, not less. If there's a way out of the Israeli/ Palestinian conflict, these men may have the answer. Rated PG-13. 95 minutes. Loft.
G.I. Joe: Retaliation ** - This sequel to 2009's execrable "G.I. Joe: The Rise of Cobra" sends the super-agents (including Dwayne "The Rock" Johnson and Bruce Willis) on a hunt to uncover the traitor in their ranks. Rated PG-13. 110 minutes. Cinemark, Desert Sky, El Con, Foothills, Marketplace, Oasis, Park Place, Spectrum.
A Good Day to Die Hard * 1/2 - Bruce Willis is the last hope of the 1980s action-movie stars with this fifth installment of the smash franchise. Rated R. 97 minutes. Crossroads, Gateway.
Hansel & Gretel: Witch Hunters * 1/2 - This version of the fairy tale recasts brother and sister (Jeremy Renner, Gemma Arterton) as bounty hunters. PG-13. 86 minutes. Gateway, Oracle View
The Hobbit ** 1/2 - Director Peter Jackson ("The Lord of the Rings") returns to Middle Earth with this first installment in a $500 million trilogy of films based on J.R.R. Tolkien's novel. Rated PG-13. 169 minutes. Gateway, Oracle View.
The Host ** 1/2- Now that the "Twilight" saga is completed, another Stephenie Meyer novel gets a big-screen adaptation. Andrew Niccol ("Gattaca") directs Saoirse Ronan as a young woman who discovers aliens are taking over the bodies of people and erasing all their memories. Rated PG-13. Cinemark, Desert Sky, El Con, Foothills, Marketplace, Oasis, Park Place, Spectrum.
Identity Thief ** - Jason Bateman goes on a road trip to find the woman (Melissa McCarthy) who has stolen his identity and wrecked his life in the process. Directed by Seth Gordon ("Horrible Bosses"). Rated R. 110 minutes. Spectrum.
The Impossible **** - Naomi Watts and Ewan McGregor star as a couple vacationing with their three sons in Thailand when the 2004 tsunami hit. Based on a true story. Rated PG-13. 122 minutes. Crossroads.
The Incredible Burt Wonderstone ** 1/2 - Two famous Vegas magicians (Steve Carell and Steve Buscemi) are forced to up their act after a street performer (Jim Carrey) makes them look like amateurs. Rated PG-13. Park Place, Spectrum.
Jack Reacher *** - Christopher McQuarrie directs Tom Cruise as a homicide investigator involving a military-trained sniper. Rated PG-13. 130 minutes. Oracle View.
Les Miserables ** 1/2 - In 19th-century France, Jean Valjean, who for decades has been hunted after he breaks parole, agrees to care for a factory worker's daughter. Rated PG-13. 158 minutes. Crossroads, Oracle View.
Life of Pi *** 1/2 - Ang Lee won the Oscar for best director for this adaptation of Yann Martel's Booker Prize-winning novel about an Indian boy who finds himself adrift on an ocean alongside a Bengal tiger. Rated PG. 127 minutes. Crossroads, Gateway.
Lincoln *** - Steven Spielberg's big-screen portrayal of the 16th president earned 12 Academy Award nominations, including best picture. Daniel Day-Lewis won the Oscar for best actor for his portrayal of Abraham Lincoln. Rated PG-13. 150 minutes. Crossroads, Gateway, Oracle View.
Olympus has Fallen **- In the midst of a terrorist attack on Washington, D.C., a security agent (Gerard Butler) is the only person capable of saving the life of the president (Aaron Eckhart). Then Katherine Heigl shows up and romance blooms, complicating everything. Rated R. 113 minutes. Cinemark, Desert Sky, El Con, Foothills, Marketplace, Oasis, Park Place, Spectrum.
On the Road *** - Walter Salles' warm but strangely staid adaptation of a piece of literature reduces Jack Kerouac's breathless Beat Generation prose-poetry and reduces it to the conventional elements of plot, character and setting. Sam Riley, Garrett Hedlund, and Kristen Stewart star. Rated R. 124 minutes. Loft.
Oz The Great and Powerful *** - Sam Raimi directs this special effects-intensive fantasy, based on L. Frank Baum's novel, about a small-time magician (James Franco) who is whisked away to a distant land where he has the power to become a great wizard. Rated PG. 130 minutes. Cinemark, El Con, Foothills, Marketplace, Park Place, Spectrum.
Parental Guidance ** - Billy Crystal and Bette Midler play grandparents who agree to babysit their grandkids when their type-A helicopter parents (Marisa Tomei, Tom Everett Scott) leave town. Rated PG. 100 minutes. Oracle View.
Quartet *** - At a home for retired opera singers, the annual concert to celebrate Verdi's birthday is disrupted by the arrival of Jean, an eternal diva. Rated PG-13. 98 minutes. Desert Sky, Loft.
Rise of the Guardians * 1/2 - This CG-animated feature sounds like "The Avengers" for the little guys, as Jack Frost, the Easter Bunny and Santa team up. Rated PG. 97 minutes. Oracle View.
Safe Haven *** - Another Valentine's Day, another Nicholas Sparks adaptation. Julianne Hough stars as a woman who shares a dark secret with a widower (Josh Duhamel). Directed by Lasse Hallstrom ("The Hoax"). Rated PG-13. 115 minutes. Crossroads, Gateway.
Searching for Sugar Man **** - The Oscar for Documentary feature went to this inspiring documentary about Rodriguez, a forgotten singer/songwriter who recorded a pair of great albums in the 1970s. Rated PG-13. 86 minutes. Crossroads.
Side Effects *** - Steven ("Magic Mike") Soderbergh directs this immensely playful thriller about a woman (Rooney Mara) who falls into a depression after her husband (Channing Tatum) gets out of prison for insider trading. Rated R. 105 minutes. Crossroads.
Silver Linings Playbook *** 1/2 - After losing his wife, house and job and spending time in a mental institution, a former teacher tries to rebuild his life. Bradley Cooper and Jennifer Lawrence star. This film earned eight Oscar nominations, including for best actress, which went to Lawrence. Rated R. 122 minutes. El Con.
Spring Breakers ** 1/2 - Director Harmony Korine ("Gummo") returns with this raunchy comedy about a sleazebag (James Franco) who bails four wild-and-crazy gals out of prison and leads them on a series of adventures involving wet T-shirt contests and beer bongs. Rated R. 92 minutes. El Con, Foothills, Park Place, Spectrum.
Tyler Perry's Temptation: Confessions of a Marriage Counselor - Jurnee Smollett-Bell, Lance Gross, Kim Kardashian and Vanessa Williams star in the prolific filmmaker's latest comedy-drama, about a married woman who gives in to temptation and has an affair, leading to disastrous consequences. Rated PG-13. 111 minutes. Not reviewed. El Con, Foothills, Oasis, Park Place, Spectrum, Uptown.
Warm Bodies ** 1/2 - Zombies are played for laughs in this comedy about a flesh-eating teen (Nicholas Hoult) who starts to develop feelings for a girl (Teresa Palmer). Rated PG-13. 92 minutes. Crossroads, Gateway.
Wreck-It Ralph *** 1/2 - A villain of a video game sets out to fulfill his dream to be a hero. Rated PG. 108 minutes. Oracle View.
Zero Dark Thirty *** 1/2- An elite team of intelligence and military operatives working in secret across the globe engage in a tireless manhunt to eliminate the terrorist mastermind Osama bin Laden. With Jessica Chastain. Directed by Kathryn Bigelow. Rated R. 157 minutes. Crossroads, Oracle View.
Staff and wire services


text:
How many of you have spent time trying to look up credit cards and try to find ones with good rates in the past? I haven't done that for a while but I have in the past. It can be confusing sometimes can't it? As with anything that I'm putting my name to or signing up for I like to clearly know the facts of the product before I go ahead and get it, and what I've found with some of the credit card sites that I've gone to before, is that the information is hard to find, buried deep within the site. It just makes the whole process so much more confusing.
Actually, I think one of the main reasons some of those sites bury the information and make it's so hard to find is because they are charging extraordinarily high interest rates or extra fees on their products.
So I was pleased when I came across CardGuide.co.UK earlier today. They claim to list only the best credit cards and after looking over the site I believe their claim is true. I even found some interest free credit cards. Now that is something that might interest most people!
They make it easy to search for the kind of card that's right for you. You can compare cards quickly and easily, or you can search for a particular type of credit card and quickly see all of the important information about the card when it comes up in a table with a few other similar card types. If you want you can even apply online directly from the Card Guide site.
Another thing that I enjoyed about the site was that they have a number of articles. I didn't count them but at a glance I'd say that there are more than 50 different articles on the site that discuss the different aspects of the various types of credit cards, the pro's and con's of particular types of cards and so on. Check it out for yourself. I'm sure that at the very least you'll learn a bit more about credit cards on this site.


text:
Made from heat-resistant carbon, the ghd Tail Comb is perfect for use with the ghd Air Dryer or your ghd styler. The tail end can also be used to separate sections of hair ready for blow drying or tucking stray hairs into up-do's. The anti-static, fine teeth of this comb make it perfect for backcombing and intricate styling.
How to use ghd Tail Comb
- For damage-free backcombing (that's also easy to brush out), take a small section of hair and hold it away from the head.
- Place the comb in the section a few centimetres away from the root.
- Push the comb down the hair, against the direction of growth, in two short strokes, stopping short of the roots.
- For the third stroke, push back right to the roots. Continue with this three-stroke method on every section you need to backcomb.
FREE Standard UK delivery available on orders over £20.
Rush Shop ships internationally, as well as to the UK and Ireland. Services include:
- Standard UK Delivery: £3.00
Royal Mail Standard Delivery service: 2 - 5 working days
- Next Day UK Delivery: £3.99
Interlink Express Tracked Courier service: next working day
- Standard EU Delivery: £6.99
Royal Mail Standard Delivery service: 2 - 10 working days
- Standard International Delivery: £9.99
Royal Mail International Delivery Network: 5 - 21 working days
Please read our Delivery Policy for more information on International and UK delivery times before completing purchase.


text:
Eagles build early lead in win over Panthers
New York Mills jumped out to a 33-0 lead en route to a 49-22 victory over the Park Rapids wrestling team Tuesday night at the Century School gym.
The Eagles won the first six matches, three via forfeits, to take control.
Jeremiah Harper got the Eagles started with a fall at 2:41 against Devon Eischens.
Shane Novak added an 11-3 decision over Ben Baumgartner at 119 pounds. Tyler Ehnert recorded a fall at 1:45 to get the Eagles up big early.
Park Rapids' Zachary Steffen ended that run with a 13-0 major decision at 140 pounds. Steffen used a first-period takedown, a takedown and nearfall in the second period, and another takedown and nearfall in the third period for the win.
New York Mills won the next three matches to build a 49-4 cushion.
Michael Meyer scored a fall at 2:28 over Adam Branstrom. Peter Stark added bonus points in a 10-1 decision over Zac Haugland and Seth Hofland pinned Nick Schulz at 3:18 at 160 pounds.
The Panthers ended the match with four victories.
Kevin Just's reversal in the second period and takedown in the third period led to a 4-2 win at 171 before Danny Pike used takedowns in the first and third periods for a 4-0 decision at 189.
Brandon Ritter used three takedowns to build an 8-0 lead before recording a pin at the 4:38 mark at 215. Cole Tretbar ended the dual with a forfeit win as the Panthers fell to 3-3 in dual meets. New York Mills improved to 3-1.
NYM 49, Park Rapids 22
103: Jeremiah Harper, NYM, pinned Devon Eischens 2:41. 112: Tommy Selander, NYM, won by forfeit. 119: Shane Novak, NYM, decision over Ben Baumgartner 11-3. 125: Tyler Ehnert, NYM, pinned Laine Jensen 1:45. 130: Jake Hessig, NYM, won by forfeit. 135: Kyle Vordeburgen, NYM, won by forfeit. 140: Zachary Steffen, PR, major decision over Andrew Mindermann 13-0. 145: Micheal Meyer, NYM, pinned Adam Branstrom 2:28. 152: Peter Stark, NYM, major decision over Zac Haugland 10-1. 160: Seth Hofland, NYM, pinned Nick Schulz 3:18. 171: Kevin Just, PR, minor decision over Ty Bell 4-2. 189: Danny Pike, PR, minor decision over Tyler Patron 4-0. 215: Brandon Ritter, PR, pinned Max Carlson 4:38. 285: Cole Tretbar, PR, won by forfeit.


text:
New Facility for SRA Shops
We are now in the final stages of the move to our larger facility! Our new address is 24 Walpole Park S. STE10 Walpole, MA 02081 and It is located directly across the street from our old building. We will still offer local pickup as an option for customers who wish to pickup their orders in person. Thank you for working with us in this busy time while we get situated.
Posted in Company News By Sam Skinner


text:
I left home at about 7.50am and cycled east out of Cambridge along the river and across the meadows to Fen Ditton, where we had planned to rendezvous at 8.15am. It had been a cold night, and I had to watch out for early-morning frost on the paths by the river, but the sky was clear and before long the sun was up and shining brightly down on us.
8.10am. Fen Ditton church bathed in morning sunshine
We set off east to Little Wilbraham (where I stopped to mend a puncture) and Six Mile Bottom from where we made the gentle but long climb to Brinkley. With a light breeze behind us and the warmth of the sun keeping us comfortable we made good progress as we continued via Carlton Green and Little Thurlow to Stradishall. Here, with 20 miles covered we stopped for breakfast at Tubby T's Cafe. Gareth ordered coffee and a bun and, rather to my surprise, asked for a receipt. He reminded me that on a DIY Audax ride like this he needed to produce proof that he had followed the route, and that submitting a cafe receipt, with location, date and time printed on it, was an easy way to do this.
I ordered beans on toast. The cafe was quiet so my breakfast was served quickly and we were soon back on our way. I agree with Gareth that when you're riding a long way it's best to avoid spending too long at the stops.
We continued east through Hawkedon and Hartest, where we climbed Hartest Hill which at more than 1 in 7 was the only significant hill of the day.
Hartest Hill - the steepest climb of the day
We continued east through Shrimpling and Bridge Street and after a short distance further we arrived in Lavenham, where Gareth made a token purchase from the co-up in order to obtain yet another receipt.
The pace so far had been comfortable, unlike the last time I rode a 200km Audax, helped no doubt by the gentle tailwind.
From Lavenham we followed the A1141 south-east to Hadleigh. Despite its A-road designation this was in fact a very quiet, pleasant road. At Hadleigh we stopped outside Greggs for a rest and for Gareth to buy another bun.
From Hadleigh we continued south-east along the B1070 to East Bergholt. We passed the sign to Flatford, reminding me that this is "Constable Country", though the only sign telling us this was the one outside the Constable Country Medical Practice. After a few more minutes we reached the bridge over the River Stour just north of Manningtree. This is the point at which an already wide river turns onto an even wider estuary, and there was definitely a feeling that we'd "reached the sea".
Crossing the River Stour at Manningtree
Close-up of Cormorant on the River Stour
After crossing the Stour we turned off towards Manningtree. This took us east along the south bank.
River Stour near Mistley with swans and a little flock of mostly sandpipers (but at least one of them is a curlew).
We rode through Manningtree, which I had thought of as just a railway junction but is in fact a small town and on to Mistley, where we stopped for lunch at the Mistley Quay Cafe. It was 1pm and we had covered about 57 miles: a little less than half-way.
After lunch we set off west back for the long ride back towards Cambridge. Almost immediately Gareth began suffering from some kind of stomach cramp and was clearly in discomfort, and we made slow progress, not helped by the fact that we were riding back into the wind now. We pressed on carefully, through Dedham, Langham, Nayland and Boxted.
Track between Langham and Boxted
Near Nayland we crossed the River Stour once more. Our slow progress had meant that by now the sun was gettting low in the sky and would soon be setting.
Sunset over the (rather smaller) River Stour near Nayland
We continued west. As the sun set the full moon rose.
Full moon with a bite taken out of it. See Gareth's comment below for an explanation.
Gareth was still not 100% and although he was still riding at a very respectable pace it wasn't as fast as he would have liked and by the time we reached Bures it was quite dark. It was 3.50pm. We were now running behind schedule and there was now a definite possibility that we would not be able to complete the ride within the time permitted under Audax rules.
We stopped in a pub to warm up and discussed what to do. Gareth was clearly unwell but after briefly contemplating abandoning the ride and taking the train back from Bures (via Liverpool Street) he suggested we carry on west towards Sible Headingham and Finchingfield. We reached Finchingfield at about 5.45pm, where we stopped in The Fox for a drink and a rest. It was now clear that any hope of completing the ride had disappeared. We were going too slowly to complete the ride within Audax time limits and Gareth still wasn't feeling well. The plan had been to continue west to Saffron Walden and from there to Royston, from where we would return to Cambridge via Kneesworth. However we now agreed that we should continue to Saffron Walden and catch the train back to Cambridge.
We reached Saffron Walden at 7.35pm. The next train from Audley End was at 8pm, and I suggested to Gareth that he catch the train whilst I cycle back on my own to Cambridge. As I had rather expected, Gareth changed his mind and suggested he ride back to Cambridge with me.
Nigel resting at Saffron Walden before the final leg to Cambridge
Our mileage to this point was 103 miles, so to take things easy we eschewed our normal route via Catmere End and Coploe Hill and instead followed a fairly level route via Littlebury and Great Chesterford to Ickleton and from there along our usual route via Duxford, Whittlesford and the Shelfords back to Cambridge. I was home at 9pm, having cycled a very satisfying 120 miles. That's 193 km, so we didn't miss our 200km target by too much. Missing the Royston stop meant that Gareth's ride wouldn't qualify under Audax rules, but we were very close, and I had certainly achieved my own goal which was to allow me to eat a large Christmas lunch the next day without guilt. Gareth recovered from the ride and was able to be there as well.
View this GPS track on a larger map


text:
Peggy Corthouts was born in 1959 in Coventry, Connecticut. In 1983, she received her Bachelor of Fine Arts degree in printmaking from Arizona State University. Ms. Corthouts also studied with Wayne Kimball, master printer at the famed Tamarind Atelier.
Among fine art prints, Corthouts is known as a printmaker of remarkable skill and sensitivity. More recently, she has concentrated on her own work, which is receiving considerable attention in the art field. Masterfully executed, her beautiful landscapes are contemporary, yet possess a softness and quality of light reminiscent of the Impressionistic Period.
Corthouts' work has been exhibited throughout the United States and her pieces are featured in the collections of the Markland Corporation, National Medical Enterprises, Piedmont Airlines, the John C. Lincoln Hospital, Arizona State University, and the Embassy Suites Hotels.


text:
Buster Creatives called us to design an exclusive new typeface family for the History Channel rebrand.
The usage of an exclusive typeface in the design of a corporate or product brand is a powerful resource creating a strong and original identity. Also, using typefaces that were designed for specific needs is a trend in the design of newspapers and magazines.
Our team offers original and exclusive type design for corporate use, with a high quality and low cost.
Editorial Estrada requested a font to improve the 6 years old students learning
Banco Hipotecario Example of custom type designed for a bank in Argentina.
Prip para Nextel. Custom font for telephone company Ad campaign.
Net-a-Porter group asked us to design a new custom script typeface for the UKs brand new fashion magazine Porter.
In the publishing business usually is necessary to make changes, an adaptations and adjustments in the typefaces that are used to optimize the printing and the text behavior.
This activity requires a particular study of the print technology (printing, monitor, etc.) to redesign the font and optimize its legibility and performance.
Bold Example of custom lettering for Procter & Gamble.
Pease, feel free to call us for more information about our services. A professional team specialized in typography, with a high knowledge in editorial design, animation, web, packaging will help you, as soon we understand your problem.
Contact us: email@example.com


text:
Jerome Horton
Horton Confirmed for Board of Equalization
Jerome Horton Wins Unanimous Vote for Confirmation to State Board of Equalization
Governor Appointee Jerome Horton was unanimously confirmed to the California State Board of Equalization by the California State Senate on Wednesday, September 9.
Jerome Horton is the first African American to serve on the State Board of Equalization (BOE) since its inception in 1879. He also became the 3rd African American constitutional officer in California's history. The Assembly joined them by overwhelmingly supporting Horton's confirmation.
The BOE administers taxes and fees that last year produced $53 billion to provide essential services for the people of California. It employs over 4,000 staff members from auditors to attorneys and has offices throughout the State and in Texas, Chicago and New York. They are also the appellate body for Franchise Tax matters. Eminently qualified for the job, Horton served 21 years with the Board of Equalization as a tax expert. He also served 6 years in the State Assembly and one term as a Inglewood Council Member.
"Mr. Horton is very well-prepared for the position of member of the Board," Senator Feinstein said. "His extensive knowledge and experience clearly make him the most qualified candidate for this position."
The Speaker of the Assembly, Assemblywoman Karen Bass referred to Horton as the equalization equalizer because of his efforts to ensure parity in employment at the executive and entry levels and his proven record of protecting California taxpayers.
"I am pleased that the legislature confirmed Jerome Horton's nomination to the Board of Equalization," Assembly Speaker Karen Bass (D-Los Angeles) said. "I'm confident his experience and commitment to public service will be a great addition to the Board's important work."
Horton began his career with the BOE as a summer intern while obtaining his Bachelor of Science degree in finance and accounting from Cal State University Dominquez Hills. That early experience shaped his resolved to give back and be of service to his community.
Horton said, "I have been blessed with an opportunity to lay a foundation and pave the way for others. I believe that success requires a successor and that power is measured by ones ability to empower others. Accordingly I intend to expand youth leadership and internship programs to empower others to lead."
"I also want to empower California taxpayers to prosper by making it easier to start, maintain, and grow a business, and streamlining the appeals process to minimize penalties, interest and unwarranted legal fees. I believe, leveling the playing field by arresting illegally operating businesses that steal billions from and compete unfairly with California taxpayers is equally important to revitalizing our economy," said Horton.
Mayor Antonio Villaraigosa said, "Jerome Horton will provide the experienced leadership in tough economic times that we need as a member of the Board of Equalization. He will make a positive difference for the people of California."
Known as a solution oriented consensus builder Horton was supported by the Business and Labor, Republicans and Democrats, and Liberals, Moderates, and Conservatives. Leaders in the Armenian, Latino, Asian, and African American community also expressed enthusiastic support of Horton's confirmation.
Maria Elena Durazo, president of the Los Angeles Federation of Labor said, "Horton has the ability to bring people, from all walks of life, together to forge real solutions that generate good jobs and prosperity in California. He has been a loyal friend and confidant and we were proud to support this historic confirmation"
Alice Huffman, President of the NAACP said, "Horton's appointment is a hard fought gain for all Californians and we intend to help him help us rebuild our economy and equalize things for all well beyond 2010."
A devoted family man, Horton, who enjoys gardening, fishing and his new grandchild, resides in Inglewood with his wife and two children, Matthew and Myeshia.


text:
GioiaPuraAdd to shopping bag
necklace woman jewellery GioiaPura
Code: GPSRSCL2269
€ 36.95 € 49.00 You save € 12.05
shipping cost: € 20.90
Delivery within Wednesday 29 November, if you order within 7 hours and 10 minutes
Product Info
Product: necklace woman jewellery GioiaPura GPSRSCL2269
Gioiapura Jewel, 925 Silver Necklace And Zircon. Chain With Pendant Rosé Heart-shaped, length 43 cm Chain and Pendant 2.3 X 1.5 cm, Closing A Snap Type. News Gioiapura, Reference: Gpsrscl2269
this necklace will be shipped with the original box GioiaPura
30 days to return the product
this necklace is shipped worldwide with UPS
See more articlesGioiaPura woman GioiaPura jewellery GioiaPura jewellery necklaces
Features necklace GPSRSCL2269 GioiaPura
brand: GioiaPura
package: original box GioiaPura
Product Guarantee: International Warranty GioiaPura
kind: woman
category: jewellery
Subcategory: necklaces
style: trendy
producer code: GPSRSCL2269
Clasp type: Karabiner
Jewel Material: 925 Silver
Necklace Type: pendants
Necklace length: 43 cm - 49 cm
Stone type: Zircons
Symbol: Heart
You might also like
Other products GioiaPura


text:
Plasticville & Lionel Village Houses & Accessories for Train Displays, etc.
Sold for:
Start Free Trial
or Sign In to see what it's worth.
- Sold Date:
- Source: eBay
This auction is for a variety of Vintage Plasticville & Lionel VillageHouses and Accessories that could be used in your train display or festive Christmas Village display! Picture #1 and #3 are the Plasticville houses and #2 is the Lionel House. Picture #1 is the Motel and the only one with a box. The box ix in fair condition, with some tears on the corners of the flaps. The train station (picture #2) is in good condition, however, the previous owner taped the doors open from the inside. The door on the side does not stay on. The church is in very good condition. The steeple is not permanent. The extra pieces in picture #4 are telephone poles, pond with bridge, part of a log cabin, a flag, bench and R.R crossing gate . Any questions feel free to contact me. All sales are final. Thanks for looking.


text:
The Issey Miyake W Black Watch was an idea by renowned Japanese car designer, Satoshi Wada, who worked for Audi in Germany and made remarkable achievements in designing many series. The inspiration for this designer watch comes from the powerful and dynamic case of an aluminum car wheel and the long hands indicate the time on its precise gauge-like dial. In the aim of achieving high legibility and accuracy, the dial is made wide and hands are designed fine and long. The band's material is cow leather provided by a long established tanned leather manufacturer located in Tokyo, Japan. With the emphasis on the beauty of nature, this leather is tanned using vegetable tannin.
Tax is only charged if shipping to California. Visit our Shipping Info page for additional information.
We honor returns within 30 days from the original delivery date and offer free exchange shipping. Some restrictions do apply for built-to-order items, or very large items like furniture.
For additional details, or to initiate a return, please visit our Returns Page.
*Please note that while we do our best to have the most up to date product imagery, in-line changes will happen with brands and the actual product shipped may differ slightly.