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Journal of Thyroid Research
Volume 2011 (2011), Article ID 815826, 10 pages
Medullary Thyroid Carcinoma: Molecular Signaling Pathways and Emerging Therapies
1Department of Endocrinology, Hospital San Juan de Dios, Avenida 14, Calles 6 Y 7 Paseo Colon, 1475-1000 San José, Costa Rica
2Department of Endocrine Neoplasia and Hormonal Disorders, Unit 1461, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
Received 16 January 2011; Accepted 10 March 2011
Academic Editor: Ana O. Hoff
Copyright © 2011 Karen Gómez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Research on medullary thyroid carcinoma (MTC) over the last 55 years has led to a good understanding of the genetic defects and altered molecular pathways associated with its development. Currently, with the use of genetic testing, patients at high risk for MTC can be identified before the disease develops and offered prophylactic treatment. In cases of localized neck disease, surgery can be curative. However, once MTC has spread beyond the neck, systemic therapy may be necessary. Conventional chemotherapy has been shown to be ineffective; however, multikinase inhibitors have shown promise in stabilizing disease, and this year will probably see the approval of a drug (Vandetanib) for advanced unresectable or metastatic disease, which represents a new chapter in the history of MTC. In this paper, we explore newly understood molecular pathways and the most promising emerging therapies that may change the management of MTC.
1. Introduction
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from parafollicular cells of the thyroid gland [1]. MTC represents less than 3% of thyroid carcinomas in the United States [2]. The first description of its major histological features and characterization as a separate entity was done in 1959 by Hazard et al. [3]. It was then rapidly recognized that this carcinoma had distinctive clinical features, in that MTC was found to be associated with pheochromocytomas and other tumors, an association now known as multiple endocrine neoplasia type 2 (MEN2) [4]. The identification of familial cases led to the conclusion that many MTCs were probably hereditary [5]. In 1966, MTC was found to arise from the calcitonin-secreting parafollicular cells [6]. Subsequently, calcitonin provocation tests with calcium and/or pentagastrin were used to identify individuals susceptible to familial MTC, and those individuals were offered prophylactic thyroidectomy [7].
Activating mutations of the Rearranged during Transfection (RET) proto-oncogene were described for the first time in patients with familial forms of MTC in 1993 [8, 9]. Since then, several germline RET proto-oncogene mutations have been found in almost 100% of hereditary MTCs. Additionally, somatic RET proto-oncogene mutations have been found in approximately 40% of patients with sporadic MTC [10, 11]. These discoveries created new paradigms for the management of MTC: (1) the identification of germline RET proto-oncogene mutation carriers would allow the removal of the thyroid cells at risk for transformation early in life (this paradigm is perhaps the most perfect example of primary cancer prevention in humans to date), (2) the identification of several hidden familial medullary thyroid cancers [12], and (3) the abnormally activated RET gene might become a target to treat patients with advanced sporadic and hereditary MTC. Our goal in this paper is to describe the molecular pathways associated with MTC tumorigenesis and emerging therapies against this disease (Figure 1).
2. MTC and the RET Proto-Oncogene
Autonomous cell growth is the defining feature of all benign or malignant tumors. Malignant neoplasms have the capacity to invade the surrounding normal tissue and metastasize to distant sites. Molecules that are responsible for growth and other fundamental cell functions are frequently mutated in cancers. An example of such molecules is the tyrosine kinase (TK) receptors (Figure 2). TK receptors are membrane-spanning proteins with large N-terminal extracellular domains that act as ligand-binding sites and intracellular domains that catalyze the transfer of the γ phosphate of adenosine-5′-triphosphate (ATP) to hydroxyl groups of tyrosines of target proteins. TKs control a wide range of fundamental processes of cells such as the cell cycle, proliferation, angiogenesis, differentiation, motility, apoptosis, and survival.
The RET proto-oncogene is located in chromosome 10q11.2 [13]. The gene has 21 exons [14] and codes for a receptor TK [15]. The RET receptor is a transmembrane protein constituted by extracellular, transmembrane, and cytoplasmatic domains. The extracellular domain has a stretch of approximately 100 amino acids that are similar to members of the cadherin family of Ca2+dependent cell adhesion molecules [16]. The binding of calcium to this cadherin-like domain is needed for conformational changes necessary for the interaction with different glial cell line-derived neurotrophic factor ligand family members (GDNF, neurturin, artemin, and persephin) [17]. These ligands in conjunction with a ligand-specific coreceptor (GFRα 1–4) activate RET [18]. These ligands or coreceptors are not always needed for RET activation [19]. Following RET activation, specific tyrosine residues are phosphorylated. These residues serve as docking sites for adaptor proteins that link the receptor to the main signal transduction pathways. Different activated sites trigger the activation of different pathways. For instance, tyrosine 1015 is a binding site for phospholipase C that activates protein kinase C (PKC). Other examples are given by the phosphorylated γ tyrosine 981 which is responsible for Src activation upon RET engagement [20] and the phosphorylation of tyrosine 1062, several adaptor or effector proteins are recruited including Shc, FRS2, Dok family proteins, insulin receptor substrate 2, and Enigma [21]. Then, various pathways that regulate cell survival, differentiation, proliferation, and chemotaxis [20] are activated, including RAS-extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)-Akt, p58 mitogen-activated protein kinase (MAPK), and Jun N-terminal kinase (JNK) [22] (Figure 3).
Mutated RET is expressed in derivatives of neural crest cells, including hereditary and sporadic MTC and pheochromocytoma [23]. These mutations are referred to as gain-of-function, because they lead to either a constitutively active TK or decreased specificity of the TK for its substrate [24].
3. RET Genotype-Phenotype Correlations
3.1. Sporadic MTC
Sporadic MTC constitutes 65% to 75% of MTC cases [25]. The most frequent clinical presentation is that of a thyroid nodule. Up to 75% of patients with palpable MTC have nodal metastases in the central and ipsilateral neck compartments, and 47% of patients with palpable MTC have nodal metastases in the contralateral neck [26]. Distant metastases frequently occur in the liver, lungs, and bones.
Somatic mutations occur in 30% to 40% of cases [10, 11]. Exon 16, codon 918 ATG → ACG mutation is the most common somatic mutation in sporadic MTC [27]. This mutation is associated with larger tumors and a more advanced disease stage at diagnosis [11].
3.2. Hereditary MTC
Hereditary MTC constitutes 25% to 35% of MTC cases [25]. Hereditary MTC is preceded by C-cell hyperplasia and is usually bilateral and multicentric [28]. Hereditary forms of MTC are caused by germline RET proto-oncogene mutations and occurs as part of the MEN2 syndromes. MEN2A is characterized by MTC in almost 100% of gene carriers, pheochromocytomas, and parathyroid tumors. The most common mutations in MEN2A occur in one of six cysteine residues (codons 609, 611, 618, 620, 630, and 634) in the RET extracellular domain. The most frequently mutated residue found in patients with MEN2A is cysteine 634, in which removal of one-half of an intramolecular disulfide bond allows formation of an intermolecular disulfide bond with a second mutant molecule, thus leading to constitutive receptor dimerization [29]. PI3K-Akt and MAPK pathways have been implicated in MEN2A [30].
There are three variants of the syndrome: (1) MEN2A with Hirschsprung disease, (2) MEN2A associated with cutaneous lichen amyloidosis, and (3) familial MTC, in which MTC is the only manifestation. Familial MTC RET-mutation affects the extracellular cysteine-rich region and the TK domain. This variant tends to be the least aggressive form of hereditary MTC.
MEN2B is the most distinctive and aggressive MEN2 syndrome. The most common mutations associated with MEN2B are M918T and A883F. These mutations, unlike MEN2A, are in the TK domain and lead to an activated monomeric form, thus altering substrate specificity [29]. The PI3K/Akt cascade has been shown to be important in the pathogenesis of MEN2B in cell lines [31].
4. TK Receptors Other Than RET Involved in MTC Tumorigenesis
4.1. Epidermal Growth Factor Receptor
The epidermal growth factor receptor (EGFR/HER-1/erbB1) is a TK receptor. It is one of four homologous transmembrane receptors (the others are HER-2/erbB-2, HER-3/erbB-3, and HER-4/erbB-4) that mediate the actions of different growth factors, such as epidermal growth factor, transforming growth factor-α, and neuregulins [32]. The binding of ligands to these receptors induces EGFR homo- and/heterodimer formation, kinase domain activation, and phosphorylation of specific tyrosine residue that serve as docking sites for molecules that lead to the activation of several cascades, including the MAPK and PI3K pathways [33].
EGFR oncogenic activation can occur due to several mechanisms: excess ligand or receptor expression, activating mutations, failure of inactivation, or transactivation through receptor dimerization [34]. To date, two major types of EGFR-targeting agents exists monoclonal antibodies and small-molecule ATP-competitive TK inhibitors (TKIs) [35, 36]. PKI166, a potent EGFR kinase inhibitor, also decreases RET autophosphorylation and signaling in cell extracts despite lacking an effect on RET kinase activity. PKI166 was tested in clinical trial in patients with MTC amongst others. However, due to liver toxicities the development of this drug was halted [37]. AEE788, another EGFR kinase inhibitor, inhibits RET-induced growth at concentrations below its half maximal inhibitory concentration (IC50) [38]. However, AEE788 does not have any active clinical trials in MTC patients. A study of 153 primary and metastatic MTC samples revealed that although EGFR mutations were rare, EGFR expression was higher in metastatic sites than in primary tumor sites [39]. MTC samples associated with RET 883 and 918 mutations had a significantly lower number of EGFR polysomes and a tendency toward less EGFR immunopositivity compared with samples associated with other RET mutations. Therefore, it is speculated that the most aggressive RET mutations are less dependent on EGFR activation, thereby explaining why EGFR inhibitors are less effective in codon 918-mutated cell lines than in codon 634-mutated cell lines.
4.2. Vascular Endothelial Growth Factor
The vascular endothelial growth factor (VEGF) family of growth factors stimulates angiogenesis, endothelial cell proliferation, migration, survival, and vascular permeability by various TK receptors: VEGFR-1, VEGFR-2, and VEGFR-3 [40]. There are several ligands for VEGFRs: VEGF-A (VEGF) binds to both VEGFR-1 and VEGFR-2; VEGF-B and placenta growth factor bind to only VEGFR-1; and VEGF-C and VEGF-D are specific ligands for VEGFR-3 [41].
Angiogenesis is one of the essential alterations in cell physiology that predispose to malignancy in many tumors, and it is fundamental in tumor growth and metastasis. Many molecules have been implicated as positive regulators of angiogenesis, including VEGF, hepatocyte growth factor, interleukin-8, and platelet-derived growth factor (PDGF). The major mediator of tumor angiogenesis is VEGF, which signals mainly through VEGFR-2. Activation of this receptor leads to a cascade of different pathways, including PLC γ-PKC-Raf-MEK-MAPK and PI3K-Akt [42]. Lymphangiogenesis is also involved in tumor biology, and since lymphatic vessels arise from blood vessels, some of the angiogenic mechanisms are also used in this process. VEGF-C and VEGF-D stimulate both angiogenesis and lymphangiogenesis and link both processes [43]. VEGFR-3 is expressed mainly in lymphatic endothelial cells and is thought to be primarily involved in lymphangiogenesis.
MTC has at least twofold expression when compared with normal thyroid tissue of VEGF and VEGF-R2 [44]. There is also an up to 20-fold increased expression of VEGF-C and VEGF-R3 in metastatic MTC [45]. Overexpression and activation of VEGFR-2 in MTC correlate with metastasis [39].
4.3. c-MET
The c-met (MET) proto-oncogene codes for the TK receptor of the hepatocyte growth factor [46]. MET is an important factor in tumorigenesis. Deregulated activation of MET confers unrestricted proliferative, antiapoptotic, cell motility/migration, invasive, metastatic, and angiogenenic properties to cancer cells [47]. Silencing the endogenous MET proto-oncogene, which is overexpressed in tumor cells, has been proven to impair the invasive growth in vitro, to decrease the generation of metastases in vivo, and to promote the regression of already established metastases [48]. MET and hepatocyte growth factor coexpression has been seen in a subset of MTC tumors and is associated with multifocality in MTC [49].
5. Targeted Therapy
Different TKs and pathways are abnormally activated in MTC cells. Inhibiting only one receptor may induce other TKs compensatory activation [50]. Therefore, simultaneous inhibition of different activated TKs may be the best way to approach MTC (Table 1) [51]. To date, systemic targeted therapy for MTC has been administered in the context of clinical trials or has consisted of off-label use of drugs approved for other solid tumors. In this section, we review the most promising TK inhibitors against MTC.
5.1. Vandetanib
Vandetanib is a 4-anilinoquinazoline that is available as an oral daily agent. It inhibits VEGFR-2, VEGFR-3, RET, and to a lesser extent EGFR and VEGFR-1 [52]. The 4-anilinoquinazoline docks to the ATP binding pocket of RET kinase, inhibiting it [53].
At pharmacologically relevant doses, vandetanib inhibits tumor cell proliferation, survival, and angiogenesis without leading to direct cytotoxic effects on tumor or endothelial cells [52]. In 2002, vandetanib was shown to inhibit the kinase activity of NIH-RET/C634R (MEN2A) and NIH-RET/M918T (MEN2B) oncoproteins in vitro and to inhibit RET/MEN2B phosphorylation and RET/MEN2B-dependent MAPK activation in vivo in NIH-RET/MEN2B [54]. Two years later, a panel of point mutations targeting the RET kinase domain in MEN2 and sporadic MTC was screened for susceptibility to vandetanib. Most of the mutant oncoproteins (RET/E768D, RET/L790F, RET/Y791F, RET/S891A, and RET/A883F) were sensitive to vandetanib, while mutations substituting valine 804 either to leucine or to methionine (as occur in some cases of MEN2A) rendered the RET kinase significantly resistant. This is probably due to steric hindrance, because the Val804Gly mutation increased the sensitivity of RET to vandetanib [55]. Mice carrying a RET C634R mutation from a sporadic human MTC treated with vandetanib had inhibition of tumor growth [56].
Inhibition of other kinases seems to be very important, too. MTC metastases express more EGFR and VEGFR-2 than primary tumor sites. Both EGFR and VEGFR-2 have been shown to be phosphorylated in TT and MZ-CRC-1 cells and inhibited by vandetanib. Yet, in the presence of active RET, neither plays a prominent role in TT cell proliferation. However, when RET activity is inhibited, overstimulation of EGFR is able to partially replace RET through a partial rescue of the MAPK pathway. In such scenario, the inhibition of EGFR by vandetanib was shown to prevent this rescue of the MAPK pathway. These data support the idea that dual inhibition of RET and EGFR is important, as it may overcome the risk of MTC cells' escaping from RET blockade through compensatory overstimulation of EGFR [50].
In phase I clinical studies of patients with solid tumors (not including MTC) [57], doses of vandetanib up to 300 mg/day were well tolerated, and adverse effects were generally mild and controlled with either dose adjustments or symptomatic therapy. The most common adverse events were rash, diarrhea, fatigue, asymptomatic QTc prolongation, proteinuria, and hypertension. Since QT prolongation was note as an adverse event, patients should have EKG and electrolytes at baseline and at regular intervals during the course of treatment.
In a phase II study, 30 adult patients with unresectable, locally advanced, or metastatic hereditary MTC received 300 mg/day of vandetanib [58]. The primary endpoint was the objective response rate (ORR) according to the 2000 Response Evaluation Criteria in Solid Tumors (RECIST) guidelines [59]. Objective partial responses (PRs) were observed in 20% of patients, and the median duration of PR was 10.2 months. Additionally, 53% of patients had stable disease (SD) for a median of 24 weeks. In another trial of vandetanib at 100 mg/day (or up to 300 mg/day in cases with disease progression), patients with similar disease characteristics achieved similar results (ORR 68%) [60]. Both trials showed a ≥50% reduction in calcitonin and carcinoembryonic antigen levels from baseline. However, the reduction in calcitonin levels did not correlate with the degree of tumor growth inhibition. It seems that RET activity is required for ligand-induced calcitonin gene expression [61]. In that sense, carcinoembryonic antigen levels may be a better marker of tumor response to vandetanib. Of interest, there was no apparent association between specific RET germline mutations and response to treatment (no patients with 804 RET mutation were included). Other phase I and II studies are ongoing to determine the effectiveness of vandetanib in sporadic MTC and its safety and efficacy in children and adolescents. (http://www.ClinicalTrials.gov/).
Data on vandetanib have been presented to the United States Food and Drug Administration (FDA), including results from the largest randomized, double-blind, placebo-controlled trial, which was conducted in 331 patients with advanced unresectable or metastatic MTC, "Study D4200C00058". This trial showed that median progression-free survival (PFS) was 11 months longer in the group randomly assigned to vandetanib and 45% had an ORR. As the drug seems to be effective in stabilizing symptomatic and/or progressive disease, it will likely become the first FDA-approved drug for MTC.
Nuclear factor κB (NF-κB) activation can block cell-death pathways and contribute to the oncogenic state by driving proliferation, enhancing cell survival, and promoting angiogenesis and metastasis. NF-κB has a high baseline activity in MTC cell lines through RET-induced phosphorylation, ubiquitination, and proteosomal degradation of inhibitors of NF-kB (IkB), which allows NF-κB to enter the nucleus and bind to the DNA [62]. Bortezomib inhibits proteosome-mediated IkB degradation in MTC cells, resulting in its accumulation and thus preventing NF-κB translocation to the nucleus [63], thereby leading to apoptosis. A phase I/II trial of the combination of vandetanib plus bortezomib is currently recruiting patients (http://www.ClinicalTrials.gov/). Patients with MTC will participate in the phase II study.
5.2. Sorafenib
Sorafenib is a small TKI that targets RET, VEGFR-2, VEGFR-3, Flt3, PDGFR-β, KIT, and the RAF family serine/threonine kinases RAF-1 and BRAF. It inhibits the growth of RET-driven tumors by a combination of activities that target RET-dependent thyroid cancer cell proliferation and VEGF-dependent tumor angiogenesis. In vitro, sorafenib inhibits RET signaling and the growth of RET-transfected fibroblasts and human thyroid cancer cells that harbor RET/PTC and RET/MEN2 oncogenes. Sorafenib action is mainly cytostatic, but the drug also exerts a proapoptotic effect. Sorafenib has been shown to significantly reduce tumor growth in nude mice with xenograft tumors derived from MTC cell lines [64]. Sorafenib has been investigated in four phase I trials with different doses and administration schedules. A dose of 400 mg orally twice daily was found to be safe and generally well tolerated, and the most frequently reported drug-related adverse events were fatigue, anorexia, diarrhea, rash/desquamation, and hand-foot syndrome. Hand-foot syndrome is characterized by painful erythematous lesions that affect the palmo-plantar surface. It is the most common reported adverse effect in patients taking the multikinase inhibitors like sorafenib and sunitinib. The lesions are pronounced on the pressure points on the palms and the soles but can also affect the margins of the feet and skin between fingers and toes. These lesions are not life threatening but significantly impair the quality of life requiring dose reduction or even discontinuation of the drug [65].Severe hematological, cardiovascular, hepatic, and renal toxic effects were not reported. Treatment-related hypertension was reported in 5% to 11% of patients in all four phase I trials. Sorafenib demonstrated evidence of antitumor activity by inducing disease stabilization in patients with refractory tumors, a finding that was consistent with the results of preclinical studies [66]. No patients with thyroid cancer were included in the phase I study. Because of the role of RET signaling in MTC and the antitumor activity exhibited by sorafenib in preclinical and in vitro studies, MTC was recognized as a potential target for sorafenib. In a small 2007 pilot study that included five patients with metastatic MTC with excessive calcitonin secretion, calcitonin secretion was decreased by >50% in all patients after 3 months of treatment, and all patients were free of calcitonin-related symptoms. After 6 months of therapy, one patient had a complete response (CR), and patient had a PR [67]. Sorafenib was administered orally at a dose of 400 mg twice daily continuously in a larger, open-label phase II study in patients with histologically confirmed metastatic or locally advanced MTC. Patients were monitored regularly with physical examination and biochemical and radiologic testing. In the event of any significant drug-related adverse event, the drug was withheld and restarted at a lower dose of 400 to 600 mg/day with dose re-escalation as tolerated. The median duration of therapy with sorafenib was 15 months. ORR was assessed using RECIST version 1.0. Of the 15 evaluable patients in this study, all showed some degree of tumor shrinkage. One patient achieved PR; 14 patients had SD, eight of whom had SD ≥15 months; and one patient had clinically progressive disease. Most patients had decreased calcitonin levels 2 months after treatment initiation, but they did not correlate with the degree or duration of response as assessed using RECIST [68]. Sorafenib has been approved by the FDA for treatment of renal cell and hepatocellular carcinoma. Therefore, sorafenib is an option for patients with advanced MTC who are not eligible for clinical trials [69].
5.3. Tipifarnib
Tipifarnib inhibits farnesylation of RAS and other proteins. Farnesylation is a type of lipid modification that is critical for the biological functionality including several signal transduction proteins. Farnesyltransferase inhibitors target multiple pathways, including the RAS pathway, and are among the first systematically investigated drugs in oncogene-targeted therapy. RAS genes encode proteins involved in cell proliferation, differentiation, and adhesion and apoptosis regulation. At least three associated genes (H-RAS, K-RAS, and N-RAS) are present in mammalian cells. Of all human tumors, 30% might have a mutated RAS isoform. Thyroid cancer has mutations in all three RAS genes. In in vitro studies, tipifarnib inhibited the growth of several human tumor cell lines, and in in vivo studies, tipifarnib was shown to inhibit colon and pancreatic cancer xenografts in a dose-dependent manner. The antitumor effects were mainly due to decreased cell proliferation, antiangiogenesis, and apoptosis. A phase I trial of tipifarnib in combination with sorafenib in patients with advanced malignancies included 15 patients with thyroid cancer, eight of whom had MTC. Three of the six patients who reached first restaging had PRs, whereas the others had some minor regressions and hence SD lasting from 12 to 16 months. The most common side effects reported were rash, hyperglycemia, and diarrhea. RET mutational analysis in these six patients revealed RET mutations; thus, it is unclear whether the response to sorafenib and tipifarnib was entirely due to RET inhibition by sorafenib [70]. In a previously reported case, the rate of response rate to combination therapy was higher than that reported for sorafenib alone. It should be noted that the RET pathway is complex and the RET kinase can activate a cascade of signaling pathways. Tipifarnib can also affect various other pathways, including Akt and MAP/ERK, and may have acted synergistically to produce the clinical response [71]. The FDA has not approved tipifarnib because of its inferior outcomes in phase III trials in patients with other malignancies [72]. However, the data from trials of thyroid cancer so far seem encouraging, and studies combining various oncogene-targeted therapies are needed.
Preclinical studies have shown that activating RET mutations in V804 (V804L and V804M) causes resistance to various structural classes, including vandetanib. Mutations in V804 slightly affect RET susceptibility to sorafenib, thus indicating that a structurally different inhibitor may be used to overcome the mutational resistance to a particular TKI [73]. This might be clinically significant as a recent study showed RET V804M (19.6%) is a prevalent cause of hereditary MTC [74].
5.4. Sunitinib
Sunitinib is a derivative of indolinone and inhibits the activity of many TKs, including VEGFR, PDGFR, KIT, and RET. Sunitinib exerts antitumor activity by affecting cell proliferation and survival in cancers in which these receptors are involved [75]. Its inhibitory effect on VEGF and RET makes this drug a rational choice for treating MTC. In a phase II study of sunitinib in patients with progressive thyroid cancer that included six patients with MTC, disease stabilization was seen in five of the six patients (83%) [76]. Results from another phase II study that included only patients with progressive MTC also showed responses. Among the 23 patients evaluated, eight (35%) achieved PR, with a median response duration of 37 weeks, and 13 (57%) had SD, with a median response duration of 32 weeks [77]. A trial using a lower dose of 37.5 mg/day in a continuous manner included six patients with MTC. Three of the six patients had an objective response [78]. The most common drug-related adverse events were fatigue, diarrhea, palmar-plantar erythrodysesthesia, neutropenia, and hypertension. Sunitinib has been approved by the FDA as the treatment of renal cell carcinoma and is therefore available for use in selected patients with MTC not enrolled in a clinical trial [69].
5.5. Cabozantinib (XL184)
Cabozantinib (XL184) is a small molecule that inhibits MET, VEGFR-2, RET, KIT, Flt-3, and Tie-2 [79]. In the context of MTC, preclinical data have demonstrated that XL184 can inhibit the proliferation of cells harboring activated RET. In 2009, results of a phase I trial that included 37 patients with MTC revealed that 44% of patients achieved at least 30% reduction in tumor size, and 29% of patients confirmed PR. There was no correlation between RET mutation status (either germline or somatic) and tumor response [80]. Side effects included fatigue, diarrhea, appetite loss, weight loss, hair hypopigmentation, and hypertension. Other effects, such as elevated aspartate aminotransferase, alanine aminotransferase, lipase elevations, palmar/plantar erythema, and mucositis, were dose dependent. Because of the noted antitumor effects of XL184, a phase III clinical trial called the "Efficacy of XL184 in Advanced Medullary Thyroid Cancer (EXAM)" is recruiting patients (http://www.ClinicalTrials.gov/). The purpose of the study is to evaluate PFS with XL184 compared to PFS with placebo in subjects with unresectable, locally advanced, or metastatic MTC.
Recently, in addition to giving XL184 a generic drug name, FDA had granted XL184 an orphan drug designation for treatment of follicular, medullary, and anaplastic thyroid carcinoma, and metastatic or locally advanced papillary thyroid cancer.
E7080 inhibits VEGFR-1, VEGFR-2, VEGFR-3, KIT, FGFR1, PDGFR, and to a lesser extent EGFR. This drug has been shown to be a potent inhibitor of in vitro angiogenesis in human small cell lung cancer via inhibition of VEGF/VEGF-2 and the stem cell factor/KIT signaling pathways. Via dual inhibition of VEGFR-2 and VEGFR-3, E7080 has also been shown to decrease lymphatic vessel density in the primary tumors of VEGFC-overexpressing MDA-MB-231 mammary fat pad xenograft models as well as within the metastatic nodules in the lymph nodes of nude mice [81].
In phase I trials, E7080 caused hypertension and proteinuria, which were the major dose-limiting toxic effects [82]. Other observed adverse events included thrombosis, tachycardia, febrile neutropenia, and thrombocytopenia.
A phase II trial to evaluate the safety and efficacy of oral E7080 in medullary and iodine-131-refractory, unresectable differentiated thyroid cancers is ongoing (http://www.clinicaltrials.gov/). The primary purpose of the trial is to determine the effect of E7080 on the objective tumor response rate according to RECIST.
5.7. Pazopanib
Pazopanib is an oral multikinase inhibitor. In vitro studies have shown that it is a potent inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α and −β, and KIT [83]. The antineoplastic activity of pazopanib is primarily due to its effect on the angiogenic pathways. Phase II studies of pazopanib for MTC are ongoing [84].
6. Conclusion
Research on MTC over the last 55 years has led to a good understanding of the genetic defects and altered molecular pathways associated with its development. Subsequently, promising targeted therapies have been developed for progressive and advanced MTC. Multikinase inhibitors have shown good results in terms of stabilizing disease, and this year will probably see the approval of a drug for advanced unresectable or metastatic MTC, which would represent a new chapter in the history of this disease. The challenge for the years to come is to discover more effective ways to target multiple key pathological pathways as well as the identification of the individuals who will benefit the most.
Conflict of Interests
The authors do not have any conflict of interest to disclose.
This research is supported in part by the National Institutes of Health through MD Anderson's Cancer Center Support Grant CA016672. K. Gómez and J. Varghese equally contributed to this work and should be rewarded as joint first authors.
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Deepika Padukone's selfie moment with 'Ip Man' star on 'xXx 3' sets
Deepika Padukone was clicked on the set of her Hollywood film 'xXx: The Return of Xander Cage' with Hong Kong's action star Donnie Yen, who featured in the 'Ip Man' franchise flick in 2015.
Also read: Serena unleashed! Deepika Padukone's fierce avatar in 'xXx 3'
Also read: When Vin Diesel photobombed Deepika Padukone's picture
Donnie took a selfie with Deepika who did not forget to pout for the camera. Donnie has replaced Jet Li in 'xXx: The Return of Xander Cage'.

subset: commoncrawl


text:
Fesenjoon Sauce
- 2 cups walnuts
- 2 cloves garlic
- ½ teaspoon olive oil
- Salt
- 1 to 2 tablespoons minced fresh jalapeño chili
- 1 to 2 tablespoons minced fresh jalapeño chili
- ½ teaspoon olive oil
- + 5 more ingredients
- ¼ cup pomegranate concentrate (see notes)
- 2 cups walnuts
- ¼ cup pomegranate concentrate (see notes)
- Salt
- 2 cloves garlic
In a 10- to 12-inch nonstick frying pan over medium-high heat, stir garlic in olive oil until garlic is lightly browned and soft when pressed, about 2 minutes. Remove from pan. To pan, add walnuts; stir until toasted, about 6 minutes. In a blender or food processor, purée walnuts, garlic, minced ...
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Attorney General Koster is an active and aggressive protector of Missouri's consumers. After taking office, as the mortgage crisis was heating up, he declared "Zero Tolerance" on businesses that were cheating consumers trying to avoid foreclosure or lower their month house payments. Koster took legal action to stop these businesses, and actively warned consumers not to do business with them. Similarly, Koster has gone after businesses that promise to obtain lower credit card payments for consumers.
Koster also has taken on businesses that sold consumers auto service contracts that did not do what they promised. After filing lawsuits against a number of businesses, Koster created an Auto Service Contract Task Force. The Task Force's recommendations led to legislation passed by the General Assembly in 2011 to set rules for selling these products and to regulate those who sell them.
The Attorney General has pursued many other businesses and industries that have taken advantage of consumers, including:
Satellite companies DISH Network for not providing programming as promised to consumers, and Direct TV for misleading sales practices
Bank of America for violating Missouri's no-call laws
Office Depot for overcharging government and not-for-profit customers
The world's leading makers of LCD screens for price-fixing
American Express for anti-trust violations relating to transaction fees
In the past two years, Koster's office has obtained restitution and penalties of more than $16 million for Missouri's consumers who had filed consumer complaints with his office. In addition, through litigation and formal settlement agreements, he has obtained almost $15 million for the state on behalf of consumers.
Other areas in which the Attorney General has been out-front for consumers include mishandled pre-need funeral plans, unfair debt-collection practices, anti-competitiveness in the credit card industry, and fraudulent charities.
Source: http://www.chriskoster.com/issues/consumerprotection


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"Begin doing what you want to do now. We are not living in eternity. We have only this moment, sparkling like a star in our hand – and melting like a snowflake."
~ Marie Beyon Rey
Passion, as defined in the dictionary, refers to a powerful or compelling emotional feeling similar to desire, amorous love, and ardor. Passion can also go beyond the emotion, and into the intellectual passion of research, study, science, and discovery. No matter what the studies and experts might tell us – passion, or what we enjoy to do, is a highly tuned individual response, it can mean something different to any one person, and can change throughout our lifetime.
Business studies have shown us that people will have higher performance, better efficiency, less sick days and are happier at work – if they are doing what they enjoy. At the same time if we become too involved in our passions we can actually damage our relationships with others and our own health as well. The trick is to find the balance between living our passions and having a healthy social and physical life as well.
Some people have difficulty finding out what their passion is in life – and there are some helpful tools to help them identify this. Personality assessment tools are fantastic for helping people realize what is important to them, what they enjoy, activities they like to do – and what they don't like to do as well. Alternatively we can look at things around us that appeal to our soul, that really tug at our emotions. Something that we are inclined to put more energy in than is actually required, that is our passion.
So few of us understand the value our daily actions have and the impact we can make on the world. In fact studies show that a large percentage of the population is depressed and consumed with feelings of inadequacy, 66% of us would become more proactive if we knew our actions had a measurable impact. Following our passions can have a real and measurable ripple effect, creating an avenue for us to act as an agent of positive change. Whether we realize it or not, people are watching us – our children, spouse, neighbors and co-workers – so simply by doing, we can influence others. Every encounter we have is a chance to create a positive ripple that will carry on to create unknown wonders.
Sometimes we just have to break away from the routines of the day and try something new in order to discover our passions. Psychologists have long known that simply performing one small proactive step will aid in defining a positive outlook on life and will inspire further participation from the individual.
For myself, the discovery of my passion didn't happen overnight. I knew that I enjoyed writing, that I was able to use it as a healing tool personally, but when I embarked on a writing career I found a way to feel like I was being that agent for positive change with the topics I focused on. Later on, as I evolved into an author and then a radio host and managed a blog, I found that I could expand this impact to a wider audience. This concept that my life is valuable, that I can play a role in making the world a better place, became my passion. Writing, hosting the radio show, managing the blog, and other activities in my daily grind are just tools that help me reach for that passion.
I would like to encourage our readers today to spend time learning about themselves, who they are, what they enjoy and make the steps to get you closer to living your passions every day. I guarantee that you will feel so much more empowered, joyful, inspired and creative then you thought possible.
"Perhaps then, if we listen attentively, we shall hear amid the uproar of empires and nations, a faint flutter of wings, a gentle stirring of life and hope. Some will say that hope lies in a nation; others in a person. I believe rather that it is awakened, revived, nourished by millions of solitary individuals whose deeds and works every day negate frontiers and the crudest implications of history. As a result, there shines forth fleetingly the ever-threatened truth that each and every person, on the foundation of his or her own sufferings and joys, builds for all."
~ Albert Cammus – The Artist and His Time
Purple Snowflake Marketing blurb:
Purple Snowflake Marketing offers a realistic guide to what authors can expect to face and how to employ research and preparation to make a memorable first impression. As you put together a marketing plan, you will be able to proceed with the confidence of a seasoned writer. This book is packed with value, with over 1000 resources along with stats and inspiring quotes to assist you in developing that unique marketing plan for each book you write.
Lillian Brummet: Award winning author of 5 books – including Purple Snowflake Marketing. She is also a renowned book-marketing guru, owner of the award-winning Brummet's Conscious Blog, and both the host and executive producer of the Conscious Discussions Talk Radio show. Visit her site at: http://www.brummet.ca


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MOVIE SYNOPSIS [ General Audiences ] Film of Eddie Fernandez. Introduced in movie theaters in 2011, with a production coming from USA. You can watch Final Level online on TV cable or theaters with original audio in English at different dates. This film premiered in theaters in 2011.
Rating: 5 by 5 users./
Runtime: 80 minutes
Oneira Acosta, Kelly Adames, Matt Augenstein, Guile Branco, Wayne Chang, Karina Colon, Angela Diaz, Sarah Loren Gerber, Clarence Gilliard, Brandon Goins, Teddy Hernandez, Shane Hobel, Mark Jackson, Erick Murph, Vincent Perretta and Zack Roberts.
Drama, Criminal.
80-minute film (full movie) directed by Eddie Fernandez.
The original audio of Final Level has dialogues in Dolby Digital, it was produced in USA.
It premiered in cinemas or television in 2011.
Screenplay written by Eddie Fernandez.
Eddie Fernandez.
Eddie Fernandez, Lawrence O. Berds, George Ladd and Sybelle Silverphoenix.
This film was produced and / or financed by Eternal Eye Entertainment.
Composed by Jose Mercado and Alexis Fairweather.
Without commercial breaks, the full movie Final Level has a duration of 80 minutes; the official trailer can be watched in streaming on the Internet. You can watch this full movie free in EnglishDolby Digital in movie TV channels, renting the DVD or with VoD services (Video On Demand player, Hulu) and PPV (Pay Per View, Netflix).
See the page of this full movie, Final Level in FULLTV Movies.


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A quick easy fruity smoothie to make.
1 DOLE Banana, medium1 cup DOLE Frozen Sliced Strawberries1 cup DOLE Frozen Blueberries3/4 cup vanilla almond milk
Combine banana, strawberries and blueberries in blender or food processor. Add almond milk. Cover; blend until smooth.
*For a sweeter smoothie, add 1/4 cup fruit juice, such as apple, pineapple or orange.
Tip: can use regular or almond milk.
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Wow I could'nt believe what a
Super Deal I got on MJM's magic
and DVD with Bonuses! Thank You.
Read More ->
I recently ordered Butter Coin by Alex Lourido. When it came I was horrified to see I had gotten a defective product. I contacted MJM, and they were...
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Fun Diving
Fun diving or leisure diving (LD) is the right dive package for licensed divers. Fun diving package with Diverse Borneo will bring you to different dive sites around Kota Kinabalu Marine Park to explore with close guidance from our experienced PADI dive instructors. READ MORE about fun diving package from Diverse Borneo.
Refresher Course
The Refresher Course in the Tunku Abdul Rahman Park 15 minutes from Kota Kinabalu, Sabah is designed for divers that has not got wet for several months or longer, either needing a brush up or completely forgot how to breathe underwater. Even if your considering to take the PADI Advanced Diver Course, Diverse Borneo's Professional team of diving instructors and PADI Divemasters will bring right up to speed.
We will introduce the basic skills to you at one the dive sites in Kota Kinabalu, such as equipment assembly, buddy checks, water entries, snorkel clearing, regulator breathing, mask clearing, buoyancy skills and much more. We will also fine tune your theory to ensure you understand how to use your recreational dive planner and be readily available to answer any questions that you may have about scuba diving in Kota Kinabalu. Read more about Refresher Course in TARP
Guided Snorkeling
Snorkeling in the waters off Kota Kinabalu, Sabah with Diverse Borneo in Kota Kinabalu Marine Park offers fun filled entertainment with Professional snorkeling guides showing you how to use the equipment to sea turtles underwater. Feeling excited already? Want to get in the water? Don't want to fully submerge?
Snorkeling is perfect for floating on the surface which we are able to supply life jackets, life rings or even hold the Professional snorkeling guides hand whilst relaxing, gazing into the blue, or if you would like to know if a PADI diving course is the next step? Snorkeling tours follow the custom designed boats that are fitted with built in GPS and depth finders and captained by qualified boat handlers that have lived in the Tunku Abdul Rahman Park dive sites since birth.
With your Diverse Borneo Professional snorkeling guide, you can snorkel either from the boat at the diving site, or enjoy the crystal blue waters at the white sandy beach on one of the islands inside the Tunku Abdul Rahman Park. Want to try to fly from one island to another? Try our Coral Flyer Zipline tour. READ MORE About Snorkeling.
PADI Discover Scuba Diving Course
If you want to find out but aren't quite ready to take the plunge into the PADI Open Water Diver Course in Kota Kinabalu then Diverse Borneo introduces non scuba divers or first timers to the underwater world with PADI Discover Scuba Diving.
When you choose to take Discover Scuba Diving course you will get intensive knowledge about scuba diving basics and you will get a personal experience of being underwater with someone you trust – the instructor. Click here to read more about PADI Discover Scuba Diving course with Diverse Borneo.
Coral Flyer Zipline With Snorkeling
Diverse Borneo's Coral Flyer With Zipline tour is combined with snorkeling package. So, if you choose to take this package, you will get a chance to do two different activities in all-in-one complete package. You can do snorkeling in the morning then go to Coral Flyer Zipline in the afternoon during lunch break time.
Coral Flyer Zipline enable to you 'fly' from one island to another like a flying fox. This activity popularly called as island hopping. You will move to one island to another across a beautiful, blue and turquoise sea water. Want to watch video about Coral Flyer Zipline and read more about it? Click here to for further information.
Sunset And night Dive
Sunset and night dive package is for licensed divers and certified divers who wants to go diving during unusual time – sunset and night. The dive sites for sunset and night dive is just 15 minutes from jetty point.
The sunset dive provides so much marine life as most of the fish are trying to find a place to hide whilst the nocturnal fish are waking up and going for their hunt. Sunset and night dive is very different from usual dive during daytime because everything is very dark in the water and you have to rely on the instructor who guide you and your underwater torch light. Click here to read more about sunset and dive night dive package with Diverse Borneo.
Multiple Days Dive Package
One day not enough to explore the local dive sites in the Tunku Abdul Rahman Park in Kota Kinabalu? we have two, three, four and five day packages for the keen divers as our Professional dive team has so much to show you.
Tunku Abdul Rahman Park (TARP) is made up of five islands of Gaya, Sapi, Manukan, Mamutik and Sulug and even three dives at each island is not enough with more than 25 dive sites in the national park there is so much marine life to be found. Our Professional PADI Divemasters know the best dive sites in Kota Kinabalu and if you're lucky to dive with our PADI Course Director he is always willing to bring you to special dive sites not dived by other diving centres.
Our dive guides are glued on customer service and will try to get your perfect shot with the blue ringed octopus, frog fish, garden eels, sea horse, ghost pipefish and much more so let our Professional PADI Divemasters what you want to see. Read more: Multiple Days Dive Package.


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September 17, 2011 BY Aaron Hope
Trying to nail that classic basketball look but know that your favorite suede and/or nylon pairs simply cannot handle the kind of nasty weather we're about to experience across the northern hemisphere? Look no further than the Nike ACG Lava Dunk High, a beefed up take on the 1985 classic with a little Lava Dome thrown in in the form of a classic proto-ACG trail-ready sole. These two Lava Dunk High Premiums come in high-contrast colorways that feature flipped colorblocking but the same material layout, and you can find both the Max Orange and High Voltage pairs at Nike Sportswear retailers including id4shoes on eBay.
Nike ACG Lava Dunk High Premium
Midnight Fog/Max Orange-Orange Peel-White
High Voltage/Anthracite-Bold Berry-White
Filed under: Dunk eBay Hybrid Just Released Nike ACG Nike Boots
Tags: Nike ACG Lava Dunk High
Pages: 1 2


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Owned since new?
Owned for how long?
8 year(s)
Buy this make again?
Price and equipment6.0/10
Was well priced at the time however it is so disappointing how vehicles lose their value as soon as you leave the lot. We have kept this vehicle very well serviced and maintained and still find it is not worth trading it in to upgrade to a new car.
How it drives8.0/10
Drives really well and has excellent pick up on passing vehicles.
Comfort and practicality8.0/10
people often comment how comfy back seat is
Quality and reliability6.0/10
had some initial troubles which luckily we had warranty for, but in the end it was worth it. Things like the front seat just fell backwards whilst we were driving along. Then the window fell into the door frame and the air conditioner also died twice on us. This was in Darwin so was extremely hot and we were very disappointed in this.
Overall verdict6.0/10
Have enjoyed the car and done many thousands of kilometers. Overall we have been happy with the way the car has handled and the overall running costs and maintenance of the vehicle. Hubby seems to think it has done well and was happy with under the bonnet. However would of liked the 8 cylinder at the time. Was more a money thing than the need for 8 cyclinder vehicle.


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http://hansgraffs.tumblr.com/tepone kok mmxvi
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Kon_dom On 01/11/2016
unknown - 31/12205 PhotosBARBAROV, Praha, Hlavní M?sto, Czech Republic
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text: The Donkuwah were a tribe of Duloks on Endor. AppearancesEdit Star Wars Galaxies: An Empire Divided SourcesEdit CorSec Database A-G The Complete Star Wars Encyclopedia Retrieved from "http://starwars.wikia.com/wiki/Donkuwah?oldid=6645101" Ad blocker interference detected! Wikia is a free-to-use site that makes money from advertising. We have a modified experience for viewers using ad blockers Wikia is not accessible if you've made further modifications. Remove the custom ad blocker rule(s) and the page will load as expected. Categories: Legends articlesDulok tribes


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Contractor Mortgages
Contractor mortgages can often be a struggle to secure because many of the High Street lenders don't understand your unique working status. Here at the cps group we realise that too many of you have missed out on your perfect property because a mortgage lender assumes that you will only be working on your contract for a short period of time.
The independent advisers at ContractorFinancials understand the needs of Contractors and over the past 10 years have helped many thousands of Freelancers find and secure competitive mortgages based on an annualised multiple of their contract rate alone. Their experience and in-depth knowledge of the market has enabled them to build unique relationships with lenders, ensuring that your mortgage is processed quickly and with minimum fuss.
Getting you into your new home quickly
ContractorFinancials have been able to secure special terms for you to gain contractor mortgages with little deposit. The selective lender criterion that they use means that the whole mortgage application process can be much quicker than trying to source a scheme direct with lenders. Mortgages can even be agreed within days of your very first contract.
Unlike many brokers, ContractorFinancials will not charge clients of the cps group a fee for their services. They cover their costs solely from introducer's payments from whichever lenders you decide to work with but as a result of FSA regulation you will have the option to pay 0.6% of the loan instead and they will instead refund the commission.
What next?
Contact Contractor Financials on 0845 0628888 or email them via email@example.com and one of their independent mortgage specialists will discuss your needs in detail.
You will then be emailed recommendations which can be discussed further at your convenience. You will be assigned a dedicated contact to handle your case personally who will help ensure that your application runs smoothly.
Your home may be repossessed if you do not keep up repayments on a mortgage or any other debt secured on it.
Financial advice is given by ContractorFinancials, which is a trading name of Contractor Financials Ltd and is regulated and authorised by the Financial Services Authority.


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Cutting-Edge Technology at Block Island Wind Farm Helping S...
Project will aid researchers from U.S. Fish and Wi...Learn More
Jumpstarting a brand new clean energy industry, putting hundreds to work on leading edge projects.Learn More
Powering America's coastlines with an abundant, clean source of domestic energy.Learn More
Improving air quality by displacing harmful carbon emissions from fossil fuel power plants.Learn More
America's first offshore wind farm. The 30-megawatt, 5 turbine Block Island Wind Farm began commercial operations in 2016.Learn More
America's first utility-scale offshore wind farm, the 90 MW South Fork Wind Farm will help the State of New York meet its renewable energy goals and avoid the need for costly new energy infrastructure on the East End of Long Island. This 15-turbine project will be the first wind farm constructed in the Deepwater ONE Wind Energy Area. It will be located "over the horizon" 30 miles off the coast of Montauk, N.Y. and will generate enough clean, cost-effective energy to power more than 50,000 homes on Long Island's South Fork. Construction could start as early as 2019.Learn More
Deepwater ONE is an offshore wind energy area located roughly halfway between Montauk, N.Y., and Martha's Vineyard, Mass., with the potential for more than 1,000 MW of offshore wind development. Deepwater Wind plans to build multiple phases in this wind energy area to serve Long Island, Massachusetts and Rhode Island. Our 90 MW South Fork Wind Farm will be the first project constructed in the Deepwater ONE wind energy area. Deepwater Wind won the nation's first competitive lease auction in 2013 for exclusive rights to develop this 256-square mile site.Learn More
Project will aid researchers from U.S. Fish and Wildlife Service, URI and UMass as they study migration of Atlantic Coast species Providence, R.I. – September 18, 2017 – Deepwater Wind is partnering with researchers from the U.S. Fish and Wildlife Service, the University of Rhode Island (URI) and the University of Massachusetts (UMass) Amherst to […]
Revolution Wind Farm Bid into Massachusetts Clean Energy RFP New Bedford, Mass. – July 31, 2017 – Deepwater Wind today unveiled plans for its newest project off the American coast: Revolution Wind, a utility-scale offshore wind farm paired with an energy storage system. "Revolution Wind will be the largest combined offshore wind and energy storage […]
Deepwater Wind is a leading U.S. offshore wind and transmission developer. Led by a veteran team with extensive experience in developing renewable-energy projects, Deepwater Wind is making offshore wind in the U.S. a reality. Our Block Island Wind Farm is America's first offshore wind farm.
Headquartered in Providence, RI, we are actively planning offshore wind projects to serve multiple East Coast markets located 15 or more miles offshore, including New York, Massachusetts, Rhode Island, Maryland, and New Jersey.
Project will aid researchers from U.S. Fish and Wi...Learn More
Revolution Wind Farm Bid into Massachusetts Clean ...Learn More
First Offshore Wind Company to Commit to Base Oper...Learn More
America's First Offshore Wind Farm Honored with ...Learn More
NORTH KINGSTOWN, R.I. — Seven years after first ...See More
Providence, R.I. – June 28, 2016 – Offshore co...See More
All five jacket foundations now installed; turbin...See More
Offshore wind energy, combined with new on-island ...See More
For all media inquiries, please call Meaghan Wims at (401) 274-0001 ×434 or firstname.lastname@example.com


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Accessibility Links
One statement. One username. Manage all your investments on one of the UK's leading fund supermarkets.
Our ISA transfer service makes it easy for you to bring everything together. Just tell us where your other ISAs and funds are and we'll contact the companies on your behalf. All you have to do is check, sign and return the forms to us and we'll take care of the rest. Before you apply please read the Moving Your Investments Guide.
We'll also cover up to £500 for any exit fees you may incur. Terms & Exclusions apply.
your investment funds
* Please note you cannot currently transfer a Junior ISA to us
Applying to transfer your ISA only takes a few minutes and once you have submitted your online application we'll take care of the rest.
Currently, completion times can be between 4-6 weeks but could be considerably longer as the transfer is reliant on prompt action by other providers whose time frames can be variable. Please note that once the ISA transfer begins you are unable to switch, top up or sell your funds until the process is complete. We will send you a confirmation letter once everything is done.
Please remember the value of tax savings in an ISA depends on individual circumstances. All tax rules may change. The value of investments can go down as well as up and you may not get back the amount you invest.
Please note that when transferring your ISA as cash you will be out of the market while your money is being transferred, so you could miss out on growth and income if the market rises during this time. However, there is also a chance that you will benefit if the market falls while your money is being transferred. There will also be a bid-offer spread on dual priced funds.
Fidelity Personal Investing does not offer advice. If you are unsure of the suitability of an investment, please contact an authorised financial adviser.
Our UK-based Fidelity Personal Investing team may call you to help you with any queries you may have concerning the process.


text: Hi everyone! I'm so elated with my MotoDroid and I am looking forward to learning and sharing ways to fully exploit the phone and this fantastic OS which I am totally new to. A bit about me...I'm a 30-something y/o father of 2 girls. I love taking road trips here in the Sunshine State of Florida. To pay the bills I'm a .Net/SQL Developer. I'm looking to expand my skillset and maybe it'll be into Android (right now I'm looking into Ruby/PHP)...but this seems so much more fun. Just to get warmed up...Can some tell me what a Trackback is and how I would get the URL for one? I'm assuming that it's the barcode boxes I see in the posts throughout this and other sites (a/k/a called mobile barcodes) but I am likely WAY off...lol God bless and warm regards, Leo


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PTR Industries is happy to announce that PTR 32 KFR'S are in stock and ready to ship at Williams Shooters Supply. If interested, please get in contact with Williams Shooter Supply at:
Williams Shooters Supply
1813 Quintron Wa
Quincy, IL 62305
(217) 222-4195
Please feel free to contact PTR Customer Service at email@example.com or (843) 358-2222 with any questions.
Thank you.


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Hamilton band DateMonthYear has released three new music videos, and fans may notice they are all completely different.
Which is to be expected when you give three local filmmakers complete artistic freedom.
Founder Trevor Faville took a leap of faith by allowing three independent filmmakers free rein to pick any song from the band's four albums, and then without input or oversight, to interpret the music and create their own video.
Trevor said although this was break from his usual practice, it was actually a relief to leave the filming in other peoples' hands.
"When you run things you want to control all the time, but in this case it was great to just let go and see what people do. I loved the result. It's not what I expected but that's the best thing about it," Trevor said.
"We're all about artistic freedom and artistic expression and not being told what to do."
Filmmaker Elysia Koretz chose the song River, which was originally written for a musical.
"It was meant to invoke a river, but she approached it entirely differently with this guy doing creepy stuff for a person behind the door. It's kind of dark."
Fellow filmmaker Matthew Mason chose Ghost.
"What he did was he jumped on one line in the chorus - 'they say you are the only one' - and basically did that as his concept. There's one guy in the video and he constantly meets himself going to work, and when he goes to work he's his own boss. "
The third filmmaker, Kathleen Christian, who works at Melville High School as a media studies teacher, chose the song Haunter.
"It's a really freaky song with a long intro featuring an EVP (electronic voice phenomenon) - a recorded ghost voice we found on the internet. It's got a horror movie kind of feel and she did a whole lot of images to go with it. "
As well as play the drums, Trevor also manages and writes for the band. He is also a member of the Tron Music Trust.
"We've always insisted on being independent and doing things our own way," he said.


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Leicester, United Kingdom (PressExposure) February 18, 2012 -- Is there a gap between management academics and practice? The subject is the latest debate on Leicester Exchanges, a popular online debating forum in the UK. A recent feature on the forum analyses why it is hard to find research which can be actually used by the managers.
The feature underlines how the management research has been limited to the esoteric academic journals, which are read only by other academics and not by the managers, who have to actually use it. Current management research abounds in theory, but is wanting in practical lessons. Management research papers do not have substantial following among managers. The research work values theoretical advances on practical lessons, in-depth discussions on concise summaries, and methodological detail on clear communication, making it devoid of any real value for the managers.
The debate provides insight into why evidence-based approach hasn't been implemented in management research, quite opposite to the field of medicine. While day-to-day clinical practice is based on research, the efforts for advancing the evidence-based management haven't produced the expected results. Part of the answer lies in the academics' tendency to produce research which helps them advance their career in the competitive university system, rather than the business association which is funding the research.
Readers can comment by filling up the form provided right below the article. Leicester Exchanges has emerged as a popular platform for discussing social issues in the UK. This latest article on the website follows other topics recently discussed such as Comprehensive Schools & The Future, The Law on Abortion, Arts Funding Cuts, and many more. The debate forum has emerged as a preferred platform for the academics to raise social, political, environmental and economic issues which help in shaping our society. It has made sharing insights so easy for the participants.
About Leicester Exchanges
Leicester Exchanges conducts online debates on a variety of issues. For discussing social, environmental, scientific, educational or political issues, UK citizens now pick the platform over other debate medium for the advantages it provides. It helps them to get apprised with the views of leading academics in the country that are willing to share their valuable insight on the website.
Contact Information
Email: email@example.com For details, please visit the website: http://leicesterexchanges.com/


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We take your privacy seriously! AFBN will not disclose any information you provide to a third party. We maintain a strict security protocol so your information is safe with us. We have a longstanding policy that maintains the confidentiality of your personal data necessary to provide service.
We do not sell or rent your name or your records to any other organization or business concern. Review our privacy policy for more information.


text: This weeks Inspired Service Award goes to Shane Hickerson for his dedication in an urgent time and still producing a perfect solution for the customer. Last week Shane was given the task of completing a custom job for a customer. And the customer needed it quick. Shane works on the team that does custom fabrication on Rolland safes. Every security solution is custom tailored to the customers need. Many times this requires paint jobs and special welds. Shane worked extra hard to complete the job for the customer under the time crunch. He did so without sacrificing the quality of his work. It is dedication and attention to detail like this that embody the inspired service Rolland creates.


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Status: Closed
Know more about this business than we do? Cool! Please submit any corrections or missing details you may have.Help us make it right
I-Ron-X Industries specializes in the design and installation of custom metal pieces for residential, commercial and industrial properties. Our experienced team has been serving the area for almost 40 years. We are licensed and insured. Contact us today for more information.
Manufacture of custom ornamental iron, aluminum, and stainless steel railings. Custom gates, and window guards. Miscellaneous welding and repairs. Light structural steel fabrication and sheet metal. Core drilling and sand blasting service available. Powder coated aluminum rails.
I-Ron-X Industries was started in 1976 as a custom ornamental iron shop. Specializing in handcrafted railings mostly for residential applications. Over the years our business has expanded to become a full-service steel fabrication shop, still with an emphasis on custom-made ornamental railings. Our services have now grown to encompass all phases of miscellaneous steel and aluminum fabrication....
Be the first NJ.com user to add photos or videos of I-Ron-X Industries
I was referred to I-Ron-X Industries by a neighbor. Paul was extremely professional and did a fantastic job. I am very pleased with the job that he did and will use his services again in the...
Quality workmanship done on time with reasonable prices. Would definitely recommend this contractor
Window Guards, Steel Fabrication, Ornamental Iron Work
I-Ron-X Industries Llc is located at 134 Wheat Rd, Buena, NJ. This business specializes in Welding Services and Manufacturing & Industrial Supplies.


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Since it's New Year's Day, one must wonder: How are you, Johnny Manziel? There was an interesting observation about the Browns QB recently from his for-now coach. Here's what Mike Pettine told Cleveland.com in an article that appeared on Thursday:
"Here is a guy that has an NFL skill set, he's very talented, if you spend some time with him, he's a likable guy, you root for him. But there are problems there that we'll talk as we're headed to the offseason about getting addressed. And I've said this before, we want to make sure that all of our players are in good shape as people first, players second. Because I don't think you can be as effective as you can be as a player if things aren't right off the field. And he's a good example of that."
Johnny Manziel (Getty Images)
For the record, Manziel won't play in Sunday's season finale against the Steelers because of a concussion. So any progress he made this season can be judged now, and has been by the Plain Dealer's Terry Pluto. It's a decidedly mixed bag.
MORE: NFL Week 17 picks | Against the spread | Changes coming for Browns?
Trevone Boykin issued an apology on Twitter for the actions that got him suspended from Saturday's Alamo Bowl.
The last thing TCU and its fans wanted was to see him walking through media members after being released from custody.
Yet there he was, as shown by Fox Sports.
There was reaction, of course, from TCU's opponent in the game. "I thought they were joking," Oregon defensive coordinator Don Pellum told Oregon Live.
Pellum also said the Ducks aren't taking a Boykin-less flock of Frogs lightly. "We're expecting a more fiery team because they've lost something. I think they'll come back. Sometimes when you're injured or sometimes when you lose someone, when the troops rally, you can come back stronger. I think that's what we're going to get."
Look, Boykin has nobody to blame but himself. As the Fort Worth Star-Telegram pointed out, players were given detailed information on team rules of conduct that included a series of pointers from the San Antonio police department.
Boykin decided to ignore everything but his own interests. We can't say it better than this, by Star-Telegram columnist Mac Engel.
I never thought I would say this about Trevone Boykin, but what an idiot.
End of story ... except for images the Houston Chronicle posted of Boykin's night at a San Antonio bar, and its aftermath.


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In excellent period comedy drama Fair Game it's 1970 and Carl returns to his northern home from university to go on a walking holiday with his girlfriend Ellie. Carl is rather more keen on canvassing for the upcoming General Election and watching England's games in the world cup but is convinced that the holiday will allow him to take his relationship with Ellie to the next step.
Meanwhile Marco is a very wealthy young Italian man who discovers that he is in fact adopted and that his dad was a POW in England during World War II. He heads off to Preston in search of his roots and soon his path is crossing with that of Ellie and Carl.
Fair Game is full of wonderful period flavour and with strong central performances from the three young leads in particular the gorgeous Lena Headey, there is also a cute cameo from Prunella Scales as a hippyish photographer who offers wannabe designer Ellie some words of wisdom.
Great soundtrack too, most of The Beatles' Abbey Road gets an airing as do songs from Mungo Jerry (In The Summertime), Thunderclap Newman (Something in the Air), Canned Heat, etc. Also watch out for a cameo from writer Stephen Bill who pops up playing one half of a boring Youth Hostelling couple.
classic quote
"I don't bore the arse off people by having one topic of conversation"
production details
UK / BBC1 / 1×110 minute episode / Broadcast 11 June 1994 @ 9.00pm
Writer: Stephen Bill / Idea: Alan Dossor / Music Advisor: John Altman / Costumes: Janice Rider / Production Design: Rob Hinds / Executive Producer: Michael Wearing / Director: Alan Dossor
LENA HEADEY as Ellie
JULIAN KERRIDGE as Carl
MASSIMO BELLINZONI as Marco
PRUNELLA SCALES as Marjorie
DAVID ROSS as Carl's Dad
POLLY HEMINGWAY as Carl's Mum
MAGGIE OLLERENSHAW as Eileen
SIMONE BENDIX as Elena
GABRIELLE LLOYD as Auntie Alice
EAMON BOLAND as Uncle Jack
VENANTINO VENANTINI as Claudio
JOSEPH LONG as Giampaolo
MAGGIE OLLERENSHAW as Eileen
ANITA ZAGARIA as Maria
BUONVILI GAVINO as Monk
SARA SAVASTA, ELISABETA BUONSIGNORI as Maids
DAVID BRADLEY as Whitby Policeman
PAUL SLACK as Mechanic
ANGELA CURRAN as Librarian
JANE WADDINGTON as Assistant Librarian
HENRY LIVINGS as Bernie
GEORGE A. COOPER as George
NICHOLAS LANE as Kevin
JACK DEAM as Brendan
STEVE HALLIWELL as YHA Warden
GAYNOR FAYE as Goggle Hole Girl
NICHOLA CORDEY as Lucinda
STPEHEN BILL, SUE WALLACE as YHA Couple
HARRY BEETY as Helpful Masham Man
NICHOLAS GLEAVES as Nigel
JEFFREY ROBERT as Gordon
RICHARD BONNEVILLE as Jerry
MARSTON BLOOM as Simon
SIMON ROBSON as Barnaby
GORDON LANGFORD ROWE as Passerby
MICHAEL WARDLE as Lorry Driver
ANTHONY BENSON as Holiday Maker
MARTIN GREENWOOD, ANDREW GROSE, JOANNE WOOTTON as Youth Hostellers


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Taaffes Bar Galway, Galway
Bustling and friendly, this 150 year old cheery village pub is enjoyed by locals and visitors alike. As you pass by its stone facade you can hear traditional Irish music passing through the windows. The bustling bar is well-known for its atmosphere and traditional Irish music which has been playing here for over 20 years. Anyone is welcome to come along and listen or play (if you can) and there's no cover charge. Sharon Shannon and Sean Keane have performed here, as well as a number of wandering read more


text:
Committee backs ecodesign rules for lighting
Member state experts have backed new ecodesign standards for directional light bulbs and LEDs. Draft energy labelling rules have also been finalised
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Red Pyramid Pan
Red Pyramid Pan Nonstick Silicone Baking Mat Mould Cooking Mat Oven Baking Tray 1pc Hot Sale
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Oven safe to 428 Farenheit degrees /220 Celsius degrees/
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The shipment takes 15 to 30 days, everything is guaranteed
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- Please select a date to see the proper prices!
- Meal can be requested on the spot
Best offer
39.10 € / person / night, no meal
Description of the accommodation:
Rooms, services We are glad to present you the offers of Sögüt Hotel Istanbul, our partner in Turkey. 50 comfortably furnished rooms are offered by the hotel to guests looking for accommodation in Istanbul. The hotel is happy to have you in the restaurant for a hearty lunch or a romantic dinner. Parking possibility is available nearby for guests arriving by car. If you are curious to discover the highlights of the area, you may also rent a car or take an organized city tour nearby. Fans of actively spent leisure time will also have the chance to play table tennis, rent a bike, play billiard and minigolf nearby. Airport transfer is available upon preliminary request. The café and the bar have excellent atmosphere for a relaxed evening talk or a personal meeting. Your valuables can be the safely secured in the safe. At the hotel you may go online via wireless Internet connection (WiFi). The exact list of services available at Sögüt Hotel Istanbul (including those for an extra fee) and the exact list of equipment in a room can be found on the information sheet below.
Payment Depeding on the selected room, date and price, you may be asked to provide credit card guarantee or to pay by credit card in advance.
Arrival, opening hours The earliest time to arrive is 10:00, the latest time to leave the rooms is 13:30. The personnel of the hotel can speak in Turkish and English with you.
Sögüt Hotel Istanbul rooms Rooms
- Please select a date to see the proper prices!
Accommodation services
Parking (10 €/night)
Free WiFi in shared places
Relaxation: Table-tennis, Billiard, Minigolf, Bike rental at the accommodation
Organized sightseeing nearby, Car rental nearby
- Steam room
- Jacuzzi
- Finnish sauna
- Hairdresser's parlour
Default services: Garden, Bar, Cafe, Elevator, Safe deposit box, Roof garden
Airport transfer
Own restaurant
Hairdryer, Mini-bar


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The Great Love Debate with Brian Howie
Thursday, May 25, 2017 7:30 PM MDT
(6:30 PM Doors)
Denver Improv, Denver, CO
21 years and over
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BIO - BRIAN HOWIE: Brian Howie is an award-winning director, producer, author & the creator of "How to Find Love in 60 Seconds". He has been the subject of features on FOX, ABC, CNN, Entertainment Weekly, the New Yorker and Esquire Magazine. He is the host & creator of The Great Love Debate, Time Magazine named him America's #1 Dating Enthusiast - yet he is still single!
SHOW DESCRIPTION - THE GREAT LOVE DEBATE: The Great Love Debate national tour hits Denver, with guys seated on the left, girls seated on the right, at this wild, feisty, hilarious, interactive debate where the audience, host, and special guests try to answer the question, "Why is everyone still single?"


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@bguken — 374 followers, 2,769 tweets
@jfhurtig I am sorry. I just saw this. Yes, Montana faces particularly difficult challenges.
@jfhurtig I have been working slowly on mental health and kids. Fascinating.
'Alarming' numbers of #youth are using handguns to #kill themselves. #suicide http://bgz.tt/kx1hz
RT @ZachBenoit: On his 37th anniv. at the Gazette, it's clear photo editor @BGMayer learned the way to our hearts. Congrats! http://t.co/wGiixEdeiG


text: Edgar Sia II is Youngest Filipino Billionaire by Josiah Go Posted by: Josiah Go August 29, 2016 1 Comment Today is National Heroes Day. Here is a entrepreneur rock star that we can all emulate — Edgar Sia II. Forbes recently released the 2016 list of billionaires in the... Read More »