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I got this flyer about a week ago:
|Official Flyer SL Avi Choice Awards.
It's for the Second Life Avi Choice Awards which I have never heard of because I generally keep myself to myself in Second Life so social networking is my weakness.
I glanced at it, wondered why it had been sent to me then forgot all about it.
Today, I was sent a notecard congratulating me on being nominated and asking me to prepare an acceptance speech if I planned on attending and assuming I had enough votes to win, the speech would be read out by the radio host.
I was also instructed to sit on the chair marked "X" if I heard my name called out by the radio DJ.
Sadly, 6pm SL time is 2am UK time :(
I went to the website and researched what I had been nominated for and the categories and I am guessing its the "Home and Gardens"category but I really do not know.
This is the first I knew anything about it.
I have to say, I am baffled. It's deeply flattering and a huge honor but I cannot understand who or why anyone would nominate me.
I did write a little speech but then it's hard to write a thank you speech when I don't believe for one minute I would ever win.
There are so many designers out there and many much more skilled than I so I can only assume I was nominated because of how old my account and TRU Textures is.
I opened TRU Textures within Second Life in 2005 so it's close to eight years old and I guess most of us oldies have vanished over the years. I guess the fact I am "still kicking" is an achievement of sorts :)
Anyway, I won't be attending and so by default, I won't be collecting any awards.. lol (I might have if I believed I had a cat in Hells chance! As if!)
But I felt I should say "Thank you" to those people (Or person? lol) who put my name forward.
It's very touching; But really, I am no different to the thousands of other SL designers who are working from their homes and just trying to make an income from doing something they love....and that's reward enough really.. how many people can say "I love what I do for a living?" I am blessed and grateful.
So anyway, thank you for the gesture and kind thoughts...who ever you are!


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Strong Start to 2010 Season at Parker 425 Rick Backus/Dave Mason 2nd Place in ProTruck Backus Brothers Leading 7200 Class until Mechanical Ends Race Early Western Motorsports wasted no time setting the tone for their level of performance ...
Strong Start to 2010 Season at Parker 425
Rick Backus/Dave Mason 2nd Place in ProTruck
Backus Brothers Leading 7200 Class until Mechanical Ends Race Early
Western Motorsports wasted no time setting the tone for their level of performance inParker 425 Protruck Mason Moffatt 2010. They kicked off the season with a 2nd place finish in the #1265 Eleven Western Builders Protruck Ford at the Blue Water Resorts and Casino Parker 425 in Parker, Arizona. The day began with Dave Mason behind the wheel along with co-driver Rob Fox. Mason maintained a fast but somewhat conservative pace for the first half of the race. Despite one flat tire the Mason/Fox pair turned the truck over to driver Rick Backus and co-driver Mark Moffatt at the halfway point in a solid position. Down to the leader by 8-minutes Rick Backus drove flawlessly clicking off time gaining on the race leader, Troy Vest. The final 20 miles was a nose to tail battle for the win. In the end Backus would cross the finish line a very close 2nd place.
"Everyone had fun and that was first on our list heading into this year," expressed Backus. "Our plan was to start out conservative and be contending for the win in the end. We did just that. Dave [Mason] brought the truck to me in good shape and from there we picked up the pace and took time away from Vest. It was a lot of fun battling for the win those last 20-miles. It was kind of anyone's race at that point and [Troy] Vest just barely got us. I'm proud of our team and how we did overall."
7265 Truck Leading Race until Mechanical Issue Ends Race Early
Parker 425 7265 Truck The debut of the #7265 Eleven Western Builders Chevy was bitter sweet. Sean Backus kicked off the driving duties for the team and despite some wheel trouble early in the race he had placed the truck well inside the top five at the halfway point. Sean wasn't scheduled to drive due to a previous off-track injury, but a little pain wasn't enough to hold him back from the historic Parker 425 off road race event. Sean turned the truck over to brother Brett Backus, who impressively drove to the lead position. Through some attrition of other race vehicles the #7265 team had a very strong lead and appeared to be on their way to winning the first race of 2010. But at mile 115 the transmission failed and ended their day early.
"It was pretty disappointing to have such a strong lead and then have it all over due to a mechanical issue," said Brett Backus. "Sean did a great job getting the truck up front. We took over and once in the lead were running somewhat conservatively knowing we had such a good amount of time over the field. These guys at Western Motorsports do an excellent job of preparing the trucks. It was just one of those unfortunate finishes. The good part is that we know we can win. We have the truck, the crew and all the components to be a winning team. I'm really looking forward to the next race."
The next race for the #1265 Protruck and #7265 Truck will be the Best in the Desert's Bilek Racing Silver State 300 April 23rd-25th near Las Vegas, Nevada. Stay tuned to www.WesternMotorsports.org for all the latest news and results.
-source: western motorsports


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The majority of tumors arising in BRCA1 mutation carriers exhibit inactivation of p53, a key effector of cell death following DNA damage. Despite the loss of p53, BRCA1-deficient tumor cells exhibit increased sensitivity to cisplatin, and patients with BRCA1-associated ovarian carcinomas experience improved outcomes with platinum-based chemotherapy compared to sporadic cases. While it is known that chemosensitivity in BRCA1-associated cancers is associated with unrepaired DNA damage, the specific effector pathway mediating the cellular response to platinum-induced damage in these tumors is poorly understood. Here we demonstrate that the p53-related gene p73, encoding a pro-apoptotic protein which is linked to chemosensitivity in many settings, is upregulated through a novel epigenetic mechanism in both human and murine models of BRCA1-associated ovarian carcinoma. BRCA1-deficient ovarian carcinoma cells exhibit hypermethylation within a p73 regulatory region which includes the binding site for the p73 transcriptional repressor ZEB1, leading to abrogation of ZEB1 binding and increased expression of transactivating p73 isoforms (TAp73). Cisplatin chemotherapy induces TAp73 target genes specifically in BRCA1-deficient cells, and knockdown of TAp73 in these cells causes chemoresistance while having little or no effect on BRCA1-expressing tumor cells. In primary ovarian carcinomas, ZEB1 binding site methylation and TAp73 expression correlate with BRCA1 status and with clinical response. Together, these findings uncover a novel regulatory mechanism that supports the contribution of TAp73 as an important mediator of the response to platinum chemotherapy in a subset of ovarian carcinomas. TAp73 may represent a response predictor and potential therapeutic target for enhancing chemosensitivity in this disease.
Ovarian cancers arising in the setting of germline mutation of the BRCA1 tumor suppressor gene exhibit particular clinical and molecular features, including predominantly serous histology, a high grade suggestive of a more aggressive malignancy, and distinct gene expression profiles (1, 2). Furthermore, these tumors exhibit mutational inactivation of p53 in up to 80% of cases (3). Inactivation of p53 is thought to promote tumor cell survival in the face of BRCA1-dependent defects in DNA repair (3). The unfavorable histological features and loss of functional p53 in BRCA1-associated ovarian cancers initially suggested that these tumors might be associated with chemoresistance and potentially a poor prognosis (1). Multiple studies, however, have confirmed that patients with BRCA1-associated ovarian carcinomas in fact experience a higher response rate and a more prolonged disease-free interval following platinum-based chemotherapy, as well as improved overall survival (3–5). In vitro studies of human ovarian cancer-derived cell lines have supported the view that loss of BRCA1 function is associated with selective chemosensitivity to platinum agents (6, 7). We and others have previously demonstrated that platinum sensitivity is associated with unrepaired DNA damage in BRCA1-deficient ovarian carcinoma cells (7, 8). Nevertheless, the specific effector pathway that mediates the response to this DNA damage in the absence of functional p53 has not been defined.
We have developed a murine model in which defined genetic events induce BRCA1-associated ovarian carcinomas that recapitulate the serous histology, the genetic instability, and the DNA damage sensitivity of human BRCA1-deficient ovarian carcinomas (8–10). We demonstrate here that BRCA1-deficient human and murine ovarian carcinoma cells exhibit selective up-regulation of transactivating isoforms of the p53-related gene p73 (TAp73), which is known to function as a mediator of the DNA damage response and chemosensitivity in many cellular contexts (11–14). We provide evidence that this TAp73 up-regulation occurs through a novel epigenetic mechanism, and that TAp73 serves as an important contributor to the platinum-induced DNA damage response and to chemosensitivity in ovarian carcinoma, both in vitro and in vivo. Our findings therefore define an epigenetic regulatory mechanism for p73 that plays a role in the clinical behavior of BRCA1-associated ovarian tumors.
We (D. X., S. O.) generated the murine ovarian carcinoma cell lines (T1, T2, T3, TBR2, TBR5, TBR6). Western analysis was carried out to confirm the absence of whole-length BRCA1 proteins. These lines were maintained in DMEM/F12 containing 10% FBS, 100 IU/ml penicillin, and 100 μg/ml streptomycin (Invitrogen). The UWB1.289 human cell line was established (E. M. S.) as described (15); reconstituted BRCA1 expression was verified by QRT-PCR. Cells were maintained in 1:1 RPMI 1640/MEGM (Lonza) supplemented with 3% FBS. Chemosensitivity assays and antibody reagents are described in Supplementary Methods.
QRT-PCR analysis was performed as described (13). Specific forward and reverse primer sequences are provided in Table S1. High-titer amphotrophic retroviral and lentiviral stocks were generated by cotransfection with packaging vectors into 293T cells as described previously (13, 16). The targeted sequences are provided in Table S2. ChIP was carried out as described (16) using primers spanning different regions of p73 intron 1 (Table S3).
For each cell line and tumor, 200–500ng of genomic DNA was used for bisulfite conversion using the EZ DNA Methylation-Gold Kit (Zymo Research Corp.). The 1.6 kb intronic region upstream of exon 2 of p73 was PCR amplified with primer sets designed using the program EpiDesignerBETA by Sequenom ® (Table S4). Following confirmation of desired product and quantification, methylation was quantitated in sequenced products by measurement of the height of the C and T peaks as described (17) using Chromas-Lite version 2.01 (Technelysiun Pty Ltd), and was expressed as C/(C+T) for each CpG site, and averaging the forward and reverse sequence results. Hypermethylation in clinical samples was defined as a value ≥ the methylated fraction in BRCA1-deficient UWB1.289 cells. Methylation status was validated in cell lines and in a representative subset of cases by HpaII/MspI digestion of unconverted DNA following PCR using primers shown in Table S4.
Tumor specimens were obtained from the MGH Gynecologic Tissue Repository, from Cedars-Sinai Medical Center, and from the University of Washington. Use of tissues for this study was approved in each case by the respective Institutional Review Boards. Designation of tumors as BRCA1 wild-type or mutant resulted from clinical genetic testing. RNA/DNA was isolated from dry frozen tumor samples that had evidence of greater than 80% tumor volume with the GenElute Mammalian Total RNA and Genomic DNA Miniprep Kits following the manufacturer's instructions (Sigma). For fixed specimens, microdissection or macrodissection of tissue sections was carried out following pathology review, and DNA was extracted using the RecoverALL Total Nucleic Acid Isolation Kit (Applied Biosystems), according to manufacturer's instructions.
Additional methods are detailed in Supplemental Data.
To begin to explore pathways contributing to chemosensitivity in BRCA1-associated tumors, we first took advantage of our established murine model of BRCA1-deficient ovarian carcinoma (8). This model uses the RCAS avian retroviral system in order to infect primary ovarian surface epithelium (OSE) cells which express the TVA retroviral receptor transgene driven by the Keratin 5 (K5) promoter (Figure 1A) (18). To develop a model for BRCA1 loss of function we established K5-TVA mice harboring homozygous conditional p53lox/lox plus BRCA1lox/lox alleles. By infecting OSE cells derived from these mice with RCAS-Cre we showed that combined loss of p53 and BRCA1 along with one additional virus expressing the c-Myc oncogene was sufficient to induce tumors that exhibit many key features of human metastatic BRCA1-associated ovarian carcinoma (8). Three independent BRCA1-deficient tumor lines were derived from explants of these tumors (TBR2, TBR5, TBR6). As a control, we compared their phenotypic properties to three tumor lines (T1, T2, T3) resulting from p53 loss along with different combinations of any two of the oncogenes c-Myc, K-Ras, and AKT, which are required for ovarian tumorigenesis in the absence of BRCA1 deletion (Figure 1A) (9).
In quantitative chemosensitivity assays, BRCA1-associated tumor lines consistently exhibited significantly increased sensitivity to cisplatin, but not to paclitaxel chemotherapy compared to BRCA1 wild-type tumor lines (Figure 1B and Figure S1) (8). The difference in platinum sensitivity was not related to the oncogenes used to transform these cells, since all three BRCA1 wild-type tumor cells exhibited significantly reduced sensitivity relative to BRCA1-deficient cells (Figure 1B), and the expression of either Akt or K-Ras in the BRCA1-deficient tumor cells did not significantly affect cisplatin sensitivity in these cells (not shown). As expected, chemosensitivity in BRCA1-deficient tumor cells was associated with substantial unrepaired DNA damage (8). Thus, this model recapitulates the BRCA1-associated chemosensitivity of human ovarian carcinomas.
In order to study cisplatin sensitivity in human ovarian carcinoma cells we tested UWB1.289 cells, which are derived from an ovarian cancer arising in a germline BRCA1 mutation-carrier and which lack expression of BRCA1 (15). These tumor cells are also deficient in p53 function due to an acquired somatic inactivating mutation (15). We compared cisplatin sensitivity in parental UWB1.289 cells stably reconstituted with either wild-type BRCA1 or the control vector. This reconstitution is physiologically relevant as it substantially restores defective checkpoint responses following ionizing radiation (15). BRCA1 reconstitution substantially abrogated platinum sensitivity in UWB1.289 cells as assessed in a quantitative dose-response curve (Figure 1C and Figure S1). Importantly, a clonogenic assay demonstrated the same result, confirming the increased platinum sensitivity of UWB1.289 cells relative to their isogenic BRCA1-expressing counterparts (Figure S1). We then sought to uncover the specific mechanisms involved in the response to cisplatin. We found that cisplatin induces apoptotic cell death in both murine and human BRCA1-deficient cells, as evidenced by cleavage of poly(ADP-ribose) polymerase-1 (PARP-1) on western analysis and by Annexin V staining on FACS analysis (Figure 1D and data not shown). Given that both the murine and human cells lack functional p53, our findings imply that cisplatin induces cell death in BRCA1-deficient cells at least in part through an apoptotic mechanism that is independent of p53.
Following cisplatin treatment, we observed robust induction of the p53-regulated pro-apoptotic target genes Noxa, Puma, and p53AIP1 selectively in BRCA1-deficient murine and human cells, but little or no induction in their isogenic counterparts expressing wild-type BRCA1, even using cisplatin doses that cause substantial cell death in both populations (Figure 2A,B). These findings suggest a distinct cell death pathway in the absence of BRCA1. In particular, the p53-independent induction of these genes led us to consider that the related p53 family member p73 might contribute to the effects of cisplatin chemotherapy, given that p73 is known to be a direct activator of these particular target genes (19–21). Consistent with a role for p73 in the p53-independent DNA damage response in the specific context of BRCA1 deficiency, we first showed that lentiviral knockdown of BRCA1 led to induction of p73 following chemotherapy treatment of p53-deficient cells (Figure S2). We next examined p73 expression in wild-type and BRCA1-deficient murine ovarian carcinoma cells using an isoform-specific, quantitative reverse-transcription/real-time PCR (QRT-PCR) approach to distinguish between pro-apoptotic transactivating p73 isoforms (TAp73) and N-terminally truncated isoforms (ΔNp73). Remarkably, both murine and human BRCA1-deficient tumor lines showed substantially higher expression of TAp73 than any of the BRCA1-expressing lines (Figure 2C, D). In contrast, levels of ΔNp73 isoforms were comparable irrespective of BRCA1 status. Taken together, these data show that loss of BRCA1 function and platinum sensitivity correlate with both increased TAp73 and induction of TAp73 target genes in human and murine ovarian carcinoma.
We then sought to address directly whether TAp73 itself is an important mediator of the response to cisplatin in BRCA1-deficient cells in vitro and in vivo. We first ablated TAp73 expression using lentiviral RNA interference (RNAi) in both human and murine ovarian carcinoma cells, then quantitatively assayed cisplatin sensitivity. Consistently, knockdown of TAp73 induced significant cisplatin resistance in human BRCA1-deficient UWB1.289 cells, even though it did not affect proliferation or cell viability in the absence of cisplatin (Figure 3A and Figure S3). This chemoresistance was comparable to that observed in matched BRCA1-expressing UWB1.289 cells (Figure S3). TAp73 does not play a role in the BRCA1-expressing cells, which exhibit low levels of TAp73, as knockdown of TAp73 had little or no effect on chemosensitivity over a 5-log dose range of cisplatin (Figure 3A). Similarly, knockdown of TAp73 in all three murine BRCA1-deficient ovarian carcinoma lines using a distinct shRNA construct also induced substantial cisplatin resistance, while it showed no effect in BRCA1 wild-type cells at any dose (Figure 3B and Figure S3). Further supporting the specificity of these effects, TAp73 knockdown essentially abolished cisplatin-induced Noxa expression in the three murine BRCA1-deficient ovarian carcinoma lines (Figure 3C), while little or no effect was observed in BRCA1 wild-type cells (Figure 3C). The ability of TAp73 ablation to induce resistance to cisplatin was then confirmed in UWB1.289 cells using a clonogenic assay (Figure S3). Finally, retroviral overexpression of TAp73β was sufficient to induce significant cisplatin sensitivity in BRCA1-expressing cells (Figure S3). These experiments together argue that a TAp73-dependent transcriptional program is an important contributor to the chemosensitivity pathway in BRCA1-deficient ovarian carcinoma cells.
Given that a subset of sporadic ovarian cancers are thought to phenotypically resemble tumors arising in BRCA1/2 mutation carriers (22, 23), we hypothesized that some of these ovarian cancers would demonstrate increased expression of TAp73 in association with platinum sensitivity. To test this prediction we examined a series of unselected tumors from ovarian carcinoma patients treated with platinum-based chemotherapy following surgical resection. We first quantitated TAp73 expression by isoform-specific QRT-PCR in chemotherapy-responsive tumors (> 6 months recurrence-free survival, a standard clinical measure) versus unresponsive cases (24). The two groups of patients were otherwise well-matched for clinical characteristics including tumor histology, tumor grade and stage (Table S5). Remarkably, we observed a mean 10-fold higher level of TAp73 expression in responsive versus unresponsive tumors, a finding that was statistically significant (Figure 3D). Thus, TAp73 expression is associated with clinical platinum sensitivity, consistent with the data in our model systems demonstrating a direct role for p73 as a mediator of the cellular effects of cisplatin-induced DNA damage.
We then sought to uncover the regulatory mechanism by which TAp73 was differentially expressed in BRCA1-deficient and -proficient human and murine ovarian carcinoma cells. Several mechanisms have been identified that may contribute to regulation of p73 expression in tumor cells, including 5′ promoter methylation (25), EGR-1 expression (26), and E2F1 dysregulation (27). We detected no significant methylation of the p73 promoter in any of our ovarian carcinoma cells, consistent with prior reports (Figure S4) (28). Furthermore, we did not find large differences in mRNA or protein levels of EGR-1 or of E2F family members by microarray analysis or immunoblot, respectively (data not shown).
An additional mechanism that is thought to contribute to endogenous p73 regulation involves the transcriptional repressor ZEB1 (also known as δEF1/zfhx1a). ZEB1 is a zinc finger and homeodomain-containing factor that binds to a regulatory region within the first intron of the TAp73 transcription unit and potently represses TAp73 mRNA expression (29, 30). However, we observed no consistent difference in ZEB1 expression levels between BRCA1-deficient and BRCA1-expressing cells (Figure S5). In order to test directly whether ZEB1 contributed to p73 regulation in these cells we inhibited endogenous ZEB1 using lentivirally expressed shRNA constructs (Figure 4A). Remarkably, knockdown of ZEB1 induced dramatic (5–15 fold) upregulation of TAp73 in all three ovarian lines expressing wild-type BRCA1, but had no effect on TAp73 expression in any of the three BRCA1-deficient lines (Figure 4A). Similarly, in human cells we observed high-level induction of TAp73 following ZEB1 knockdown in reconstituted UWB1.289 cells expressing wild-type BRCA1, but no induction in parental cells lacking BRCA1 function (Figure 4B). Thus, endogenous ZEB1 potently represses TAp73 only in cells expressing wild-type BRCA1. These results suggest that high levels of TAp73 observed in BRCA1-deficient cells may be due to loss of the repressive effect of ZEB1.
To pursue this hypothesis we next tested whether differential binding of ZEB1 to TAp73 regulatory sequences might explain a loss of ZEB1-mediated repression in BRCA1-deficient cells. ZEB repressors contain dual zinc fingers that bind to bipartite E-boxes (CACCT and CACCTG) whose orientation and spacing vary in different target genes (31, 32). In order to identify the endogenous ZEB1 binding site in murine cells we performed chromatin immunoprecipitation (ChIP) in ovarian carcinoma cells expressing wild-type BRCA1. We mapped robust and specific binding of ZEB1 to a 1kb region within the first intron of the TAp73 transcription unit that contains such a bipartite E-box motif (Figure 4C). Although significant binding of ZEB1 was consistently observed within this region in murine BRCA1 wild-type cells, in the isogenic BRCA1-deficient ovarian carcinoma cells ZEB1 binding was reduced to background levels (Figure 4C). Similarly, in human cells expressing wild-type BRCA1 we observed robust and specific binding of endogenous ZEB1 to a 550bp region containing bipartite E-box motifs (29, 30), yet virtually no specific binding was detected in isogenic BRCA1-deficient cells (Figure 4D). Taken together, these findings demonstrate that endogenous ZEB1 represses TAp73 expression in murine and human ovarian carcinoma cells expressing wild-type BRCA1, and that loss of BRCA1 function is associated with a loss of ZEB1 binding and its repressive effect on TAp73.
Since ZEB repressors are thought to bind directly to DNA (32), we asked whether chemical modification of DNA itself (e.g. methylation) might mediate differential binding of ZEB1 in cells expressing or lacking wild-type BRCA1. We first examined methylation of the ZEB1 binding region in these cells by digesting genomic DNA with either methylation sensitive or insensitive isoschizomeric restriction enzymes (HpaII or MspI, respectively), followed by PCR amplification. All three murine BRCA1 wild-type lines demonstrated hypomethylation of this locus, as assessed by the absence of a significant PCR product following HpaII digestion (Figure 5A). In contrast, in all BRCA1-deficient lines this locus was highly methylated and the DNA was therefore resistant to HpaII digestion. A remarkably similar pattern was observed upon analysis of the ZEB1 binding locus in human ovarian carcinoma cells: hypomethylation in BRCA1-reconstituted UWB1.289 cells, and hypermethylation in the BRCA1-deficient parental cells (Figure 5B).
To characterize the methylation of this locus in detail we performed bisulfite sequencing across the entire ZEB1 binding region identified by ChIP in UWB1.289 cells (Figure 5C). This region contains approximately 20 CpG dinucleotides, and we observed substantial hypomethylation of each CpG within this binding region in BRCA1-reconstituted cells compared to parental BRCA1-deficient cells (Figure 5C), in agreement with our results from MspI/HpaII digestion analysis in both murine and human cells. Based on these findings it is reasonable to hypothesize that hypermethylation may inhibit binding of the ZEB1 repressor, leading to a loss of ZEB1-mediated repression and a consequent increase in TAp73 levels.
In order to test this model directly we asked whether treatment with a 5-Azacytidine (5-Aza, a demethylating agent) would alter binding of ZEB1 to this locus. We observed more than 100-fold increase in ZEB1 binding in BRCA1-deficient cells following 5-Aza treatment compared to mock-treated cells, as assessed by quantitative ChIP (Figure 5D). Furthermore, 5-Aza treatment of BRCA1-expressing cells (which are already relatively hypomethylated) only increased ZEB1 binding by less than 2-fold (Figure 5D). Taken together, these data demonstrate that the binding of ZEB1 to the TAp73 regulatory region is controlled through an epigenetic mechanism, and that ZEB1 is bound and suppresses TAp73 expression in BRCA1-expressing but not BRCA1-deficient cells.
Our findings predict that ovarian cancers arising in patients with germline BRCA1 mutations will exhibit hypermethylation of the ZEB1 binding site within the p73 transcription unit compared to cancers arising in patients without such mutations. To test this prediction we obtained a series of such tumors that were well-matched in terms of both clinical stage and histological subtype (Table S6). Bisulfite sequencing within the ZEB1 binding region demonstrated higher methylation in BRCA1-associated tumors than in those expressing wild-type BRCA1 (Figure 6A). This finding was confirmed in a subset of cases by an independent method involving MspI/HpaII digestion of primary tumor DNA followed by PCR as shown in Figure 5 (data not shown). These findings support the association of BRCA1 deficiency with epigenetic regulation of the p73 locus in ovarian cancers in vivo.
Recent reports have demonstrated that one mechanism by which both BRCA1 and BRCA2-associated ovarian cancers acquire resistance to chemotherapy in vivo is through re-expression of a functional protein (33–35). We therefore tested methylation of the ZEB1 binding site in patient-matched primary and recurrent tumors, in which the primary tumor contained only the mutant BRCA1 allele (185delAG) and exhibited no BRCA1 protein expression, while the recurrent, chemoresistant tumor exhibited expression of a wild-type sequence and detectable BRCA1 protein (35). We performed methylation-specific PCR at the ZEB1 binding locus within p73 (Figure 6B), after validating that this technique correlates with results obtained by both MspI/HpaII analysis and direct bisuphite sequencing (not shown). Remarkably, a substantial decrease in methylation was observed in the platinum-resistant, recurrent tumor relative to the hypermethylated primary tumor (Figure 6B). Thus, these results support our findings and provide in vivo evidence that functional BRCA1 status, which affects platinum chemosensitivity, is associated with epigenetic regulation of the pro-apoptotic TAp73 locus.
Finally, we tested the association of TAp73 expression with methylation of the ZEB1 binding locus in the entire cohort of unselected and BRCA1-associated tumors (Figures 3D, ,6A).6A). Thus, we performed bisulfite sequencing across the entire 500bp ZEB binding region, as well as QRT-PCR for TAp73. As predicted, those tumors exhibiting hypermethylation of this locus were more likely to express high levels of TAp73 (Figure 6C). In contrast, hypomethylated tumors almost exclusively expressed low levels of TAp73, comparable to the level expressed in BRCA1-reconstituted UWB1.289 cells. The pattern of methylation in the tumors recapitulated that seen in the UWB1.289 cell line (Figure 5C), in that differences in methylation were observed across all the CpG residues in region, rather than being restricted to a few residues (not shown). All together, these findings support the view that TAp73 is regulated through this epigenetic pathway and is an important mediator of the response to platinum-induced DNA damage in a subset of ovarian carcinomas (Figure 6D).
Using murine and isogenic human ovarian carcinoma models, we demonstrate that BRCA1 is associated with a pathway for epigenetic regulation of TAp73, which we find to be an important contributor to chemosensitivity in BRCA1-deficient tumors. Previous studies have documented that TAp73 mediates cellular sensitivity to DNA damage in a variety of contexts (11, 12, 36, 37). Furthermore, we and others have demonstrated that TAp73 is activated specifically in the context of platinum chemotherapy (11, 13). We show here that TAp73 expression is substantially increased in BRCA1-deficient human and murine ovarian carcinoma cells. Treatment with cisplatin induces the pro-apoptotic transcriptional target genes of TAp73 selectively in these cells, and ablation of TAp73 promotes chemoresistance exclusively in BRCA1-deficient cells and blocks induction of these target genes. Together these findings strongly argue that a direct, TAp73-dependent effector pathway contributes to the chemotherapy response in these cells. Further support for this concept is provided by recent clinical studies that find a correlation between poor clinical outcome and increased expression of mRNA for non-transactivating p73 isoforms, which are thought to function as TAp73 antagonists, in ovarian and other cancers (38–40).
We provide substantial evidence that upregulation of TAp73 in BRCA1-deficient ovarian carcinoma cells is mediated through an epigenetic mechanism that controls DNA binding of the ZEB1 transcriptional repressor. The ability of DNA methylation to block binding by a transcriptional regulatory factor has been described in several other contexts (41). Regulation of a transcriptional repressor such as ZEB1 through this mechanism appears less common, however, as most described cases involve differential binding of transcriptional activators. It is also notable that methylation of the TAp73 proximal promoter was not correlated with methylation of the intronic ZEB1 binding region, consistent with prior reports that TAp73 promoter methylation is quite rare in ovarian carcinomas (28). Differential regulation of DNA methylation at these two loci is in keeping with emerging data from genome-wide studies that have uncovered distinct patterns of regulation in CpG-rich versus CpG poor regions (42). Thus, the proximal TAp73 promoter is a CpG-rich region that is bound by polycomb factors (43) and that exhibits a tumor-specific pattern of hypermethylation (44). In contrast, the intronic ZEB1 binding locus is a relatively CpG-poor region that may be subject to more dynamic changes in methylation status (42). While BRCA1 has not been previously associated with regulation of site-specific methylation, a putative BRCA1-regulated gene, GADD45, has been implicated in a demethylation pathway in zebrafish (45). However we did not find a difference in GADD45α or GADD45β expression between BRCA1-deficient and reconstituted ovarian carcinoma cells, and knockdown studies did not yield a GADD45-dependent difference in methylation at the ZEB1 binding locus (not shown). It will be of interest to determine whether the ability of BRCA1 to control site-specific methylation that we have uncovered is mechanistically related to its reported regulation of facultative heterochromatin formation on the X chromosome (46).
We show that TAp73 expression is correlated with the clinical response in unselected ovarian cancers, and we provide evidence that TAp73 is regulated in at least some of these tumors through the BRCA1-associated epigenetic mechanism. These observations are consistent with data demonstrating that chemosensitivity of a subset of sporadic ovarian carcinomas is associated with inactivation of a BRCA1/2-dependent pathway that also involves the Fanconi anemia proteins (22, 23, 47). Intriguingly, a recent report suggests that TAp73 is upregulated in cells from Fanconi anemia patients through a ZEB1-dependent epigenetic mechanism (48). An ongoing challenge for the field is to identify and classify the many mechanisms by which the BRCA1/2 pathway may be abrogated during ovarian epithelial tumorigenesis. Nevertheless, our findings do suggest that low levels of TAp73 may identify patients who will not benefit from standard platinum-based therapy, and who might therefore pursue other treatment options. Additionally, this work supports an emerging consensus that the TAp73 pathway might represent an attractive therapeutic target (14). Thus, future targeted therapeutics might be developed that trigger p73 expression and/or activation, thereby inducing apoptosis or sensitizing otherwise insensitive cells to DNA damaging agents.
We acknowledge Carolyn Koulouris, Petra Sergent, Darrell Borger and Susan Boisvert for technical and database support. This work was supported by the MGH ECOR Fund for Medical Discovery (CL); RO1 CA103924 (SO); the American Cancer Society Early Detection Professorship (SIOP-06-258-01-CCE) and the Milken Family Foundation (BYK); P50CA105009 and the Ovarian Cancer Research Fund (SO, BRR); the Ovarian Cancer Education and Awareness Network, and the Advanced Medical Research Foundation (BRR).
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Tinsquo's curatorial project, Adjacent To Life, presents Traces: Paintings and Prints by Kaitlin Pomerantz.
Absence fills Kaitlin Pomerantz's paintings, implying tales, lives and loves removed, relocated or forgotten. What remains is an arena of opaque nostalgia that also reveals a witty parallel narrative of Painting's resilience. With earnest irony, Pomerantz's act of painting a vacated picture asserts Painting's continued, albeit problematized, mysterious power: absence becomes a presence.
Traces runs through October 10 at the Adjacent to Life pop-up gallery housed in Ninth Street Espresso (341 E. 10th Street at Ave B, NYC).


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4 Items You May Not Have Known Tim Horton's Will Make For You In Presque Isle
Whether it's coffee, breakfast sandwiches or doughnuts, you probably have your favorite at Tim Horton's. But they're willing to go beyond the usual for you.
Here are 5 items that the good folks at Tim Horton's will make for you if you ask.
They'll gladly add Kettle Chips in any and all of your sandwiches. A nice crunchy touch to a dinner or lunch item.
Genius. RT @JimByersTravel: The secret to @TimHortons turkey bacon: putting the kettle cooked chips in the sandwich. pic.twitter.com/E66yIAolI5
— Thea (@AnatheaT) August 17, 2014
The hashbrown can go in your breakfast sandwich, not just with it. You just need to make sure that your mouth is big enough to go over it.
#TimHortons when someone says they want the hash brown with the breakfast sandwich: Next question should be.. in it? pic.twitter.com/tsVQFX0SOC
— Liam (@dialup_ninja) July 5, 2014
No comment needed.
Doesn't get any more Canadian than this. #timhortons #canada pic.twitter.com/BD06tHHI5K
— Susan Werner (@SusanWerner13) March 4, 2017
If you like chocolate and Chai Tea, just ask them to put a Chai Tea bag in your hot chocolate. Can you say, "Deeeeelish?"
True love right here #TimHortons #coffee #thenorthrules pic.twitter.com/tNW6qdDrME
— Makaeley (@Makaeley2) March 5, 2017
What are some favorite specialty items you have had the great crew at Tim Horton's make for you? We're always looking for good ways to enjoy Timmy's. Share them with us in the comments section below.


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Central Carolina Technical College ultrasound technician program
Think about what career is best suited for you, and where you want to study. Request more information now.
Think about what career is best suited for you, and where you want to study. Request more information now.
Think about what career is best suited for you, and where you want to study. Request more information now.
Find information about Central Carolina Technical College ultrasound technician program, and registering for elective discussion sections and seminars. Which college degrees give you the best chances of finding employment after graduation? You can enter nursing with either an associates degree or BSN. As a licensed vocational nurse (LVN), you may provide patient care under the supervision of a registered nurse (RN). Concentrating on Central Carolina Technical College ultrasound technician program, for example, you may gain an advantage in job recruiting on-campus. Check with the MRI department for course registration deadlines, and ultrasound program requirements. Please use the form above to request admissions info for Central Carolina Technical College.
MRI technologists operate magnetic resonance imaging (MRI) scanners to create diagnostic images, whereas radiologic technologists perform diagnostic medical imaging using x-rays. An X-Ray Scan utilizes a collimated X-ray beam to produce an image on film. Several different views are obtained of the body part being imaged. The films are then passed on for review by a radiologist and your primary care physician. This is the oldest method of imaging, but is still the standard in general medical practice. Magnetic Resonance Imaging (MRI), on the other hand, provides detailed pictures of the body without ionizing radiation. During this procedure, the patient is placed within a large magnet and radio waves are passed through the body. Computer-generated images clearly show diseased tissue in the brain, spine, and joints.
For further definition, a Cat Scan utilizes a high tech, 16-slice scanner. The computer is able to render different perspectives, in order that the image may be viewed in various planes. Images appear on the technologist's monitor in a matter of seconds, and because there is no waiting for film to be developed it reduces the need for repeat exams. Digital images are easily stored and transferred, eliminating the dependency on one set of originals, which can be misfiled or otherwise lost. Beyond major requirements within the MRI department, you may consider Freed-Hardeman University speech-language pathology as a complementary elective to your primary course of study.
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Beyond Anger Management: Master Your Anger as a Strategic Tool is an easy-to-understand guide that picks up where typical anger management books end. It explains what your anger is and why you have it and shows you how to identify and master your anger. Beyond Anger Management: Master Your Anger as a Strategic Tool empowers you to apply your anger as a strategic tool to improve your life and your relationships. You will learn how to know when your anger isn't genuine but is covering over other feelings as well as how to deal strategically with someone else's anger directed at you.
This book is for you if feel your anger controls you, and you want to learn how to master and strategically apply your anger. This guide is also for you if you want to learn to effectively deal with others whose anger controls them.
©2016 Edward Daube (P)2016 Edward Daube
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Thank you so much for shopping with Grah-Toe Studio! You are greatly appreciated! We have coupon specials for our Facebook and Instagram followers, come join us !! We are open for custom orders! We will also have a booth every saturday at the Ft. Pierce Jazz and green market from 8-12. Stop by for some great art, food and music!
Waterproof Threnody hair forks will have a different shipping rate than is posted on the listing. Because it will depend on how many you buy, I will REFUND the overage to you with a message!! The waterpoof forks are not inlcuded in any coupon specials.
How can I pay?
We use PayPal as our payment processor, so we accept Visa, MasterCard, American Express, and Discover. Or, you can pay using your PayPal balance.
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Yes. You pay through PayPal, the world's premier electronic payment solution, not through this site. We never even see your credit card number; PayPal just tells us that you've paid and we ship you your stuff. We get your money through PayPal later.
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No, you can pay with your credit card without a PayPal account.


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This property has been removed by the agent. It may be sold or temporarily removed from the market
1 bedroom flat for saleBattlefield Avenue, Glasgow
Sold STC £95,000
Property Description
Key features
- One double bedroom
- Box room
- Spacious lounge with dining
Full description
RE/MAX Professionals present to the market this one bedroom flat with box room, in Glasgow.
The property comprises of entrance hallway, spacious living room with dining area, kitchen, bathroom and one double bedroom with box room.
Adequate local shopping, educational and public transport facilities are available close by.
More information from this agent
To view this media, please visit the on-line version of this page at www.rightmove.co.uk/property-for-sale/property-45332736.html
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Disclaimer - Property reference 7324455. The information displayed about this property comprises a property advertisement. Rightmove.co.uk makes no warranty as to the accuracy or completeness of the advertisement or any linked or associated information, and Rightmove has no control over the content. This property advertisement does not constitute property particulars. The information is provided and maintained by RE/MAX Professionals, Shawlands. Please contact the selling agent or developer directly to obtain any information which may be available under the terms of The Energy Performance of Buildings (Certificates and Inspections) (England and Wales) Regulations 2007 or the Home Report if in relation to a residential property in Scotland.
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text: So i know its been like forever since i posted in here really havnt had time with my new job and all but i have a question for all my dbstalkers out there. We leave for our first cruise in a week and our first time in san diego also. So suggestions for what to do on the ship and in SD would be great!


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Table of Contents:
On the Murder of Herodes
[37] If we are to judge from probability, it is obviously the second which is the truer; he was lying to benefit himself, but on finding that those lies were proving fatal, he thought that he would be saved by telling the truth. However, he had no one to stand up for the truth, as I, who was vindicated by his second, true statement, was unfortunately not present; while there were those who were ready to put his first, his false one, beyond all reach of future correction. As a rule, it is the victim who quietly seizes an informer and then makes away with him. In this case, it is the very persons who arrested the slave in order to discover the truth who have done so;


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Held at Firslea, Yealm Rd, Newton Ferrers at 7.00 pm on Thursday 26th May 2011.
1. WELCOME AND APOLOGIES. Apologies were received from Kate Wood.
2. MINUTES OF COMMITTEE MEETING & A.G.M dated 11th January 2011were received and approved and 27th April 2011 were received and approved with two amendments.
3. MATTERS ARISING FROM THE MINUTES. None
· New Chairman. We still do not have a Chairman to take over from Bill Taylor and no one has come forward since the A.G.M to be considered for the position.
· Honorarium- A cheque for £120 was issued to Eric Rodmell, following approval at A.G.M in connection with the work undertaken in the production of the new Village Directory.
· Speaker for 2012 A.G.M. The Secretary would check with Professor Thompson whether his offer to speak at next years A.G.M was still available and on what subject he might speak.
· Devon Wildlife Trust-The trust had sent a flyer to the Secretary asking for help with a survey of hedgehogs in the vicinity. Apparently it is thought that hedgehogs are in decline and would like reports of whether hedgehogs had been sited (or not) in local gardens. To take part in the survey please visit www.devonwildlifetrust.org , you will also find details of outdoor events planned for this summer. The Trust magazine 'Wild Devon 'is available for loan from the Secretary.
· Village Design Statement/ Conservation Area. The Secretary will contact the Parish Clerk and inform her that John Prosser has withdrawn from work necessary to produce a revised Design Statement and extension of the Conservation area. In addition, due to the amount of work required, would ask whether someone could be commissioned on behalf of the Parish to achieve the desired result. The view of the committee was that both should proceed separately with the priority to achieve the extension of the Conservation Area first. Peter Pritchard had looked at the existing Conservation Area documents and would forward the web link to the committee so they could view it as it did not appear to be as onerous as first thought. It was reported that Village Design Statements had been superceded by Village Plans therefore it was considered very important to have a Village Plan. The trip up the river with Stephen Munday and Susie Cooper which had been planned for February had been postponed due to adverse weather.
· Directory sales and membership update. Approx 8 Directories had been sold since the A.G.M. New Directories had been distributed as follows 25 to the Post Office and Chemist, 10 each to Luscombe and Maye and Marchand Petit. There had been three new members join since the A.G.M.
There is £ 690 on deposit with the Charities Foundation £250 in the bank giving a total of £940. The Village Directory had cost £1350 and Luscombe and Maye would be making a contribution of £600. Alan Lomax would contact L&M to ask for their contribution.
The Secretary would ask for contributions for the Harbour Clean up for 2012 from the Parish Council and harbour Authority.
· Letter to Dept Communities and local Govt. There were concerns expressed about the nature of development in the Parish at the A.G.M and that it appeared that little weight had been given by the Inspector at Appeal even though large numbers of residents had written and objected to one notable site. The letter to be sent to the Dept for Communities and Local Government was approved; members and non members of the R.Y.D.A would be approached to sign it prior to it being sent off.
· Parsonage Road, Affordable Housing Site. The committee considered a number of attributes of the scheme and agreed the plan C option considered at the A.G.M was the preferred layout of the southern end of the site i.e. houses at right angles to the road. An objection to the layout would therefore be submitted.
· Planning discussion group-It was encouraging to note that twenty people had signed up for the website since the A.G.M.
· Review of planning applications. Objections had been submitted on, land opposite 60 Noss Mayo (Appeal), 'Crispins' and 'Woongara', all had been turned down. It was noted that Revelstoke had re-applied and 'Crispins' had appealed. 'Spindrift' 39 Court Rd some concern that it look like a 5 storey building.
'Riverside House' has been turned down. 17 Yealm Rd Has been withdrawn, some residents opposed it but the R.Y.D.A didn't; the best place to view is from Noss Church car park to assess the impact.85 Court Rd Outstanding will bring forward to next meeting. The 'Point Bungalow', Noss Mayo has been withdrawn, a letter was sent from the R.Y.D.A objecting to the type of property proposed prior to withdrawal.
● Village Directory- Thanks were extended to Peter and Alan who had delivered the Directories which had not been picked up at the A.G.M.
● Tithe Map. The Devon Record Office had digitised all the Devon Tithe Maps (c. 1840) and was looking for volunteers to transcribe the 1840 apportionments for each Parish. A volunteer is sought to spend about approx 40 hours transcribing the details onto an Excel Spreadsheet. Details of the project can be found on www.devon.gov.uk/dro_tithe_map_project_pdf. Please contact John Draisey on 01392 384253 firstname.lastname@example.com .
9. DATE OF NEXT MEETING. Unless there is an issue that would call for an emergency meeting, the next meeting would be on Wednesday 7th September 2011.
There being no further business the Chairman closed the meeting at 8.20p.m Denise Marchant, Hon Secretary R.Y.D.A


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About Arts Midwest World Fest
Arts Midwest World Fest presents international musical ensembles in intensive week-long residencies in smaller Midwest communities. Its purpose is to foster an understanding of and appreciation for global uniqueness and differences.
Arts Midwest World Fest's objectives are to:
- present high-caliber, accessible international artists to small- or mid-sized Midwest communities;
- provide a multifaceted experience to community residents, particularly young people;
- integrate the artists and their music into a broader social, cultural, political, and historical framework;
- encourage young people to explore issues and understand concerns of diverse cultures; and
- create a lasting musical and cultural impact on participants.
Each cycle of Arts Midwest World Fest occurs over a two year period in which four global musical ensembles conduct week-long intensive residencies in selected communities throughout the Midwest. The residencies consist of school concerts, workshops, and outreach activities, and culminate in a public concert.
To extend the cultural experience to the classroom, Arts Midwest provides participating communities with a curriculum that helps students and teachers better understand and appreciate the customs and traditions of the visiting ensembles. We hope that studying other cultures will spark a lasting curiosity in both teachers and students that will result in further exploration of the diverse and fascinating cultures of the world.
A program of Arts Midwest, the 2017–2019 Arts Midwest World Fest cycle is generously supported by the National Endowment for the Arts, The Hearst Foundations, 3M, the Japan Foundation through the Performing Arts JAPAN program, the Kaufman Family Fund for Israeli Cultural Exchange, the Nordic Culture Fund, and the BNSF Railway Foundation. Additional support is provided by the Ministry of Culture of the People's Republic of China and the Chinese Heritage Foundation Grants Fund of The Minneapolis Foundation for Manhu. Funding for Sofi & the Baladis is provided in part by contributions from the Consulate General of Israel to the Midwest, Israel Lottery Council for Culture & Arts, and Music Port. This activity is made possible by the voters of Minnesota through a grant from the Minnesota State Arts Board, thanks to a legislative appropriation from the arts and cultural heritage fund.


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88 & Half's Cocoon Gilet is crafted in pure sheepskin and features contrasting fur texture that adds a fun element to this longer length classic gilet. One side is a smooth leather finish and the other side is soft sheepskin fur, offering great versatility and wearability. Effortlessly stylish, layer over everything from a chunky sweater and jeans to dresses.
FREE UK Standard Delivery on all orders over £50.00
£5.95 UK Express Delivery (Next Day Courier Delivery - Orders placed before 2pm Monday to Thursday). Express delivery orders placed on a Friday before 2 pm will be delivered on Monday. Orders placed over the weekend cannot be dispatched until Monday)
£9.95 European Delivery
£18.95 Rest Of World Delivery
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|1,076 sq. ft.
|Property type
|Minimum Stay
|1 - 2 nights
This cave bio climatic villa is in Oia, the crown jewel of Santorini,is a model of OIA's unique architecture, hanging from the cliff of caldera overlooking the volcano and the endless blue of the Aegean sea. Very close to the center of the village and 20 steps down of the main street. It is located a few meters from shops, restaurants market, galleries, bus and taxi terminal. Very near to the Castle which is the most famous sunset of Greece!
The house is 90 sqm and It consists of 3 bedrooms, 2 fully autonomous master bedrooms, 1 wooden loft,a large living room, 2 bathrooms and a unique small traditional kitchen. It can comfortably accommodate 4-5 people, whether couples or family with children
The residence is decorated with antiques and the kitchen is equipped with refrigerator,oven,microwave,coffee maker,etc.
It has a private patio/ /balcony with ocean-caldera view, sun umbrellas and chairs. The house has free Wi-Fi internet access and it is fully air conditioned.
The villa has Authorised Licence by the Ministry of Tourism of Greece.
Oia Villas is gorgeous, well equipped and comfortable. Haris, Maria and George take exceptional care of their guests, arranging tours and transfers and checking in periodically to make sure all is well. We thoroughly enjoyed our stay and highly recommend this house.
We were a family of 6 and were very comfortable! We can't say enough about this wonderful villa! The location was truly superb! The only issues were how many steps it was to the villa 56😞But we have to say the view was spectacular😊
Great place, great staff. We would highly recommend it. The jacuzzi pool was so nice to get in and cool off. The kitchen was fine for our needs. It was clean and well organized. They left a delicious bottle of wine in the fridge for us. When we arrived our kids said they wanted to stay for the whole week, not just two days! Oia is absolutely everything you think it would be plus so much more! Magical🌟
We could hardly believe our eyes when we arrived at the property, right in the heart of beautiful Oia, amidst all the whitewashed houses with a sensational view over the ocean, the iconic bell tower right in our front yard! It was amazing!
The gorgeous cave house was decorated beautifully with crisp white sheets and fluffy white towels, changed part-way through our stay. We were also supplied with beach towels and the bins were emptied every day. The house had ample room for our family of 5. The wi-fi was fast and the pool was refreshing and got lots of use after climbing stairs in the heat of the day.
The kitchen was a little bit basic but we still managed to cook a couple of times - a bit like camping! We ate out most nights so it didn't matter too much.
George and Maria were super helpful, organising transfers for us and we can't thank the boys enough for carrying all our heavy bags up all those stairs in the hot sun!
We loved sitting out on the front balcony, watching the sun go down, with drink in hand, pinching ourselves so we'd know that we were actually there.
We sure do hope we can come back one day!
Our family of 5 recently stayed in Oia for 6 nights. This property has an excellent location and the view is even better in real life. It was very hot while we were there and the airconditioning was not really adequate in 2 of the sleeping areas. The kitchen is barely a kitchen and needs review. There is no plug in the sink, or bucket, making washing dishes difficult. There is no tea towel.The oven, very small, was dirty. We had to ask for more plates--only 4 there and we are a family of 5. We also had to ask for a chopping board and bread knife. The hot plate took an hour to simmer a pot of water for pasta. There is no toaster. Whilst I appreciate that alot of people eat out on holiday, our 6 nights were towards the end of a holiday and we were sick of eating every meal out, hence we rented a self contained property. Also, because it was so hot, walking out for every meal was not really what we wanted to do. But the kitchen , with barely any bench space at all, is virtually unusable. Also, the back bathroom smelled funny intermittently. The view and the Jacuzzi make this property rentable, but knowing that cooking is not a great option. If the kitchen and appliances were updated then my review would be very different.
George looked after us. He was lovely and showed us around Oia when we arrived, which was extremely helpful.
But he did say that the bins would be emptied every day and this didn't happen. There is no washing machine so George organised a bag of washing to go to the laundry. We were told this would take 24 hours, but it took more than 48 hours and there were items in the returned bag that did not belong to us. After 2 weeks away and with a family of 5, I was unable to tell you if all our clothes were returned.
The lights in the property were not fully functioning. The globes had blown and despite requesting these be addressed some of the rooms have inadequate lighting. Also, quite a number of times the safety switch flicked all the power off. Whilst this can be reset, this definitely presents a problem when you are in the shower.
Overall location is outstanding, but the property is tired and needs some maintenance. Despite this we had a lovely time in Oia and would still recommend staying here but with the expectation of eating out for most meals.
This "cave" house was an amazing experience! It is the iconic Santorini white cave house set on a hillside overlooking the caldera. The view from the house was absolutely gorgeous! From the house, is is about 20 steps up to the main pedestrian street, which is full of shops and restaurants and cafes, most with amazing views. The house is equipped with all the amenities and the wifi is good. There are 4 different sleeping areas, which was nice to allow our kids each their own space. The host was extremely helpful, especially bringing a helper to carry our heavy luggage up & down the steps. If you come here, we would recommend a private sailing tour around the caldera, as well as Pitogryos for a cheap, delicious meal!
The house is in center of Oia. Very close to the center of the village and 20 steps down of the main street. It is located a few meters from shops, restaurants market, galleries, bus and taxi terminal. Very near to the Castle where the world famous sunset .
|Additional Guest Fee
|$59.97 per person per night
contact the owner


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A million times Pattrn
Featuring Lucas Rocha
In this talk, you'll learn a bit about the story behind Pattrn as well as some useful Android design and development tips that might help your app stand out.android google firefox layout nokia gnome
A New View: Layout Editor + ConstraintLayout
Featuring Huyen Tue Dao
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Rules of (Visual) Design for Developers
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A million times Pattrn
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By Okey Ndiribe, Asst. Political Editor
There are strong indications that the intense pressure that has been mounted on the Federal Executive Council this week may be extended to the Senate President this weekend.
This may become imperative since section 144 of the 1999 Constitution provides that it is the president of the Senate who should establish the five member medical panel that is vested with the constitutional power to examine the health of ailing President Umar Yar'Adua.
The section further stipulates that if the panel – whose membership must include the president's personal physician[-submits a report which indicates that the President is incapacitated to the Senate president and the Speaker of the House of Representatives, and these two officers of the national assembly go ahead to publish the report of the panel in the official gazette of the federal government, the president would then cease to hold office.
Indeed, sub-section four of section 144 reads in full: "the medical panel to which this section relates shall be appointed by the president of the senate and shall comprise five medical practitioners in nigeria…â€
However, subsection I (a) of the same section provides that "the president or vice-president shall cease to hold office if by a resolution passed by two-thirds majority of members of the executive council of the federation (same as fec) it is declared that the president or vice-president is incapable of discharging the functions of his office.â€
Indeed, the severe pressure that has been piled on fec in the last few weeks by different groups and individuals is based on this provision of the constitution.
Already members of the body which is composed of ministers appointed by ailing president yar'adua have been threatened with jail sentences for failing to comply with an earlier order that was made by an abuja high court presided over by justice dan abutu. The judge had ordered on january 22 that fec within 14 days fec should investigate and pass a resolution on the health status of president yar'adua in line with section 144 of the constitution.
Two of the litigants who filed the suit which led to the order that was handed down to fec last tuesday went back to same the court to file contempt proceedings against the federal ministers. The litigants- a former minority leader in the House of Representatives Alhaji Farouk Aliyu and Sanni Gabbas, chairman of the Jigawa State Branch of the Nigeria Bar Association (NBA)-Â want all the ministers jailed for failing to comply with the order.
Although nobody is sure how events would unfold next week, the prevailing situation is clearly a fall-out from last week's proclamation of Dr. Goodluck Jonathan as Acting President by the national assembly. However, the proclamation which was anchored on the doctrine of necessity has generated diverse reactions across the nation.
Ever since the controversy erupted many have hailed the move by the national assembly as politically expedient but others have condemned it as legally defective. For instance, former President of the Nigeria Bar Association (NBA), Mr Olisa Agbakoba SAN) said he endorsed the proclamation of the federal legislature even though it was based more on political expediency rather than a sound legal foundation.
Said he: "the resolutions passed by the national assembly were more based on political expediency than constitutional law. I think it represents a good way to move forward to get us out of the cul-de-sac in which we were. We couldn't move forward or backward.â€
He expressed confidence that those who have gone to court to challenge the resolutions would not succeed.
"In my view the role played by the national assembly was in order and I don't see how a court of law would rule that it was outside the spirit of the constitution†he said.
Former Governor of Edo State John Odigie-Oyegun shared Agbakoba's views.
Commenting on fears that have been expressed in some quarters that the jonathan presidency could be terminated through a court ruling similar to how the interim national government headed by Chief Ernest Shonekan was booted out in the heat of the crisis which trailed the annulment of the June 12 1993 Presidential election, Oyegun had this to say: "The Interim National Government that was headed by chief ernest shonekan and the present administration headed by acting president Dr. Goodluc Jonathan are not comparable.â€
He continued: "under the Shonekan arrangement we had a contraption controlling an illegal government. It was very different. What is happening now is totally different. We had a situation in which the public interest was being severely injured by the inability or unwillingness of a public official to do his duty.â€
The factional chairman of Conference of Nigerian Political Parties (CNPP) Mr Maxi Okwu expressed a similar view.
Said he: "the resolution of the logjam by the national assembly came 87 days too late, but it is better late than never. Yes, following strictly, the letters of the constitution, it is a little bit untidy, but laws are made for man and not man for law. The National Assembly especially the Senate, invoked a part of the law which we know in jurisprudence that is applicable to countries that practice common law which  and that includes nigeria.â€
He further stated that what was important was that the National Assembly's resolution were effective.
"Nigerians have generally accepted it. It is only a few extremists that are saying no " he said.
However, several prominent Nigerians have also expressed their dissatisfaction with the national assembly's solution to the constitutional crisis which has pervaded the land as a result of the long absence of President Yar'Adua. Among those who do not agree that the federal legislature's resolutions have moved the nation forward are the President of the Nigeria Bar Association Mr Rotimi Akeredolu.
He insisted that only the strict provisions of the constitution should be applied to resolve the logjam. The Chairman of Arewa Consultative Forum (ACT) Maj. Gen Ibm Haruna (rtd) also dismissed the national assembly's resolutions as unconstitional.


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5 kreveta
Our chic family home is located in the Midlevels Central district. Quiet yet ultra convenient, the apartment is walking distance to Central, Pacific Place, Hong Kong Park, Botanical Gardens and Zoo. A supermarket is also within walking distance.
Our chic and comfortable home contains everything you could possibly need, and is just a stone's throw from Central Hong Kong.
Perfect for families travelling with children (we have three!), the apartment is equipped with toys, books, high chairs, a stroller and even dress up clothes.
The Master bedroom (with ensuite) has a King sized bed. The ensuite has a bath, but is not huge.
Bedroom two features bunks and an additional single trundle, as well as lots of books and toys.
Bedroom three has a cot as well as a pull out sofa (double) and a desk.
Dostupno gostima
Guests will have access to all areas of our home.
You can also access our building's shared rooftop for sundowners overlooking Hong Kong's famous skyline.
Interakcija s gostima
We will be travelling while you are here, however will be available via email and (SENSITIVE CONTENTS HIDDEN).
We are happy to provide restaurant and activity recommendations.
Ostale napomene
WE HAVE NO TV, however please feel free to use our fibre optic cable wifi to download movies and shows onto your own device.
For an additional fee, our housekeeper/nanny is available for daily or midweek cleaning and babysitting.
This is our family home, in a building full of other lovely families. Please respect this.
1 recenzija
Ovaj domaćin ima 25 recenzije za druge smještaje.Prikaži druge recenzije
We are an Australian couple living in Hong Kong. I my own business, and my husband works in finance. We have three gorgeous daughters.
We love to travel, and promise to treat your home as well as we treat our own. We home you will do the same if you stay at our place.


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Library Bookcase with Ladder in 2 Finishes
was £2,499.00
Fantastic piece that will house all your book and storage requirements easily. Make the 'grande' home library - add 2 or 3 side by side for amazing storage satisfaction.
If you require 2 or more please email us and we may be able to offer a larger discount.
Width: 1690mm
Depth: 390mm
Height: 2370mm
Delivery Included within UK (up to $150)
See more: Furniture
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September 11, 2003
To increase their marketability, each FasTraK unit is designated ABC Select, indicating the unit has been completely inspected and comes with a seven-day guarantee to the purchasing dealer covering all arbitrative items. The FasTraK lane is open to all buyers, both onsite and via the Internet using OnLine RingMan®. Following the sale, ABC West Michigan immediately moves any unsold FasTraK vehicles to FastLot, an Internet bulletin board, where they remain available for seven days.
Any franchise dealership may enter vehicles into the program. For example, DaimlerChrysler dealerships may enter DaimlerChrysler products for the DaimlerChrysler FasTraK week; Ford dealerships may enter Ford, Lincoln, Mercury products for the Ford week. All units entered into the FasTraK program must be 2000 or newer with less than 50,000 miles.
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The Department of Transportation was established by an act of Congress on October 15, 1966.
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The Department of Transportation was established by an act of Congress on October 15, 1966.
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This property has been removed by the agent. It may be sold or temporarily removed from the market
3 bedroom apartment for saleThe Beach House, 14 Estura, Cliff Road, Salcombe
Property Description
Key features
- Newly converted.
- Modern and individual home.
- Impressive interior specification.
- Close to facilities.
- One off design above a cove.
Full description
Tenure: Leasehold
A Beach House that really does sit on a beach. Nestling just above a small cove on Salcombe's famous estuary, a fabulous modern home with use of private slipway and membership to Harbour Spa.
<iframe width="560" height="315" src="https://www.youtube.com/embed/Fd6_AKua6EY " frameborder="0" allowfullscreen></iframe>
Link to e-brochure
Developers Website - www.estura.co.uk
Kingsbridge 6 miles, A38 Devon Expressway 15 miles, Totnes 18 miles (Paddington about 3 hours)
The Beach House combines the irresistible romance of living right on the edge of the shore with the all practical and luxurious delights of having a fabulous modern home. The Beach House perches just above a small secluded cove in the very heart of Salcombe. Backing onto Cliff Road, the Beach House is so close to town you can wander down to the centre merely for the pleasure of an ice cream, a pub lunch or to catch the ferry across the estuary to one of Salcombes golden beaches.
Salcombe is now one of England's premier holiday destinations. And no wonder: glorious golden sands, yachts and boats continually plying their way up and down the estuary, while crabbing and paddling, shrimping and rockpooling opportunities abound. Salcombe is the yachting mecca of South Devon so offers courses and classes for people of all ages, which range from the very basics to advanced levels. The narrow winding village streets of the town centre are lined with sophisticated retail outlets of the Fat Face, White Stuff and Crew clothing genre, and there are about a dozen good restaurants, pubs and bistros. Salcombe is surrounded by arguably the most magical coastline in England delineated by the heritage coastal path threading its way all along the rim of the South West peninsula.
As owners of the Beach House you will enjoy a two year complimentary membership of the luxurious Harbour Spa, part of the prestigious Salcombe Harbour Hotel, which is right next door.
For specification and frequently asked questions please see the brochure.
South Hams District Council, Follaton House, Plymouth Road, Totnes, Devon TQ9 5NE. Tel: 01803 861234.
All items in the written text of these particulars are included in the sale. All others are expressly excluded regardless of inclusion in any photographs. Purchasers must satisfy themselves that any equipment included in the sale of the property is in satisfactory order.
Strictly by appointment with the agents, Marchand Petit. Telephone 01548 844473.
On reaching Salcombe from Kingsbridge via the A381, continue past the first crossroads along Main Road. Follow this road around the side of the hill and at the next junction do not fork right into Devon Road but continue straight on into Bennett Road. Follow this road down the hill and the Salcombe Harbour Hotel will be found on the right, The Beach House being at the eastern end of the hotel.
Alternatively, from Salcombe town centre, proceed along Fore Street into Cliff Road and, after passing the Yacht Club on the right, The Beach House will be found on the left hand side.
1. These particulars are for guidance only. They are prepared and issued in good faith and are intended to give a fair description of the property, but do not constitute part of an offer or contract.
2. Any description or information given should not be relied on as a statement or representation of fact that the property or its services are in good condition. Neither Marchand Petit, nor any of its employees, has any authority to make or give any representation or warranty whatsoever in relation to the property.
3. The photographs show only certain parts and aspects of the property at the time they were taken. Any areas, measurements or distances given are approximate only.
4. Any reference to alterations to, or use of, any part of the property is not a statement that any regulations or other consent has been obtained. These matters must be verified by any intending purchaser.
5. Descriptions of a property are inevitably subjective, and the descriptions contained herein are used in good faith as an opinion and not by way of statement of fact. If any points of particular importance need clarifying before viewing, please do not hesitate to contact our office.
More information from this agent
To view this media, please visit the on-line version of this page at www.rightmove.co.uk/new-homes-for-sale/property-31921828.html
Energy Performance Certificates (EPCs)
To view this media, please visit the on-line version of this page at www.rightmove.co.uk/new-homes-for-sale/property-31921828.html
Listing History
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Market Info
Disclaimer - Property reference 64152. The information displayed about this property comprises a property advertisement. Rightmove.co.uk makes no warranty as to the accuracy or completeness of the advertisement or any linked or associated information, and Rightmove has no control over the content. This property advertisement does not constitute property particulars. The information is provided and maintained by Marchand Petit, Salcombe. Please contact the selling agent or developer directly to obtain any information which may be available under the terms of The Energy Performance of Buildings (Certificates and Inspections) (England and Wales) Regulations 2007 or the Home Report if in relation to a residential property in Scotland.
Map data ©OpenStreetMap contributors.


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Increased rear grip spurs Rossi to fifth on Ducati during free practice at Motegi, Italian "especially happy" with fastest lap less than 0.6s behind pace-setter Dani Pedrosa
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Valentino Rossi finished fifth fastest on day one at Motegi in Japan, declaring himself "happy" with the set-up of his Desmosedici.
Rossi's best time of 1m 46.687s left him less than 0.6s off the fastest Friday lap set by MotoGP title contender Dani Pedrosa on the Repsol Honda.
Factory Ducati rider Rossi said a set-up change for FP2 enabled him to get on the gas earlier on the exit of corners without spinning up and was content with his progress on opening practice day at the Twin Ring circuit.
"Today went pretty well, especially in the afternoon because we made a set-up change that helped us to improve grip on acceleration," he said.
"When I open the gas I'm able to exit the turns better, without spinning too much, and that's why I went pretty fast.
"I'm especially happy because the gap isn't too big. Tomorrow, though, we'll have to improve our pace as well, because for now I'm able to ride well for some laps, and then the tyre starts to slide a bit too much."
Rossi expects rear tyre selection on Sunday to prove crucial and the Italian will continue to assess the best option for a full race distance tomorrow.
"The rear-tyre choice will be very important because the performance of the soft and the hard are very similar," he said.
"The former works a little better but we have to understand if it can last the race distance.
"Tomorrow we'll try some more changes and then we'll also consider the temperature for Sunday when making a decision."


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Why Daenerys Will Win The Game Of Thrones
She is young, beautiful, a civil rights activist, hates the status quo, commands a massive army, keeps mythical fire-breathing beasts for pets, has great hair, and is not above eating a horse heart. Tell us that doesn't sound like a ruler you'd like to bend the knee to? A lot of wannabe kings and queens have made sham claims on the Iron Throne of Westeros, most of whom are long gone or just waiting in line to get choked out, poisoned, sliced, diced, Mountained, or murdered in their homes by shadow baby assassins. But there is one lady in waiting that outshines all the rest and is a safe place to hedge your bets that, when all is said and done, and Winter has come and gone, she will be crowned victorious.
Of course, winning the Game of Thrones isn't just about sitting on a spiky seat. It is about dominating the entire realm and all of its inhabitants – and making them like it. Which makes Daenerys Targaryen the perfect candidate for the job. Sure, there are plenty of reasons why Kahleesi shouldn't win the Iron Throne, but let's be honest, those all look pretty insignificant when put beside three dragons and an entire army of eunuchs. Shall we begin?
Here are the 15 Reasons Daenerys Will Win The Game Of Thrones.
15. She Might Be the Promised Prince (or Princess)
Thanks to a grammar lesson from translator extraordinaire Missandei, we now know there's more to the myth of The Prince That Was Promised than meets the eye. Bleeding comets, dragons, salt, smoke and flaming weaponry, Daenerys definitely has shown signs of being Azor Ahai reborn. Sure, so has Jon Snow, Jamie Lannister, Beric Dondarrion, Sam Tarly, and Hot Pie, along with a whole lot of others, but few fit the bill better. Of course, there's no reason why the promised one can't be two, or even three heads of the same dragon, but at the moment, Dany is definitely in the lead.
For those not familiar with their Game of Thrones lore, the legend of The Prince That Was Promised is one of several closely related tales about a legendary hero that will save the world from darkness. In the version associated with Azor Ahai, a great figure who some eight thousand years prior forged a sword of fire (whose name is Lightbringer) by stabbing it through his wife's heart to help defeat the White Walkers and restore peace to the realm, so that one day Sean Bean could have his head chopped off. Since then, worshippers of the Lord of Light have prophesied Azor's return to repeat the feat in preventing the zombie apocalypse. If Daenerys is truly going to win the Game of Thrones, then she will need to conquer the White Walkers, and right now, the prophesies appear to be on her side, which would make her brother Rhaegar very proud.
14. She Has Literally Walked Through Fire (Twice)
Call it fate, God, the Lord of Light, George R. R. Martin – take your pick – somebody wants Daenerys Targaryen around till the end of Game of Thrones. After all, there have been no shortage of opportunities to knock her off or hardships to keep her from getting there. But every time Dany gets burned, she walks out unscathed, often naked, stronger and wiser then ever before. That's because rulers aren't born, they are forged.
When during season 6 the dosh khaleen plan on making Daenerys their eternal prisoner, she walks out scorch-free as her would-be overlords have their faces melted off, and she takes their place as the commander of the Dothraki. (They don't call her "the Unburnt" for no reason.) This mirrors the finale of season 1, when she steps into the flaming funeral pyre of Khal Drogo and comes out sans clothes with three newly hatched dragon pups. While GRRM has stated she is not immune to fire (at least in the books), Dany's resistance to getting burned alive is just one of the many signs that this Kahleesi is unstoppable, and shows if nothing else, her talent for survival suggests a larger purpose.
13. She is Benevolent
If there is one thing the characters of Game of Thrones can never be accused of, it is being good. But just like her infamous brother (the one that wasn't a dick), Daenerys is not your typical Targaryen. She is fair, just and compassionate. After all, you don't lock up your awesome dragons if you could care less about the sanctity of life.
Her moral compass may run askew occasionally, and oftentimes conveniently align with her actions to veil vengeance as charity, but she cannot be called inherently malevolent. If she acts harshly, it is never done lightly, and always in response to an inhumanity committed against either herself or her people. Daenerys may have stumbled in her ruling over Meereen and not always known the best way to do so, but her heart is primarily in the right place, and she is a staunch protector of the weak. All traits that will easily find support in obtaining the crown.


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