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MicroRNAs (miRNAs) are increasingly implicated in regulating the malignant progression of cancer. Here we show that miR-9, the level of which is upregulated in breast cancer cells, directly targets CDH1, the E-cadherin-encoding mRNA, leading to increased cell motility and invasiveness. miR-9-mediated E-cadherin downregulation results in the activation of β-catenin signaling, which contributes to upregulated expression of the gene encoding vascular endothelial growth factor (VEGF); this leads, in turn, to increased tumor angiogenesis. Overexpression of miR-9 in otherwise-non-metastatic breast tumor cells enables these cells to form pulmonary micrometastases in mice. Conversely, inhibiting miR-9 using a 'miRNA sponge' in highly malignant cells inhibits metastasis formation. Expression of miR-9 is activated by MYC and MYCN, both of which directly bind to the mir-9-3 locus. Significantly, in human cancers, miR-9 levels correlate with MYCN amplification, tumor grade, and metastatic status. These findings uncover a regulatory and signaling pathway involving a metastasis-promoting miRNA that is predicted to directly target expression of the key metastasis-suppressing protein E-cadherin.
Metastases are responsible for >90% of cancer-related mortality. These secondary growths arise as products of a multi-step process that begins when caner cells within primary tumors break away from neighboring cells and invade through the basement membrane1. This initial step of local invasion may frequently be triggered by contextual signals that carcinoma cells receive from the nearby stroma, causing them to undergo an epithelial-mesenchymal transition (EMT), a multi-faceted transdifferentiation program that enables tumor cells to acquire malignancy-associated phenotypes2. Subsequently, metastasizing cells can enter the circulation, doing so either directly or via lymphatics. Size constraints in the microvasculature cause many of these cells to be arrested at distant tissue sites, where they may extravasate and enter the foreign tissue parenchyma. At this point, they may remain dormant or, with low efficiency, proliferate from occult micrometastases to form angiogenic, clinically detectable metastases. The absence of EMT-inducing signals in the microenvironment of distant tissues may cause such disseminated cells to revert to an epithelial phenotype via a mesenchymal-epithelial transition (MET). Much research has been focused on identifying the critical regulators of the metastatic process; these regulatory molecules include both proteins and microRNAs (miRNAs)3,4.
MiRNAs are small non-coding RNA molecules that suppress gene expression by interacting with the 3′ untranslated regions (UTRs) of target mRNAs. These interactions may result in either inhibition of translation of the targeted mRNAs or their degradation5. In an initial real-time RT-PCR-based screen for differentially expressed miRNAs, we identified three miRNAs that are most significantly upregulated in human breast cancer cell lines – miR-155, miR-9, and miR-10b6. The subsequent functional studies of miR-10b validated its candidacy as a mechanistically important miRNA in cancer progression, as demonstrated by experiments showing that overexpression of miR-10b in otherwise-non-metastatic breast tumors initiated tumor invasion and distant metastasis in xenograft models6. Subsequently, several other miRNAs, including miR-373, miR-520c, miR-335, miR-206, miR-126, miR-21, and miR-31, have also been identified as either promoters or suppressors of metastasis7–11. In addition, the miR-200 family, whose role in regulating metastasis remains unclear, has emerged as a silencer of ZEB1 and ZEB2, two established EMT-inducing and metastasis-promoting transcription factors12,13, thereby representing yet another set of regulators of the EMT program.
A second miRNA that stood out in our initial screen is miR-96, a miRNA that is selectively expressed in neural tissues under normal conditions14 and regulates their development15. Expression of this miRNA is higher in brain tumors than in tumors of other histological types, further demonstrating a tissue-specific expression pattern16. In the context of clinical breast cancer, miR-9 has been found to be upregulated in primary tumors relative to its expression in normal mammary tissues17. Interestingly, miR-9 was recently shown to be upregulated by 1,000-fold in c-myc-induced mouse mammary tumors18.
In a preliminary survey, we used several computational algorithms, including the two most widely tested programs, TargetScan19 and PicTar20, to search for miRNAs that target evolutionarily conserved sequences present in the CDH1 mRNA; this survey revealed that miR-9 was the only known miRNA that was predicted to target the CDH1 mRNA (Fig. 1a). CDH1 encodes the epithelial cell adhesion molecule E-cadherin, a trans-membrane glycoprotein that forms the core of the adherens junctions between adjacent epithelial cells21. The cytoplasmic tail of E-cadherin associates with a number of intracellular proteins that link E-cadherin to the actin cytoskeleton21. Given its well-established function in maintaining adherens junctions, E-cadherin inactivation presumably promotes metastasis by enabling the first step of the metastatic cascade – the dissociation of carcinoma cells from one another. In addition, its loss liberates β–catenin molecules that may move into the nucleus and activate pro-metastatic genes22. The significance of E-cadherin inactivation for metastasis has been demonstrated in a variety of in vitro and in vivo models22–27. Recently, we have found that E-cadherin loss in certain cell types can also trigger an EMT and a wide range of transcriptional and signaling changes that contribute to metastatic dissemination27. Thus, miR-9's potential role as a suppressor of E-cadherin expression made this miRNA a strong candidate for promoting the acquisition of malignant phenotypes by carcinoma cells.
To determine whether miR-9 can indeed downregulate E-cadherin expression, we stably expressed miR-9 and, as a control, miR-10b, in two epithelial cell lines (Supplementary Information, Fig. S1). Ectopic expression of miR-9, but not miR-10b, led to an EMT-like conversion in HMLE non-transformed, immortalized human mammary epithelial cells28: these cells became scattered and assumed a spindle-like or star-like morphology (Fig. 1b) and displayed a 70% reduction in E-cadherin and a 5-fold increase in the mesenchymal marker vimentin (Fig. 1c). In contrast, in SUM149 human breast carcinoma cells29, miR-9 downregulated E-cadherin expression by ~50% but failed to induce vimentin, other mesenchymal markers, and a fibroblastic cell morphology (Fig. 1c, and data not shown). These differences in response were intrinsic to the two cell lines rather than a consequence of different degrees of E-cadherin suppression, because knockdown of E-cadherin by >90% using small-interfering RNA (siRNA) in both cell lines caused an EMT in HMLE cells27 but not in SUM149 cells (T.T.O. and R.A.W., unpublished observations). Hence, while miR-9 succeeds in suppressing E-cadherin expression in two epithelial cell lines, it only induces an EMT in one of them.
To determine whether miR-9 directly targets the CDH1 mRNA, we performed reporter assays and found that miR-9 reduced the activity of a luciferase reporter that was fused to the wild-type 3′ UTR of the CDH1 mRNA but not to a mutant 3′UTR (Fig. 1d); the latter carried altered nucleotides that were introduced in the miR-9 'seed-pairing'19 recognition site (Fig. 1a). Hence, the observed downregulation of E-cadherin by miR-9 depends directly on a single cognate recognition site in the CDH1 3′UTR.
Inactivation of E-cadherin has been shown to promote cell migration and invasion in the presence or absence of an EMT27. Consistent with this, we found that ectopic expression of miR-9 led to a 3- to 5-fold increase in the motility and invasiveness of both HMLE and SUM149 cells in vitro (Fig. 1e, f). In order to determine whether these effects depend specifically on E-cadherin suppression, we employed an expression construct that encodes the entire E-cadherin coding sequence but lacks the 3′ UTR, yielding an mRNA that is resistant to miRNA-mediated suppression. Ectopic expression of E-cadherin with this construct reduced migration and invasion in the miR-9-overexpressing cells, but not in the control cells, which have a low basal level of miR-9 (Fig. 1e, f). This suggests that following miR-9 overexpression, a resulting reduction in E-cadherin is required in order for cells to exhibit increased motility and invasiveness. However, we cannot exclude the possibility that miR-9-mediated suppression of other targets is also required for the observed effects of this miRNA on cell phenotypes.
Having validated E-cadherin as a miR-9 target, we next sought to determine whether miR-9-mediated E-cadherin suppression would affect intracellular signaling. Binding of Wnt ligands to their receptors results in the stabilization of β-catenin, allowing it to enter the cell nucleus, interact with the TCF/LEF family of transcription factors, and promote the transcription of genes 30. Independent of this, E-cadherin binds and sequesters a large pool of β-catenin at the cytoplasmic membrane, thereby preventing its nuclear translocation and its function as a component of the TCF/LEF transcription factor complex22,31,32. Our previous work demonstrated that knockdown of E-cadherin in the experimentally transformed human mammary epithelial cells caused relocalization of β-catenin from adherens junctions to the cytoplasm and nucleus. Of note, this suppression of E-cadherin expression also led to a reduction of β-catenin phosphorylation by GSK-3β through unknown regulatory mechanisms, thereby enabling the liberated β-catenin to escape proteasome-mediated degradation27.
In the present work, we found that miR-9-expressing SUM149 cells exhibited both cytoplasmic and nuclear localization of β-catenin, whereas in the control SUM149 cells this protein was predominantly associated with cell-cell junctions, presumably with the cytoplasmic tails of E-cadherin molecules (Fig. 2a). Moreover, the β-catenin in miR-9-expressing cells showed a reduced level of GSK-3β-dependent inhibitory phosphorylation (Fig. 2b) and was therefore present in a more active functional state27,30.
To provide the definitive proof of β-catenin functional activation, we performed β-catenin reporter assays using both the Topflash construct with multiple TCF/LEF-binding sites in the promoter of a firefly luciferase reporter gene and the derived Fopflash construct with mutated TCF/LEF binding sites33. These assays demonstrated that miR-9 increased β-catenin activity by >10-fold in E-cadherin-positive cells (HMLE and SUM149) but not in E-cadherin-negative human breast cancer cells (SUM159) (Fig. 2c). Of note, the basal β-catenin activity was far higher in SUM159 cells than in HMLE and SUM149 cells (Fig. 2c), which provided further indication of the inverse correlation between E-cadherin expression and β-catenin activity.
Because E-cadherin inactivation has recently been shown to promote tumor angiogenesis in genetically engineered mouse models22,26, and because the pro-angiogenic factor VEGFA has been described as a transcriptional target gene of β-catenin22,34, we used the SUM149 and SUM159 breast cancer cell lines, described above and in further detail in Supplementary Information, Fig. S2, to determine whether miR-9 would increase the levels of VEGFA. We found that upon miR-9 overexpression, the VEGFA mRNA levels increased by 3- to 4-fold in the SUM149 cells but not in the SUM159 cells (Fig. 2d). In addition, miR-9 also suppressed E-cadherin expression and induced VEGFA expression by 3-fold in MCF7-RAS breast carcinoma cells (Supplementary Information, Fig. S3). Thus, the ability of miR-9 to upregulate VEGFA is correlated with its ability to modulate E-cadherin expression.
We undertook to determine whether the ability of miR-9 to upregulate VEGFA mRNA depended on its ability to downregulate E-cadherin expression and activate β-catenin-mediated transcription. We discovered that expression of either an E-cadherin siRNA or a constitutively active β-catenin (the ΔN90 non-degradable mutant27, Fig. 2e) in parental SUM149 cells was not sufficient to phenocopy the observed induction of VEGFA mRNA expression by miR-9; however, ectopic expression of either an E-cadherin mRNA (without 3′UTR) or a β-catenin siRNA (Fig. 2e) in miR-9-expressing SUM149 cells was indeed able to reverse the ability of miR-9 to induce VEGFA mRNA (Fig. 2f). These data indicate that E-cadherin downregulation and β-catenin activation are necessary but not sufficient for mediating miR-9-dependent VEGF upregulation. Stated differently, E-cadherin is a critical target of miR-9, but other functionally important miR-9 targets remain to be identified.
We next implanted miR-9-expressing or mock-infected SUM149 cells into orthotopic sites – the mammary fat pads of non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. At 12 weeks post implantation, we found an approximately 4-fold increase in the plasma level of human-specific VEGF in mice bearing miR-9-expressing SUM149 tumors compared to mice implanted with mock-infected SUM149 cells (Fig. 2g), which was accompanied by a 1.5-fold increase in primary tumor weight (Fig. 2h). We then normalized the VEGF level to the primary tumor weight for individual recipients and found that the normalized VEGF levels were still significantly higher in the miR-9 group (Fig. 2i), indicating that miR-9-expressing tumor cells do indeed secrete more VEGF in vivo. Finally, we found in a control experiment that miR-10b, which did not reduce E-cadherin expression in SUM149 cells (Fig. 1c), could not upregulate VEGF levels in these cells (Supplementary Information, Fig. S4).
SUM149 cells forced to express miR-9 grew more slowly in vitro than the corresponding control cells (Supplementary Information, Fig. S5); in contrast, in vivo the miR-9-expressing SUM149 tumors displayed an approximately 2-fold increase in the levels of the Ki-67 cell proliferation marker compared with those having basal levels of miR-9 expression (Fig. 3a). Hence, the observed increase in primary tumor size appeared to reflect a cell-non-autonomous effect of this miRNA, such as its ability to enhance tumor-associated angiogenesis. To address this possibility, we performed immunohistochemistry to detect expression of the MECA-32 mouse endothelial cell antigen, which should serve as a specific marker of angiogenesis. Consistent with previous observations6, the control SUM149 tumors displayed only low levels of staining. In stark contrast, miR-9-expressing SUM149 tumors exhibited a >10-fold increase in the density of intratumoral microvessels (Fig. 3b), which is in consonance with the observed higher levels of VEGF secreted by these tumor cells.
In fact, an even more robust vessel formation was observed at the outer edges of these miR-9-expressing tumors than in the intratumoral regions (Supplementary Information, Fig. S6a). Of additional interest, some of the cells within the lumina of vessels at the tumor edge were nucleated and were positive for cytokeratin expression, providing evidence for miR-9-induced intravasation of carcinoma cells (Supplementary Information, Fig. S6a, b). Although the great majority of carcinoma cells within the miR-9-expressing and control tumors exhibited similar morphology (Fig. 3a, b), the carcinoma cells located near vessels at the tumor edge (Supplementary Information, Fig. S6a) were cytologically different from the bulk populations of carcinoma cells (Fig. 3a, b) in the miR-9-overexpressing tumors. We reasoned that these cytologically distinctive cells were either stromal cells of host origin or, alternatively, carcinoma cells undergoing an EMT in vivo.
To distinguish between these possibilities, we performed immunostaining with antibodies reactive with E-cadherin and human vimentin. As expected, the miR-9-expressing human tumor xenografts had weaker E-cadherin staining than control tumors (data not shown). More strikingly, a significant number of carcinoma cells at the edges of the miR-9-expressing tumors exhibited strong human vimentin staining, while intratumoral regions only displayed occasional human vimentin-positive cells (Fig. 3c). The control tumors, which expressed lower levels of miR-9, were essentially vimentin-negative (Fig. 3c). Moreover, as anticipated, mouse fibroblasts in the tumor stroma were completely negative for human vimentin (Fig. 3c), demonstrating that the observed vimentin-positive cells did indeed derive from implanted human carcinoma cells. Because miR-9-induced vimentin expression in cultured HMLE cells but not in SUM149 cells (Fig. 1c), we propose that this miRNA can induce an EMT in a cell type- and context-dependent manner, and that in certain cell types, such as SUM149 carcinoma cells, miR-9 sensitizes cells to EMT-inducing signals emanating from the tumor microenvironment rather than eliciting an EMT on its own.
SUM149 cells have been reported to exhibit little, if any, metastatic ability6,35. Indeed, we observed that mouse hosts bearing control SUM149 primary tumors were essentially free of lung micrometastases except for one mouse, which showed a single micrometastatic cluster that was immunostained by the AE1/AE3 anti-cytokeratin antibodies at 12 weeks after cancer cell implantation (Fig. 3d). In stark contrast, the lungs of mice implanted in the mammary fat pads with miR-9-overexpressing SUM149 cells exhibited clusters of dense hyperchromatic cells that were positive for cytokeratins, as demonstrated by both histological examination (Fig. 3e) and AE1/AE3 immunostaining (Fig. 3f). On average, we found ~14 micrometastases per 5-μm section (Fig. 3d). This provided direct evidence that miR-9 operates as a pro-metastatic miRNA.
We also wished to determine whether miR-9 expression is required for metastasis formation by cancer cells that are naturally highly malignant. To address this, we used 'miRNA sponges'11,36 to stably knock down miR-9 in the highly metastatic 4T1 mouse mammary tumor cells that naturally express a very high level of miR-9 (data not shown). A 'miRNA sponge' is a construct encoding an mRNA (e.g., the gfp mRNA) that contains in its 3′UTR multiple tandem binding sites for a miRNA of interest36. We assessed the level of functional knockdown of miR-9 by a reporter assay, in which the predicted miR-9 binding site was introduced into the 3′UTR of a luciferase reporter gene6, and found that infection of 4T1 cells with the miR-9 sponge caused a >2-fold increase in luciferase activity compared with the control sponge (Fig. 4a); this suggested that a greater than 50% inhibition of the actions of miR-9 had been achieved by the miR-9 sponge. We then implanted the infected 4T1 cells into the mammary fat fads of syngeneic immunocompetent Balb/c mice. Four weeks later, mice were moribund due to primary tumor burdens in both groups, and no difference in primary tumor size was observed between the 4T1 tumors expressing a control sponge and those expressing the miR-9 sponge (Fig. 4b). Examination of lungs revealed an average of 35 visible metastases in mice implanted with 4T1 cells expressing the control sponge (Fig. 4c, d); in contrast, an approximately 50% reduction in lung metastases (average: 17 visible metastases per mouse) was observed in mice bearing 4T1 tumors expressing the miR-9 sponge (Fig. 4c–e). Thus, inhibition of miR-9 can suppress metastasis formation by otherwise-highly malignant cancer cells.
We undertook to determine how miR-9 expression is regulated. Consistent with our previous findings6, immortalized, non-transformed HMLE cells naturally expressed a low level of miR-9, whereas the breast cancer cell lines examined expressed higher levels of this miRNA (Fig. 5a). Interestingly, a correlation between RAS status and miR-9 levels was observed in various cell lines; for instance, both the MCF7-RAS human breast cancer cells, which express an introduced, activated RAS oncoprotein (H-RASV12)37, and the MDA-MB-231 human breast cancer cells, which contain an activating K-RAS, codon 12 mutation38, showed significantly higher miR-9 levels than did the HMLE and MCF7 cells, both of which lack an activated RAS oncogene38 (Fig. 5a). Of note, relative to miRNA expression in normal mammary tissues, miR-9 stood out as the most significantly upregulated miRNA in mammary tumors arising in the MMTV-c-myc transgenic mice18. We found this to be particularly interesting, because RAS can potentiate MYC activity to promote tumor angiogenesis39. Moreover, oncogenic RAS is capable of inducing VEGF expression40.
Responding to these various observations, we were particularly interested in the actions of MYC, because this transcription factor has been shown to directly regulate expression of a diverse set of miRNAs (e.g., the oncogenic miR-17-92 miRNA cluster) that contribute in one way or another to tumorigenesis41–43. For this reason, we ectopically expressed MYC in HMLE cells and found that a 4-fold increase in MYC expression level resulted in an approximately 3-fold increase in the level of mature miR-9 (Fig. 5b). miR-9 can be generated by the processing of any of three primary transcripts encoded by three distinct genes. Among the three encoding genes, the transcription of mir-9-3 is upregulated most strongly (3.9-fold, Fig. 5b) by the MYC transcription factor.
Another MYC gene family member, N-MYC (MYCN), is frequently amplified in neuroblastomas. Operating as transcription factors, MYC and MYCN share a common set of target genes and are, from this perspective, functionally interchangeable. To evaluate whether MYCN can also upregulate miR-9, we measured its expression in a MYCN-inducible model system, SHEP-MYCN-ER42. Upon 4-hydroxy-tamoxifen (4-OHT)-mediated activation of the MYCN-ER fusion protein, miR-9 expression level was increased by 4-fold, which was comparable to the increase in the expression of the miR-17-92 positive control, whose expression is known to be activated by MYCN through direct promoter binding44 (Fig. 5c).
To determine whether MYC and MYCN regulate the expression of miR-9 by binding directly to the corresponding genomic sequences, we performed genome-wide ChIP-on-chip experiments using the Kelly and SJ-NB-12 neuroblastoma cells, which express high levels of endogenous MYCN and MYC, respectively, due in both cases to gene amplification. We observed that the endogenously expressed MYCN and MYC proteins bound directly to a conserved CpG island region encompassing canonical MYC binding sites (CACGTG) in the mir-9-3 locus; this was observed in both the Kelly and SJ-NB-12 neuroblastoma cells (Fig. 5d).
The association of chromatin-bound MYC with H3K4Me3 (a mark of activated chromatin) at MYC-regulated genes has been described previously45. Indeed, we found that MYC binding at the mir-9-3 locus was associated with elevated H3K4me3 binding (Supplementary Information, Fig. S7). Although we also observed a peak for MYC binding at mir-9-1 and mir-9-2 loci, respectively, these two regions exhibited low occupancy by H3K4me3 and relatively high occupancy by H3K27me3 (a mark of repressed chromatin, data not shown). Hence, among the three miR-9-encoding genes, the transcription of mir-9-3 is the most responsive to transcriptional activation by MYC/MYCN.
Recently, others have identified candidate transcriptional start sites (TSSs) and promoters of the great majority of human and mouse miRNA genes46. They exploited yet other findings that histone H3 is trimethylated at lysine 4 (H3K4me3) at the TSSs and promoters of most genes (>90%) in the genome. This study identified position 87712233 of chromosome 15 as the putative human mir-9-3 TSS46. In the present study, we observed co-occupancy by H3K4me3 and MYC of this putative mir-9-3 TSS region (close to position 87712000; Supplementary Information, Fig. S7), as well as of a region upstream of this putative mir-9-3 TSS (near position 87708500, where a canonical E-box is located; Supplementary Information, Fig. S7). Hence, the regions in which we observed MYC binding appear to encompass the mir-9-3 TSS and promoter, providing further evidence of transcriptional regulation of the mir-9-3 gene by MYC.
To extend our analysis to clinical cancers, we measured the expression of miR-9 in a cohort of 45 neuroblastoma tumor samples. Twenty-two tumors exhibited normal MYCN copy number and were classified as Stage 1 (n = 10), Stage 2 (n = 6) or Stage 3 (n = 6) neuroblastomas. Twenty-three tumors were classified as Stage 4 neuroblastomas and these showed MYCN gene amplification. Compared to tumors with normal MYCN copy number, tumors that exhibited an amplification of the MYCN gene showed a 2.5-fold upregulation of miR-9 expression (p = 9 × 10−4, Fig. 6a). The observed increase of miR-9 expression was similar to that of the miRNAs belonging to the miR-17-92 cluster (average miR-17-92 fold increase = 2.6, Supplementary Information, Fig. S8), which was previously shown to be upregulated in MYC/MYCN-overexpressing tumors42,47.
We also examined miR-9 levels in clinical breast cancers. Consistent with our expression analyses of cultured cell lines, miR-9 levels were significantly elevated in primary breast tumors from patients with diagnosed metastases compared to those from metastasis-free patients (fold increase = 4.33, p = 0.007, Fig. 6b).
Our findings identify miR-9 as a pro-metastatic miRNA and a negative regulator of the key metastasis suppressor, E-cadherin. On the basis of our results, we propose that the MYC and MYCN oncoproteins, acting on the mir-9-3 locus, cause activation of miR-9 expression in tumor cells. The resulting miR-9 miRNA can suppress the expression of E-cadherin, resulting in the promotion of carcinoma cell motility and invasiveness and, in addition, causing the activation of β-catenin signaling; the latter, in turn, contributes to elevated expression of VEGFA, leading to induction of tumor-associated angiogenesis. Ultimately, both increased cell motility and invasiveness, as well as enhanced angiogenesis, can contribute to metastasis formation (Fig. 6c). Since E-cadherin downregulation and β-catenin activation appear to be necessary but not sufficient for mediating miR-9-dependent VEGF upregulation (Fig. 2f), yet other miR-9 targets must also operate to enable VEGF induction by this miRNA (Fig. 6c). Indeed, the E-cadherin-independent roles of miR-9 in tumor cells warrant further investigation.
Paradoxically, a recent study proposed that miR-9 might be a candidate metastasis-suppressing miRNA, based on the observation that miR-9-encoding gene promoters, as well as the promoters of genes encoding two other miRNAs (miR-34b/c and miR-148a), were methylated in a relatively large fraction of primary tumors present in patients with lymph node metastases; in contrast, only a small fraction of primary tumors from patients without lymph node metastases exhibited this promoter methylation, while the status of distant metastases of these tumors was not determined48. Importantly, because the miR-9 expression levels in these tumors were not determined, it remains unclear whether there was a correlation between miR-9 gene methylation status and miR-9 miRNA levels. Furthermore, when ectopically expressed in several highly malignant cells, miR-34b/c and miR-148a suppressed metastasis formation, while miR-9 did not48.
Yet other lines of evidence indicate that miR-9 is positively associated with malignancy of human cancers. Some have demonstrated that miR-9 expression is significantly upregulated in both clinical breast cancers17 and in c-myc-induced mouse mammary tumors18. We have found that miR-9 is upregulated in various breast cancer cell lines compared with non-transformed mammary epithelial cell lines, and that metastatic breast cancer cells express even higher miR-9 levels than non-metastatic tumor cells. miR-9 is also upregulated in metastatic breast tumors compared to non-metastatic breast tumors from patients (Fig. 6b). These results suggest that methylation of the promoters of miR-9 genes reported in the cited study48 does not indicate a wider role of this miRNA in inhibiting metastasis.
In contrast to miR-10b, which is specifically upregulated in metastatic cancer cells6, miR-9 expression is upregulated in both metastatic and non-metastatic tumor cells relative to non-transformed cells. These observations, together with the fact that miR-9 expression can be increased by the actions of MYC and MYCN oncoproteins, cause us to propose that miR-9 expression is often induced at earlier stages of multi-step tumor progression when elevated MYC and MYCN expression is already apparent49 but before tumors become actively invasive and metastatic.
Can miR-9, acting on its own, initiate the EMT program? In the SUM149 carcinoma cells, the partial reduction of E-cadherin levels mediated by this miRNA does not directly induce an EMT in vitro (Fig. 1c and data not shown); instead, it seems to sensitize these tumor cells to EMT-inducing signals arising from the tumor microenvironment. This leads to the acquisition by carcinoma cells of mesenchymal traits late in tumor progression (Fig. 3c), which could in turn contribute to metastatic dissemination.
A contrasting response was observed in HMLE cells, in which we did indeed observe an EMT-like conversion resulting from overexpression of miR-9 (Fig. 1b, c). One possibility is that miR-9 might induce an EMT in a cell type-dependent and context-dependent manner; for example, HMLE cells have undergone functional inactivation of both p53 and Rb, which might prime these cells for induction of an EMT. Alternatively, the apparent ability of miR-9 to induce an EMT in HMLE cells might be explained by selection for a pre-existing rare mesenchymal subpopulation present within this particular cell line50. Unlike the HMLE cell line, the SUM149 cell line used in this study does not contain a detectable mesenchymal subpopulation, based on the absence of detectable levels of the mesenchymal marker vimentin (Figure 1c) and on FACS profiles (data not shown). For this reason, the selection mechanism, if it ever occurs, applies to HMLE cells but not to SUM149 cells, and the conclusions drawn from SUM149 experiments are unaffected.
Inactivation of the key metastasis suppressor E-cadherin can occur via a variety of distinct mechanisms, such as promoter hypermethylation and the actions of various EMT-inducing transcription factors. Our findings identify an additional mechanism for downregulating E-cadherin and indicate that elevated expression of the miR-9 miRNA contributes to EMT and metastasis in some and possibly many human tumors.
Methods and any associated references are available in the online version of the paper.
We thank Johannes Schulte, Martin Eilers, Rosa Noguera, Margaret Ebert, and Phillip Sharp for providing tumor samples and reagents; the Histology Core Lab at MIT and MSKCC for assistance with sectioning and IHC; and members of the Weinberg Lab for useful discussions. L.M. is a recipient of a Life Sciences Research Foundation Fellowship, a Margaret and Herman Sokol Award, and an NIH Pathway to Independence Award (K99/R00). J.Y. and E.P. are supported by a Howard Hughes Medical Institute Undergraduate Fellowship. J.T-F. is supported by the MSKCC Cancer Core Grant. T.T.O. and S.V. are recipients of a U.S. Department of Defense Breast Cancer Research Program Predoctoral Fellowship. R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor. This research is supported by an NIH grant to R.A.W. and the Ludwig Center for Molecular Oncology at MIT.
AUTHOR CONTRIBUTIONSL.M. conceived the project. R.A.W. supervised research. L.M. and H.P. designed experiments. L.M., J.Y., H.P., E. P., J.T-F., and F.R. performed most of the experiments and analyzed data. P.M., D.M., F.W., F.P., and J.V. contributed MYCN and ChIP-on-chip data. T.T.O. contributed some of the constructs and shared unpublished observations. S.V. modified the miRNA sponge design for stable expression. L.M. and R.A.W. wrote the manuscript.
The authors declare no competing financial interests.
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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The Confabulators Trailer (2013)
22 April 2013 Comedy, Thriller, Romance 74 mins
THE CONFABULATORS is a feature film about WALTER, a young man struggling to balance his relationship with his long-term girlfriend MARNY and his attempts to climb the corporate ladder at Cobb Inc. Walter's life takes an unexpected turn when his second cousin, TED, moves into his apartment. Soon, Ted starts showing up at Walter's office and infiltrating his social life. Meanwhile, Walter realizes there is more than meets the eye to Cobb Inc., and that it may be involved in a vast international conspiracy.
Watch the official The Confabulators 2013 trailer in HD below or find more The Confabulators videos on Vidimovie.

subset: commoncrawl


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Traveling Luck for Slates Wharf, Virginia, United States
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- York Point (5.1km)
- Fish Neck (5.3km)
- Hunts Point (6.6km)
- Hunts Neck (7km)
- church;
- a building for public Christian worship.
- Dandy Church (2km)
- Zion Church (2.2km)
- Seaford Church (3.6km)
- Providence Church (5.7km)
- Seaford Church (5.8km)
- Grafton Church (7.2km)
- Yorkminister Church (7.6km)
- Local Feature;
- A Nearby feature worthy of being marked on a map..
- Slates Wharf (0km)
- Yorktown Refinery (3.5km)
- Tue Marshes Lighthouse (5.5km)
- Hunts Wharf (7.1km)
- Bennett Creek Light (7.2km)
- Grafton Shopping Center (7.5km)
Accommodation around Slates Wharf
- bay;
- a coastal indentation between two capes or headlands, larger than a cove but smaller than a gulf.
- Willett Cove (4.4km)
- Hodges Cove (5.2km)
- school;
- building(s) where instruction in one or more branches of knowledge takes place.
- Seaford School (3.9km)
- Dare School (7.3km)
- island;
- a tract of land, smaller than a continent, surrounded by water at high water.
- Goodwin Islands (2.8km)
- Allens Island (6.7km)
- inlet;
- a narrow waterway extending into the land, or connecting a bay or lagoon with a larger body of water.
- Cabin Creek (3.9km)
- post office;
- a public building in which mail is received, sorted and distributed.
- Seaford Post Office (2.3km)
- channel;
- the deepest part of a stream, bay, lagoon, or strait, through which the main current flows.
- Thorofare (1.5km)
- cemetery;
- a burial place or ground.
- Zion Cemetery (2.2km)
- park;
- an area, often of forested land, maintained as a place of beauty, or for recreation.
- Back Creek Park (2.1km)
Wikipedia entries close to
Slates Wharf
- Yorktown (Virginia) city city n
- Poquoson, Virginia city city o
- Gloucester Point, Virginia city city o
- Newport News/Williamsburg International Airport airport airport
- Thomas Jefferson National Accelerator Facility science
- Langley Air Force Base
- Port Warwick city city o
- Grove, Virginia city city o
- Hampton (Virginia)
- United States Navy reserve fleets landmark military
- Fort Magruder city city o
- James River Bridge bridge
- Newport News Shipbuilding landmark landmark
- Fort Monroe landmark fortress
- Newport News city city e
- Gloucester Courthouse, Virginia city city o
Airports close to Slates Wharf
Newport news williamsburg international(PHF), Newport news, Usa (13km)
Langley afb(LFI), Hampton, Usa (18.1km)
Felker aaf(FAF), Fort eustis, Usa (23.1km)
Norfolk ns(NGU), Norfolk, Usa (39.6km)
Norfolk international(ORF), Norfolk, Usa (49.1km)


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Tanya Aguiniga's Felted Folding Chairs
Tanya Aguiniga's hand-felted pieces since we first spied them. They bring a cozy factor to the classic industrial folding chair (and some welcome color). As part of Design Miami's series of performance events, Tanya will be felting chairs with the help of participants. Via: Dezeen...
Tanya uses natural fleece and felts with the aid of ecologically-friendly soap and water to create a seamless cover for a chair. Has anyone tried to felt a chair in the spirit of Tanya Aguiniga?
(Pics: Aguiniga Design)


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Cumbria's Museum of Military Life
01228 532774
Alma Block,
The Castle,
Ordinary people doing extraordinary things.
Cumbria's Museum of Military Life tells a 300-year story of courage, loyalty and service. Fantastic exhibits and interactive displays follow the lives of soldiers, their families and communities during periods of conflict and times of peace.
As well as sharing our collections with thousands of visitors, we also answer hundreds of enquiries from ex-servicemen and their families, and bring history to life for local schools.
Adults: £4
Concessions: £3
Children: £2
Family (2 adults x 2 children) £10
English Heritage Members: Discounted entry (see website for details)
From M6 jct 43 via A69 towards city centre or from jct 44 via A7 south towards city centre. No parking at the castle except for disabled badge holders.
- Baby changing facilities
- Coach parties accepted
- Credit cards accepted (no fee)
- Disabled toilets
- Education/study area
- Facilities for groups
- Facilities for educational visits
- Gift shop
- On-site light refreshments
- Picnic site
- Public toilets
- Wheelchairs available
- Accepts groups
- Facilities for conferencing
- Facilities for corporate hospitality
- Children welcome
- Disabled access
- Dogs not accepted (except guidedogs)
- Smoking not allowed
Self-Assessed Accessibility Details
- Designated parking for guests with disabilities
- Within 50 metres approx. of entrance
- The surface of the car park and pathway leading to entrance:
- is solid
- Drop-off point for guests outside entrance
- The route from the parking area to the entrance:
- Is flat (i.e. without steps)
Public Areas
- Level access (no steps/thresholds) or access by ramp or lift:
- From the entrance to reception / ticket area
- To a specially adapted public toilet suitable for wheelchair users
- To the gift shop
- Good contrast between the floor and walls
- Baby changing facilities
- Hearing loop installed in public areas
- Hearing loop system
- Seating available for visitors with limited mobility
- Clear signage
- Effective lighting for visually impaired visitors
- Good colour/tonal contrast for visually impaired visitors
- Routes/pathways suitable for wheelchair users or visitors with limited mobility
- Displays at suitable height for wheelchair users / children
- Audible alarm system
- Entrance is well lit
- Level access (no steps/thresholds) or access by ramp or lift to cafeteria
- Good contrast between the floor and walls
- Seating suitable for wheelchair users, ie moveable and good height for person sitting in a wheelchair
Our conference and research facilities on the first floor are accessible for the disabled via a wheelchair stair lift.


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Relax at one of our inspiring five star hotels in Portimao - whether you're looking for a spa holiday, romantic break, honeymoon destination or a spot of golf.
Browse guest reviews, images and choice offers for each of our properties.
Reservations can be made at anytime by using the form on the left-hand side, or for specialist and personal travel advice and bookings over the phone our luxury travel advisors are standing by.
Exclusive luxury hotel offers at many of our member hotels are regularly added and updated. Our offers have something for everyone: including free nights, choice extras and unforgettable experiences.
To find the perfect five star hotel deal to suit you just visit the dedicated offers page by clicking the link above.
If you have not found the perfect hotel in the above listings, you can try to use our handy browse tool located in the top right corner of the page to find more luxury hotels by city or country.
Alternatively why not take a look at some of our dedicated luxury hotel collections:
Need inspiration? Browse our list of popular destinations to help you make an informed choice:
Order one of our gorgeous hotel directories.
Enter our draw to win a two-night bed and breakfast stay at Elba Estepona Gran Hotel & Thalasso Spa in Estepona, southern Spain.
Enter the draw
Smooth, warm volcanic stones are used to create a cleaning, harmonising and soothing effect on the body leaving you feeling energised read Hot stone massage
This hotel boasts a lovely view from the balconies where you can see the colours of the sunset change from orange to red. A perfect end to a perfect afternoon! read The colours of the sun
For those after a little indulgence, why not relax with a vintage bottle of champagne or enjoy some Moroccan specialities at the exclusive Harira restaurant. read A touch of class


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TRAC-X Emerging Markets is a liquid and transparent tool that provides investors with access to the broad emerging market asset class in a single transaction" said Neal Elkin, vice president and head of emerging market credit derivatives marketing at JPMorgan in New York.
What does EMCD stand for?
EMCD stands for Emerging Market Credit Derivatives (investment tool)
This definition appears very rarely and is found in the following Acronym Finder categories:
- Business, finance, etc.
See other definitions of EMCD
Other Resources:
We have 3 other meanings of EMCD in our Acronym Attic
- Abbreviation Database Surfer
- « Previous
- Next »
- Economic and Monetary Community of Central Africa
- Equipment Modular for Command and Control Application (India)
- East Mill Creek Community Council (Washington)
- Eastern Montgomery County Chamber of Commerce (Jenkintown, PA)
- Electron Multiplying Charge Coupled Device
- EMC Customer Engineer
- Electromagnetic Compatibility Control Plan
- En Masse Coolant Channel Replacement (nuclear reactor)
- Electro-Mechanical Control Diagram (US NASA)
- ElectroMagnetic Compatibility Directive
- Energy-loss Magnetic Chiral Dichroism
- Equimolar Counter-Diffusion
- Extractive Metallurgy Chapter of Denver (Denver, CO)
- Elastomer Modified Cast Double Based
- European Monitoring Centre for Drugs and Drug Addiction
- East Midlands Centre of Excellence (UK)
- Eerste Monteur Consumenten Elektronica (Dutch: First Consumer Electronics Technician)
- Electromagnetic Controlled Environment
- Electronic Materials Center Europe
- Emergency Mockup Critical Experiment
Samples in periodicals archive:
Contents include: Cross-Border Reviews - Strategic and tactical asset selection for structured credit products by Citigroup - Inflation derivatives - stepping beyond infancy by Barclays Capital - An introduction to emerging market credit derivatives by ING - Tranched credit derivatives: different or unique?


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Skill Analysis for Runoff Forecasts on the Western Slope of the Sierra Nevada . B. D. Harrison; R. C. Bales Sierra Nevada Research Institute University of California, Merced (Email: [email protected]). H21C-1189. Introduction. Summary and Correlation Measures of Forecast Skill.
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
Skill Analysis for Runoff Forecasts on the Western Slope of the Sierra Nevada
B. D. Harrison; R. C. Bales
Sierra Nevada Research Institute
University of California, Merced
(Email: [email protected])
Summary and Correlation Measures of Forecast Skill
Categorical Measures
The purpose of the research project was to investigate the skill level of April to July runoff forecasts for the thirteen major river basins on the west slope of California's Sierra Nevada. April to July runoff is considered the runoff from snowpack in the Sierra Nevada. Bulletin 120, Water Conditions in California, is published in February, March, April and May of each year and contains the snow survey data and runoff forecasts analyzed in this work. The Bulletin 120 forecasts are prepared by the Cooperative Snow Survey Program at the California Department of Water Resource (DWR) and are organized by hydrologic region within California. For this study we found that forecasts for the Sacramento River, San Joaquin River, and Tulare Lake hydrologic regions represent the west slope of the Sierra Nevada. Within those hydrologic regions there are thirteen major watersheds ranging from the Feather River in the north to the Kern River in the southas shown in the figure and listed in the table. Accordingly, for those watersheds, we obtained from DWR tabulations of Bulletin 120 runoff forecasts for the April-July runoff period as available for the years 1930 to 2010, the period of record. We then obtained the Full Natural Flow (FNF) tabulation for each watershed from the DWR for those watersheds for the years 1930 to 2010, the same period of record of Bulletin 120 water supply forecasts.
Results of Analysis
The figure showing the summary measures of MAE and MSE over the forecast season indicates a decrease in error as the forecast season progressed from February to May. Percent bias calculations showed over-prediction of runoff in the Tuolumne River in February (4.4) and March (2.9) with the April (-0.82) and May (-2.3) percent bias values showing under prediction for the same river. No trends over the 80 years of forecasts were evident in these calculated values. Direct measures of forecast skill such as the Nash-Sutcliffe (NS) score again showed strong improvement over the forecast season as exemplified by the February NS score for the American River of 0.36 with the corresponding May score of 0.92. The calculated hit rate (proportion correct) showed improvement during the forecast season in all runoff years with particular improvement in near normal and wet years. The threat score showed improvement during the forecast season (from around 0.5 to 0.7) in all runoff years. The remaining categorical measures POD , FAR and BIAS show similar improvement over the forecast season. The False Alarm Rate and BIAS ratio appeared elevated in early forecasts for years with near normal runoff.
Development and Evaluation of Improvements to Water Supply Forecasts
Recently developed remote sensing techniques for quantifying snow coverage or water content may prove to be useful in improving water supply forecasts. A method to develop an estimate of runoff utilizing remote sensing SCA data to estimate SWE in the central Sierra Nevada has been reported. They utilized daily remotely sensed fractional snow-covered area (SCA) at 500-m resolution to estimate snow water equivalent (SWE) on the Upper Merced and Tuolumne River basins of the Sierra Nevada of California for 2004 and 2005. They compared two methods of estimating SWE from SCA: blending fractional SCA with SWE interpolated from snow pillow measurements, and estimating SWE from degree-day calculations. They found that the interpolation approach (from snow pillows) estimates a lower snowmelt volume above 3000 m and a higher snowmelt contribution at elevations between 1500- 2100 m. Additionally they found that snowmelt timing from the depletion approach using degree-day information matches observed streamflow timing much better than snowmelt estimated by the interpolation method. The authors point out that variability in lower-elevation snow shows its sensitivity to climate variability and change.
Increased forecast skill earlier in the water year may provide significant economic benefits to water users. Agricultural water users will know earlier and with more confidence the amount of water available and improved and earlier cropping decisions can be made. Municipal or industrial water users will know the availability of surface water supplies at an earlier date and can make improved and more timely decisions on utilization of surface or conjunctive water supplies. Power generation utilities will know with increased confidence the amount of water available for diversion and for hydroelectric generation. The public will receive benefits if additional water such as increased in-stream flows can be made available for environmental and recreation purposes.
The authors thank the California State Department of Water Resources for providing the raw data utilized in this study.
Map showing locations of runoff forecast and flow measurement


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Louis Farrakhan railed against Hillary Clinton during a sermon this past Sunday.
The Nation of Islam leader first commended Donald Trump for taking away power from the media.
Farrakhan noted that the Republican nominee had been plastered across the television networks' election coverage as a means to embarrass him, but that only resulted in free campaign advertising for the Trump campaign.
"You don't even realize that you [the media] are no longer in power," he stated. "Can't you see you've failed?"
More @ The Daily Caller


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A beautiful accent piece with a linear and elongated shape can create an Art Deco statement. Iron metal frame in a rich copper bronze finish with a rope twist surround an elegant beveled mirror. Mirror can hang vertically or horizontally.
- Transitional styling
- Rich copper bronze finish
- Beveled edge mirror adds a decorative touch
- Hang vertically or horizontally


text:
Product Description
The pendant is attached to your mobile phone by a stylish connector made from matching gold plated metal findings with a black woven cord, which is strong but slim to loop back on self after passing through the tiny attachment loop, which is usually positioned on the bottom right corner of a mobile phone. The pendant is attached to the other end of this connector by an "O" ring.
Important Information
Always try to use a photo where the background is contrasting.
If in doubt as to the suitability of your photo for engraving please email us the photo before placing your order and we will advise you. Our email address is email@example.com. Please browse through the ranges of photo pendants and upload an image to try our preview option to find the perfect piece of personalised jewellery.
Shipping: We Aim to dispatch your order within 3-5 working days.
Returns Policy: Please ensure you read the Terms and Conditions as well as the Photo Requirements.


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I agree w/ everything that MK said. When I was first diagnoised, I thought that I would lose weight when I began chemo but just the opposite happened. It depends on the type of chemo that an individual is given plus the type of premeds. For example, I was given steriods as premeds before the chemo and this is one cause of weight gain.
If you doubt your friend, ask for some facts. Did she have a mastectomy? Reconstruction? What stage was it? Who is her oncologist at MD Anderson? Ask for some info about MD Anderson...where does she receive chemo? Does she see her onco before her treatment? Offer to take her to one of her appts. You could also use the excuse that you have a friend or acquaintance that is facing breast cancer and wanted the info to give to her.
Good luck.
I too have people telling me how well I look (I'm one third of the way through my chemo) and they often compliment me on my hairdo (my wig).
Here in the UK I recently watched a TV programme about a woman who ended up in prison for fraud. She had had relationships with several men who she had defrauded out of quite a large amount of money by telling the most amazing lies over a period of several years. At one point during this saga she pretended to have an inoperable brain tumour and actually shaved off her hair and eyebrows ! I found this pretty incredible but there are people out there who do this sort of thing.
Let's hope that all turns out well for your friend and for you.
Good luck
Post Edited (Cathi) : 2/25/2007 6:40:25 AM (GMT-7)


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Superstar Rajnikanth is infectious. Apart from his millions of his fans mega brands are joining in hordes to ride the huge success of Rajnikanth's new film Kabali, set to release next week. Amazon, Cadbury's, Air Asia, Shopcj, Emami, Muthoot Finance and Airtel are some of the mega brands that have tied up with Kabali's producers in an attempt to reach the mega star's millions of fans.
An entire range of merchandise – mugs, phone covers, T shirts – are flying off the shelves. But there is more. All the Rajni fans can fly in an AirAsia aircraft with a "Kabali menu" on the flight. Airtel is also offering special "Kabali" recharge packs, 'Kabali' branded SIM packs and popular dialogues and songs from the film as "hello tunes."


text:
"I was referred to the hospital ..."
About: Alexandra Hospital Alexandra Hospital Redditch B98 7UB
Posted via NHS Choices (as ),
What I liked
I was referred to the hospital by my GP and arrived for a 10.20 appointment. After registering at outpatients I was sent to the relevant clinic and saw the Sister within a few minutes, she was professional but friendly and was very supportive. I was seen by the consultant very quickly and after diagnosis, he said he would do laser treatment immediately. The nurse who assisted him was also very supportive and held my hand throughout the treatment. I have nothing but praise for my treatment at the Alex. My appointment was for 10.20 and I was diagnosed, treated and given a follow up appointment within 1 and a half hours. I would like to thank all the staff concerned for making my treatment a very positive experience.


text:
Posted 08 Feb 2011
Link to this post
Posted 11 Feb 2011
Link to this post
What I assume is that you do not update the TargetControls collection when needed and it keeps the old values. To resolve the problem , please go through the following steps:
1) When you change the page, clear the TargetControls collection on the server by calling
2) If you have ajaxified the ListView, ajaxify the tooltip manager as well so that when the view with the targets gets updated, the manager also does.
In case you need further assistance, please prepare a fully runnable page (use a fake programmatic datasource if needed) and share its source code here along with detailed reproduction steps and explanations and I will help you get the desired result.


text:
All the Universe
- Artist: Enchanted Forest
- Format: CD
- Release Date: 12/20/2005
|your cart is empty
Enchanted Forest ™ was formed in 1989 by James E. White as part of the D.V.C, electronic Midi project and has performed and sold many records and CD throughout the years with it's refreshing electronic soundscapes. Universe one was used in conjuction with a film project in 1997 with the original Mp3.com. New Age music that refreahes the spirt with electronic soundscapes. Copyright & TM 1989-2005, Enchanted Forest ™ James E. White, All Rights Reserved.


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COLUMBUS, Ga. — They lived daily in constant fear of discovery and had no food from nearby farms.
Thursday the National Infantry Museum held a day of remembrance for those who survived the holocaust. Students from McBride Elementary School conducted a candle light ceremony and called out survivors names one by one to celebrate their legacy.
Art work created by local children is a symbol of hope for those that were of what could be described as one of the darkest times in history.
"We dedicate this candle to those who we miss spiritual and physical resistance of our people during Nazi Regime. We dedicate this candle to those people who were called upon as public witnesses and the world's crime child's. May they find strength and courage to cope through their surgent's of their darkest memories."
The remembrance ceremony wrapped up with a documentary showing what it was like to be forced to live during such a horrific event.
It's something those who survived the ordeal will never forget.


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Kill Trailer (2011)
"This is no vacation." 13 September 2011 Horror, Comedy, Thriller 90 mins
Six strangers awake to find themselves the new tenants of a mysterious old house. Terrorized by insane Tiki-men in masks and taunted by their deranged captors,it soon becomes clear that only one singular action will save them: Kill.
Watch the official Kill 2011 trailer in HD below or find more Kill videos on Vidimovie.


text:
Legal Question in Wills and Trusts in Florida
estate settlement
What is the time limit to settle an estate in Florida? I was told five years.
Asked on 5/12/09, 1:48 pm
2 Answers from Attorneys
Frank J. Pyle Probate Attorney Throughout Florida
Re: estate settlement
According to Florida Rule of Probate Procedure 5.400 (c), it is to be closed within one year unless the judge extends the time after a petition to do so is filed with the court, and notice of the petition given to all "interested persone". The Rules are at the following website: http://www.floridabar.org/TFB/TFBResources.nsf/Attachments/6C2FEF97C5969ACD85256B29004BFA12/$FILE/Probate.pdf?OpenElement
Answered on 5/13/09, 11:13 am
Alan Wagner Wagner McLaughlin, P.A.
Re: estate settlement
The is no absolute limit. Some are fast, some are slow -- depending on the facts. Five years is longer than the great majority of estates.
Answered on 5/12/09, 2:23 pm
Related Questions & Answers
Probate do all wills go through probate Asked 5/12/09, 12:19 pm in United States Florida Probate, Trusts, Wills & Estates


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The East Coast Group was established in 1960 in the UK manufacturing of plastics and expanded with application of their distinction in high quality plastics to baby changing mats and highchair insert cushions. In recent years they have acquired the licences of nursery favourites: Fisher-Price, Tiny Tatty Teddy and The Very Hungry Caterpillar; catapulting sales in these categories. The Company's success led to the formation of the East Coast Nursery division, which still operates from the original site in Norfolk, UK and is managed by the same family.
The Company is also well known for its beautiful, high quality, modern nursery furniture that is produced from sustainably sourced timber. It offers a wholesome co-ordinating collection of cot beds, cots, cribs, dressers and wardrobes at a range of price points, colours and designs. Wholesaler, Baby Brands Direct appreciates the heritage and caring approach to product development and quality of the award-winning nursery brand; ensuring supply is readily accessible to approved retailers.
Baby Baths are a vital purchase for new parents looking to bathe their newborn safely in an enjoyable environment. Baby Brands Direct stocks a variety of baths from the 3 in 1 baby bath by Fisher-Price to the portable inflatable bathtub by Munchkin. In addition, the Fisher-Price trusted brand offers a variety of safety features and accessories to be used as baby grows. Browse our wide selection of bath time products available for wholesale here. Discover our product line of baby baths, bath time accessories, hooded towels, bath inserts & supports, toiletries, bath and room thermometers, bath mats, baby grooming essentials and bath water temperature indicators.
Baby Brands Direct works in association with expert names in the industry providing our clients immediate access to the most sought after nursery brands. Our suppliers work closely with paediatricians who endorse using water as a great way to engage with the little one's senses. The more parents want to make bath time engaging the more bath time products sales keep growing. Our clients can shop bath time goods in different shapes, colours and designs from leading international industry brands.
The Company boasts a series of nursery awards particularly for their highchairs and design features encouraging longevity of product use including dressers with removable changing frames so that they can be used once baby is out of nappy.
Baby Brands Direct wholesales and supplies the range of East Coast Nursery products directly to independent retailers and offers a drop ship service on the wooden furniture items. Phil Bosher, Account Development Manager at East Coast Nursery comments, 'We have worked with Baby Brands Direct since 2008 and continue to strength our relationship in order to deliver the best service to our retailers in selling these quality products.'
As a worldwide supplier, Baby Brands Direct has made it convenient for retailers to stock on brands and items that they often have scarce or no access to locally. For instance, Babymoov has introduced innovative inflatable bathtub, perfect for parents looking for a comfortable, safer bath for their baby. From mats that tell you when the water is too hot to T bars that help hold the baby in place. You can choose from the Earth Friendly Baby range offering organic shampoos, body lotions, baby wipers, massage oil and bubble bath. Hooded towels have been a growing hit among retailers and parents.
Our partners, Munchkin, have introduced a line of bath time ducks to help parents check the temperature of their baby's bath, doubling as fun, exciting toys for baby to play with while in the tub. Our range of bath inserts and supports are designed to make bath time easier for parents. We have made available a range of bath time accessory products, from the practical Tommee Tippee and Beaba who are providing you with baby scissors and combs to nail clippers and nose aspirators.


text:
Canoeing in New York + Add to My Sports
Canoeing in New York
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Players & Teams in New York
Age: 27 · Location: New York, NY
Sports: Cornhole, Camping, Airsoft, Adventure Racing, Hunting, Trail Running, Fishing and more...
Friends: Simon Dana P. Dimon NYC Soccer Collective
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Create and organize your own Canoeing team! Sportsvite has the web's best team management tools, and they just got even better, with overhauled rosters, schedules and more!
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text:
Sumarin Kanojo-tachi Chapter 81 Page 1
You are reading Sumarin Kanojo-tachi Chapter 81 Page 1 on MangaSee. To see more information about this Manga, please visit the Chapter List. Sumarin Kanojo-tachi is a Manga that was published in 2014by OKITA Ryuji. Sumarin Kanojo-tachi Manga is Ongoing. Its scanslation status is Ongoing. Sumarin Kanojo-tachi Chapter 81 was added on . Genres: Adult, Drama, Harem, Mature, Romance, Seinen
2016 MangaSee Copyrights and trademarks for the manga, and other promotional materials are held by their respective owners and their use is allowed under the fair use clause of the Copyright Law. Privacy Policy


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Useful properties of cheese for children and adults .Benefits and harms of curd daily diet rules with cheese dishes
Diet / / August 12, 2017
fermented milk product obtained by fermentation of milk, cottage cheese called.
For this yogurt is heated so that it curled, and then remove all the excess liquid.
quality cheese with useful properties is a lot of loose milk hue with delicate sour aftertaste.
composition of fermented milk product
Cottage consists of curdled milk from which whey has been removed.Due to the excellent taste and cheese is not only added to various dishes, but also eaten as a standalone product.Useful properties of cheese as a milk concentrate known nutritionists.Curd not contain enzymes with remote whey.Because of their lack of cheese retains its flavor much longer than other dairy products.
The nutritional composition includes the following nutrients:
• fats, proteins and carbohydrates
• vitamins A, PP, C, group B
• potassium, iron, phosphorus, etc.
• amino
• folic acid
addition of nutrients, in the cottage include lactic acid bacteria, ozdoravlivayusche intestinal microflora.Easy digestibility of cheese is due to the almost complete absence of milk sugar.Invaluable curd children, as it contains a record amount of protein needed for a growing organism.
Calorie cheese
Calorie cheese depends on the nutritional raw milk, from which it was made.An important factor is also the method of manufacturing the product.
are the following varieties of cheese:
• fat (the fat content of 1, 8%)
• Classic (4-18%)
• fat cottage cheese (19-23%)
The higher the percentage of fat content, thehigher calorie cheese.For the production of cottage cheese 23% fat using fresh cream, respectively, fat cottage cheese has a high calorie content.
|Variety cheese
|fat content of 5%
|fat content of 9%
|fat content of 23%
Cottage cheese products manufactured inproduction conditions, contains starch, sometimes sweet curds add oil or dried fruit.All this affects the calorie cheese.
Applying curd cheese Nutrient
useful as a dietary product is recommended by nutritionists for inclusion in the daily diet of adults and children.Besides the fact that cheese is used for the preparation of dietary dishes, cheese use as dietary meals invaluable.
As the main component of cottage cheese is used for the following purposes:
• diets for weight reduction
• sports nutrition
• in folk medicine
• homemade cosmetics
curd made compresses for bruises and sprains from curd massmade nourishing cream and a mask for the care of skin and body.Useful properties of curd are helping athletes recuperate after grueling workouts.
Use cheese for the body
Regular consumption of fermented milk curds are the benefits of a tangible body.Cottage cheese helps to normalize metabolic processes in tissues and organs, blood saturates nutrients, improves digestion.
Compared to other fermented milk products, cheese contains a record amount of protein.Unlike proteins, which are rich in meat products, curd protein is fully absorbed by the body.Therefore, cheese is recommended to eat the weakened patients and children with digestive disorders.This product does not irritate the stomach.
Getting in the human body, protein is composed of cottage cheese begins to split into the amino acids necessary for the proper functioning of organs and tissues.Cottage cheese contains folic acid and calcium, necessary for bone growth.The use of cheese for the body of pregnant and lactating women is particularly important.
Facts: The composition of cheese includes natural antiseptic lactic acid.This chemical compound is involved in metabolism, providing the body with energy.
What injury can cause curd?
considered to be universally useful cheese product recommended for the power of people of all ages.Digestible and nutritious cheese has almost no contraindications.The only exception is an individual intolerance of lactic acid products.To avoid unexpected complications, you need to take the recommendations of a nutritionist.Your doctor will help determine the feasibility of intolerance curd body also determine the daily rate of consumption of healthy and nutritious product.Recommended daily rate of 250 grams of cheese.adult organism.
should not forget that in the cottage includes a large amount of fats and proteins, which are the breeding ground for the development of pathogenic micro-organisms.Harm curd is obvious if eating it is not fresh.In the refrigerator cheese can not be stored for more than three days, at a temperature above 20 C is recommended to eat raw product within days.If the shelf life have been violated, cottage cheese can be used as a filling for cooking casseroles and cheesecakes.Heat treated cottage cheese will not bring harm to the body.
Useful properties of cheese in the diet of pregnant women
Cottage cheese is a dietary useful product, which is required in the diet of a pregnant woman.It contains everything necessary for the proper development and formation of the fetus.The use of cheese for the health of a pregnant woman to bear a child, due to the record number of the missing protein, which contains the product.Calcium curd composition necessary for the formation of bone tissue of the fetus.
daily requirement of cheese to the body of a pregnant woman is 1600-1900 mg.This quantity of cheese for the benefit of pregnant women enough.The diet of a woman to bear a child, to be curd exceptional freshness.Contraindicated include food spoiled or stale cheese.During pregnancy, doctors, nutritionists recommend to include in the diet of fat cottage cheese no more than 7%.
Facts: Argued that pregnant women are recommended cottage cheese because of its high calcium content.In fact, the calcium in the curd only 120 mg per 100 g of cheese legkousvaevaemogo Value determined by the presence of protein, vital for the formation of the fetus.
Use cottage cheese in the diet of lactating women
Availability of cottage cheese in the diet of lactating mother affect the composition and quality of breast milk.The curd contains the optimal amount of nutrients needed to promote health nursing mother and her baby.Enter in your daily diet cottage cheese should be with caution.After eating cottage cheese in food should watch the reaction of breast baby body.If the skin appeared red rash, there are signs of gastrointestinal disorders, should be excluded from the diet of cottage cheese nursing mothers.In this situation, the body of the child harm curd obvious.It serves as a worthy substitute cottage cheese or yogurt yogurt.
Benefits and harms of cheese in the diet of children
Fermented milk products have a positive effect on the intestinal microflora, heals the body, saturating it with the necessary nutrients.Cottage cheese in a child's nutritional needs as a highly nourishing product containing a large amount of easily digestible protein.
only contraindication is idiosyncrasy curd and its components.In the absence of a negative reaction to cheese can begin to give children aged 7 months as foods.Curds give infants a teaspoon once a day.With age, the amount of cheese in the diet gradually increases.To supply children up to 3 years is better to choose low-fat cottage cheese varieties.Older children can be given cheese moderate fat content.
health benefits of cheese wishing to lose weight
invaluable health benefits of cheese weakened patients after a serious illness.Dietary food on the curd normalizes metabolism and restores the balance of nutrients in the body.Low-fat cheese included in the diets recommended by nutritionists for weight loss.
popular so-called mono-diet , in which the curd acts as the primary and often the only meals.Use monodient not scientifically proven.Nutritionists have found useful diet for weight loss, which in addition to cheese, are allowed to eat lean meats and vegetables.
to prescribe diet cottage cheese with low-fat diet, which includes a large amount of riboflavin involved in the regulation of metabolism.Overweight curd helps get rid of excess body fat.Will benefit the health of cottage cheese, enriching the body with beneficial vitamins and minerals.
Dietitians developed the following common options for weight loss diets:
• A three-day curd diet
• Diet on cottage cheese and yogurt
• Diet on cottage cheese and fruit curd
Benefits more pronounced during the three-day duration diet.With this diet diet included only low-fat cottage cheese with yogurt.As a supplement is recommended to drink a decoction of wild rose or green tea without sugar.
Diet cottage cheese and yogurt designed for a week.The recommended daily five meals.Each time you need to eat 100 grams.low-fat cottage cheese and drink a glass of kefir.
Fruit and cottage cheese diet 6-7dney observed.The day is recommended to eat 400 grams.low-fat cottage cheese mixed with a small amount of wheat bran, infused in boiling water.The dish can add apples, pears, raisins, cooked vegetables.Cottage cheese is recommended to wash down with a glass of kefir.
12, 08, 2017
12, 08, 2017
12, 08, 2017


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Transfer Rumors: Barcelona, Real Madrid fighting for Premier League's rising star
Alli signed from MK Dons in 2015 and has recently signed a new contract keeping him at White Hart Lane until 2022. The 20-year-old midfielder has 21 goals in 71 games for Tottenham, a club that hasn't been afraid to let talent go to Spain at the right price.
Chappell insults Pakistan cricket, says improve or go home
Australian pacer Josh Hazlewood and off-spinner Steve O'Keefe wrecked havoc on Pakistan as the host completed a 3-0 whitewash by winning the last and final Test of the three-match series by 220 runs here at the Sydney Cricket Ground (SCG) on Saturday.
Belotti will not be going to Arsenal, insist Torino
Torino President Urbano Cairo warned Arsenal that Andrea Belotti "has a € 100m clause and we've no intention of selling for less than that". Torino have told Arsenal that they will have to dig very deep if they want to sign their star striker Andrea Belotti this month .
Dillon Brooks ejected for kicking opponent
Bothered by Washington's press, Oregon State committed 15 turnovers, which led to 29 points by the Huskies. Junior forward Matthew Atewe went up strong for a layup with less than a second remaining, allowing the Huskies to head to the half with a 43-28 advantage.
Liverpool vs. Plymouth Argyle 2017
Liverpool's side had an average age of 21 years and 296 days - even taking into account the presence of captain Lucas Leiva, 30 on Monday - with nearly half the team coming through the club's academy. "I don't think the lineup was a mistake, but I am 100% responsible, I have no problem with it". We can piss and moan as much as we'd like about having another game on the cards, but it's pretty safe to say that Klopp will be naming a pretty similar if not the same side when we visit Home Park ...
Injuries too much to overcome as Texans beat Raiders 27-14
They see the talent, they see the coaches, the schemes, all the stuff that's going on, and they know they're going to have to deal with us for the next couple years in the playoffs. The Texans will look to rely on a defense led by Jadaveon Clowney to help carry them to victory. "I can't wait for Saturday to be here, said Osweiler".


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The British Museum in London is hosting Celts: art and identity, 'the first major exhibition to examine the full history of Celtic art and identity'. The exhibition covers the history of the Celts over 2500 years, and its centrepiece is the magnificent Gundestrup cauldron, which is illustrated on the front cover of the Amber Books edition of Celts.
To quote the British Museum website:
'The fascinating art and history explored in the exhibition have deep resonances for those in Britain, Ireland and the global Celtic diaspora today, influencing everything from music and literature to sport and spirituality.'
Here is a link to Amber's Celts book: Celts: The History and Legacy of One of the Oldest Cultures in Europe
Here is a link to the British Museum's Celts exhibition: British Museum [external site]
The exhibition runs from 24 September 2015 – 31 January 2016.


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This evening Carrie Pilto, SFMOMA project assistant curator, looks at the later period covered by The Steins Collect, after World War I. She explores the relationship of the Steins to the new tendencies that emerged in modern art in France in those years.
The Steins Collect is a guide to the personal and artistic relationships that formed the crucible of modern art. This series of five talks by curators and historians explores those relationships and describes how and why the story of modern art owes so much to that moment in history. It looks at the work of Henri Matisse, Pablo Picasso, and Gertrude Stein, three of the most adventurous artists of the period.


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When we last checked in with San Francisco baker Josey Baker, it was 2011, and he was baking his addictive, imaginatively flavored levain loaves in Oakland's Pizzaiolo kitchen and selling the bread by subscription, like a sourdough CSA. Now Baker runs The Mill, a San Francisco coffee house and bakery with Four Barrel Coffee (www.themillsf.com), and his first cookbook, "Josey Baker Bread" (Chronicle Books, $27.50, 224 pages), lands on bookshelves this week.
Even if you've never made bread before, Baker's playful bro prose, encouraging exhortations ("Man oh man, it's worth it. Trust me!") and enticing recipes — everything from seed-studded country loaves to chocolate-cherry pocketbread and strawberry scones — will send you straight to the kitchen. We're thinking those scones will be perfect for Easter.
— J. Burrell, Staff


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FIGURE 22-1. Needle insertion for saphenous nerve block of the ankle.
General Considerations
An ankle block is essentially a block of four terminal branches of the sciatic nerve (deep and superficial peroneal, tibial, and sural) and one cutaneous branch of the femoral nerve (saphenous). Ankle block is simple to perform, essentially devoid of systemic complications, and highly effective for a wide variety of procedures on the foot and toes. For this reason, this technique should be in the arma mentarium of every anesthesiologist. At our institution, an ankle block is most commonly used in podiatric surgery and foot and toe debridement or amputation.
Functional Anatomy
It is useful to think of the ankle block as a block of two deep nerves (posterior tibial and deep peroneal) and three superficial nerves (saphenous, sural, and superficial peroneal). This concept is important for success of the block because the two deep nerves are anesthetized by injecting local anesthetic under the fascia, whereas the three superficial nerves are anesthetized by a simple subcutaneous injection of local anesthetic.
Common Peroneal Nerve
The common peroneal nerve separates from the tibial nerve and descends alongside the tendon of the biceps femoris muscle and around the neck of the fibula. Just below the head of the fibula, the common peroneal nerve divides into its terminal branches: the deep peroneal and superficial peroneal nerves. The peroneus longus muscle covers both nerves.
Deep Peroneal Nerve
The deep peroneal nerve runs downward below the layers of the peroneus longus, extensor digitorum longus, and extensor hallucis longus muscles to the front of the leg (Figure 22-2). At the ankle level, the nerve lies anterior to the tibia and the interosseous membrane and close to the anterior tibial artery. It is usually sandwiched between the tendons of the anterior tibial and extensor digitorum longus muscles. At this point, it divides into two terminal branches for the foot: the medial and the lateral. The medial branch passes over the dorsum of the foot, along the medial side of the dorsalis pedis artery, to the first interosseous space, where it supplies the web space between the first and second toe. The lateral branch of the deep peroneal nerve is directed anterolaterally, penetrates and innervates the extensor digitorum brevis muscle, and terminates as the second, third, and fourth dorsal interosseous nerves. These branches provide innervation to the tarsometatarsal, metatarsophalangeal, and interphalangeal joints of the lesser toes.
FIGURE 22-2. Anatomy of the ankle. artery dorsal pedis, deep peroneal nerve.
Superficial Peroneal Nerve
The superficial peroneal nerve (also called the musculocutaneous nerve of the leg) provides muscular branches to the peroneus longus and brevis muscles. After piercing the deep fascia covering the muscles, the nerve eventually emerges from the anterolateral compartment of the lower part of the leg and surfaces from beneath the fascia 5 to 10 cm above the lateral malleolus (Figure 22-3). At this point, it divides into terminal cutaneous branches: the medial and the lateral dorsal cutaneous nerves (Figure 22-4A and B). These branches carry sensory innervation to the dorsum of the foot and communicate with the saphenous nerve medially, as well as the deep peroneal nerve in the first web space and the sural nerve on the lateral aspect of the foot.
FIGURE 22-3. Anatomy of the ankle. superficial peroneal nerve, sural nerve.
FIGURE 22-4. (A) Anatomy of the ankle. Sural nerve. , Superficial peroneal nerve. (B) Anatomy of the ankle. Sural nerve, Superficial peroneal nerve.
Tibial Nerve
The tibial nerve separates from the common popliteal nerve proximal to the popliteal fossa crease and joins the tibial artery behind the knee joint. The nerve runs distally in the thick neurovascular fascia and emerges at the inferior third of the leg from beneath the soleus and gastrocnemius muscles on the medial border of the Achilles tendon (Figure 22-5). At the level of the medial malleolus, the tibial nerve is covered by the superficial and deep fasciae of the leg. It is positioned laterally and posteriorly to the posterior tibial artery and midway between the posterior aspect of the medial malleolus and the posterior aspect of the Achilles tendon. Just beneath the malleolus, the nerve divides into lateral and medial plantar nerves. The posterior tibial nerve provides cutaneous, articular, and vascular branches to the ankle joint, medial malleolus, inner aspect of the heel, and Achilles tendon. It also branches to the skin, subcutaneous tissue, muscles, and bones of the sole.
FIGURE 22-5. Anatomy of the ankle. flexor digitorum longus tendon, posterior tibial artery, tibial nerve, flexor hallucis longus.
Sural Nerve
The sural nerve is a sensory nerve formed by a union of the medial sural nerve (a branch of the tibial nerve) and the lateral sural nerve (a branch of the common peroneal nerve). The sural nerve courses between the heads of the gastrocnemius muscle, and after piercing the fascia covering the muscles, it emerges on the lateral aspect of the Achilles tendon 10 to 15 cm above the lateral malleolus (Figure 22-4A and B). After providing lateral calcaneal branches to the heel, the sural nerve descends behind the lateral malleolus, supplying the lateral malleolus, Achilles tendon, and ankle joint. The sural nerve continues on the lateral aspect of the foot, innervating the skin, subcutaneous tissue, fourth interosseous space, and fifth toe.
Saphenous Nerve
The saphenous nerve is a terminal cutaneous branch (or branches) of the femoral nerve. Its course is in the subcutaneous tissue of the skin on the medial aspect of the ankle and foot (Figure 22-6).
FIGURE 22-6. Anatomy of the ankle. , saphenous nerve, medial malleolus.


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Charlton Heston - Moses & Michelangelo
I was never a big fan of Charlton Heston, but reading his obituary in this morning's NY Times is like reading a history of America in the last century - and not just the movies. Wars, social movements, unions, name it and he was involved.
Not my cup of tea, but a fascinating and amazingly accomplished man.


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Home > Festivals & Events > Bright Nights: The 7th Baltic-Nordic Film Festival > The Happiest Day In the Life of Olli Maki
Hymyilevä Mies (The Happiest Day In the Life of Olli Maki)
dir. Juho Kuosmanen
Finland, 2016, 92 minutes
Finland, 2016, 92 minutes
Finnish, English sub-titles
Bright Nights: The 7th Baltic-Nordic Film Festival
Richcraft Hall Theatre (formerly River Building), Carleton University, Saturday, February 18, 2017, 7:00 pm
"Funny, forlorn, and irresistibly charming, Juho Kuosmanen's assured debut feature, which won the top prize in the Un Certain Regard section at Cannes, is inspired by the true story of Finland's most successful boxer of the 1960s. Shot in black and white, the film centres on the prelude to Mäki's historic fight in Helsinki with American Davey Moore, the bantamweight champion of the world. Almost painfully open and ingenuous, Olli is a small-town boy who is just as happy baking bread as he is in the ring — and he's even happier when he's with Raija, the level-headed beauty he finds himself falling for. Elis, Olli's manager, is the exact opposite: a hyperbolic showman who promises the press corps a 'spectacle never seen in Finland.' As Olli begins wilting under the pressure, his desperate attempts to lose weight, and his separation from Raija, Elis faces his own challenges from his wife, his financial backers, and his American partners." (Toronto International Film Festival)
CFI Members, Students, Seniors (65+): $9.00 (HST incl)
Seating is limited. Get your tickets early — tickets are on sale now!
CFI Members, Students, Seniors (65+): $9.00 (HST incl)
Seating is limited. Get your tickets early — tickets are on sale now!


text: Does anyone know of a good music player app that will allow me to download the album artwork and fix song titles/artist on the fly? I'm tired of looking at the music icons. Does anyone know of a way to set notifications as different sounds. Text messages one sound and emails as another. Also I know you can change the ringtone for individual people how about text messages. Thank You Roman


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Burhanuddin Rabbani, (born 1940, Faizabad, Badakhshan, Afg.—died Sept. 20, 2011, Kabul, Afg.), Afghan Islamic scholar and political leader who instituted strict Islamic laws as the president (1992–96) of Afghanistan but was driven into exile after the rise of the even more fundamentalist Islamist Taliban. Rabbani, a member of Afghanistan's Tajik minority, attended a religious school in Kabul. He then studied Islamic law and theology at Kabul University and Islamic philosophy at Cairo's al-Azhar University, from which he obtained a master's degree (1968). As a strong opponent of King Mohammad Zahir Shah's secular reforms, he became the head of an Islamic political party, which evolved into a powerful mujahideen rebel group during the Soviet occupation of Afghanistan (1979–92). Rabbani was the second president after the Soviet withdrawal, but he refused to step down from the rotating presidency. Four years later he was forced out by Taliban forces, though he retained international recognition. He returned home in the wake of the U.S.-led attacks in 2001 and briefly served as interim president until the election that November of Hamid Karzai. From 2010 Rabbani was head of the High Peace Council, which sought to pursue peace talks with the Taliban. He was assassinated by a suicide bomber claiming to be a Taliban emissary.
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Theme >> WordPress - Chloe Emerson WordPress Social Media 276972 by Studio Mommy @ CreativeMarket
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The Maryland, Virginia and Washington D.C. DUI lawyers at Price Benowitz are dedicated to fighting for their clients' rights. If you are facing DUI or DWI charges, contact an experienced DUI attorney today.
Address: 10605 Judicial Drive, Suit 200, Fairfax, VA 22030
Phone: (202) 552-0897
When problems are serious, you want a lawyer with experience. Call The Law Office of Thomas E. Pyles. We serve Maryland residents throughout Charles and Prince George's counties, as well as St. Mary's, Calvert, Montgomery and Anne Arundel counties.
Address: 2670 Crain Highway, Suite 106, Waldorf, MD 20601
Phone: (301) 705-5006
Baltimore Criminal Attorney Super Lawyers Maryland Criminal Defense Lawyer Representing Defendants in Baltimore, Annapolis and Throughout Maryland A "Serious Maryland Criminal Trial Lawyer" Ready to Fight for Your Rights
Address: 1435 Sulphur Spring Road, Baltimore , MD 21227
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Being a defense attorney is my passion and I am dedicated to protecting and enforcing your rights. I am a zealous advocate and strive to achieve the best possible results. I believe in being receptive & responsive to my clients concerns.
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