Molecular biomarkers involved in the tumor dedifferentiation process of thyroid carcinoma of epithelial origin: perspectives | Endocrinología y Nutrición (English Edition)

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The latter is one of the most aggressive tumors, with a mean 5-month survival rate from the time of diagnosis and a one-year survival rate of only 20%.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Most well differentiated tumors have a favorable clinical course, with survival rates close to 90% 10 years after diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0020">4–6</a> There is however a proportion of tumors with more aggressive behavior including local recurrence and metastases either at diagnosis (in less than 5% of cases) or follow-up, and it has been estimated that approximately 10–15% of patients with differentiated carcinoma will develop local or distant metastases.<a class="elsevierStyleCrossRefs" href="#bib0035">7,8</a> Survival rates ranging from 49% to 68% have been reported 10 years after the occurrence of cervical metastases, which are responsible for one third of deaths related to the disease. Distant metastases occur in lung (50%), bone (25%), lung and bone (20%), and other sites (5%). The survival rate following the diagnosis of distant metastases decreases to 25–42%.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>The treatment of low-risk differentiated thyroid carcinoma has not changed substantially over the past decades and is based on surgery, ablation with 131I, and suppressant treatment with levothyroxine,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> although there is an increasing trend to base both treatment and follow-up recommendations on individualized risk assessment.<a class="elsevierStyleCrossRefs" href="#bib0035">7,11</a> Most evaluation systems are based on clinical and pathological data, and different risk factors have been identified, including age at diagnosis, sex, size, the presence of metastasis, and the initial treatment used.<a class="elsevierStyleCrossRefs" href="#bib0030">6,12,13</a>The response rate to the standard treatment is high, with overall survival rates higher than 75%. However, patients with dedifferentiation processes (poorly differentiated thyroid carcinoma [PDTC]) who have iodine refractory disease (the presence of at least one lesion with no 131I uptake or progression within one year of 131I ablation) show a mean survival of 3–6 years after the diagnosis of distant metastases, and although growth is slow, most metastases progress. These patients are therefore candidates for other treatment modalities,<a class="elsevierStyleCrossRef" href="#bib0070">14</a> and one of the main objectives of clinicians is to distinguish this subgroup from DTCs of good prognosis.It is therefore essential to know the process of dedifferentiation or anaplastic transformation of these tumors. Our understanding of the molecular biomarkers related to this process, and thus with prognosis and survival, has increased in recent years, so allowing for new therapeutic targets to be established.Biomarkers: DefinitionBiomarkers are defined as biological parameters that may be measured or detected and may in turn be correlated to a pathological process. However, for these parameters to be considered as true biomarkers, they must meet the following criteria, described by Herberman in 1977: (1) their measurement should be simple, reproducible, and easily available; (2) they should discriminate between normal and pathological states; (3) they should be highly sensitive and specific; and (4) they should be able to monitor recurrent disease processes.<a class="elsevierStyleCrossRef" href="#bib0075">15</a>In recent years, the development of new technologies applied to the molecular understanding of disease has significantly contributed to the identification of new biomarkers, called molecular biomarkers. These new biomarkers have undoubtedly become highly relevant because they have made possible a deeper understanding of the etiopathogenesis of many diseases by identifying, at least partly, the molecular mechanisms involved, especially in neoplastic conditions, and have provided valuable diagnostic, prognostic, and therapeutic information. However, there are many factors, not only genetic or epigenetic, but also environmental, directly or indirectly involved in the development and metastatic progression of tumors, which often makes selection of these new biomarkers difficult. This is one of the most significant limitations in clinical practice. The different types of biomarkers in thyroid tumor disease are discussed below.Serological markersIn epithelial thyroid tumors, thyroglobulin (TG), a glycoprotein produced by thyroid follicular cells, was one of the first tissue-specific biomarkers used. However, although this is a helpful serum marker for assessing the presence of residual or metastatic tumor in patients undergoing total thyroidectomy, many studies have reported that it is of no use in detecting populations at high risk of developing this type of tumor.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> In addition, TG tests may not be reliable in patients on suppressing levothyroxine therapies and in patients who develop some types of benign conditions such as thyroiditis, thyrotoxicosis, thyroid adenoma, or iodine deficiency. In these latter cases, false positive results are frequently seen because of increased serum TG levels.<a class="elsevierStyleCrossRef" href="#bib0085">17</a>Genomic and transcriptomic markersIt is well known that the process of carcinogenesis results from the random accumulation of genetic and epigenetic aberrations in tissue. At least 10–20% of gene expression changes have been reported in tumor cells. These changes are directly induced by changes in cell DNA, significantly contributing to the oncogenetic process in virtually all human cancers.<a class="elsevierStyleCrossRefs" href="#bib0090">18,19</a> Early studies focused on the identification and subsequent analysis of either one or of several genes implicated in tumor start, development, and metastases. Thus, in the specific case of the thyroid gland and because of the discrepancies found by different authors in serum TG measurements in patients, one of the first choices proposed was the detection of the TG transcript in the blood of these patients instead of protein. However, the results obtained showed a great variability, and no differences in expression could be seen between the control subjects used in the studies and those with disease.<a class="elsevierStyleCrossRefs" href="#bib0085">17,20–22</a> The transcript of the thyroid-stimulating hormone (TSH) receptor was another marker proposed. This receptor acts as the main regulator, through TSH, of the differentiation and division process in thyroid follicular cells, but not in pathological follicular cells, which are insensitive or refractory to such stimulation. However, although different gene expression studies showed total or partial modification of gene expression in differentiated thyroid carcinomas, the results were not conclusive because neither TG nor TSH alone allowed for discrimination between the different degrees of malignancy of tumors or their progression to more aggressive tumors.<a class="elsevierStyleCrossRefs" href="#bib0115">23–25</a>The most relevant findings in terms of the expression of genomic and transcriptomic markers in tumors of different histological characteristics are discussed below.Well differentiated tumors: Papillary and follicular variants of differentiated thyroid carcinomaEarly changes reported included mutations in RAS family oncogenes affecting both GTP in codons 12, 13 and the GTPase domain in codon 61 of the protein, with a similar prevalence in benign and malignant tumors. Some authors found these mutations in approximately 50% of FTCs analyzed, which may suggest their implication in associated early changes in the transformation process of thyroid follicular cells.<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a>The RET proto-oncogene located in chromosome 10q112 has been reported in 50% of PTCs diagnosed, and is called RET/PTC. Active forms of the RET proto-oncogene result from oncogenic rearrangements and fusions of the tyrosine kinase domain of the RET gene with the 5′ of the domain of different genes, leading to different variants (RET/PTC1, –2, –3, –4, and –5).<a class="elsevierStyleCrossRef" href="#bib0140">28</a> However, while there are studies identifying RET/PTC as a good genetic marker in PTCs, others have found the mutations in benign nodules.<a class="elsevierStyleCrossRefs" href="#bib0145">29,30</a>Tyrosine kinase, which may be inadequately activated in PTCs, has also been studied. However, the molecular mechanism is unknown, and no validation exists in benign tumors.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>Angiogenic factors identified in DTC thyrocytes include VEGF (vascular endothelial growth factor), whose expression has been correlated to the degree of tumor dedifferentiation. It has therefore been proposed as a poor prognostic marker involved in metastatic processes in PTC.<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> An additional growth factor implicated in tumorogenesis is EGF (epidermal growth factor), which in addition to promoting cell proliferation in the thyroid gland, acts by inhibiting specific thyroid functions such as iodine transport and organification and peroxidase and TG synthesis. That is to say, EGF promotes thyroid cell proliferation, but not differentiation. Finally, TGF-alpha (tumor growth factor-alpha) interacts with the EGF receptor (EGFR) and contributes with EGF to stimulate cell proliferation. However, the expression of both EGF and its receptor (EGFR) in the nucleus is not only detected in FTC, but also in Graves’ disease and adenomas.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>However, it was not until the advent of mass sequencing of human genoma and the subsequent technological advances, such as array and/or microarray techniques, that new molecular targets involved in key cell regulation processes (signaling pathways, transcription factors, changes in adhesion molecules as markers of tumor aggressiveness) and specific molecular profiles (also called genetic signatures) associated with a variety of clinical patterns could be identified. In many cases, advances made in the search for these specific genetic profiles have been crucial for improving our ability to ascertain differences in the biological behavior of closely related conditions which have no differential histological patterns but show major differences in their clinical course. In the thyroid gland, comparative tests performed in follicular adenomas or benign tumors and carcinomas have allowed for the identification of a number of differential genetic changes such as different galectin-3 gene expression, differences in telomerase activity, and detection of PAX8/PPARγ gene translocation, among others. However, none of these markers have proved sufficiently reliable to allow for the safe differentiation of benign and malignant tumors in cytological samples.<a class="elsevierStyleCrossRefs" href="#bib0175">35,36</a>These new diagnostic approaches were simultaneously used to study PTC.<a class="elsevierStyleCrossRefs" href="#bib0185">37–40</a> Thus, Huang et al. reported in 2001 one of the first studies using array techniques in this type of tumor. The authors were able to identify 220 differentially expressed genes. However, some of these could not subsequently be validated in a new PTC cohort, which is a critical point in the study.<a class="elsevierStyleCrossRef" href="#bib0205">41</a>Subsequent studies by Giordano et al. in 2005 identified a genetic signature associated with mutations in BRAF, RAS, and RET/PTC genes in PTC. Testing for this signature allowed for the differentiation of tumors of epithelial origin which showed different histological patterns (classical papillary pattern and its different variants). This was thus the first study that identified gene expression patterns and their mutational correlation. This allows not only for the prediction of the potential success of the treatment used, but also for contemplating new cellular targets that allow for designing new treatment strategies.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> Thus, Capella et al.<a class="elsevierStyleCrossRef" href="#bib0215">43</a> detected RAS gene mutations in different types of thyroid lesions, including ATC, thus confirming their role in tumorogenesis, although the relationship with prognosis could not be determined. Subsequent detection of hypermethylation of the PTEN promoter, especially in follicular tumors, suggested its potential role during tumor development or course.<a class="elsevierStyleCrossRef" href="#bib0220">44</a>An increasing number of studies aimed at the identification of new clinically useful markers and genetic signatures were subsequently conducted on larger series. Recent studies including significant numbers of patients (n=1168) confirmed that BRAFv600E gene mutations were relevant in PTC and were associated with greater increases in recurrence, mortality, and loss of the capacity to take up 131I. They could therefore be used as a biomarker for these tumors. However, they had little prognostic power in sporadic tumors that lacked the mutation. Thus, their value as a diagnostic and prognostic test was not conclusive.<a class="elsevierStyleCrossRefs" href="#bib0225">45,46</a> A recent study examined the relationship of the presence of the BRAFT1799A mutation to PTC recurrence or persistence, and was unable to conclude that its presence confers a poorer prognosis.<a class="elsevierStyleCrossRef" href="#bib0235">47</a>A meta-analysis by Griffith et al. of 21 published studies using the same Affimetrix technology found that among the 1785 differentially expressed genes, 39 were the most significant, including 12 candidate genes, of which six had previously been reported (MET, TFF, SERPINA1, TIMP1, FN1, and TPO) and six were candidate genes (TGFA, QPCT, CRABP1, FCGBP, EPS8, and PROS1) identified for the first time in the thyroid gland, which could represent, together with the previous ones, a valid diagnostic tool in a clinical setting.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>Dedifferentiated and anaplastic tumors (undifferentiated or anaplastic carcinoma and poorly differentiated carcinoma)Undifferentiated or anaplastic carcinomaFew gene expression studies have been conducted in more aggressive tumors, the etiology of which continues to be highly controversial. No key specific agent for the development of such tumors has been identified yet (a role for TSH and/or external irradiation in the promotion of the development of these tumors has been suggested).<a class="elsevierStyleCrossRef" href="#bib0245">49</a>A correlation exists between the frequency of a loss of heterozygosity and a prognosis of thyroid carcinoma. A loss of heterozygosity occurs more frequently in ATC as compared to PTC and FTC, where it is found in 19p in up to 36% of cases.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> Localized loss in the short arm of chromosome 16 has also frequently been noted. This would suggest the probable lack of a suppressor gene at that location. This observation is supported by the fact that ATC cell lines have been seen to frequently have losses in 16p as compared to cell lines of differentiated carcinoma, which suggests the presence at this location of some gene that may be associated with the transformation from well differentiated to undifferentiated carcinoma.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>On the other hand, microarray studies in these tumors have identified groups of genes related to different signaling pathways, including transcription factors, mitosis, cell proliferation and differentiation, apoptosis, cell adhesion molecules, cytoskeleton, etc.,<a class="elsevierStyleCrossRefs" href="#bib0225">45,46,51–53</a> but have found no consistent genetic signature. As in differentiated tumors, mutations have been identified in RAS and BRAF genes, and this has led to the hypothesis that they could be the first steps in the dedifferentiation process and that they could allow in turn for the acquisition of new mutations (late mutations), including those identified in TP53, catenin (cadherin-associated protein), beta 1, and PIK3CA. It has been suggested that all these cumulative mutations in these types of tumors contribute to their extremely aggressive behavior. By contrast, rearrangements in the RET/PTC gene identified in childhood and in post-radiation PTC or fusion protein PAX8/PPARγ detected in FTC are not identified in poorly differentiated or anaplastic tumors.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> From this postmalignant transformation associated with genetic mutations arises the interesting but controversial concept of “anaplastic transformation”.<a class="elsevierStyleCrossRef" href="#bib0275">55</a>Poorly differentiated carcinomaPDTCs, recognized in 2004 by the World Health Organization as a separate pathological condition, have a differential molecular expression as compared to all other tumors described. Thus, our group<a class="elsevierStyleCrossRef" href="#bib0280">56</a> studied in 2008 these types of tumors (n=6) and compared their differential expression from ATCs (n=6) and a group of well differentiated tumors (n=31). This study identified 1031 differential genes implicated in different cell-signaling pathways: MAPKinases, genes involved in cell cycle regulation, cell adhesion, cytoskeleton, and TGFβ pathways. Of all these genes, 23 represented a genetic signature conferring a poor prognosis (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) which is currently being validated in a new patient cohort. To date, 22 of the 23 genes identified have been analyzed using low density array technology in a total of 19 well differentiated tumors at the time of diagnosis, of which 7 were FTCs and 12 PTCs. The data analyzed identified differential gene groups between the two types of tumors. Specifically, PTPRN2, TWIST1, ANLN, PRC1, and RRM2 were found in PTCs, and APLP2, PPAP2B, SIAH1, and CEP55 were found in FTCs.<a class="elsevierStyleCrossRef" href="#bib0240">48</a> The next step will be a prospective analysis of the different expression of these gene groups in tumors which experience a dedifferentiation process during their course and those which do not.<a class="elsevierStyleCrossRef" href="#bib0285">57</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>ConclusionThyroid carcinoma is the most common endocrine tumor, accounting for 2% of all human cancers, and its incidence has constantly increased over the past three decades (3% annually), especially at the expense of papillary microcarcinoma.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Ninety percent of thyroid carcinomas arise in follicular cells, and most of them are considered well differentiated and have an excellent prognosis. DTC usually has an indolent course, with a mean 10-year survival close to 90%. By contrast, ATC cause 50% of deaths related to thyroid cancer, with a mean survival of 6 months,<a class="elsevierStyleCrossRefs" href="#bib0015">3,58</a> and some patients with DTC have an unfavorable prognosis mainly related to dedifferentiation processes. An understanding of the different processes involved in carcinogenesis and in dedifferentiation processes would allow for a better understanding of the disease and of the potential uses of targeted therapies. In addition, the possibility of recognizing the genetic signatures associated with a poor prognosis among all the biomarkers identified would represent a tool of great diagnostic and prognostic value that would help us to better stratify the risks. This would in turn be very helpful for the application of adequate treatment strategies and for developing new pharmacological alternatives. In this regard, the availability of an animal model of undifferentiated/anaplastic carcinoma would be of great value for in vivo research of the biological mechanism of these tumors. Such a model would also allow for the testing of new treatment alternatives, such as the application of nanoparticles targeted to the tumor cell able to release drugs and gene therapies using cells carrying suicide genes. This work is currently being performed by our group in cooperation with other institutions within the CIBER-BBN project (Cell-Nano-Thyroid [website caber-bbn.es]).Conflicts of interestThe authors state that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres148809" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec136715" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres148808" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec136714" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Biomarkers: Definition" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Serological markers" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Genomic and transcriptomic markers" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Well differentiated tumors: Papillary and follicular variants of differentiated thyroid carcinoma" ] 1 => array:3 [ "identificador" => "sec0030" "titulo" => "Dedifferentiated and anaplastic tumors (undifferentiated or anaplastic carcinoma and poorly differentiated carcinoma)" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Undifferentiated or anaplastic carcinoma" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Poorly differentiated carcinoma" ] ] ] ] ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-09-09" "fechaAceptado" => "2011-12-12" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec136715" "palabras" => array:3 [ 0 => "Thyroid carcinoma" 1 => "Dedifferentiation" 2 => "Molecular markers" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec136714" "palabras" => array:3 [ 0 => "Carcinoma de tiroides" 1 => "Desdiferenciación" 2 => "Marcadores moleculares" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Although papillary or follicular well-differentiated thyroid carcinoma usually has a good prognosis, a proportion of well-differentiated thyroid carcinomas show a more aggressive behavior with local recurrence and metastases, either at diagnosis (in less than 5% of cases) or over time. Although there are several scoring systems to assess prognosis of well-differentiated thyroid carcinoma, mainly based on clinical and pathological data, there is currently no valid criterion to define an adequate, differential treatment for patients with low risk carcinomas as compared to those with more aggressive tumors. Identification of patients with a high risk at the time of diagnosis would be essential to develop new therapeutic strategies and to improve follow-up, and molecular biomarkers could be a highly useful tool for this purpose." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Aunque el carcinoma diferenciado de tiroides, papilar o folicular, tiene habitualmente un buen pronóstico, existe un porcentaje de casos que presentan un comportamiento más agresivo con recurrencias locales y metastatización, ya sea en el momento del diagnostico (en menos de un 5% de los casos) ya en el seguimiento. A pesar de que existen diferentes sistemas de evaluación del pronóstico del carcinoma diferenciado de tiroides, basados especialmente en datos clínicos y patológicos, no hay en la actualidad un criterio válido que permita definir un tratamiento diferencial entre los pacientes con carcinomas de bajo riesgo y aquellos con carcinomas más agresivos. La identificación de los pacientes de riesgo en el momento del diagnóstico sería clave para desarrollar nuevas estrategias terapéuticas y mejorar el seguimiento, siendo en este sentido los biomarcadores moleculares una herramienta de gran valor." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: González Blanco C, et al. Biomarcadores moleculares implicados en el proceso de desdiferenciación tumoral del carcinoma de tiroides de origen epitelial: perspectivas. Endocrinol Nutr. 2012;59(7):452–8." ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Source: Montero-Conde et al.<a class="elsevierStyleCrossRef" href="#bib0280">56</a>" "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Alias \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Name of gene \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Biological function \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ANLN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Actin binding protein (ANLN) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Necessary for cytokinesis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">APLP2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Amyloid beta (A4) precursor-like protein 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regulation of hemostasis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ASPM \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abnormal spindle-like microcephaly-associated protein \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mitotic spindle regulation, mitotic process coordination \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">BIRC5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Survivin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Member of the family of apoptosis inhibitory (API) genes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CCNB2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">G2/mitotic-specific cyclin-B2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cell cycle control in the G2/M transition \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CDH1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">E-cadherin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cell-to-cell regulation of epithelial cell adhesion, motility, and proliferation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CENPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Centromere protein A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mitotic progression and chromosome segregation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CEP55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Centrosomal protein 55 kDa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mitotic death and cytokinesis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DIAPH3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diaphanous homolog 3 (Drosophila) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Promotes actin polymerization, cytokinesis, stress fiber formation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL1RN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interleukin 1 receptor antagonist \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Related to immune and inflammatory responses \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NUSAP1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nucleolar and spindle associated protein 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Promotes the organization of microtubules in mitotic spindle \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ORMDL3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ORM1-like 3 (S. cerevisiae) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regulation of Ca-mediated signaling in endoplasmic reticulum \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PDK2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pyruvate dehydrogenase kinase, isozyme 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regulation of glucose metabolism \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PPAP2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phosphatidic acid phosphatase type 2B \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May be implicated in cell adhesion and cell interaction \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRC1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Protein regulator of cytokinesis 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cytokinesis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PTPRN2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Protein tyrosine phosphatase, receptor type, N polypeptide 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Development of the nervous system and endocrine pancreatic cells \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RRM2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ribonucleotide reductase M2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Precursor needed for DNA synthesis. Inhibits the Wnt signal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SDK2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sidekick homolog 2 (chicken) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cell adhesion protein \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SH3BGRL2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SH3 domain binding glutamic acid-rich protein like 2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Apoptosis, tumor suppression, cell cycle, TNF-α signaling \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SIAH1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Seven in absentia homolog 1 (Drosophila) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proteosomal degradation of target proteins \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TWIST1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Twist homolog 1 (Drosophila) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Transcriptional regulator \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">UBE2 C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ubiquitin-conjugating enzyme E2 C \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cell cycle regulation by ubiquitin ligase progression through mitosis \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab242863.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Genetic signatures identified by Montero et al. which are being analyzed in a new patient cohort." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:58 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Increasing incidence of thyroid cancer in the United States, 1973–2002" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L. 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Review article

Molecular biomarkers involved in the tumor dedifferentiation process of thyroid carcinoma of epithelial origin: perspectives

Biomarcadores moleculares implicados en el proceso de desdiferenciación tumoral del carcinoma de tiroides de origen epitelial: perspectivas

Cintia González Blancoa,b,

Corresponding author

cgonzalezb@santpau.cat

Corresponding author.

, Eugenia Mato Matuteb,c, Alberto de Leiva Hidalgoa,b,c

a Servicio de Endocrinología y Nutrición, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

b Centro de Investigación Biomédica en Red (CIBER-BBN) ISCIII, Ministerio de Ciencia e Innovación, Madrid, Spain

c Universidad Autónoma de Barcelona, Spain

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            "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Scheme depicting the most relevant signaling pathways in neuroendocrine carcinomas and the main mechanisms of action of targeted therapies&#46; EGFr&#58; epithelial growth receptor&#59; ERK 1&#47;2&#58; extracellular signal regulated kinase&#59; IGFr&#58; insulin-like growth factor receptor&#59; JAK 1&#47;2&#58; Janus kinases 1 and 2&#59; MEK 1&#47;2&#58; mitogen-activated protein kinase&#59; mTOR&#58; mammalian target of rapamycin&#58; PIP2&#58; phosphoinositol biphosphate&#59; PIP3&#58; phosphoinositol triphosphate&#59; PI3 K&#58; phosphoinositol 3-kinase&#59; PTEN&#58; phosphatase and tensin homolog protein&#59; RAF&#58; RAS-associated factor&#59; RAS&#59; protein associated with rat sarcoma&#59; SOS&#58; son of sevenless protein&#59; STAT 1&#47;3&#58; signal transducer and activator of transcription proteins 1 and 2&#59; VEGFr&#58; vascular endothelial growth factor receptor&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Differentiated thyroid carcinoma is the most common endocrine neoplasm&#44; with an increasing incidence in recent years&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> More than 90&#37; of these tumors have their origin in follicular cells&#44; and they are classified as well differentiated carcinoma &#40;DTC&#41;&#44; including the papillary &#40;PTC&#41; and follicular &#40;FTC&#41; variants&#44; and undifferentiated or anaplastic carcinoma &#40;ATC&#41;&#46; The latter is one of the most aggressive tumors&#44; with a mean 5-month survival rate from the time of diagnosis and a one-year survival rate of only 20&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Most well differentiated tumors have a favorable clinical course&#44; with survival rates close to 90&#37; 10 years after diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#8211;6</span></a> There is however a proportion of tumors with more aggressive behavior including local recurrence and metastases either at diagnosis &#40;in less than 5&#37; of cases&#41; or follow-up&#44; and it has been estimated that approximately 10&#8211;15&#37; of patients with differentiated carcinoma will develop local or distant metastases&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a> Survival rates ranging from 49&#37; to 68&#37; have been reported 10 years after the occurrence of cervical metastases&#44; which are responsible for one third of deaths related to the disease&#46; Distant metastases occur in lung &#40;50&#37;&#41;&#44; bone &#40;25&#37;&#41;&#44; lung and bone &#40;20&#37;&#41;&#44; and other sites &#40;5&#37;&#41;&#46; The survival rate following the diagnosis of distant metastases decreases to 25&#8211;42&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The treatment of low-risk differentiated thyroid carcinoma has not changed substantially over the past decades and is based on surgery&#44; ablation with <span class="elsevierStyleSup">131</span>I&#44; and suppressant treatment with levothyroxine&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> although there is an increasing trend to base both treatment and follow-up recommendations on individualized risk assessment&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;11</span></a> Most evaluation systems are based on clinical and pathological data&#44; and different risk factors have been identified&#44; including age at diagnosis&#44; sex&#44; size&#44; the presence of metastasis&#44; and the initial treatment used&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;12&#44;13</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The response rate to the standard treatment is high&#44; with overall survival rates higher than 75&#37;&#46; However&#44; patients with dedifferentiation processes &#40;poorly differentiated thyroid carcinoma &#91;PDTC&#93;&#41; who have iodine refractory disease &#40;the presence of at least one lesion with no <span class="elsevierStyleSup">131</span>I uptake or progression within one year of <span class="elsevierStyleSup">131</span>I ablation&#41; show a mean survival of 3&#8211;6 years after the diagnosis of distant metastases&#44; and although growth is slow&#44; most metastases progress&#46; These patients are therefore candidates for other treatment modalities&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> and one of the main objectives of clinicians is to distinguish this subgroup from DTCs of good prognosis&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">It is therefore essential to know the process of dedifferentiation or anaplastic transformation of these tumors&#46; Our understanding of the molecular biomarkers related to this process&#44; and thus with prognosis and survival&#44; has increased in recent years&#44; so allowing for new therapeutic targets to be established&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Biomarkers&#58; Definition</span><p id="par0030" class="elsevierStylePara elsevierViewall">Biomarkers are defined as biological parameters that may be measured or detected and may in turn be correlated to a pathological process&#46; However&#44; for these parameters to be considered as true biomarkers&#44; they must meet the following criteria&#44; described by Herberman in 1977&#58; &#40;1&#41; their measurement should be simple&#44; reproducible&#44; and easily available&#59; &#40;2&#41; they should discriminate between normal and pathological states&#59; &#40;3&#41; they should be highly sensitive and specific&#59; and &#40;4&#41; they should be able to monitor recurrent disease processes&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In recent years&#44; the development of new technologies applied to the molecular understanding of disease has significantly contributed to the identification of new biomarkers&#44; called molecular biomarkers&#46; These new biomarkers have undoubtedly become highly relevant because they have made possible a deeper understanding of the etiopathogenesis of many diseases by identifying&#44; at least partly&#44; the molecular mechanisms involved&#44; especially in neoplastic conditions&#44; and have provided valuable diagnostic&#44; prognostic&#44; and therapeutic information&#46; However&#44; there are many factors&#44; not only genetic or epigenetic&#44; but also environmental&#44; directly or indirectly involved in the development and metastatic progression of tumors&#44; which often makes selection of these new biomarkers difficult&#46; This is one of the most significant limitations in clinical practice&#46; The different types of biomarkers in thyroid tumor disease are discussed below&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Serological markers</span><p id="par0040" class="elsevierStylePara elsevierViewall">In epithelial thyroid tumors&#44; thyroglobulin &#40;TG&#41;&#44; a glycoprotein produced by thyroid follicular cells&#44; was one of the first tissue-specific biomarkers used&#46; However&#44; although this is a helpful serum marker for assessing the presence of residual or metastatic tumor in patients undergoing total thyroidectomy&#44; many studies have reported that it is of no use in detecting populations at high risk of developing this type of tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In addition&#44; TG tests may not be reliable in patients on suppressing levothyroxine therapies and in patients who develop some types of benign conditions such as thyroiditis&#44; thyrotoxicosis&#44; thyroid adenoma&#44; or iodine deficiency&#46; In these latter cases&#44; false positive results are frequently seen because of increased serum TG levels&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Genomic and transcriptomic markers</span><p id="par0045" class="elsevierStylePara elsevierViewall">It is well known that the process of carcinogenesis results from the random accumulation of genetic and epigenetic aberrations in tissue&#46; At least 10&#8211;20&#37; of gene expression changes have been reported in tumor cells&#46; These changes are directly induced by changes in cell DNA&#44; significantly contributing to the oncogenetic process in virtually all human cancers&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a> Early studies focused on the identification and subsequent analysis of either one or of several genes implicated in tumor start&#44; development&#44; and metastases&#46; Thus&#44; in the specific case of the thyroid gland and because of the discrepancies found by different authors in serum TG measurements in patients&#44; one of the first choices proposed was the detection of the TG transcript in the blood of these patients instead of protein&#46; However&#44; the results obtained showed a great variability&#44; and no differences in expression could be seen between the control subjects used in the studies and those with disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;20&#8211;22</span></a> The transcript of the thyroid-stimulating hormone &#40;TSH&#41; receptor was another marker proposed&#46; This receptor acts as the main regulator&#44; through TSH&#44; of the differentiation and division process in thyroid follicular cells&#44; but not in pathological follicular cells&#44; which are insensitive or refractory to such stimulation&#46; However&#44; although different gene expression studies showed total or partial modification of gene expression in differentiated thyroid carcinomas&#44; the results were not conclusive because neither TG nor TSH alone allowed for discrimination between the different degrees of malignancy of tumors or their progression to more aggressive tumors&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#8211;25</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The most relevant findings in terms of the expression of genomic and transcriptomic markers in tumors of different histological characteristics are discussed below&#46;</p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Well differentiated tumors&#58; Papillary and follicular variants of differentiated thyroid carcinoma</span><p id="par0055" class="elsevierStylePara elsevierViewall">Early changes reported included mutations in <span class="elsevierStyleItalic">RAS</span> family oncogenes affecting both GTP in codons 12&#44; 13 and the GTPase domain in codon 61 of the protein&#44; with a similar prevalence in benign and malignant tumors&#46; Some authors found these mutations in approximately 50&#37; of FTCs analyzed&#44; which may suggest their implication in associated early changes in the transformation process of thyroid follicular cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">RET</span> proto-oncogene located in chromosome 10q112 has been reported in 50&#37; of PTCs diagnosed&#44; and is called <span class="elsevierStyleItalic">RET&#47;PTC</span>&#46; Active forms of the RET proto-oncogene result from oncogenic rearrangements and fusions of the tyrosine kinase domain of the RET gene with the 5&#8242; of the domain of different genes&#44; leading to different variants &#40;RET&#47;PTC1&#44; &#8211;2&#44; &#8211;3&#44; &#8211;4&#44; and &#8211;5&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> However&#44; while there are studies identifying RET&#47;PTC as a good genetic marker in PTCs&#44; others have found the mutations in benign nodules&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Tyrosine kinase&#44; which may be inadequately activated in PTCs&#44; has also been studied&#46; However&#44; the molecular mechanism is unknown&#44; and no validation exists in benign tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Angiogenic factors identified in DTC thyrocytes include VEGF &#40;vascular endothelial growth factor&#41;&#44; whose expression has been correlated to the degree of tumor dedifferentiation&#46; It has therefore been proposed as a poor prognostic marker involved in metastatic processes in PTC&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> An additional growth factor implicated in tumorogenesis is EGF &#40;epidermal growth factor&#41;&#44; which in addition to promoting cell proliferation in the thyroid gland&#44; acts by inhibiting specific thyroid functions such as iodine transport and organification and peroxidase and TG synthesis&#46; That is to say&#44; EGF promotes thyroid cell proliferation&#44; but not differentiation&#46; Finally&#44; TGF-alpha &#40;tumor growth factor-alpha&#41; interacts with the EGF receptor &#40;EGFR&#41; and contributes with EGF to stimulate cell proliferation&#46; However&#44; the expression of both EGF and its receptor &#40;EGFR&#41; in the nucleus is not only detected in FTC&#44; but also in Graves&#8217; disease and adenomas&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">However&#44; it was not until the advent of mass sequencing of human genoma and the subsequent technological advances&#44; such as array and&#47;or microarray techniques&#44; that new molecular targets involved in key cell regulation processes &#40;signaling pathways&#44; transcription factors&#44; changes in adhesion molecules as markers of tumor aggressiveness&#41; and specific molecular profiles &#40;also called genetic signatures&#41; associated with a variety of clinical patterns could be identified&#46; In many cases&#44; advances made in the search for these specific genetic profiles have been crucial for improving our ability to ascertain differences in the biological behavior of closely related conditions which have no differential histological patterns but show major differences in their clinical course&#46; In the thyroid gland&#44; comparative tests performed in follicular adenomas or benign tumors and carcinomas have allowed for the identification of a number of differential genetic changes such as different galectin-3 gene expression&#44; differences in telomerase activity&#44; and detection of PAX8&#47;PPAR&#947; gene translocation&#44; among others&#46; However&#44; none of these markers have proved sufficiently reliable to allow for the safe differentiation of benign and malignant tumors in cytological samples&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">These new diagnostic approaches were simultaneously used to study PTC&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#8211;40</span></a> Thus&#44; Huang et al&#46; reported in 2001 one of the first studies using array techniques in this type of tumor&#46; The authors were able to identify 220 differentially expressed genes&#46; However&#44; some of these could not subsequently be validated in a new PTC cohort&#44; which is a critical point in the study&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Subsequent studies by Giordano et al&#46; in 2005 identified a genetic signature associated with mutations in <span class="elsevierStyleItalic">BRAF</span>&#44; <span class="elsevierStyleItalic">RAS</span>&#44; and <span class="elsevierStyleItalic">RET&#47;PTC</span> genes in PTC&#46; Testing for this signature allowed for the differentiation of tumors of epithelial origin which showed different histological patterns &#40;classical papillary pattern and its different variants&#41;&#46; This was thus the first study that identified gene expression patterns and their mutational correlation&#46; This allows not only for the prediction of the potential success of the treatment used&#44; but also for contemplating new cellular targets that allow for designing new treatment strategies&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> Thus&#44; Capella et al&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> detected <span class="elsevierStyleItalic">RAS</span> gene mutations in different types of thyroid lesions&#44; including ATC&#44; thus confirming their role in tumorogenesis&#44; although the relationship with prognosis could not be determined&#46; Subsequent detection of hypermethylation of the <span class="elsevierStyleItalic">PTEN</span> promoter&#44; especially in follicular tumors&#44; suggested its potential role during tumor development or course&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">An increasing number of studies aimed at the identification of new clinically useful markers and genetic signatures were subsequently conducted on larger series&#46; Recent studies including significant numbers of patients &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1168&#41; confirmed that <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup">v600E</span> gene mutations were relevant in PTC and were associated with greater increases in recurrence&#44; mortality&#44; and loss of the capacity to take up <span class="elsevierStyleSup">131</span>I&#46; They could therefore be used as a biomarker for these tumors&#46; However&#44; they had little prognostic power in sporadic tumors that lacked the mutation&#46; Thus&#44; their value as a diagnostic and prognostic test was not conclusive&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#44;46</span></a> A recent study examined the relationship of the presence of the <span class="elsevierStyleItalic">BRAF</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">T1799A</span></span> mutation to PTC recurrence or persistence&#44; and was unable to conclude that its presence confers a poorer prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">A meta-analysis by Griffith et al&#46; of 21 published studies using the same Affimetrix technology found that among the 1785 differentially expressed genes&#44; 39 were the most significant&#44; including 12 candidate genes&#44; of which six had previously been reported &#40;<span class="elsevierStyleItalic">MET</span>&#44; <span class="elsevierStyleItalic">TFF</span>&#44; <span class="elsevierStyleItalic">SERPINA1</span>&#44; <span class="elsevierStyleItalic">TIMP1</span>&#44; <span class="elsevierStyleItalic">FN1</span>&#44; and <span class="elsevierStyleItalic">TPO</span>&#41; and six were candidate genes &#40;<span class="elsevierStyleItalic">TGFA</span>&#44; <span class="elsevierStyleItalic">QPCT</span>&#44; <span class="elsevierStyleItalic">CRABP1</span>&#44; <span class="elsevierStyleItalic">FCGBP</span>&#44; <span class="elsevierStyleItalic">EPS8</span>&#44; and <span class="elsevierStyleItalic">PROS1</span>&#41; identified for the first time in the thyroid gland&#44; which could represent&#44; together with the previous ones&#44; a valid diagnostic tool in a clinical setting&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Dedifferentiated and anaplastic tumors &#40;undifferentiated or anaplastic carcinoma and poorly differentiated carcinoma&#41;</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Undifferentiated or anaplastic carcinoma</span><p id="par0100" class="elsevierStylePara elsevierViewall">Few gene expression studies have been conducted in more aggressive tumors&#44; the etiology of which continues to be highly controversial&#46; No key specific agent for the development of such tumors has been identified yet &#40;a role for TSH and&#47;or external irradiation in the promotion of the development of these tumors has been suggested&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">A correlation exists between the frequency of a loss of heterozygosity and a prognosis of thyroid carcinoma&#46; A loss of heterozygosity occurs more frequently in ATC as compared to PTC and FTC&#44; where it is found in 19p in up to 36&#37; of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> Localized loss in the short arm of chromosome 16 has also frequently been noted&#46; This would suggest the probable lack of a suppressor gene at that location&#46; This observation is supported by the fact that ATC cell lines have been seen to frequently have losses in 16p as compared to cell lines of differentiated carcinoma&#44; which suggests the presence at this location of some gene that may be associated with the transformation from well differentiated to undifferentiated carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">On the other hand&#44; microarray studies in these tumors have identified groups of genes related to different signaling pathways&#44; including transcription factors&#44; mitosis&#44; cell proliferation and differentiation&#44; apoptosis&#44; cell adhesion molecules&#44; cytoskeleton&#44; etc&#46;&#44;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#44;46&#44;51&#8211;53</span></a> but have found no consistent genetic signature&#46; As in differentiated tumors&#44; mutations have been identified in <span class="elsevierStyleItalic">RAS</span> and <span class="elsevierStyleItalic">BRAF</span> genes&#44; and this has led to the hypothesis that they could be the first steps in the dedifferentiation process and that they could allow in turn for the acquisition of new mutations &#40;late mutations&#41;&#44; including those identified in <span class="elsevierStyleItalic">TP53</span>&#44; catenin &#40;cadherin-associated protein&#41;&#44; beta 1&#44; and <span class="elsevierStyleItalic">PIK3CA</span>&#46; It has been suggested that all these cumulative mutations in these types of tumors contribute to their extremely aggressive behavior&#46; By contrast&#44; rearrangements in the <span class="elsevierStyleItalic">RET&#47;PTC</span> gene identified in childhood and in post-radiation PTC or fusion protein PAX8&#47;PPAR&#947; detected in FTC are not identified in poorly differentiated or anaplastic tumors&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> From this postmalignant transformation associated with genetic mutations arises the interesting but controversial concept of &#8220;anaplastic transformation&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Poorly differentiated carcinoma</span><p id="par0115" class="elsevierStylePara elsevierViewall">PDTCs&#44; recognized in 2004 by the World Health Organization as a separate pathological condition&#44; have a differential molecular expression as compared to all other tumors described&#46; Thus&#44; our group<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> studied in 2008 these types of tumors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41; and compared their differential expression from ATCs &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41; and a group of well differentiated tumors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>31&#41;&#46; This study identified 1031 differential genes implicated in different cell-signaling pathways&#58; MAPKinases&#44; genes involved in cell cycle regulation&#44; cell adhesion&#44; cytoskeleton&#44; and TGF&#946; pathways&#46; Of all these genes&#44; 23 represented a genetic signature conferring a poor prognosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; which is currently being validated in a new patient cohort&#46; To date&#44; 22 of the 23 genes identified have been analyzed using low density array technology in a total of 19 well differentiated tumors at the time of diagnosis&#44; of which 7 were FTCs and 12 PTCs&#46; The data analyzed identified differential gene groups between the two types of tumors&#46; Specifically&#44; <span class="elsevierStyleItalic">PTPRN2</span>&#44; <span class="elsevierStyleItalic">TWIST1</span>&#44; <span class="elsevierStyleItalic">ANLN</span>&#44; <span class="elsevierStyleItalic">PRC1</span>&#44; and <span class="elsevierStyleItalic">RRM2</span> were found in PTCs&#44; and <span class="elsevierStyleItalic">APLP2</span>&#44; <span class="elsevierStyleItalic">PPAP2B</span>&#44; <span class="elsevierStyleItalic">SIAH1</span>&#44; and CEP55 were found in FTCs&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> The next step will be a prospective analysis of the different expression of these gene groups in tumors which experience a dedifferentiation process during their course and those which do not&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusion</span><p id="par0120" class="elsevierStylePara elsevierViewall">Thyroid carcinoma is the most common endocrine tumor&#44; accounting for 2&#37; of all human cancers&#44; and its incidence has constantly increased over the past three decades &#40;3&#37; annually&#41;&#44; especially at the expense of papillary microcarcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Ninety percent of thyroid carcinomas arise in follicular cells&#44; and most of them are considered well differentiated and have an excellent prognosis&#46; DTC usually has an indolent course&#44; with a mean 10-year survival close to 90&#37;&#46; By contrast&#44; ATC cause 50&#37; of deaths related to thyroid cancer&#44; with a mean survival of 6 months&#44;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;58</span></a> and some patients with DTC have an unfavorable prognosis mainly related to dedifferentiation processes&#46; An understanding of the different processes involved in carcinogenesis and in dedifferentiation processes would allow for a better understanding of the disease and of the potential uses of targeted therapies&#46; In addition&#44; the possibility of recognizing the genetic signatures associated with a poor prognosis among all the biomarkers identified would represent a tool of great diagnostic and prognostic value that would help us to better stratify the risks&#46; This would in turn be very helpful for the application of adequate treatment strategies and for developing new pharmacological alternatives&#46; In this regard&#44; the availability of an animal model of undifferentiated&#47;anaplastic carcinoma would be of great value for in vivo research of the biological mechanism of these tumors&#46; Such a model would also allow for the testing of new treatment alternatives&#44; such as the application of nanoparticles targeted to the tumor cell able to release drugs and gene therapies using cells carrying suicide genes&#46; This work is currently being performed by our group in cooperation with other institutions within the CIBER-BBN project &#40;<span class="elsevierStyleItalic">Cell-Nano-Thyroid</span> &#91;website caber-bbn&#46;es&#93;&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors state that they have no conflicts of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        0 => array:2 [
          "identificador" => "xres148809"
          "titulo" => "Abstract"
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        1 => array:2 [
          "identificador" => "xpalclavsec136715"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "xres148808"
          "titulo" => "Resumen"
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        3 => array:2 [
          "identificador" => "xpalclavsec136714"
          "titulo" => "Palabras clave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Biomarkers&#58; Definition"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Serological markers"
        ]
        7 => array:3 [
          "identificador" => "sec0020"
          "titulo" => "Genomic and transcriptomic markers"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Well differentiated tumors&#58; Papillary and follicular variants of differentiated thyroid carcinoma"
            ]
            1 => array:3 [
              "identificador" => "sec0030"
              "titulo" => "Dedifferentiated and anaplastic tumors &#40;undifferentiated or anaplastic carcinoma and poorly differentiated carcinoma&#41;"
              "secciones" => array:2 [
                0 => array:2 [
                  "identificador" => "sec0035"
                  "titulo" => "Undifferentiated or anaplastic carcinoma"
                ]
                1 => array:2 [
                  "identificador" => "sec0040"
                  "titulo" => "Poorly differentiated carcinoma"
                ]
              ]
            ]
          ]
        ]
        8 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conclusion"
        ]
        9 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Conflicts of interest"
        ]
        10 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2011-09-09"
    "fechaAceptado" => "2011-12-12"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec136715"
          "palabras" => array:3 [
            0 => "Thyroid carcinoma"
            1 => "Dedifferentiation"
            2 => "Molecular markers"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec136714"
          "palabras" => array:3 [
            0 => "Carcinoma de tiroides"
            1 => "Desdiferenciaci&#243;n"
            2 => "Marcadores moleculares"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Although papillary or follicular well-differentiated thyroid carcinoma usually has a good prognosis&#44; a proportion of well-differentiated thyroid carcinomas show a more aggressive behavior with local recurrence and metastases&#44; either at diagnosis &#40;in less than 5&#37; of cases&#41; or over time&#46; Although there are several scoring systems to assess prognosis of well-differentiated thyroid carcinoma&#44; mainly based on clinical and pathological data&#44; there is currently no valid criterion to define an adequate&#44; differential treatment for patients with low risk carcinomas as compared to those with more aggressive tumors&#46; Identification of patients with a high risk at the time of diagnosis would be essential to develop new therapeutic strategies and to improve follow-up&#44; and molecular biomarkers could be a highly useful tool for this purpose&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Aunque el carcinoma diferenciado de tiroides&#44; papilar o folicular&#44; tiene habitualmente un buen pron&#243;stico&#44; existe un porcentaje de casos que presentan un comportamiento m&#225;s agresivo con recurrencias locales y metastatizaci&#243;n&#44; ya sea en el momento del diagnostico &#40;en menos de un 5&#37; de los casos&#41; ya en el seguimiento&#46; A pesar de que existen diferentes sistemas de evaluaci&#243;n del pron&#243;stico del carcinoma diferenciado de tiroides&#44; basados especialmente en datos cl&#237;nicos y patol&#243;gicos&#44; no hay en la actualidad un criterio v&#225;lido que permita definir un tratamiento diferencial entre los pacientes con carcinomas de bajo riesgo y aquellos con carcinomas m&#225;s agresivos&#46; La identificaci&#243;n de los pacientes de riesgo en el momento del diagn&#243;stico ser&#237;a clave para desarrollar nuevas estrategias terap&#233;uticas y mejorar el seguimiento&#44; siendo en este sentido los biomarcadores moleculares una herramienta de gran valor&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Gonz&#225;lez Blanco C&#44; et al&#46; Biomarcadores moleculares implicados en el proceso de desdiferenciaci&#243;n tumoral del carcinoma de tiroides de origen epitelial&#58; perspectivas&#46; Endocrinol Nutr&#46; 2012&#59;59&#40;7&#41;&#58;452&#8211;8&#46;</p>"
      ]
    ]
    "multimedia" => array:1 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "<span class="elsevierStyleItalic">Source</span>&#58; Montero-Conde et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a>"
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Alias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Name of gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Biological function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ANLN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Actin binding protein &#40;ANLN&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Necessary for cytokinesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">APLP2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Amyloid beta &#40;A4&#41; precursor-like protein 2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Regulation of hemostasis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ASPM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Abnormal spindle-like microcephaly-associated protein</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mitotic spindle regulation&#44; mitotic process coordination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">BIRC5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Survivin</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Member of the family of apoptosis inhibitory &#40;API&#41; genes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CCNB2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">G2&#47;mitotic-specific cyclin-B2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cell cycle control in the G2&#47;M transition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CDH1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">E-cadherin</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cell-to-cell regulation of epithelial cell adhesion&#44; motility&#44; and proliferation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CENPA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Centromere protein A</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mitotic progression and chromosome segregation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CEP55&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Centrosomal protein 55 kDa</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mitotic death and cytokinesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DIAPH3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Diaphanous homolog 3 &#40;Drosophila&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Promotes actin polymerization&#44; cytokinesis&#44; stress fiber formation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL1RN&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Interleukin 1 receptor antagonist</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Related to immune and inflammatory responses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NUSAP1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Nucleolar and spindle associated protein 1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Promotes the organization of microtubules in mitotic spindle&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ORMDL3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ORM1-like 3 &#40;S&#46; cerevisiae&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Regulation of Ca-mediated signaling in endoplasmic reticulum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PDK2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Pyruvate dehydrogenase kinase&#44; isozyme 2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Regulation of glucose metabolism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PPAP2B&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Phosphatidic acid phosphatase type 2B</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May be implicated in cell adhesion and cell interaction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRC1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Protein regulator of cytokinesis 1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cytokinesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PTPRN2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Protein tyrosine phosphatase&#44; receptor type&#44; N polypeptide 2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Development of the nervous system and endocrine pancreatic cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RRM2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Ribonucleotide reductase M2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Precursor needed for DNA synthesis&#46; Inhibits the Wnt signal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SDK2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sidekick homolog 2 &#40;chicken&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cell adhesion protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SH3BGRL2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">SH3 domain binding glutamic acid-rich protein like 2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Apoptosis&#44; tumor suppression&#44; cell cycle&#44; TNF-&#945; signaling&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SIAH1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Seven in absentia homolog 1 &#40;Drosophila&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Proteosomal degradation of target proteins&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TWIST1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Twist homolog 1 &#40;Drosophila&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Transcriptional regulator&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">UBE2 C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Ubiquitin-conjugating enzyme E2 C</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cell cycle regulation by ubiquitin ligase progression through mitosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Genetic signatures identified by Montero et al&#46; which are being analyzed in a new patient cohort&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:58 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Increasing incidence of thyroid cancer in the United States&#44; 1973&#8211;2002"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46; Davies"
                            1 => "H&#46;G&#46; Welch"
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                    0 => array:2 [
                      "doi" => "10.1001/jama.295.18.2164"
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                        "volumen" => "295"
                        "paginaInicial" => "2164"
                        "paginaFinal" => "2167"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16684987"
                            "web" => "Medline"
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                    ]
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            1 => array:3 [
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              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Time trends for thyroid cancer in northwestern Spain&#58; true rise in the incidence of micro and lager forms of papillary thyroid carcinoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Riego-Iraeta"
                            1 => "L&#46;F&#46; P&#233;rez-M&#233;ndez"
                            2 => "B&#46; Mantinan"
                            3 => "R&#46;V&#46; Garc&#237;a-Mayor"
                          ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/thy.2008.0210"
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                        "fecha" => "2009"
                        "volumen" => "19"
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                        "paginaFinal" => "340"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19355823"
                            "web" => "Medline"
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              ]
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              "identificador" => "bib0015"
              "etiqueta" => "3"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anaplastic thyroid carcinoma&#58; pathogenesis and emerging therapies"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46;C&#46; Smallridge"
                            1 => "J&#46;A&#46; Copland"
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                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Clin Oncol &#40;R Coll Radio&#41;"
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                        "volumen" => "22"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Radioactive iodine lobe ablation as an alternative to completion thyroidectomy for follicular carcinoma of the thyroid"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "G&#46;W&#46; Randolph"
                            1 => "G&#46;H&#46; Daniela"
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                        "fecha" => "2002"
                        "volumen" => "12"
                        "paginaInicial" => "989"
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                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12490076"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Papillary thyroid carcinoma&#58; factors influencing recurrence and survival"
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                          "etal" => false
                          "autores" => array:6 [
                            0 => "A&#46; Toniato"
                            1 => "I&#46; Boschin"
                            2 => "D&#46; Casara"
                            3 => "R&#46; Mazzarotto"
                            4 => "D&#46; Rubello"
                            5 => "M&#46; Pelizzo"
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                    0 => array:2 [
                      "doi" => "10.1245/s10434-008-9859-4"
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                        "tituloSerie" => "Ann Surg Oncol"
                        "fecha" => "2008"
                        "volumen" => "15"
                        "paginaInicial" => "1518"
                        "paginaFinal" => "1522"
                        "link" => array:1 [
                          0 => array:2 [
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              "etiqueta" => "6"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prognostic factors and therapeutics strategies for differentiated carcinomas of the thyroid"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Y&#46; Ito"
                            1 => "A&#46; Miyauchi"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Endocrine J"
                        "fecha" => "2009"
                        "volumen" => "56"
                        "paginaInicial" => "177"
                        "paginaFinal" => "192"
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            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;S&#46; Cooper"
                            1 => "G&#46;M&#46; Doherty"
                            2 => "B&#46;R&#46; Haugen"
                            3 => "R&#46;T&#46; Kloos"
                            4 => "S&#46;L&#46; Lee"
                            5 => "S&#46;J&#46; Mandel"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/thy.2009.0110"
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                        "fecha" => "2009"
                        "volumen" => "19"
                        "paginaInicial" => "1167"
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              "identificador" => "bib0040"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "European consensus fort he management of patients with differentiated Thyroid cancer of the follicular epithelium"
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                        0 => array:3 [
                          "colaboracion" => "The European Thyroid cancer Taskforce 2006"
                          "etal" => false
                          "autores" => array:6 [
                            0 => "F&#46; Pacini"
                            1 => "M&#46; Schlumberger"
                            2 => "H&#46; Dralled"
                            3 => "R&#46; Elisei"
                            4 => "J&#46;W&#46;A&#46; Smit"
                            5 => "W&#46; Wiersinga"
                          ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1530/eje.1.02158"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Endocrinol"
                        "fecha" => "2006"
                        "volumen" => "154"
                        "paginaInicial" => "787"
                        "paginaFinal" => "803"
                        "link" => array:1 [
                          0 => array:2 [
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              "etiqueta" => "9"
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                0 => array:2 [
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Article information

ISSN: 21735093
Original language: English

DOI:10.1016/j.endoen.2012.08.004

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	6	1	7
2024 October	29	10	39
2024 September	23	14	37
2024 August	27	4	31
2024 July	14	5	19
2024 June	23	5	28
2024 May	22	2	24
2024 April	20	10	30
2024 March	40	0	40
2024 February	36	4	40
2024 January	32	1	33
2023 December	33	7	40
2023 November	17	13	30
2023 October	19	12	31
2023 September	29	3	32
2023 August	15	2	17
2023 July	46	7	53
2023 June	32	1	33
2023 May	46	10	56
2023 April	29	2	31
2023 March	48	5	53
2023 February	31	1	32
2023 January	57	6	63
2022 December	37	12	49
2022 November	45	5	50
2022 October	28	11	39
2022 September	38	18	56
2022 August	42	11	53
2022 July	28	17	45
2022 June	27	9	36
2022 May	24	20	44
2022 April	60	20	80
2022 March	52	21	73
2022 February	43	5	48
2022 January	79	14	93
2021 December	30	19	49
2021 November	57	21	78
2021 October	46	24	70
2021 September	48	24	72
2021 August	43	16	59
2021 July	51	30	81
2021 June	26	12	38
2021 May	48	18	66
2021 April	105	61	166
2021 March	83	10	93
2021 February	45	19	64
2021 January	53	15	68
2020 December	52	11	63
2020 November	55	11	66
2020 October	48	7	55
2020 September	28	15	43
2020 August	37	20	57
2020 July	35	14	49
2020 June	24	9	33
2020 May	25	8	33
2020 April	29	8	37
2020 March	45	14	59
2020 February	30	10	40
2020 January	28	6	34
2019 December	36	10	46
2019 November	40	7	47
2019 October	29	5	34
2019 September	33	9	42
2019 August	15	2	17
2019 July	17	15	32
2019 June	69	16	85
2019 May	116	24	140
2019 April	46	7	53
2019 March	18	3	21
2019 February	23	8	31
2019 January	30	7	37
2018 December	40	9	49
2018 November	42	0	42
2018 October	26	13	39
2018 September	75	4	79
2018 August	24	17	41
2018 July	11	3	14
2018 June	20	1	21
2018 May	13	4	17
2018 April	19	0	19
2018 March	8	1	9
2018 February	9	0	9
2018 January	9	1	10
2017 December	10	1	11
2017 November	10	1	11
2017 October	20	2	22
2017 September	12	6	18
2017 August	17	5	22
2017 July	14	6	20
2017 June	19	5	24
2017 May	33	3	36
2017 April	33	4	37
2017 March	29	23	52
2017 February	42	6	48
2017 January	11	3	14
2016 December	25	4	29
2016 November	24	4	28
2016 October	36	3	39
2016 September	30	3	33
2016 August	28	6	34
2016 July	25	4	29
2016 June	27	4	31
2016 May	29	9	38
2016 April	27	10	37
2016 March	27	12	39
2016 February	30	16	46
2016 January	35	12	47
2015 December	22	11	33
2015 November	12	12	24
2015 October	29	14	43
2015 September	25	8	33
2015 August	13	5	18
2015 July	22	4	26
2015 June	10	0	10
2015 May	19	3	22
2015 April	33	11	44
2015 March	19	13	32
2015 February	13	8	21
2015 January	34	5	39
2014 December	44	11	55
2014 November	14	0	14
2014 October	33	8	41
2014 September	32	4	36
2014 August	23	3	26
2014 July	1	0	1
2014 May	2	0	2
2014 January	1	0	1
2013 July	2	0	2
2013 June	0	1	1

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