text:
Page 1
Genetic Alterations in the Phosphatidylinositol-3
Kinase/Akt Pathway in Thyroid Cancer
Mingzhao Xing
Background: Aberrant activation of the phosphatidylinositol-3 kinase (PI3K)/Akt pathway plays a fundamental
role in thyroid tumorigenesis, particularly in follicular thyroid cancer (FTC) and aggressive thyroid cancer, such
as anaplastic thyroid cancer (ATC). As the drivers of this process, many genetic alterations activating the PI3K/
Akt pathway have been identified in thyroid cancer in recent years.
Summary: This review summarizes the current knowledge on major genetic alterations in the PI3K/Akt
pathway. These include PIK3CA mutations and genomic amplification/copy gain, Ras mutations, PTEN
mutations, RET/PTC and PPARg/Pax8 rearrangements, as well as amplification/copy gain of PIK3CB, PDK1,
Akt, and various receptor tyrosine kinase genes. Most of these genetic alterations are particularly common in
FTC and many of them are even more common in ATC; they are generally less common in papillary thyroid
cancer (PTC), in which the MAP kinase (MAPK) pathway activated by the BRAF mutation instead plays a
major role. Methylation and, thus, epigenetic silencing of PTEN, a major negative regulator of the PI3K/Akt
pathway, occurs in close association with activating genetic alterations of the PI3K/Akt pathway, constituting
a unique self-enhancement mechanism for this pathway. Many of these genetic alterations are mutually
exclusive in differentiated thyroid tumors, but with increasing concurrence from benign tumors to FTC to
ATC. RET/PTC, Ras, and receptor tyrosine kinase could dually activate the PI3K/Akt and MAPK pathways.
Most cases of ATC harbor genetic alterations in these genes or other genetic combinations that can activate
both pathways. It is proposed that genetic alterations in the PI3K/Akt pathway promote thyroid cell trans-
formation to FTC and that genetic alterations in the MAPK pathway promote cell transformation to PTC;
accumulation of multiple genetic alterations that can activate both pathways promotes thyroid cancer
aggressiveness and progression to ATC.
Conclusions: Genetic alterations are common in the PI3K/Akt pathway in thyroid cancer and play a funda-
mental role in the tumorigenesis and progression of this cancer. This provides a strong basis for the emerging
development of novel genetic-based diagnostic, prognostic, and therapeutic strategies for thyroid cancer.
of thyroid cancer, particularly those that occur in genes en-
coding for keyplayers ofmajorsignaling pathways.Follicular
epithelial cell–derived thyroid cancer accounts for >95%of all
thyroid malignancies and can be divided histologically into
papillary thyroid cancer (PTC), follicular thyroid cancer
(FTC), and anaplastic thyroid cancer (ATC). PTC can be fur-
ther divided into several subtypes: conventional variant PTC
(CPTC), follicular variant PTC (FVPTC), tall cell PTC
s in many other human cancers, genetic alterations are
the driving force for the tumorigenesis and pathogenesis
(TCPTC), and a few other rare types. There is also poorly
differentiated thyroid cancer (PDTC) that has a prognostic
risk between DTC (including PTC and FTC) and ATC. The
genetic background varies with these different types of thy-
roid cancers, and certain molecular signaling pathways are
consequently preferentially altered in them. A prominent
example of such genetic alterations is the oncogenic BRAF
mutation in the Ras?Raf?MEK?ERK/MAP kinase
pathway (MAPK pathway), which occurs preferentially and
commonly in PTC, particularly CPTC and TCPTC, and some
ATC (1,2). Other classical oncogenic genetic alterations in the
MAPK pathway in thyroid tumorigenesis include RET/PTC
Portions of this review were presented at the Spring 2010 Meeting of the American Thyroid Association, ''Thyroid Disorders in the Era of
Personalized Medicine,'' Minneapolis, Minnesota, May 13–16, 2010.
Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology and Metabolism, The Johns Hopkins University
School of Medicine, Baltimore, Maryland.
Volume 20, Number 7, 2010
ª Mary Ann Liebert, Inc.
DOI: 10.1089/thy.2010.1646
Page 2
and Rasmutations (3–6).Inrecent years,the importance ofthe
phosphatidylinositol-3 kinase (PI3K)/ Akt pathway in thyroid
tumorigenesis has been also widely recognized (7). Recent
studies have particularly explored the genetic backgrounds
for this role of the PI3K/ Akt pathway. As a result, many im-
portant genetic alterations have been identified in this path-
way in recent years, providing insights into the molecular
mechanisms in thyroid tumorigenesis and bases for the de-
velopment of novel genetic-based strategies for the manage-
ment of thyroid cancer.
Signaling of the PI3K/Akt Pathway
The PI3K/ Akt signaling pathway has long been known to
play a fundamental role in the regulation of various cellular
and molecular functions, including glucose uptake, cell
growth and proliferation, cell motility, and survival. In the
last 15 years, the role of this signaling pathway in human
tumorigenesis and its value as a therapeutic target in human
cancers have been extensively investigated (8–11). There are
several classes of PI3Ks, among which class I is the best
characterized and most important in human tumorigenesis.
It consists of heterodimers of a regulatory subunit, com-
monly the p85 unit, and one of p110 catalytic subunits.
Among the p110 subunits, the a-type (PIK3CA) and b-type
(PIK3CB) are widely expressedin different tissues andplay a
particularly important role in human cancers. PIK3CA and
PIK3CB belong to class IA that is activated by receptor
tyrosine kinases (RTK) as well as some G-protein-coupled
receptors. These p110 catalytic subunits contain a binding
site for the regulatory subunit, through which signals can be
integrated from membrane receptors and activate the cata-
but it also plays an important role in the signaling of the
PI3K/ Akt pathway. One mechanism for this function of Ras
is through its interaction with the Ras-binding site in the
p110catalyticsubunitsofPI3K.Thus,Ras can dually activate
the MAPK and PI3K/ Akt pathways. As illustrated in Figure 1,
a typical starting point of the PI3K/ Akt pathway signaling
is the various membrane growth factor receptors that
contain RTK, including vascular epithelial growth factor
receptor (VEGFR), platelet-derived growth factor receptor
(PDGFR), epidermal growth factor receptor (EGFR), c-KIT,
and c-MET. Activation of RTK by extracellular signals leads
to the activation of the PI3K with resultant activated p110
catalytic subunit (e.g., PIK3CA), which in turn phosphory-
phosphatidylinositol-3,4,5-trisphosphate (PIP3). The func-
tion of PIP3in this signaling relay is to localize Akt to the
cell membrane where Akt becomes phosphorylated and ac-
tivated by the phosphoinositide-dependent kinases (PDK),
most prominently PDK1. Akt is a Ser/Thr kinase and three
types of its isoforms are found in human tissues—Akt-1,
Akt-2, and Akt-3 (12). Activated Akt phosphorylates
downstream protein effectors, among which is the mam-
malian target of rapamycin (mTOR), which has a well-
established role in human cancers and, like Akt, is a
prominent therapeutic target in today's cancer therapy de-
signing (13). The amplified signaling cascade regulates a
wide range of molecular and cellular functions, promotes cell
proliferation, and inhibits cell apoptosis. A prominent
negative regulator of the PI3K/ Akt pathway signaling is the
protein product of the gene for phosphatase and tensin
homolog deleted on chromosome ten (PTEN). PTEN is a
phosphatase that dephosphorylates PIP3and thus terminates
the signaling of the PI3K/ Akt pathway (14,15). Given the
antagonizing function of PTEN against the PI3K/ Akt signal-
ing, PTEN is a major human tumor suppressor and its genetic
alterations, like thoseofother genesinthe PI3K/ Akt pathway,
have serious consequences. Shown in Figure 1 are the key
players in the molecular interplay in the PI3K/ Akt pathway
signaling that have been best characterized for their genetic
alterations in thyroid cancer as will be each discussed in this
Mutations and Genomic Amplifications/Copy Gain
of the PIK3CA Gene in Thyroid Cancer
Genetic alterations of the PIK3CA gene have been widely
reported in human cancer. Activating mutations in the
PIK3CA gene were initially found in colorectal, gastric, breast,
and ovarian cancers, and high-grade brain tumors, support-
ing the important oncogenic role of this gene in human tu-
morigenesis (16). PIK3CA mutation
explored in various differentiated thyroid tumors but found
was subsequently
PI3K/Akt and MAP kinase pathways in thyroid cancer.
Shown are the major elements in the two pathways. RTK,
activated by growth factors, RET/PTC, and Ras can be
coupled to both pathways. The remaining components reg-
ulate their respective pathways as described in the text.
PTEN is a negative regulator of the PI3K/ Akt pathway sig-
naling. PI3K, phosphatidylinositol-3 kinase; RTK, receptor
tyrosine kinase.
Schematic illustration of the highly simplified
Page 3
to be uncommon in them (17). In a subsequent extended
study, PIK3CA mutations in exons 9 and 20 were found to
occur in 23% of ATC (18). PIK3CA mutations were also found
in several more recent studies in FTC and ATC with lower
frequencies, around 10%–15% (19–23). Similarly to the oc-
currence of BRAF mutation in PTC-derived metastases
(24,25), PIK3CA mutation can occur in some cases of metas-
tases derived from aggressive cancers, such as PDTC and
ATC (23), consistent with the general distribution patterns of
the two mutations in primary thyroid tumors. Overall,
PIK3CA mutation can occur, particularly in PDTC and ATC
and their recurrent/metastatic disease, but does not seem to
be a major genetic event in thyroid cancer in general.
Amplification/genomic copy gain of the PIK3CA gene as
an important oncogenic event is common in human cancers,
including ovarian cancer in which PIK3CA amplification was
initially discovered (26). Lack of common PIK3CA mutations
in thyroid cancer, particularly DTC, promoted search for ge-
netic amplification or copy gain of this gene in thyroid cancer.
This led to the initial discovery of genetic copy gain of the
PIK3CA gene with a high prevalence in thyroid cancer, par-
ticularly FTC and ATC, being 24% and 42% in the former and
the latter, respectively (17,27). This common occurrence of
PIK3CA copy gain in thyroid cancer was confirmed in several
subsequent studies in different ethnic populations (19–22,28).
Fluorescent in situ hybridization studies demonstrated that
this PIK3CA copy gain in thyroid cancer represented mainly
genomic amplification of the PIK3CA gene (17,20). Several
previous studies showed that the PIK3CA amplification was
associated with overexpression of the PIK3CA protein (19)
and phosphorylation of Akt (17,22), suggesting that this
genetic alteration of the PIK3CA gene is functional and rep-
resents a relevant mechanism for the activation of the PI3K/
Akt pathway in thyroid cancer. Association of PIK3CA am-
plification with increased PIK3CA protein expression and
kinase activity or Akt phosphorylation was documented in
many other human cancers, such as ovarian and uterine
cervical cancers (26,29,30). In the Asian and American popu-
lations, PIK3CA amplification in thyroid cancer occurred
mainly in FTC and ATC and uncommonly in PTC (17,19,
21,22,27,28),which is consistent withthe notion that the PI3K/
Akt pathway plays a major role in the tumorigenesis of FTC
and ATC, as opposed to the MAPK pathway that plays a
major role in the tumorigenesis of PTC (5). In a Middle East
population, PIK3CA amplification was found to be common
also in PTC by both quantitative real-time polymerase chain
reaction and fluorescent in situ hybridization analyses (20).
The reason for this difference is not clear. PIK3CA amplifica-
tions could occur in benign thyroid adenoma (BTA), although
with a low prevalence (17,19,28), suggesting a possible early
role of this genetic alteration in thyroid tumorigenesis.
Aberrant genomic copy number has long been known to be
associated with transition from precancerous epithelial
lesions to cancers (31). PIK3CA amplification represents such
a genomic copy gain, as exemplified by its association with
progression of dysplasia into invasive squamous cell carci-
noma (32). A recent study showed that PIK3CA amplification
was strongly associated with distant metastasis, lymph node
metastasis, advanced tumor stage of nasopharyngeal carci-
noma, and decreased patient survival (33). The occurrence of
PIK3CA amplification in some cases of BTA raises the ques-
tion whether these benign thyroid tumors could progress into
malignancy if given sufficient time. There was a clear and
progressive increase in the prevalence of PIK3CA amplifica-
tions fromBTA toFTCandtoATC (19,28), which is consistent
with a role of this genetic alteration in promoting the
aggressiveness and progression of thyroid cancer.
Common Ras Mutations in Follicular Thyroid Tumors
Mutations in the three types of Ras genes—H-Ras, K-Ras,
and N-Ras—are commonly seen in human cancers with a
frequency, on average, of 30% (34,35). Ras mutations are also
common in thyroid tumors, particularly in FVPTC (36), FTC
(19,22,28,37,38), and PDTC (23,39), with a prevalence around
20%–40% in most series. Ras mutations are reported in PTC
with a varying and generally low prevalence (40), reflecting
varying compositions of FVPTC, CPTC, and TCPTC, with the
latter two rarely harboring Ras mutations. Ras mutations are
also frequently seen in BTA, with a collective prevalence of
about 20% in a meta-analysis (37) and 26% in a recent large
study (38). It is unclear whether Ras mutations with physio-
logical expression in BTA are oncogenic and can convert the
benign tumor into thyroid malignancy. In fact, when intro-
duced into normal thyroid epithelial cells, an H-Ras mutant
induced only well-demarcated and differentiated colonies
with phenotype consistent with follicular adenoma (41) and
cell proliferation without loss of differentiation (42). In a
recent transgenic mouse study, conditional physiological
expression of a K-Ras mutant alone in the thyroid gland failed
to transform thyroid cells to thyroid cancer even after 1 year
(43). It appears that additional genetic alterations are required
to transform thyroid cells but Ras mutation alone, with
physiological expression, cannot. Indeed, concurrent mutated
Ras gene expression and PTEN deletion resulted in rapid
development of aggressive FTC and animal death within
weeks in transgenic mouse studies (43).
Ras is widely known for its classical role in the MAPK
discussed above, Ras can also regulate the PI3K/ Akt pathway
by directly interacting with the Ras-binding site of p110 cat-
alytic subunits of PI3K (44,45). Ras mutants could activate the
PI3K/ Akt pathway, which also required direct interaction
with the Ras-binding site on the p110 catalytic subunits of
PI3K, such as PIK3CA (46). Interestingly, in colon cancer,
K-Ras mutant preferentially activated the MAPK pathway,
whereas N-Ras mutant did not (47). It is not clear whether
different types of Ras mutations exert different oncogenic
roles bypreferentially activating different signaling pathways
in thyroid tumorigenesis. The most common type of Ras
with H- and K-Ras mutations, in either codon 12/13 or codon
61, being much less common. This is the pattern observed by
that K-Ras mutation was the most common (48,49). The fact
that Ras mutations occur particularly in FTC and FVPTC in
which aberrant PI3K/ Akt signaling is a major signaling
abnormality whereas they rarely occur in CPTC and TCPTC
in which the BRAF mutation-activated MAPK signaling
dominates (1,2) is consistent with the expectation that Ras
mutations are major activators of the PI3K/ Akt pathway in
thyroid tumors, particularly follicular tumors. Some studies
demonstrated a good association of Ras mutations with the
phosphorylation of Akt in thyroid cancer (20,22), consistent
Page 4
with an important role of Ras mutations in the activation of
the PI3K/ Akt pathway in this cancer.
Genetic and Epigenetic Alterations
of the PTEN Gene in Thyroid Cancer
PTEN mutations are relatively uncommon in sporadic hu-
man cancers. Inactivating germline mutations of this gene are
the main cause of Cowden syndrome (50), which is charac-
terized with a propensity of patients to develop tumors, in-
cluding thyroid tumors, particularly follicular thyroid tumors,
including FTC. Asdiscussedabove, asa lipid phosphatasethat
degrades PIP3, PTENnormallyantagonizes and terminates the
signaling of the PI3K/ Akt pathway. Given the importance of
this negative regulation of the PI3K/ Akt pathway by PTEN,
Cowden syndrome provides a unique human model illus-
trating the oncogenic power of aberrant PI3K/ Akt signaling in
the tumorigenesis of follicular thyroid tumors. Somatic PTEN
mutations also occur in thyroid cancers, particularly in FTC
and ATC, although with a relatively low prevalence (19,22,28).
Loss of heterozygosity or deletion of the PTEN gene is rela-
tively common in thyroid tumors (51,52). The real extent of
genetic abnormalities of the PTEN gene in sporadic thyroid
cancer likely exceeds what is currently seen as multiple alter-
ation sites of the gene exist, some of which may be missed in
relatively limited genetic analyses in most studies.
An epigenetic inactivating mechanism through aberrant
methylation of the PTEN gene also exists in various thyroid
tumors, particularly FTC and ATC (53–55). When quantita-
tively analyzed using quantitative real-time methylation poly-
merase chain reaction, PTEN methylation was found to be
progressively and steadily increased from BTA to FTC and to
ATC (55). Methylation of a gene is usually associated with its
silencing (56). Therefore, methylation of PTEN in thyroid tu-
mors, particularly in FTC and ATC, which showed the highest
extent of this methylation (55), is consistent with the previously
reported decreased or even absent PTEN expression in a subset
of these cancers (57,58). Interestingly, PTEN methylation in
activating genetic alterations in the PI3K/ Akt pathway, in-
and mutations of the PTEN gene itself in thyroid tumors (55).
This is consistent with a previously proposed mechanistic
model for the regulation of the PI3K/ Akt pathway in thyroid
tumors (55), as illustrated in Figure 2. In this model, activation
of the PI3K/ Akt pathway by its genetic alterations may activate
the methylating system of the cell, which, in turn, causes hy-
permethylation and hence epigenetic silencing of the PTEN
gene, effectively removing the terminating mechanism of the
PI3K/ Akt signaling. This represents a unique self-enhancing
mechanism of the PI3K/ Akt pathway. This mechanism may be
particularly relevant in ATC as genetic alterations of the PI3K/
Akt pathway and, correspondingly, PTEN methylation were
shownto beparticularly commonin thisaggressivecancer(55).
The potentially and conceivably malicious nature of such a
self-enhancing mechanism for the activation of the PI3K/ Akt
pathway signaling may contribute to the pathogenesis and
aggressiveness of ATC. Thus, the oncogenic power of loss
of PTEN seems to lie in its cooperation with other genetic al-
terations of the PI3K/ Akt pathway in the tumorigenesis of thy-
roid cancer. This mechanism is consistent with the recent
or physiological expression of a Ras mutant each alone did not
cause thyroid cancer, but simultaneous introduction of the two
genetic events caused aggressive thyroid cancer (43).
RET/PTC as an Activator of the PI3K/Akt Pathway
in Thyroid Tumors
RET/PTC represents a recombinant protein product from a
chromosomal rearrangement with the combination of the 30
portion of the RET gene and the 50portion of a partner gene
(3,59). This recombination results in constitutive activation of
the tyrosine kinase in RET. Among the more than 10 types of
RET/PTC, which are mainly found in thyroid cancer, the most
common and important types are RET/PTC1 and RET/PTC3.
RET/PTC is an established oncogenic activator of the MAPK
pathway. Several studies have suggested that RET/PTC is
also involved in the signaling of the PI3K/ Akt pathway. For
example, transfection of thyroid cells with RET/PTC3 could
increase Akt phosphorylation and PI3K/ Akt signaling (60,61).
RET tyrosine kinase could activate the PI3K/ Akt pathway
through binding of several proteins, including the p85 regu-
latory subunit of PI3K, to tyrosine 1062 of RET (62). The
transforming ability of a mutant RET of MEN2A, which, like
RET/PTC, had constitutive activation of the RET tyrosine
to tyrosine 1062 of RET to activate PI3K (63). It is conceivable
that RET/PTC activates the PI3K/ Akt pathway through a
similar mechanism. Other mechanisms for the involvement of
RET/PTC in the signaling of the PI3K/ Akt pathway may also
involve direct phosphorylation and activation of PDK1 (64)
and Akt (65) by RET/PTC. Therefore, RET/PTC is an impor-
tant player in the deranged signaling of the PI3K/ Akt path-
way in thyroid tumorigenesis. This may be a particularly
important mechanism in PTC of pediatric patients as most of
these patients harbor RET/PTC (1,3,59). RET/PTC occurs in
about 15%–20% of adult PTC patients and, presumably, also
plays a role in the activation of the PI3K/ Akt pathway in these
patients. RET/PTC is generally found to be mutually exclusive
withBRAFmutationinPTC (1).This isthought tobeevidence
Genetic Alterations
mechanism of the activation of PI3K/ Akt pathway through
PTEN methylation in thyroid cancer. In this model, activat-
ing genetic alterations, including gene copy gain or muta-
tions in the PI3K/ Akt pathway activate the pathway. This in
turn leads to PTEN methylation, resulting in silencing of the
PTEN gene. Loss of PTEN removes the inhibitory pressure of
the pathway, forming a malicious self-activation cycle for the
PI3K/ Akt pathway signaling. This is seen most commonly in
aggressive thyroid cancers, such as anaplastic thyroid cancer
(ATC), as discussed in the text.
Diagrammatic illustration of a self-enhancement
Page 5
supporting the notion that either ofthe twogenetic alterations
can sufficiently and oncogenically activate the MAPK path-
way. However, some studies did also show coexistence of
RET/PTC and BRAF mutation in PTC and ATC (22,66–68).
Coexistence of RET/PTC and BRAF mutation was found to be
more common in recurrent PTC, suggesting that coactivation
of the MAPK and PI3K/ Akt pathway by coexistence of the
two genetic alterations may have a special role in thyroid
cancer aggressiveness as will be further discussed in the fol-
lowing section. Many studies also showed that RET/PTC
could occur, with high prevalences, in benign thyroid tumors
(69–71) and Hashimoto's thyroiditis (72–74). Hyalinizing
trabecular tumors of the thyroid gland also frequently har-
bored RET/PTC (75), which is largely a benign thyroid tumor
(76). Therefore, it appears that RET/PTC alone, under physi-
ological expression, may not be sufficiently oncogenic and
additional coexisting genetic alterations may be required for
thyroid cell transformation.
Genetic Alterations in the RTK Genes and Other
Genes in the PI3K/Akt Pathway in Thyroid Cancer
In addition to the several genes in the PI3K/ Akt pathway
discussed above,there aremany othergenesthat areinvolved
in the initiation or transduction of the signaling of the PI3K/
Akt pathway. Genetic alterations of these genes have been
study extensively investigated mutation and genomic copy
gain of many of these genes in thyroid cancer, particularly
1, Akt-2, and PIK3CB. Interestingly, although mutations were
not common in these genes examined on selected exons, ge-
nomic copy gain, likely representing genomic amplifications,
was common in most of these genes in thyroid cancer, par-
ticularly in ATC, up to 40%–45% for EGFR, PDGFRb, and
VEGFR1. Consistent with these results are the previous find-
ings that many of these genes were overexpressed in thyroid
cancer (79). Like the highly prevalent genetic copy gain of the
PIK3CA found in this study and as discussed above, PIK3CB
copy gain was also found to be common, with a prevalence of
around 40% in both FTC and ATC. A relatively high preva-
lence of PTEN mutation of 17% was found in ATC. This study
also analyzed Ras mutations, RET/PTC, and BRAF mutation
and showed prevalences comparable to previous reports.
Overall, virtually every case of FTC or ATC harbored at least
one geneticalteration, andcoexistenceoftwo or more was seen
in the majority of cases of ATC. Specifically, 93% of FTC and
96% of ATC harbored at least one genetic alteration, and co-
existence of two or more was seen in 77% of ATC. Many of
these genetic alterations were correlated with phosphorylation
of Akt, suggesting that they functioned as activators of the
PI3K/ Akt pathway. This study provided a strong genetic basis
for a fundamental and wide role of the aberrant PI3K/ Akt
pathway signaling in thyroid cancer, particularly FTC and
There are several other genetic alterations that can activate
the PI3K/ Akt pathway in thyroid tumors. One is the PPARg/
Pax8 rearrangement. This genetic event was initially identi-
fied in FTC (80) and latter also found in BTA (81). Through a
dominant-negative inhibition mechanism, the protein prod-
uct PPARg/Pax8 can negatively affect Pax8. As the latter is
normally an upregulator of PTEN expression (82), PPARg/
to the activation of the PI3K/ Akt signaling. The preponder-
ance of PPARg/Pax8 in follicular tumors, in which the PI3K/
Akt pathway signaling dominates as discussed above, is
consistent with the role of this recombinant protein in PI3K/
Akt signaling. A recent study showed that Akt-1 mutation
could also occur in thyroid cancer, but only in some cases of
recurrent/metastatic cancers, suggesting that this is a rela-
tively late genetic event during thyroid cancer progression
(23). Interestingly, in a mouse model with a knock-in mutant
TRb gene, the TRb mutant could directly interact with the p85
regulatory subunit of PI3K and activate the PI3K/ Akt sig-
naling in FTC that developed in these transgenic mice (83).
This represents a novel mechanism for the activation of the
PI3K/ Akt pathway. It remains to be investigated whether this
mechanism may occur in human thyroid cancer.
Accumulation of Genetic Alterations in the PI3K/
Akt Pathway and Their Concurrence with Genetic
Alterations in the MAPK Pathway in the Progression
from Low-Grade to Aggressive Thyroid Tumors
Genetic alterations in the PI3K/ Akt pathway have an in-
teresting and oncogenically important distribution pattern in
different thyroid cancer. Two studies on different ethnic pop-
ulations demonstrated that the classical genetic alterations,
including PIK3CA mutation and genetic copy gain, Ras muta-
tions, and PTEN mutations, were mutually exclusive in DTCs,
suggesting that any of these genetic alterations was a sufficient
oncogenic event for the activation of the PI3K/ Akt pathway in
thesethyroid cancers (19,28). These genetic alterations werefar
more common in FTC than in PTC, perfectly echoing hyper-
phosphorylation of Akt and over-activation of the PI3K/ Akt
pathway preferentially occurring in FTC over PTC (84). Co-
existence of these genetic alterations was occasionally seen in
differentiated thyroid tumors but occurred commonly in ATC
(19,22). There is a clear rise in the prevalence of these genetic
alterations, either individually or concurrently, from BTA to
DTC and to ATC, reaching an extremely high prevalence in
ATC (19,22). These genetic data strongly support a role of ab-
errantly activated PI3K/ Akt pathway in the development of
aggressiveness of thyroid cancer, consistent with the finding
of thyroid cancer (85).
Many of the genetic alterations found in ATC could po-
tentially activate both the MAPK and PI3K/ Akt pathways,
including RTK gene copy gain, RET/PTC, and Ras mutations.
BRAF mutation that can activate the MAPK pathway com-
monly coexisted with genetic alterations that could activate
the PI3K/ Akt pathway (e.g., the PIK3CA copy gain) in ATC.
Genetic alterations or their combinations that could activate
both the MAPK and PI3K/ Akt pathways were found in up to
81% cases of ATC (22). Common coexistence of BRAF muta-
tion with RET/PTC, Ras mutations, PIK3CA mutation and
amplification, Akt-1 mutation, and other genetic alterations
that can activate the PI3K/ Akt pathway have been recently
also reported in other studies, mostly in aggressive cancers
such as recurrent/metastatic cancers, PDTC, and ATC
(20,23,49,68). In general, the PI3K/ Akt pathway is commonly
activated in FTC, whereas the MAPK pathway is commonly
activated in PTC by their corresponding common genetic
Page 6
alterations, and the two pathways are commonly dually
activated in aggressive thyroid cancer, such as metastatic/
recurrent cancers and ATC. This is consistent with a recently
proposed model in which genetic alterations in the PI3K/ Akt
pathway and MAPK pathway promote transformation of
follicular thyroid cells to FTC and PTC, respectively, and ac-
cumulation of these genetic alterations and their concurrence
in both pathways drive the aggressiveness and progression of
DTC into aggressive thyroid cancer, such as ATC (19). This
model is illustrated in Figure 3.
Interestingly, this model seems to also be applicable to
other human cancers, such as melanoma in which simulta-
neous activation of the PI3K/ Akt pathway by silencing of
PTEN and the MAPK pathway by expression of a BRAF
mutant led to aggressive progression and metastasis of the
tumor (86).
Clinical Implications
The genetic studies discussed above on the PI3K/ Akt
pathway in thyroid cancer have important diagnostic, prog-
nostic, and therapeutic implications. Recent studies tested the
diagnostic value of combinational use of several genetic
alterations, including Ras mutation, RET/PTC, PPARg/Pax8,
and BRAF mutation in the diagnostic evaluation of thyroid
nodules (38,87,88). This approach could increase the sensi-
nodules and was thought to be particularly useful for thyroid
nodules with indeterminate cytology. However, unlike BRAF
mutation, which occurs only in thyroid cancer, Ras mutation,
RET/PTC, and PPARg/Pax8 can all also occur in BTA and
even Hashimoto's thyroiditis with relatively high preva-
lences, although lower than cancer, as discussed in the pre-
vious sections. Consequently, the specificity of this diagnostic
approach could be potentially problematic, and further
studies are required to determine how this approach can be
practically applied diagnostically. This is different than the
prognostic molecular marker, BRAF mutation, which is as-
sociated with aggressiveness of PTC and can therefore
be practically useful in guiding the risk stratification of
PTC (1,2). In this sense, the combinational use of the muta-
tion markers discussed above might be prognostically useful
less aggressive course of thyroid cancer than the BRAF mu-
tation (1,2).
Some of the genetic alterations in the PI3K/ Akt pathway
may also be prognostically useful in certain clinical settings.
For example, N-Ras mutations were recently shown to be
prevalent in PDTC and predict an increased mortality of this
known to be associated with aggressiveness of PTC (1,2). A
recent study demonstrated that coexistence of PIK3CA am-
plification with BRAF mutation conferred PTC a particularly
high risk for aggressiveness, including large tumor size, me-
the combination pattern of the two genetic markers could
identify a subgroup of BRAF-mutation-positive PTC with a
particularly high risk for aggressiveness.
The current knowledge of genetic alterations in the PI3K/
Akt pathway has also opened the possibility for development
of specific genetic-based therapeutic strategies targeting
the PI3K/ Akt pathway in thyroid cancer. BRAF-mutation-
dependent response of thyroid cancer cells to MEK and BRAF
mutantinhibitors hasbeenwell-documented andrepresents a
good example of genetic-based targeting of the MAPK path-
way in thyroid cancer (89,90). Similar dependence of thyroid
cancer cells on genetic alterations in the PI3K/ Akt pathway in
response to Akt and mTOR inhibitors has been demonstrated
recently (91), providing the first evidence that effective
genetic-based targeting of the PI3K/ Akt pathway is possible
with certain drugs for thyroid cancer. As dual involvement of
the MAPK and PI3K/ Akt pathways driven by their respective
and concurrently existing or shared genetic alterations is a
fundamental mechanism in the tumorigenesis of aggressive
thyroid cancers, such as ATC, targeting both pathways may
be needed for effective treatment of these cancers. The two
recent studies demonstrating synergism of MEK and mTOR
inhibitors in the inhibition of thyroid cancer cells support this
idea (92,93). In fact, the presence of genetic alterations in the
two pathways seemed to predict an even better synergism in
simultaneously targeting the two pathways to treat thyroid
cancer (93).
Concluding Remarks
Genetic alterations are common in the PI3K/ Akt pathway,
which is the basis for aberrant signaling of this pathway in
MAPK pathway
(BRAF Mutation, etc)
(Gene amplification
and mutation)
kinase pathways driven by the increasing accumulation of
genetic alterations in the progression from low-grade to
high-grade thyroid cancers. In this model, primary genetic
alterations in the MAP kinase pathway, such as the BRAF
mutation, transform the thyroid cell into PTC. As the genetic
alterations accumulate, particularly with those that can also
activate the PI3K/ Akt pathway, the cancer progresses into
aggressive type, such as ATC. If primary genetic alterations,
such as genetic or epigenetic silencing of PTEN, occur in the
PI3K/ Akt pathway, the thyroid cell is transformed into fol-
licular thyroid tumors. As genetic alterations accumulate in
this pathway, a follicular adenoma can progress into FTC
when tumor invasion occurs, which can progress further into
ATC when genetic alterations accumulate further, particu-
larly if there are genetic alterations that can dually activate
the PI3K/ Akt and MAP kinase pathways, such as Ras mu-
tations or genomic amplifications of the receptor tyrosine
kinase genes. The increasing intensity of the gray tint in the
circles represents increasing genetic alterations and the sig-
naling pressure of the pathways in the progression from
thyroid cells to benign thyroid tumors to differentiated thy-
roid cancers and to ATC. The figure is adapted from refer-
ence 19 with permission. FTC, follicular thyroid cancer.
Schematic illustration of the PI3K/ Akt and MAP
Page 7
thyroid cancer. The recent identification of many activating
genetic alterations, including mutations and genomic ampli-
fication/copy gain, in many key genes in this pathway rep-
resents a remarkable progress in our understanding of the
oncogenic role of this pathway in thyroid tumorigenesis.
Knowledge of the genotype of the PI3K/ Akt pathway as well
as that of the MAPK pathway will, and in fact, have already
started to have an important impact on the development of
novel diagnostic, prognostic, and therapeutic strategies for
patients with thyroid cancer.
Thisworkwas supportedbyNIHRO-1 grant R01CA134225
to the author.
Disclosure Statement
The author declares that no competing financial interests
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Address correspondence to:
Mingzhao Xing, M.D., Ph.D.
Laboratory for Cellular and Molecular Thyroid Research
Division of Endocrinology and Metabolism
Johns Hopkins University School of Medicine
1830 East Monument St.
Suite 333
Baltimore, MD 21287
E-mail: firstname.lastname@example.com


text:
about Todd FlowerdayA Roman Catholic lay person, married (since 1996), with one adopted child (since 2001). I serve in worship and spiritual life in a midwestern university parish.
about John Donaghy
John is a lay missionary since 2007 with a parish in western Honduras. Before that he served in campus ministry and social justice ministry in Iowa. His ministry blog is http://hermanojuancito.blogspot.com
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Daily Archives: 13 February 2014
Mediator Dei 191
Music adorns churches as well as the visual arts. Not only does Gregorian chant belong to the Church, it also belongs to the faithful: 191. As regards music, let the clear and guiding norms of the Apostolic See be scrupulously … Continue reading
Posted in Mediator Dei, pre-conciliar documents Leave a comment
Good News/Bad News
It seems like it's that kind of week. On two headlines pulled from the Twitter feeds … In Milwaukee, we have … … one of the largest and most contentious of the dozen or so church bankruptcy cases to date. … Continue reading
Posted in bishops, sex abuse Tagged Archdiocese of Milwaukee, cover-up scandal, Diocese of Bridgeport, VOTF 1 Comment
EG 81: Guarding Personal Freedom
Pope Francis addresses the challenge of "selfishness and spiritual sloth." He suggests it happens among both lay ministers and the clergy: 81. At a time when we most need a missionary dynamism which will bring salt and light to the … Continue reading
Posted in Evangelii Gaudium, evangelization Tagged pope francis 2 Comments

subset: commoncrawl


text:
Add extra features and styles to make SeaMonkey your own.Close
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Thankfully, unistalling and reinstalling fixed the firefox 4.9.13 problem for me. Been using this for years and it is indispensable!This review is for a previous version of the add-on (4.9.13).
To create your own collections, you must have a Mozilla Add-ons account.


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Discover a selection of top forums legacy~ communication on the internet. Come to share your passion on forums legacy~ communication and meet other fans of legacy~ communication. Then, why don't you create your own forum of legacy~ communication ?
More than a football Forum.
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MythicBliss's New Guild Forum to be used for communication and update purposes~
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Welcome, Project Phoenix Fire was created to inspire communication between people around the world. In short, we are creating a global village.
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Free forum : The legendary adventures of Glai and Will and co. continue on!
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Rising byond naruto game work in progress join now you wont regret it. Great forum greater staff amazing new things to come.
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This site is an IC/OOC player communication forum for the Rivers Run Red Pittsburgh Sabbat game of One World by Night.
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MidnightEdge's Family, Allies and Friends Communication Base
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Forum for communication between the staff of the publishing community forums.
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The movies we missed.
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i-Sobot Tiny Humanoid Robot Now Just Tiny $100
1.4-Inch Robot to Take Over Your Desk, World
i-Sobot Gets Wiimote and Nunchuck Controls
The i-Sobot may be the smallest humanoid robot that you can control, but actually controlling it requires you to enter in more difficult keypress combos than it takes to do a Babaility in Mortal Kombat. However, if you load up the i-Sobot with the Robodance 4 software, you can hook up a Wiimote and Nunchucks to… »
The I-Sobot in Action
Tomy's I-Sobot may be the world's smallest humanoid robot, but how does he move? Kind of like your dumb tubby friend from high school. He has stupid one-liner comebacks to many of your comments, "awesome" dance moves, karate actions that definitely leave something to be desired and he even loves playing the air… »
i-SOBOT, World's Smallest Humanoid Robot, Hits US Next Month
Takara Tomy's 6.5-inch, Guinness-certified "smallest humanoid robot in production," i-SOBOT, is finally making its way to our primitive shores next month. The English website and price are still "coming soon," but since this dancing, push-upping wunderbot runs about $300 in Japan, we can pretty safely guess it'll be… »


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Please help NoPowerPlant.com cover the costs of educational flyers, mailers and lawn signs for the 'YES on Measure A' campaign to phase out and retire the power plant.
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Clark Ellis brings us a rare interview with British researcher Dr. Jonathan Kerr who is now living in Colombia.
Discuss the article on the Forums.
XMRV International Advocacy Strategy: Help us start a Facebook page?
Discussion in 'Media, Interviews, Blogs, Talks, Events about XMRV' started by parvofighter, Dec 21, 2009.
Page 1 of 7
Page 1 of 7


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Partners Real Estate Investment Trust is escalating its disagreement with U.S. activist investment firm Orange Capital LLC to Ontario's securities regulator.
In a complaint filed Thursday, the REIT alerted the Ontario Securities Commission to its concerns over the hedge fund's offer to buy a 10-per-cent stake in the company. The REIT said the offer is "highly coercive" and "abusive to the capital markets" as well as investors.


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IIS is easy to implement, but if you don't configure it with security in mind, you could be setting yourself up as a hacker target. Here is a list of 17 items geared toward minimizing IIS vulnerabilities in Windows 2000.
Locking down IIS in Windows 2000
1 comments
I read a procedure to change the AM or PM part of the date/time in the systems tray. I replaced the AM with my name. The change has caused confliction with other programs. I don't remember how to enter that area to delete my name and replace it with AM as it was before Need help in restoring orginal AM PM


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open(v) To make an object accessible. Whenever you access a file (that is, you edit a text file or run a program file), the operating system opens the file. Opening a file can be simple or complex depending on the operating system. For example, in a multiprocessing operating system, in which different users can share the same resources, the operating system must decide whether the file can be accessed simultaneously by more than one user, and if so, it must ensure that different users do not try to modify the file's contents at the same time.
(adj) Accessible. When used to describe designs or architectures, open means public. See under open architecture.
Perceptual computing is the ability for a computer to recognize what is going on around it. More specifically, the computer can perceive the... Read More »Apple Pay Promises to Strengthen Payment Security
Experts believe that Apple Pay and other competitive payment systems will be far more secure than cards, even cards equipped with EMV chips. Read More »The Great Data Storage Debate: Is Tape Dead?
Tape clearly is on the decline. But remember, legacy systems can hang for a shockingly long time. Read More »
A network is a group of two or more computer systems or devices, linked together to share resources, exchange files and electronic communications.... Read More »Computer Architecture Study Guide
This Webopedia study guide describes the different parts of a computer system and their relations. Read More »Webopedia Polls
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text: http://askubuntu.com – I've recently migrated to Linux from Windows and I work on Ubuntu 12.04 LTS. I am trying to preserve my usual habits of Winodws so that I can use Linux more regularly. One of those habits is P2P activity. On Windows, to get the best of my P2P client (uTorrent), I was proceeding as follows: 1 - Set a static IP to my system and 2 - Forward a port Do I need to do the same to make Transmission work at its full capacity? If yes, how to set a static IP in Ubuntu? (hope, its not too complicated for a novice like me) ;) I can manage with forwarding a port unless its a specific process for Linux. (HowTos)


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Surprisingly insightful for a spinoff to a 70s anime franchise.
I have to be honest with how surprised I am with the insightful depth that Gatchaman Crowds offered up with its premise. While appearing to be a loose take and spinoff of the 70s costumed hero series, Gatchaman Crowds' plot revolves around aspects of communication, mainly involving social networking as ...
|2 out of 2 found this review helpful.
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product details-Tab
Restores Whiteness to all Leather, Sport & Active Footwear
Not suitable for suede or nubuck. Keep out of reach of children.
©S.C. Johnson & Son, Inc.
Clean & dry shoes. Shake bottle well with cap on. Invert bottle; gently press applicator against shoe to release polish. Spread evenly on surface of shoe. To keep applicator soft, rinse with warm water & blot after use.


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Landgasthof Adler in Rosenberg, not far from Schwäbisch Hall, is one of the best country inns in Germany.
The Bauers have transformed the country inn, which has been in their family since the mid-19th century, into a real gem that is a perfect marriage between the traditional and the modern. This is echoed by Josef Bauer's cuisine, immaculately crafted using the finest and usually locally sourced ingredients. He wows with innovative ideas, contemporary flavour accents and transparent flavour combinations which make his cuisine so distinctive and worth discovering. No wonder the Landgasthof attracts food lovers from far and wide. Bauer challenges his diners but not too much – his dishes tend to be simply prepared, sometimes tinged by irony, with brilliant accents that allow the food to shine in a fresh light.
For the amuse bouche, Bauer usually serves an exquisite Swabian or German speciality in miniature, such as lentils with spätzle noodles or his amazing pike-perch currywurst. One unmissable starter is his lukewarm vegetable salad , with just the right amount of vegetable types carefully and individually cooked, in a marriage with a succulent red mullet. Another standout dish is Bauer's tomato – tomato – tomato, a contemporary, transparent elucidation of the character of different varieties of tomato, brilliantly faceted with wild herbs. Main courses not to be missed include Bauer's tripe dishes or his Hohenlohe rib of beef with onion confit and potato purée , which is to die for. Then, to finish, one of his excellent soufflés – and all's well with the world...
© Prof. Dr. Ingo Scheuermann
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today 12°
Der Tag ist unbeständig und bringt zeitweise Regen mit längeren Trockenphasen zu Mittag.
tomorrow 6°
Vorerst etwas Sonne und es schneit gelegentlich, am Nachmittag dann immer öfter.
- open lifts 35
- open ski slopes 56
valley (slope) 63 cm
mountain 106 cm
Dr. Fuchs-Martschitz property
Networks as a way to the future
With FMI - Fuchs Martschitz international real estate market
A network around the world has been built by Kitzbuehels Christine Fuchs Martschitz in marketing their exclusive property. With charm and high tech connects providers and seekers.
The vast majority of all business deals are happening today on the Internet. A good website with all the facts and figures and their presence in all major real estate sites are the secrets for rapid commercialization. No matter where the vendors and purchasers abide or where landlords and tenants want to settle - with selected partners in the country, it is easy to make the connections. The future is in the real estate company owned by a network of partners. Finally, locally are personnel who know the market best - the efficiency of the agency is thus given a unique way.
Christine Fuchs Martschitz has completed extensive training in the real estate ÖVI Academy and is a Certified International Property Specialist (CIPS). Whether Kitzbuehel, Vienna, Salzburg, Innsbruck or anywhere else in the world - for a purposeful and easy marketing of charming, interesting and exclusive property is Christine Fuchs Martschitz the right person. Because the philosophy of FMI is to offer the customer a "comprehensive service". From the organization of the perfect appointment, with airport transfers, hotel booking and everything that is necessary for foreign customers, with assistance with legal issues, financing, insurance, and a complete interior design and planning service, means everything is in one place.
"With competent network partners the impossible can be realized" says Christine Fuchs Martschitz from experience.
Dr. Fuchs-Martschitz Immobilien GmbH
Schwendterweg 1
6370 Kitzbühel
Fax: +43 512 2199217709
E-Mail: firstname.lastname@example.com
Website: www.fmi-kitz.net
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Kitz.Live details


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Designer Nail Products shows step-by-step instructions on how to create a blue fimo acrylic nail art design.
3D Nail Art Tutorial
Shellac French Manicure with Contrasting Flower Nail Art
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March 31, 2015
Cover Look: Acrylic Watercolor Floral Nails (NAILS Feb. 2015)
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Mary Jane Nails with OPI @ Fashion Week (Jeremy Scott FW15)
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Montgomery County Public Schools Start Over Scratch
Dr. Warren ThrockmortonWarren Throckmorton, PhD is Associate Professor of Psychology and Fellow for Psychology and Public Policy at Grove City College (PA). He co-founded the Golden Rule Pledge which advocates bullying prevention in evangelical churches. His academic articles have been published by journals of the American Psychological Association and he is past president of the American Mental Health Counselors Association. He is the author with fellow Grove City College professor, Michael Coulter, of the book, Getting Jefferson Right: Fact Checking Claims About Our Third President. Over 200 newspapers have published his columns. He can be reached at email@example.com.
- 2005 May 24
If you are new to this issue, there is a long history to review regarding traditional parents complaining about proposed radical changes to the school's health education curriculum in Montgomery County, MD.
The issue has made national headlines and been the subject of several Fox News broadcasts, including the O'Reilly Factor.
A recent federal court decision found that the curriculum was one-sided on the issue of homosexuality to the point where opponents free speech rights were at risk. Further, the resources suggested for teachers made the school take sides in a religious debate over homosexuality.
After a temporary restraining order from the judge prevented the school from implementing the pilot program for the curriculum, the MCPS superindentent suspended the program.


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| Beginner Class - Fundamentals of Classical Yoga
Starts March 14, register soon
| New Intermediate and Advanced Class
Starts April 6
| A Weekend with John Fyfe
Transformation Breathin & Practical Vedic Astrology
Saturday March 28 and Sunday March 29
| Activating the "Fountain of Youth"
through the Ancient Science of Yoga -with Lalitadevi
Saturday April 11th 9:30-12:00
|Spring Cleansing Week
Yoga classes, dietary suggestions, cooking hints
April 12th to April 18th
|A Weekend with Dr. Fadel Behman, PhD
Soul Subtle Energy Structure
May 1st, 2nd and 3rd
"Yoga for Life"
Lalitadevi, Little Mango Tree
The incredible physical & emotional benefits of yoga is what attracts most of us to this ancient tradition. You may feel lighter, stronger, more flexible, grounded, energized, rejuvenated and happier. Yoga also helps us to reconnect to our full creative potential and feel more connected to the world around us. Through yoga the possibility opens up for us to learn to see ourselves and others more clearly with a loving and compassionate eye and to celebrate the joy of life in every moment.
It is interesting that in this increasingly fast paced world with so much pressure, stress and demands, yoga is becoming more and more mainstream. Why? Because it is a quick and relatively easy way for us to feel better and return to a state of mental, emotional and physical balance and harmony. We all have a deep desire to feel good and be balanced but we have never learned any simple practical tools to help us in achieving this aim.
At Little Mango Tree the classes build on each other so that you will keep learning more and go deeper into the practices, as well as have a strong theoretical and experiential understanding. We teach our classes in this way to gently guide our students towards a deeper understanding of themselves at all levels.
Another big part of our mission is to organize workshops with outstanding teachers in Yoga and the healing arts. These workshops introduce teachings that are more subtle and difficult to access without the guidance of accomplished adepts. Participation in these more intensive workshops makes it possible for us to further deepen our understanding and connection to spirit.


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GARMIN® TACTIX™ GPS WATCH :: Whether you're training, exploring or doing a little bit of both, the Garmin® Tactix™ GPS Watch is your perfect companion. You'll satisfy the Christopher Columbus in you with the high-sensitivity GPS navigator that comes complete with an altimeter, barometer and a 3-axis compass. Your top-performer potential will also get a kick-start with all the real-time data that this watch tracks, such as distance, pace calories and more! So, no matter what your day's adventure entails, you'll always count on the rugged, durable design of the Garmin® Tactix™ to keep you right on track.
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Life is not about haw to survive in the storm !!!Life is about haw to dance in the rainbannertypeclick=miniStates">
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March 8 N.Hollywood snow!!!!
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Council on Foreign Relations Publishes a Contingency Planning Memorandum on Zimbabwe
Zimbabwe, once an African garden spot, is now characterized by bad governance, ubiquitous human rights abuses, abrogation of the rule of law, and poverty. These negatives are closely associated with Robert Mugabe, 91, who rules the country with an iron hand and with no apparent succession plan in place. Mugabe's policies have resulted in humanitarian disaster and waves of refugees, mostly to South Africa. Read more »


text:
Scalable and Reliable Location Services Through Decentralized Replication
Free registration required
Executive Summary
One of the critical challenges for service oriented computing systems is the capability to guarantee scalable and reliable service provision. This paper presents Reliable GeoGrid, a decentralized service computing architecture based on geographical location aware overlay network for supporting reliable and scalable mobile information delivery services. The reliable GeoGrid approach offers two distinct features. First, this paper develops a distributed replication scheme, aiming at providing scalable and reliable processing of location service requests in decentralized pervasive computing environments.
- Format: PDF
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Extended Stay America - Chicago - Darien
No availability found through our partners. Please contact the business directly or check some of our recommended alternatives.
- Wheelchair accessibility
- Free parking
- Kitchenette
- Pets allowed
Travelers also recommend:
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TripAdvisor Reviews Extended Stay America - Chicago - Darien
Travel Blogs from Darien
Normal to Chicago and back to Normal
... our turn taking pictures by the "bean." That was fun. Ruby, Jaimie, and Chrissy decided,to down to the Navy Pier while I went to the Art Institute of Chicago. While they were at the pier, they decided to take a speed boat ride like the one we did in New York City many years ago. Meanwhile at the museum, I was enjoying seeing art by the likes of Monet, Van Gogh, Renoir, Degas, Picasso, Matisse, el Greco and Chagall. I had always heard that this was a world-class museum, and ...
Travel Visas
Why did I
pick the most complicated trip for my first outing with Road Scholar? The
online visa applications are confusing and very intimidating. But I must have
done it correctly as I have received my travel visas for China & Russia!
Exploring Dallas
... where we are staying. Our plan for today was simple - we would meet in the dining area for our complimentary breakfast, then make our way back towards the Old Red Courthouse by 11:00am in order to catch the first tourist trolley car for the day. This trolley car would take us on a 75-minute tour around the city, pointing out prominent landmarks along the way. Breakfast choices were basic - sugar-coated cereals, fresh fruit, yoghurt, a variety of light/fluffy/tasteless ...
Big Bus Day
Side note from last night - Sable the restaurant was sensational. Very very nice food :) We slept in this morning and headed out quite late to get the big bus. As I've said before we love these as you get heaps of info (some say they can ******** and tell you anything - but it's interesting ******** if it is!) Anyhow, we headed off and did the circuit hearing all the history about Chicago - very interesting, going to Bar ...
The chocolate tour
Today's weather was expected to be warm and windy, with a 90% chance of rain later in the afternoon. We chose not to take a coat and umbrella with us when we headed out from the apartment however, as we would be walking for most of the day and didn't need more paraphernalia to weigh us down. We regretted this decision later on... We began the day in the usual fashion - at the shops. We explored the Saks Fifth Avenue store on Michigan Avenue and made a few ...


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The song of the week!
by Crockett
posted Sep 27 2010 5:32AM
Well my Philadelphia Eagles are at the top of the division as predicted! After a great game, smashing the Jags, it is now time for the Eagles to dismantle, quite possibly my least favorite quarterback of all time, McNabb! So this week, I've decided to stay confident that the Eagles will stay on top, and CRUSH the Redskins. And for motivation, I chose the song Philadelphia Freedom. Yes the song by Elton John.... BUT still, it was the only song I could think of with Philadelphia in the title.... so get over it!
Also check out my blog tomorrow @ 6 for another chance at the Feel Good Phrase to win Meet and Greet dinner this Friday at Quaker Steak and Lube!
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Twenty-three years after its original release, Gatorade's "Be Like Mike" campaign is still resonating with viewers. Read More »
Feb 24, 2015
Twenty-three years after its original release, Gatorade's "Be Like Mike" campaign is still resonating with viewers. Read More »
Gatorade, which has a knack for creating ads that generate a lot of buzz, is out with a new campaign that celebrates the most iconic sports moments in the brand's 50-year history. Read More »
Gatorade paid tribute to retiring Yankee player Derek Jeter with a sentimental black-and-white commercial that captures the baseball star's relationship with his fans. Read More »
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AS APPLE SHIFTS MORE AD WORK IN-HOUSE OTHER BRANDS MAY FOLLOW: Ad firms might want to rethink how many staffers they send to Cannes for next week's annual ad festival. Traditionally a time for celebration, there are fewer reasons for partying this year. More in the full post. Read More »
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African soft fur rats. Male .50 each female 1.50
Dumbo rats 3.00 each small size
Breeder size 7.00 each
Bearded dragons - with 90 gallon, stand , 3 dragons, pair cirtus. One male rescued from person who not know how care.. everything asking for 250.00
Ball python
Male ...
Mar 28 -
Philadelphia :
Levittown - Other pets
Motley Het Albino (Male) Bought From Jeremy Stone.
Feeding on small rats weekly (Frozen). stunning looking. Re-homing fee is $150.00
Ball Pythons:
Banana Yellow Belly Ball Python (male)
well started 360 grams
Feeding on Live mice weekly Re-homing $250.00
Spider Ball ...
Mar 27 -
New York City :
Brentwood - Other pets
It have an 09 100% Het. Orange Ghost female Ball Python. She's over 1000 grams and has beautiful flames throughout her body. She's up for grabs at $140 take her while she still available, the OG gene has tons of potential and is known of making some of the top of the line ...
Mar 22 -
New York City :
New York - Other pets
Update: 3-26-15 feeling large follicles in her. Since she has been paired with my pastel clown female I am putting her sale on HOLD (probably a couple of months) right now.
Pastel Proven breeder female. 6-26-14 weight is 4144 grams! Get her even bigger for next breeding ...
Mar 21 -
Virginia Beach :
Norfolk - Other pets
Looking to trade either my baby boys:
Kingpin (Lesser Pinstripe) ball python or an Albino 50% possible het for Axanthic (snow Ball) ball python. Both were born September 2011.
Eating thawed rats easy.
Depending on what you have (specs on device with pictures) I will ...
Mar 20 -
Virginia Beach :
Norfolk - Other pets
I have 3 snakes for sale, im moving and they can't come, i want them to go to a good place.
Baby normal female ball python $25
Baby Albino California Kingsnake SOLD
Hypo. Male boa 1 1/2 $85
Contact me for pictures of the ball python and boa and for more info. Serious ...
Mar 11 -
New York City :
Bronx - Other pets
Adult albino male ball python for sale. Eats frozen thawed med rats. Docile and easy to handle. Has never struck at me. Currently not fitting into any of my breeding projects and I need to make room for babies. Wieght over 1200 grams. Pics aren't the best because snake ...
Feb 25 -
New York City :
New Hyde Park - Other pets
Rehoming my snakes :( to good knowledgeable homes.
M&F fire $150 each or $250 for both (sold)
F super pastel $250
F Russo let lucy $100 (sold)
F killer bee $450
M lesser platinum w ringer $150 (sold)
M honey bee $350
M enchi full grown proven $150 (sold)
F dinker "mystery ...
Feb 16 -
Allentown :
Allentown - Other pets
Hatched out in August. Eating live mice. Let me know which one you want to get.
Desert ball python: male $99
Desert Pinstripe ball python: Female $225
Shipping is not included. Of course hand delivery is preferred.
Form of payment: Paypal, cash and I can accept credit ...
Feb 13 -
Virginia Beach :
Norfolk - Other pets
Ball Python around 4 feet
Feb 2 -
New York City :
Bronx - Other pets
Friendly!! Loves attention. Reason for selling is because I just had a baby and I don't have time for him. He's a great snake and a very good eater. Hr eats MED SIZED LIVE RAT. HE WILL NOT EAT FROZEN! The snake himself is $75.00. But if you want the tank and all of his ...
Jan 31 -
Philadelphia :
Philadelphia - Other pets
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MONTPELIER, Vt. (AP) — After spending six years and more than $18.5 million to modernize computer systems at the Vermont Department of Motor Vehicles, the state is scrapping the effort, officials announced Wednesday.
Vermont, Hewlett-Packard agree to dissolve deal
Top aides to Gov. Peter Shumlin said the state and computer giant Hewlett-Packard had agreed that HP would return $8.37 million to Vermont and that Vermont would return to the company all "physical and virtual rights to all software and documents created by HP" to build a system that has been in the works since 2006.
"It's a no-fault divorce," said DMV Commissioner Robert Ide, "a realization by both sides that this relationship is not going anywhere."
HP is the fourth vendor on the contract, after a series of corporate takeovers that culminated with HP buying Electronic Data Systems. HP spokeswoman Ericka Floyd did not immediately respond to a request for comment.
Under its agreement with the company, Vermont will pay $262,000 to HP for a point-of-sale system that enables DMV clerks to enter customer transactions into the state system, Ide said. But he said that represents just a small fraction of the system upgrades that were envisioned when the state launched the effort in 2006 to modernize then then-30-year-old DMV computer system.
Ide and Jeb Spaulding, the state secretary of administration, said the biggest lost to Vermont taxpayers likely is the nearly $5 million in state staff time DMV employees have put into trying to implement system changes that now are deemed to have failed. Other unreimbursed state expenses include money Vermont spent for "change management consulting" and other services, they said.
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Molecular dynamics simulations create successive configurations of a system by successive integrations of Newton's Second Law. It is useful when a relatively small system's time-dependent behavior affects the understanding of a process.
Part of the Interdisciplinary Innovations in Simulations and Virtual Reality conference.
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Minding Frankie
By Maeve Binchy
(Orion, Paperback, 9781409117896)
Publication Date: February 2011
Other Editions of This Title: Hardcover, Paperback, Mass Market Paperback, Compact Disc, Compact Disc, Hardcover, Paperback, Hardcover, Paperback
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Baking With JuliaSeries Website »
Episode Guide »
This episode is a demonstration of the versatility of merengues. Chef Julia Child observes pastry chef Charlotte Akoto as she creates three different desserts: merengue sandwiches with chocolate cream center, chocolate merengues with a caramel cream filling, and a merengue Napoleon with whipped cream and fresh fruit . First, she demonstrates the techniques used to make several different kinds of merengues, forming the part of the dessert that will serve as the base for a variety of cream and fruit fillings. Then she shows Child how to make the fillings themselves, and does a final assembly of all the ingredients.
More Full Episodes
Poppyseed Torte with Markus FarbingerVanilla Chiffon Chocolate Mousse Cake with Mary BerginSavory Pizza Rustica with Nick MalgieriChocolate Mint Nightcaps with Marcel DesaulniersJohnnycake Cobblers with Johanne KilleenPumpernickel Bread & Matzos with Lauren GrovemanCreme Fraiche with Nancy SilvertonA Three-Tiered Wedding Cake with Martha Stewart, Part 2A Three-Tiered Wedding Cake with Martha Stewart, Part 1Savory Puffs and Eclairs with Norman LoveRaspberry-Fig Crostata with Flo Braker and Leslie MackieChocolate Tuiles & Gingersnaps with Gale Gand and David BlomNaan with Beatrice OjakangasLadyfingers GenoiseItalian Cookies with Nick MalgieriBanana-Chocolate Beignets with Norman LoveChocolate Napoleon & Ice Cream Sandwich with Gale GandWhite Chocolate Pattycake with Marcel DesaulniersPuff Pastry with Michel RichardRasberry Ruffle Genoise Cake with Alice MedrichFocaccia for Dessert with Craig Kominiak
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