was read the article
array:24 [ "pii" => "S1807593222023985" "issn" => "18075932" "doi" => "10.6061/clinics/2012(Sup01)12" "estado" => "S300" "fechaPublicacion" => "2012-04-01" "aid" => "2398" "copyright" => "CLINICS" "copyrightAnyo" => "2012" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "rev" "cita" => "Clinics. 2012;67 Supl 1:63-7" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "itemSiguiente" => array:19 [ "pii" => "S1807593222023997" "issn" => "18075932" "doi" => "10.6061/clinics/2012(Sup01)13" "estado" => "S300" "fechaPublicacion" => "2012-04-01" "aid" => "2399" "copyright" => "CLINICS" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "rev" "cita" => "Clinics. 2012;67 Supl 1:69-75" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">REVIEW</span>" "titulo" => "Genotype-phenotype correlation in multiple endocrine neoplasia type 2" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "69" "paginaFinal" => "75" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 194 "Ancho" => 425 "Tamanyo" => 14300 ] ] "descripcion" => array:1 [ "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Germline mutations in the <span class="elsevierStyleItalic">RET</span> proto-oncogene associated with MEN2 and FMTC. Numbers indicate the mutated codons of the <span class="elsevierStyleItalic">RET</span> gene.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Friedhelm Raue, Karin Frank-Raue" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Friedhelm" "apellidos" => "Raue" ] 1 => array:2 [ "nombre" => "Karin" "apellidos" => "Frank-Raue" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222023997?idApp=UINPBA00004N" "url" => "/18075932/00000067000000S1/v1_202212010649/S1807593222023997/v1_202212010649/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1807593222023973" "issn" => "18075932" "doi" => "10.6061/clinics/2012(Sup01)11" "estado" => "S300" "fechaPublicacion" => "2012-04-01" "aid" => "2397" "copyright" => "CLINICS" "documento" => "article" "crossmark" => 0 "licencia" => "https://creativecommons.org/licenses/by-nc/3.0/" "subdocumento" => "rev" "cita" => "Clinics. 2012;67 Supl 1:57-61" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">REVIEW</span>" "titulo" => "<span class="elsevierStyleItalic">RET</span> haplotype, not linked to the C620R activating mutation, associated with Hirschsprung disease in a novel MEN2 family" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "57" "paginaFinal" => "61" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 388 "Ancho" => 560 "Tamanyo" => 48959 ] ] "descripcion" => array:1 [ "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Identification of different haplotypes, including the rs2505533 and rs34827976 SNPs, in relatives with MTC/HSCR or MTC alone (non-HSCR) who carry the C620R <span class="elsevierStyleItalic">RET</span> mutation. The observed haplotype in the HSCR/MTC patients (red) contains the region previously recognized as related to the sporadic and familial forms of HSCR (<a class="elsevierStyleCrossRef" href="#bib1">1</a>),(<a class="elsevierStyleCrossRef" href="#bib2">2</a>). Four SNPs within this region are only homozygous (aa) in patients with HSCR.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Elisangela P.S. Quedas, Viviane C. Longuini, Tomoko Sekiya, Flavia L. Coutinho, Sergio P.A. Toledo, Uenis Tannuri, Rodrigo A. Toledo" "autores" => array:7 [ 0 => array:2 [ "nombre" => "Elisangela P.S." "apellidos" => "Quedas" ] 1 => array:2 [ "nombre" => "Viviane C." "apellidos" => "Longuini" ] 2 => array:2 [ "nombre" => "Tomoko" "apellidos" => "Sekiya" ] 3 => array:2 [ "nombre" => "Flavia L." "apellidos" => "Coutinho" ] 4 => array:2 [ "nombre" => "Sergio P.A." "apellidos" => "Toledo" ] 5 => array:2 [ "nombre" => "Uenis" "apellidos" => "Tannuri" ] 6 => array:2 [ "nombre" => "Rodrigo A." "apellidos" => "Toledo" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222023973?idApp=UINPBA00004N" "url" => "/18075932/00000067000000S1/v1_202212010649/S1807593222023973/v1_202212010649/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">REVIEW</span>" "titulo" => "The Hirschsprung's–multiple endocrine neoplasia connection" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "63" "paginaFinal" => "67" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Sam W. Moore, Monique Zaahl" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Sam W." "apellidos" => "Moore" "email" => array:1 [ 0 => "swm@sun.ac.za" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">I</span>" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor1" ] ] ] 1 => array:3 [ "nombre" => "Monique" "apellidos" => "Zaahl" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">II</span>" "identificador" => "aff2" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Division of Pediatric Surgery, Faculty of Medicine, University of Stellenbosch, Tygerberg, South Africa." "etiqueta" => "I" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "Division of Human Genetics, Faculty of Medicine, University of Stellenbosch, Tygerberg, South Africa." "etiqueta" => "II" "identificador" => "aff2" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor1" "etiqueta" => "*" "correspondencia" => "Tel.: 27 21 9389280" ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Hirschsprung's disease (HSCR), or aganglionic megacolon, occurs due to the congenital absence of parasympathetic neuronal ganglia in a segment of the hindgut, resulting in malfunction of the affected segment. The condition presents as a common cause of intestinal obstruction in neonates, with an incidence of 1 in 5,000 (0.02%) live births and an overall risk to siblings of 4% (<a class="elsevierStyleCrossRefs" href="#bib1">1–3</a>). A study of HSCR indicates several clear-cut associations that are known or are suspected to be related to an increased risk of HSCR. These include its recurrence in families and the association with the major susceptibility genes points convincingly to genetic factors in its multifactorial pathogenesis. The main susceptibility gene for Hirschsprung's disease is the <span class="elsevierStyleItalic">RET</span> (rearranged during transfection) proto-oncogene tyrosine kinase which is situated at chromosome 10q11.2.</p><p id="para20" class="elsevierStylePara elsevierViewall">There are early reports of associations between HSCR and a number of associated anomalies related to neural cell development. These include neuroblastoma (<a class="elsevierStyleCrossRef" href="#bib1">1</a>), phaeochromocytoma (<a class="elsevierStyleCrossRef" href="#bib1">1</a>),(<a class="elsevierStyleCrossRef" href="#bib4">4</a>),(<a class="elsevierStyleCrossRef" href="#bib5">5</a>) and multiple endocrine neoplasia (MEN) type 2 A and B syndromes (<a class="elsevierStyleCrossRefs" href="#bib5">5–7</a>), among others (<a class="elsevierStyleCrossRef" href="#bib1">1</a>). Reports on this relatively uncommon cosegregation of HSCR and MEN2 in the same patient (<a class="elsevierStyleCrossRef" href="#bib6">6</a>),(<a class="elsevierStyleCrossRefs" href="#bib8">8–20</a>) exist because of the common factor of the <span class="elsevierStyleItalic">RET</span> gene being associated with both conditions (HSCR, MEN type 2 and medullary thyroid carcinoma (MTC). This is an extremely interesting observation, as it involves both gain and loss of function of the same gene in the same patient.</p><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">Which patients are at risk?</span><p id="para30" class="elsevierStylePara elsevierViewall">The MEN–HSCR association has been shown to cosegregate in HSCR patients with both short- and long-segment aganglionosis (<a class="elsevierStyleCrossRef" href="#bib21">21</a>). It seems to be particularly associated with long-segment aganglionic segments, and Decker et al. (<a class="elsevierStyleCrossRef" href="#bib21">21</a>) reported a long aganglionic segment (L-HSCR) in seven out of 13 patients (54%). Our experience is of total colonic aganglionosis (TCA) in the index patient in all three families identified in our series (<a class="elsevierStyleCrossRef" href="#bib22">22</a>). It therefore appears that patients with long-segment HSCR carry the highest risk of developing MTC and should have a detailed family history taken: the presence of a long-segment HSCR should be an important selection criterion for gene testing in HSCR.</p><p id="para40" class="elsevierStylePara elsevierViewall">It is important to explore this concept further in families where HSCR and MTC coexist, as it will yield possible <span class="elsevierStyleItalic">RET</span> gene associations and insights into possible molecular reasons for the phenotypic expression. It is generally accepted that aberrant RET protein synthesis, due to inactivating genetic variations, lead to the congenital malformation of the enteric nervous system (ENS) which we call Hirschsprung's disease. <span class="elsevierStyleItalic">RET</span> gene activation occurs in MEN2A.</p><p id="para50" class="elsevierStylePara elsevierViewall">The HSCR–MTC relationship also appears to be bi-directional, and <span class="elsevierStyleItalic">RET</span> gene activation or suppression appeared to vary over succeeding generations within the same family (<a class="elsevierStyleCrossRef" href="#bib22">22</a>). Butter et al. (<a class="elsevierStyleCrossRef" href="#bib23">23</a>) reported a 50% incidence of HSCR in 20 patients undergoing a prophylactic thyroidectomy for <span class="elsevierStyleItalic">RET</span>-associated MTC risk (a <span class="elsevierStyleItalic">RET C620</span> mutation). In one further reported case of familial MTC (<a class="elsevierStyleCrossRef" href="#bib24">24</a>) with a <span class="elsevierStyleItalic">C620S</span> point mutation, the MTC developed 12 years after surgical correction of HSCR in the child plus a maternal MTC 7 years after the child's birth. In our reported series (<a class="elsevierStyleCrossRef" href="#bib22">22</a>), MTC was detected in the parent 5 years after the birth of the affected child.</p></span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">Hirschsprung's, MEN and the <span class="elsevierStyleItalic">RET</span> proto-oncogene</span><p id="para60" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">RET</span> proto-oncogene [10q11.22] is the major gene involved in the pathogenesis of HSCR with causative loss-of-function mutations being identified in more than 70% of cases (<a class="elsevierStyleCrossRef" href="#bib25">25</a>). In essence, the extracellular domain <span class="elsevierStyleItalic">RET</span> mutations alter the protein and possibly its processing in the endoplasmic reticulum (<a class="elsevierStyleCrossRef" href="#bib26">26</a>). As a result, <span class="elsevierStyleItalic">RET</span> transport to and its expression at the cell surface is decreased.</p><p id="para70" class="elsevierStylePara elsevierViewall">Multiple endocrine neoplasia also results from autosomally dominant, inherited, highly penetrant germline <span class="elsevierStyleItalic">RET</span> mutations that predispose patients to the development of tumors in cells derived from neural crest origin. Of the more than 25 <span class="elsevierStyleItalic">RET</span> proto-oncogene gene mutations which have been described in association with MEN type 2 syndromes, the most important are associated with the six cysteine alleles of the extracellular portion of the <span class="elsevierStyleItalic">RET</span> proto-oncogene in MEN2A.</p><p id="para80" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">RET</span> is a vital gene which directs the migration, proliferation and survival of the enteric neural crest-derived cells of the enteric nervous system (ENS) during embryogenesis. It is also responsible for the development of the autonomic nervous system as well as for controlling kidney development and spermatogenesis, among other functions. Genetic mutation and/or variation may result in <span class="elsevierStyleItalic">RET</span> malfunction, which has been associated with at least four clinical conditions (HSCR, MEN type 2 syndromes (A and B) and familial medullary thyroid carcinoma (FMTC). In HSCR, hypomorphic <span class="elsevierStyleItalic">RET</span> alleles may cause delayed neuroblast migration and non-apoptotic cell death. This causes ENS maldevelopment, resulting in aganglionosis (HSCR) and other related conditions of the ENS.</p><p id="para90" class="elsevierStylePara elsevierViewall">The presence of a HSCR–MEN2 association raises the question of which HSCR patients are at greatest risk and should therefore be further investigated by <span class="elsevierStyleItalic">RET</span> gene analysis. Hereditary MTC can, with rare exceptions, be traced back in family trees (<a class="elsevierStyleCrossRef" href="#bib27">27</a>) and the HSCR–MEN2 familial association may be missed because the MTC may appear later in life without the connection being made. As a result, the risk of HSCR patients later developing features of an MEN2 syndrome (with MTC) is thought to be under-evaluated. The risk of a future thyroid carcinoma remains a matter of general concern in long-term HSCR management. It is becoming clear that there is a need for screening in order to determine which patients require <span class="elsevierStyleItalic">RET</span> gene analysis as a means of determining risk.</p><p id="para100" class="elsevierStylePara elsevierViewall">The most frequently identified mutation responsible for MEN2A involves the substitution of the cysteine amino acid at position 634 (Cys634Arg or C634R) by the amino acid arginine. However, point mutations in the cysteine-rich <span class="elsevierStyleItalic">RET</span> area at the <span class="elsevierStyleItalic">620</span> position, along with some other <span class="elsevierStyleItalic">RET</span> gene areas (e.g. <span class="elsevierStyleItalic">C609, C611</span> and <span class="elsevierStyleItalic">C618</span>) have been reported as being mostly associated with the HSCR–MEN2 phenotype. By way of contrast, in >90% of MEN2B patients, the amino acid methionine is replaced by threonine at position 918 (M918T) in the intracellular portion of the gene. There are also a number of other <span class="elsevierStyleItalic">RET</span> variations that are associated with thyroid cancers and familial medullary thyroid carcinoma which may give rise to an overactive abnormal RET protein.</p><p id="para110" class="elsevierStylePara elsevierViewall">The cosegregation of HSCR and MEN2 is particularly interesting as it involves both a “switch off” and a “switch on” of the gene in the same patient. Some remarkable family lineages have been reported which demonstrate the occurrence of the two conditions in family lineages (<a class="elsevierStyleCrossRef" href="#bib17">17</a>),(<a class="elsevierStyleCrossRef" href="#bib22">22</a>).</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">Which <span class="elsevierStyleItalic">RET</span> gene variations are important?</span><p id="para120" class="elsevierStylePara elsevierViewall">Like other receptor tyrosine kinases (RTKs), <span class="elsevierStyleItalic">RET</span> is made up of at least three functional areas (extracellular, transmembrane and intracellular regions) which appear to have specific roles in cellular function (<a class="elsevierStyleCrossRef" href="#bib28">28</a>). It is interesting that, in contrast to other susceptibility areas, the <span class="elsevierStyleItalic">RET</span> mutations which have been identified as carrying both a risk for HSCR as well as MEN2 approximate the transmembrane domain of the gene (mostly <span class="elsevierStyleItalic">C620R</span> and occasionally <span class="elsevierStyleItalic">C620S</span> and rarely <span class="elsevierStyleItalic">C620W</span>) (<a class="elsevierStyleCrossRef" href="#bib21">21</a>). Although the majority of reports connect these two conditions with point mutations in the cysteine-rich <span class="elsevierStyleItalic">RET-</span>area at the <span class="elsevierStyleItalic">620</span> position, other <span class="elsevierStyleItalic">RET</span> gene areas (e.g. <span class="elsevierStyleItalic">C609, C611</span> and <span class="elsevierStyleItalic">C618</span>) have been reported as alternative sites. The high frequency with which the C620 <span class="elsevierStyleItalic">RET</span> mutation occurs in HSCR–MEN patients suggests the concept of the so-called “Janus gene” mutation in this position, which, like the Roman god of doorways, can face in both directions (i.e. activation (MEN/MTC) and inactivation (HSCR).</p><p id="para130" class="elsevierStylePara elsevierViewall">Our own studies (<a class="elsevierStyleCrossRef" href="#bib22">22</a>) have shown the <span class="elsevierStyleItalic">RET</span>-620 cysteine variations to be present in 2.5% of HSCR families (three out of 118 families investigated), which is in keeping with other reports (<a class="elsevierStyleCrossRef" href="#bib21">21</a>). There was, however, an uncertain prevalence of HSCR–MEN in related family members as not all could be tested.</p><p id="para140" class="elsevierStylePara elsevierViewall">Studies have also shown that the closer mutations are to the transmembrane domain, the higher their importance in terms of the development of cellular proliferation and tumor activation (<a class="elsevierStyleCrossRef" href="#bib29">29</a>). A strong self-association has been shown in the transmembrane portion of the gene (<span class="elsevierStyleItalic">RET</span>-TM), which has been suggested as a possible explanation of the oncogenic activation due to <span class="elsevierStyleItalic">RET</span>–cysteine mutations in oncogenesis (<a class="elsevierStyleCrossRef" href="#bib29">29</a>). This suggests an area that plays an important role in MTC risk evaluation and may identify a target area for novel therapeutic strategies.</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">How does <span class="elsevierStyleItalic">RET</span> gene variation result in cellular activation?</span><p id="para150" class="elsevierStylePara elsevierViewall">Because MEN2A relates mostly to the <span class="elsevierStyleItalic">RET</span> alleles at the six cysteine positions in the extracellular domain of the gene, it appears to induce a different set of downstream signaling genes from that carrying the MEN 2B mutation.</p><p id="para160" class="elsevierStylePara elsevierViewall">The multidocking intracellular portion of the <span class="elsevierStyleItalic">RET</span> gene where MEN2B <span class="elsevierStyleItalic">RET</span> variations are situated appears to be vital to both tyrosine kinase function and downstream signaling due to the number of signaling molecules that interact there (e.g. <span class="elsevierStyleItalic">Shc, Src, FRS2, IRS1, Gab1/2,</span> and <span class="elsevierStyleItalic">Enigma</span>) (<a class="elsevierStyleCrossRefs" href="#bib30">30–32</a>). It is therefore easier to understand how mutations within this tyrosine-kinase rich region (e.g. in 95% of MEN2B patients) alters the substrate specificity of RET tyrosine kinase and results in gene activation.</p><p id="para170" class="elsevierStylePara elsevierViewall">The mechanism whereby <span class="elsevierStyleItalic">RET</span> influences gene activation in MEN2A is more complex. Genetic variations impair the RET tyrosine kinase response to tyrosine kinase activation, thus appearing to dictate downstream signaling cascade response (<a class="elsevierStyleCrossRef" href="#bib33">33</a>). The induction of a disulfide-linked homodimerization resulting from the cysteine-related mutations within the extracellular portion of the <span class="elsevierStyleItalic">RET</span> proto-oncogene promote dimer formation within the gene as covalent receptor dimers are linked by disulfide bonds between unpaired cysteines (<a class="elsevierStyleCrossRef" href="#bib34">34</a>),(<a class="elsevierStyleCrossRef" href="#bib35">35</a>). It is known that the RET protein targets a number of intracellular signaling cascades, including the <span class="elsevierStyleItalic">RAS-RAF-ERK1/2, PIK3-AKT</span>, and <span class="elsevierStyleItalic">STAT</span> transcription pathways (<a class="elsevierStyleCrossRef" href="#bib36">36</a>). The activation of the <span class="elsevierStyleItalic">MAPK</span> and <span class="elsevierStyleItalic">Ras</span>/<span class="elsevierStyleItalic">ERK</span> molecular signaling cascades involves <span class="elsevierStyleItalic">grb2/mSOS</span> recruitment (<a class="elsevierStyleCrossRef" href="#bib37">37</a>). In addition, recent studies have suggested that the mammalian target of the rapamycin (mTOR) intracellular signaling pathway is functionally activated in MTC (especially in those with germline <span class="elsevierStyleItalic">RET</span> mutations) (<a class="elsevierStyleCrossRef" href="#bib38">38</a>), and that the role of the other downstream RET tyrosine kinase signaling cascades (e.g. BRAF, RAS isoforms and PI3 kinase) is less certain.</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">How does the <span class="elsevierStyleItalic">RET</span>-620 relationship work?</span><p id="para180" class="elsevierStylePara elsevierViewall">Oncogenic <span class="elsevierStyleItalic">RET</span> mutations mostly occur <span class="elsevierStyleItalic">de novo</span> in sporadic MTC, and it is now well accepted that <span class="elsevierStyleItalic">RET</span> gene variations produce aberrant proteins which may bypass the normal linking to growth factors outside the cell, most probably triggering cells to grow and divide abnormally and, in turn, promoting tumor formation. Ret activation then promotes Ret-dimer formation and activation of the tyrosine kinase outside of the normal ligand binding system.</p><p id="para190" class="elsevierStylePara elsevierViewall">However, little is known of the actual mechanisms whereby extracellular domain mutations (e.g. <span class="elsevierStyleItalic">C620S</span>) may result in C-cell proliferation (<a class="elsevierStyleCrossRef" href="#bib39">39</a>). Current understanding of <span class="elsevierStyleItalic">RET</span> gene activation in MTC is that the gene is activated by alterations in autophosphorylation, or alternatively by the modification of the subcellular distribution of the active kinase or the induction of unusual interactions with other proteins (e.g. RET/PTC) (<a class="elsevierStyleCrossRef" href="#bib40">40</a>).</p><p id="para200" class="elsevierStylePara elsevierViewall">It is possible that the MEN2A–HSCR connection represents a second alternative intracellular mechanism in the pathogenesis of MTC (<a class="elsevierStyleCrossRef" href="#bib41">41</a>). The less common codons <span class="elsevierStyleItalic">C620, C618</span> and <span class="elsevierStyleItalic">C611</span> within exon 10 confer a weaker transforming activity <span class="elsevierStyleItalic">in vitro</span> than exon 11 (C634) <span class="elsevierStyleItalic">RET</span> mutations (<a class="elsevierStyleCrossRef" href="#bib42">42</a>). It has been suggested that the MEN2A–HSCR connection represents a second alternative intracellular mechanism in the pathogenesis of MTC involving the endoplasmic reticulum which has been shown to decrease cell surface <span class="elsevierStyleItalic">RET e</span>xpression in HSCR (<a class="elsevierStyleCrossRef" href="#bib26">26</a>). Changes in polarity in MEN2A–HSCR may result in the unfolding of the RET protein initially failing to achieve homeostasis via the unfolded protein response (UPR) of the endoplasmic reticulum, leading to apoptosis and HSCR. Subsequent upregulation of the UPR may then induce changes which allow gene activation, thus providing a growth advantage to tumor cells.</p><p id="para210" class="elsevierStylePara elsevierViewall">Oncogenic <span class="elsevierStyleItalic">RET</span> mutations affect protein synthesis and function, which then influence a number of downstream molecular signaling pathways (<a class="elsevierStyleCrossRef" href="#bib43">43</a>). Studies have demonstrated that Ret influences the downstream phosphorylation of the insulin receptor substrate-2 (<span class="elsevierStyleItalic">IRS 2</span>) with subsequent activation of phosphatidylinositol 3 kinase (<span class="elsevierStyleItalic">PI 3-kinase</span>) and protein kinase B (<span class="elsevierStyleItalic">PKB/AKT</span>) signaling pathways (<a class="elsevierStyleCrossRef" href="#bib44">44</a>). In addition, the induction of phosphorylation of SHC results in growth factor receptor binding protein 2 (<span class="elsevierStyleItalic">Grb-2</span>) binding and activation of the mitogen-activating protein (<span class="elsevierStyleItalic">MAP</span>) kinase pathway (<a class="elsevierStyleCrossRef" href="#bib45">45</a>). The resulting <span class="elsevierStyleItalic">MAPK IRS-2, PI 3-kinase</span> and <span class="elsevierStyleItalic">PKB/AKT</span> activation could transduce the oncogenic Ret signal to promote gene transcription, possibly through activation of the jun/AP-1 transcription cascades (<a class="elsevierStyleCrossRef" href="#bib44">44</a>).</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Impact on treatment</span><p id="para220" class="elsevierStylePara elsevierViewall">This paper draws attention to the apparent genotype–phenotype correlation which exists between <span class="elsevierStyleItalic">RET</span> and the MEN2 syndromes (<a class="elsevierStyleCrossRef" href="#bib46">46</a>),(<a class="elsevierStyleCrossRef" href="#bib47">47</a>). Clinical awareness of possible MTC has led to timely intervention and early treatment of this poor prognosis chemo- and radioresistant tumor. Establishment of “risk” by genetic testing has become a classic model of molecular medicine being integrated into patient care. It is therefore fairly clear that <span class="elsevierStyleItalic">RET</span> gene screening is of considerable value in familial screening, and offering <span class="elsevierStyleItalic">RET</span> testing is considered best practice for the clinical management of patients at risk of MEN2A and MEN2B.</p><p id="para230" class="elsevierStylePara elsevierViewall">Gene mutation in the <span class="elsevierStyleItalic">RET 620</span> position carries significant risk of developing HSCR and/or MTC. In the interests of cost-effectiveness, it may be part of a targeted investigation of high-risk areas of the gene in HSCR patients at risk, thus facilitating follow-up and future management. Genetic screening is an extremely sensitive method of identifying risk in MEN2 syndromes (±98%) and prophylactic surgical intervention may prevent the onset of the radio- and chemoresistant MTC (<a class="elsevierStyleCrossRef" href="#bib48">48</a>).</p><p id="para240" class="elsevierStylePara elsevierViewall">Better understanding of the <span class="elsevierStyleItalic">RET</span>-620 relationship would also allow for a more cost-effective method of identifying those at risk by focusing <span class="elsevierStyleItalic">RET</span> gene testing to this specific area as a “hot spot”. In addition, a number of attractive targets are being identified which may be suitable for novel therapeutic signaling pathway-specific drug design (<a class="elsevierStyleCrossRef" href="#bib49">49</a>). Novel approaches to treatment based on this genetic knowledge have already resulted in randomized clinical trials into the effectiveness of multi-kinase inhibitors such as axitinib, sorafenib, motesanib, and XL-184. These have shown early promise in selected cases which may soon change the management of thyroid cancer (<a class="elsevierStyleCrossRef" href="#bib50">50</a>).</p></span></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "xpalclavsec1581204" "titulo" => "KEYWORDS" ] 1 => array:3 [ "identificador" => "cesec10" "titulo" => "INTRODUCTION" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "cesec20" "titulo" => "Which patients are at risk?" ] 1 => array:2 [ "identificador" => "cesec30" "titulo" => "Hirschsprung's, MEN and the RET proto-oncogene" ] 2 => array:2 [ "identificador" => "cesec40" "titulo" => "Which RET gene variations are important?" ] 3 => array:2 [ "identificador" => "cesec50" "titulo" => "How does RET gene variation result in cellular activation?" ] 4 => array:2 [ "identificador" => "cesec60" "titulo" => "How does the RET-620 relationship work?" ] 5 => array:2 [ "identificador" => "cesec70" "titulo" => "Impact on treatment" ] ] ] 2 => array:1 [ "titulo" => "REFERENCES" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "KEYWORDS" "identificador" => "xpalclavsec1581204" "palabras" => array:5 [ 0 => "Hirschsprung's disease" 1 => "Genetics" 2 => "Novel mutations" 3 => "<span class="elsevierStyleItalic">RET</span>" 4 => "<span class="elsevierStyleItalic">Endothelin receptor B gene</span>" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:1 [ "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><p id="spara10" class="elsevierStyleSimplePara elsevierViewall">The risk of patients with Hirschsprung's disease later developing multiple endocrine neoplasia remains a matter of concern. The multiple endocrine neoplasia 2–Hirschsprung's disease association has been shown to cosegregate in Hirschsprung's disease patients with both short- and long-segment aganglionosis, although patients with long-segment aganglionosis a to carry the greatest risk. The Hirschsprung's disease–medullary thyroid carcinoma relationship also appears to be bi-directional, and activation or suppression of the <span class="elsevierStyleItalic">rearranged during transfection</span> gene appeared to vary over succeeding generations within the same family. <span class="elsevierStyleItalic">Rearranged during transfection</span> gene variations are associated with both conditions. The cosegregation of Hirschsprung's disease and multiple endocrine neoplasia 2 is particularly interesting as it involves both “switch off” and “switch on” of the <span class="elsevierStyleItalic">rearranged during transfection</span> proto-oncogene in the same patient. This cosegregation mostly relates to the cysteine-rich area on <span class="elsevierStyleItalic">RET-620</span> (the “Janus gene”). The mechanism whereby <span class="elsevierStyleItalic">rearranged during transfection</span> influences gene activation in multiple endocrine neoplasia 2 is complex, but genetic variations impair the <span class="elsevierStyleItalic">rearranged during transfection</span> tyrosine kinase response to tyrosine kinase activation, thus appearing to dictate downstream signaling cascade responses. Better understanding of the <span class="elsevierStyleItalic">RET</span>-620 relationship allows for a more cost-effective method of identifying those at risk by focusing <span class="elsevierStyleItalic">rearranged during transfection</span> gene testing to this specific area as a “hot spot”. The clinical awareness of possible medullary thyroid carcinoma has led to timely intervention and early treatment of this chemo- and radioresistant tumor with poor prognosis. Establishment of “risk” by genetic testing has become a classic model of molecular medicine being integrated into patient care and offering <span class="elsevierStyleItalic">rearranged during transfection</span>-directed prophylactic surgical management. In addition, novel approaches to treatment based on this genetic knowledge have already shown early promise in randomized clinical trials.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:1 [ "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported.</p> <p class="elsevierStyleNotepara" id="cenpara20">Moore SW is an expert on the genetic connections and other aspects of Hirschsprung's disease and MEN2 syndromes. He wrote the review and was responsible for the clinical component and interpretation of results. Zaahl M is a scientist who collaborated for a long period on this project. She is the head of the Department of Genetics at Stellenbosch University and runs the laboratory where the genetic work was carried out. She personally oversaw most of the laboratory work presented in this study.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "REFERENCES" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec10" "bibliografiaReferencia" => array:50 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The genetics of Hirschsprungs Disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ E Passarge \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "N Engl J Med" "fecha" => "1967" "volumen" => "276" "paginaInicial" => "43" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ M Angrist \n \t\t\t\t\t\t\t\t """ 1 => """ E Kauffman \n \t\t\t\t\t\t\t\t """ 2 => """ SA Slaugenhaupt \n \t\t\t\t\t\t\t\t """ 3 => """ TC Matise \n \t\t\t\t\t\t\t\t """ 4 => """ EG Puffenberger \n \t\t\t\t\t\t\t\t """ 5 => """ SS Washington \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Nat Genet" "fecha" => "1993" "volumen" => "4" "paginaInicial" => "6" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A gene for HSCR maps to the proximal long arm of chromosome 10" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ S Lyonnet \n \t\t\t\t\t\t\t\t """ 1 => """ A Bolino \n \t\t\t\t\t\t\t\t """ 2 => """ A Pelet \n \t\t\t\t\t\t\t\t """ 3 => """ L Abel \n \t\t\t\t\t\t\t\t """ 4 => """ C Nihoul-Fekete \n \t\t\t\t\t\t\t\t """ 5 => """ M Briard \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Nat Genet" "fecha" => "1993" "volumen" => "4" "paginaInicial" => "50" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Aganglionic megacolon, phaeochromocytoma, megaloureter and neurofibromatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ E Schocket \n \t\t\t\t\t\t\t\t """ 1 => """ HA Telok \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Am J Dis Child" "fecha" => "1957" "volumen" => "94" "paginaInicial" => "91" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The neurocristopathies, a unifying concept of disease arising in neural crest maldevelopment" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ RP Bolande \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Hum Pathol" "fecha" => "1974" "volumen" => "5" "paginaInicial" => "29" ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Occurrence of MEN 2a in familial Hirschsprung's disease: a new indication for genetic testing of the RET proto-oncogene" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ RA Decker \n \t\t\t\t\t\t\t\t """ 1 => """ ML Peacock \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Pediatr Surg" "fecha" => "1998" "volumen" => "33" "paginaInicial" => "14" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Gastrointestinal manifestations of the Sipple syndrome in children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ AH Khan \n \t\t\t\t\t\t\t\t """ 1 => """ JG Desjardin \n \t\t\t\t\t\t\t\t """ 2 => """ H Gregoire \n \t\t\t\t\t\t\t\t """ 3 => """ E Seidman \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Pediatr Surg" "fecha" => "1987" "volumen" => "22" "paginaInicial" => "23" ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A novel Czech kindred with familial medullary thyroid carcinoma and Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ S Dvorakova \n \t\t\t\t\t\t\t\t """ 1 => """ K Dvorakova \n \t\t\t\t\t\t\t\t """ 2 => """ M Malikova \n \t\t\t\t\t\t\t\t """ 3 => """ R Skaba \n \t\t\t\t\t\t\t\t """ 4 => """ P Vlcek \n \t\t\t\t\t\t\t\t """ 5 => """ B Bendlova \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Pediatr Surg" "fecha" => "2005" "volumen" => "40" "paginaInicial" => "6" ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ 1 => """ C Eng \n \t\t\t\t\t\t\t\t """ 2 => """ T Attie \n \t\t\t\t\t\t\t\t """ 3 => """ S Lyonnet \n \t\t\t\t\t\t\t\t """ 4 => """ DJ Marsh \n \t\t\t\t\t\t\t\t """ 5 => """ VJ Hyland \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Hum Mol Genet" "fecha" => "1994" "volumen" => "3" "paginaInicial" => "7" ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "C618R mutation in exon 10 of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ P Caron \n \t\t\t\t\t\t\t\t """ 1 => """ T Attie \n \t\t\t\t\t\t\t\t """ 2 => """ D David \n \t\t\t\t\t\t\t\t """ 3 => """ J Amiel \n \t\t\t\t\t\t\t\t """ 4 => """ F Brousset \n \t\t\t\t\t\t\t\t """ 5 => """ P Roger \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1996" "volumen" => "81" "paginaInicial" => "3" ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ H Peretz \n \t\t\t\t\t\t\t\t """ 1 => """ R Luboshitsky \n \t\t\t\t\t\t\t\t """ 2 => """ E Baron \n \t\t\t\t\t\t\t\t """ 3 => """ A Biton \n \t\t\t\t\t\t\t\t """ 4 => """ R Gershoni \n \t\t\t\t\t\t\t\t """ 5 => """ S Usher \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Hum Mutat" "fecha" => "1997" "volumen" => "10" "paginaInicial" => "9" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Association of multiple endocrine neoplasia type 2 and Hirschsprung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ G Romeo \n \t\t\t\t\t\t\t\t """ 1 => """ I Ceccherini \n \t\t\t\t\t\t\t\t """ 2 => """ J Celli \n \t\t\t\t\t\t\t\t """ 3 => """ M Priolo \n \t\t\t\t\t\t\t\t """ 4 => """ N Betsos \n \t\t\t\t\t\t\t\t """ 5 => """ G Bonardi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Intern Med" "fecha" => "1998" "volumen" => "243" "paginaInicial" => "20" ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oncological implications of RET gene mutations in Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ RH Sijmons \n \t\t\t\t\t\t\t\t """ 1 => """ RM Hofstra \n \t\t\t\t\t\t\t\t """ 2 => """ FA Wijburg \n \t\t\t\t\t\t\t\t """ 3 => """ TP Links \n \t\t\t\t\t\t\t\t """ 4 => """ RP Zwierstra \n \t\t\t\t\t\t\t\t """ 5 => """ A Vermey \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1136/gut.43.1.7" "Revista" => array:5 [ "tituloSerie" => "Gut" "fecha" => "1998" "volumen" => "43" "paginaInicial" => "7" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9771398" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hirschsprung's disease in a family with multiple endocrine neoplasia type 2" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ M Verdy \n \t\t\t\t\t\t\t\t """ 1 => """ AM Weber \n \t\t\t\t\t\t\t\t """ 2 => """ CC Roy \n \t\t\t\t\t\t\t\t """ 3 => """ CL Morin \n \t\t\t\t\t\t\t\t """ 4 => """ M Cadotte \n \t\t\t\t\t\t\t\t """ 5 => """ P Brochu \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Pediatr Gastroenterol Nutr" "fecha" => "1982" "volumen" => "1" "paginaInicial" => "7" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6310073" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ MJ Borst \n \t\t\t\t\t\t\t\t """ 1 => """ JM VanCamp \n \t\t\t\t\t\t\t\t """ 2 => """ ML Peacock \n \t\t\t\t\t\t\t\t """ 3 => """ RA Decker \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Surgery" "fecha" => "1995" "volumen" => "117" "paginaInicial" => "91" ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical presentations and RET protooncogene mutations in seven multiple endocrine neoplasia type 2 kindreds" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ RD Blank \n \t\t\t\t\t\t\t\t """ 1 => """ CA Sklar \n \t\t\t\t\t\t\t\t """ 2 => """ AB Dimich \n \t\t\t\t\t\t\t\t """ 3 => """ MP LaQuaglia \n \t\t\t\t\t\t\t\t """ 4 => """ MF Brennan \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Cancer" "fecha" => "1996" "volumen" => "78" "paginaInicial" => "2003" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular analysis of the ret and GDNF genes in a family with multiple endocrine neoplasia type 2A and Hirschsprung disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ S Borrego \n \t\t\t\t\t\t\t\t """ 1 => """ C Eng \n \t\t\t\t\t\t\t\t """ 2 => """ B Sanchez \n \t\t\t\t\t\t\t\t """ 3 => """ ME Saez \n \t\t\t\t\t\t\t\t """ 4 => """ E Navarro \n \t\t\t\t\t\t\t\t """ 5 => """ G Antinolo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1998" "volumen" => "83" "paginaInicial" => "4" ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutational analysis of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ K Inoue \n \t\t\t\t\t\t\t\t """ 1 => """ T Shimotake \n \t\t\t\t\t\t\t\t """ 2 => """ K Inoue \n \t\t\t\t\t\t\t\t """ 3 => """ K Tokiwa \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Pediatr Surg" "fecha" => "1999" "volumen" => "34" "paginaInicial" => "4" ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ B Pasini \n \t\t\t\t\t\t\t\t """ 1 => """ R Rossi \n \t\t\t\t\t\t\t\t """ 2 => """ MR Ambrosio \n \t\t\t\t\t\t\t\t """ 3 => """ MC Zatelli \n \t\t\t\t\t\t\t\t """ 4 => """ M Gullo \n \t\t\t\t\t\t\t\t """ 5 => """ M Gobbo \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1067/msy.2002.118316" "Revista" => array:5 [ "tituloSerie" => "Surgery" "fecha" => "2002" "volumen" => "131" "paginaInicial" => "81" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11812967" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple endocrine neoplasia syndromes, children, Hirschsprung's disease and RET" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ SW Moore \n \t\t\t\t\t\t\t\t """ 1 => """ MG Zaahl \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Pediatr Surg Int" "fecha" => "2008" "volumen" => "24" "paginaInicial" => "30" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ RA Decker \n \t\t\t\t\t\t\t\t """ 1 => """ ML Peacock \n \t\t\t\t\t\t\t\t """ 2 => """ P Watson \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Hum Mol Genet" "fecha" => "1998" "volumen" => "7" "paginaInicial" => "134" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 “Janus” genetic variation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ SW Moore \n \t\t\t\t\t\t\t\t """ 1 => """ M Zaahl \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Pediatr Surg" "fecha" => "2010" "volumen" => "45" "paginaInicial" => "6" ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prophylactic thyroidectomy in pediatric carriers of multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma: mutation in C620 is associated with Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ A Butter \n \t\t\t\t\t\t\t\t """ 1 => """ J Gagne \n \t\t\t\t\t\t\t\t """ 2 => """ A Al Jazaeri \n \t\t\t\t\t\t\t\t """ 3 => """ MA Emran \n \t\t\t\t\t\t\t\t """ 4 => """ C Deal \n \t\t\t\t\t\t\t\t """ 5 => """ D St Vil \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Pediatr Surg" "fecha" => "2007" "volumen" => "42" "paginaInicial" => "6" ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Total thyroidectomy for hereditary medullary thyroid carcinoma 12 years after correction of Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ Y Sasaki \n \t\t\t\t\t\t\t\t """ 1 => """ T Shimotake \n \t\t\t\t\t\t\t\t """ 2 => """ S Go \n \t\t\t\t\t\t\t\t """ 3 => """ N Iwai \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Eur J Surg" "fecha" => "2001" "volumen" => "167" "paginaInicial" => "9" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ RM Hofstra \n \t\t\t\t\t\t\t\t """ 1 => """ Y Wu \n \t\t\t\t\t\t\t\t """ 2 => """ RP Stulp \n \t\t\t\t\t\t\t\t """ 3 => """ P Elfferich \n \t\t\t\t\t\t\t\t """ 4 => """ J Osinga \n \t\t\t\t\t\t\t\t """ 5 => """ SM Maas \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Hum Mutat" "fecha" => "2005" "volumen" => "15" "paginaInicial" => "29" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intrinsic susceptibility to misfolding of a hot-spot for Hirschsprung disease mutations in the ectodomain of RET" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ S Kjaer \n \t\t\t\t\t\t\t\t """ 1 => """ CF Ibanez \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Hum Mol Genet" "fecha" => "2003" "volumen" => "12" "paginaInicial" => "44" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Familial prevalence and age of RET germline mutations: implications for screening" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ A Machens \n \t\t\t\t\t\t\t\t """ 1 => """ H Dralle \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Clin Endocrinol (Oxf)" "fecha" => "2008" "volumen" => "69" "paginaInicial" => "7" ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Exon structure and flanking intronic sequences of the human RET proto-oncogene" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ I Ceccherini \n \t\t\t\t\t\t\t\t """ 1 => """ R Bocciardi \n \t\t\t\t\t\t\t\t """ 2 => """ Y Luo \n \t\t\t\t\t\t\t\t """ 3 => """ B Pasini \n \t\t\t\t\t\t\t\t """ 4 => """ R Hofstra \n \t\t\t\t\t\t\t\t """ 5 => """ M Takahashi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Biochem Biophys Res Commun" "fecha" => "1993" "volumen" => "196" "paginaInicial" => "95" ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ S Kjaer \n \t\t\t\t\t\t\t\t """ 1 => """ K Kurokawa \n \t\t\t\t\t\t\t\t """ 2 => """ M Perrinjaquet \n \t\t\t\t\t\t\t\t """ 3 => """ C Abrescia \n \t\t\t\t\t\t\t\t """ 4 => """ CF Ibanez \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Oncogene" "fecha" => "2006" "volumen" => "25" "paginaInicial" => "95" ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib30" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ M Santoro \n \t\t\t\t\t\t\t\t """ 1 => """ F Carlomagno \n \t\t\t\t\t\t\t\t """ 2 => """ A Romano \n \t\t\t\t\t\t\t\t """ 3 => """ DP Bottaro \n \t\t\t\t\t\t\t\t """ 4 => """ NA Dathan \n \t\t\t\t\t\t\t\t """ 5 => """ M Grieco \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Science" "fecha" => "1995" "volumen" => "267" "paginaInicial" => "3" ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Identification of Shc docking site on Ret tyrosine kinase" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ E Arighi \n \t\t\t\t\t\t\t\t """ 1 => """ L Alberti \n \t\t\t\t\t\t\t\t """ 2 => """ F Torriti \n \t\t\t\t\t\t\t\t """ 3 => """ S Ghizzoni \n \t\t\t\t\t\t\t\t """ 4 => """ MG Rizzetti \n \t\t\t\t\t\t\t\t """ 5 => """ G Pelicci \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Oncogene" "fecha" => "1997" "volumen" => "14" "paginaInicial" => "82" ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "RET alternate splicing influences the interaction of activated RET with the SH2 and PTB domains of Shc, and the SH2 domain of Grb2" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ MJ Lorenzo \n \t\t\t\t\t\t\t\t """ 1 => """ GD Gish \n \t\t\t\t\t\t\t\t """ 2 => """ C Houghton \n \t\t\t\t\t\t\t\t """ 3 => """ T Stonehouse \n \t\t\t\t\t\t\t\t """ 4 => """ T Pawson \n \t\t\t\t\t\t\t\t """ 5 => """ B Ponder \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Oncogene" "fecha" => "1997" "volumen" => "14" "paginaInicial" => "71" ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "No one-way street: cross-talk between e-cadherin and receptor tyrosine kinase (RTK) signaling: a mechanism to regulate RTK activity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => """ CD Andl \n \t\t\t\t\t\t\t\t """ 1 => """ AK Rustgi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Cancer Biol Ther" "fecha" => "2005" "volumen" => "4" "paginaInicial" => "31" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => """ N Asai \n \t\t\t\t\t\t\t\t """ 1 => """ T Iwashita \n \t\t\t\t\t\t\t\t """ 2 => """ M Matsuyama \n \t\t\t\t\t\t\t\t """ 3 => """ M Takahashi \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Mol Cell Biol" "fecha" => "1995" "volumen" => "15" "paginaInicial" => "9" ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib35" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular defects in thyroid carcinomas: role of the RET oncogene in thyroid neoplastic transformation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ M Santoro \n \t\t\t\t\t\t\t\t """ 1 => """ M Grieco \n \t\t\t\t\t\t\t\t """ 2 => """ RM Melillo \n \t\t\t\t\t\t\t\t """ 3 => """ A Fusco \n \t\t\t\t\t\t\t\t """ 4 => """ G Vecchio \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Eur J Endocrinol" "fecha" => "1995" "volumen" => "133" "paginaInicial" => "22" ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib36" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "In vitro transforming potential, intracellular signaling properties and sensitivity to a kinase inhibitor (Sorafenib) of RET proto-oncogene variants Glu511Lys, Ser649Leu and Arg886Trp" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ H Prazeres \n \t\t\t\t\t\t\t\t """ 1 => """ JP Couto \n \t\t\t\t\t\t\t\t """ 2 => """ F Rodrigues \n \t\t\t\t\t\t\t\t """ 3 => """ J Vinagre \n \t\t\t\t\t\t\t\t """ 4 => """ J Torres \n \t\t\t\t\t\t\t\t """ 5 => """ V Trovisco \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Endocr Relat Cancer" "fecha" => "2011" "volumen" => "18" "paginaInicial" => "12" ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib37" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations of the <span class="elsevierStyleItalic">RET</span> proto-oncogene in Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ P Edery \n \t\t\t\t\t\t\t\t """ 1 => """ S Lyonnet \n \t\t\t\t\t\t\t\t """ 2 => """ LM Mulligan \n \t\t\t\t\t\t\t\t """ 3 => """ A Pelet \n \t\t\t\t\t\t\t\t """ 4 => """ E Dow \n \t\t\t\t\t\t\t\t """ 5 => """ L Abel \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/367080a0" "Revista" => array:5 [ "tituloSerie" => "Nature" "fecha" => "1994" "volumen" => "367" "paginaInicial" => "80" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7906389" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib38" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mammalian target of rapamycin pathway activation is associated to RET mutation status in medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ I Rapa \n \t\t\t\t\t\t\t\t """ 1 => """ E Saggiorato \n \t\t\t\t\t\t\t\t """ 2 => """ D Giachino \n \t\t\t\t\t\t\t\t """ 3 => """ N Palestini \n \t\t\t\t\t\t\t\t """ 4 => """ F Orlandi \n \t\t\t\t\t\t\t\t """ 5 => """ M Papotti \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jc.2010-2704" "Revista" => array:5 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2011" "volumen" => "96" "paginaInicial" => "53" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21118827" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib39" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular targets in medullary thyroid carcinoma" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => """ SW Moore \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Gene Ther Mol Biol" "fecha" => "2008" "volumen" => "12" "paginaInicial" => "8" ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib40" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular mechanisms of RET activation in human cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ M Santoro \n \t\t\t\t\t\t\t\t """ 1 => """ RM Melillo \n \t\t\t\t\t\t\t\t """ 2 => """ F Carlomagno \n \t\t\t\t\t\t\t\t """ 3 => """ A Fusco \n \t\t\t\t\t\t\t\t """ 4 => """ G Vecchio \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1749-6632.2002.tb04091.x" "Revista" => array:5 [ "tituloSerie" => "Ann N Y Acad Sci" "fecha" => "2002" "volumen" => "963" "paginaInicial" => "21" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12095925" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib41" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Two distinct mutations of the RET receptor causing Hirschsprung's disease impair the binding of signalling effectors to a multifunctional docking site" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ O Geneste \n \t\t\t\t\t\t\t\t """ 1 => """ C Bidaud \n \t\t\t\t\t\t\t\t """ 2 => """ G De Vita \n \t\t\t\t\t\t\t\t """ 3 => """ RM Hofstra \n \t\t\t\t\t\t\t\t """ 4 => """ S Tartare-Deckert \n \t\t\t\t\t\t\t\t """ 5 => """ CH Buys \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/hmg/8.1.99" "Revista" => array:5 [ "tituloSerie" => "Hum Mol Genet" "fecha" => "1999" "volumen" => "8" "paginaInicial" => "99" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9887337" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib42" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Modification of multiple endocrine neoplasia 2A phenotype by cell membrane proximity of RET mutations in exon 102" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => """ A Machens \n \t\t\t\t\t\t\t\t """ 1 => """ S Hauptmann \n \t\t\t\t\t\t\t\t """ 2 => """ H Dralle \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Endocr Relat Cancer" "fecha" => "2009" "volumen" => "16" "paginaInicial" => "7" ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib43" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Molecular heterogeneity of RET loss of function in Hirschsprung's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ F Carlomagno \n \t\t\t\t\t\t\t\t """ 1 => """ G De Vita \n \t\t\t\t\t\t\t\t """ 2 => """ MT Berlingieri \n \t\t\t\t\t\t\t\t """ 3 => """ V de Franciscis \n \t\t\t\t\t\t\t\t """ 4 => """ RM Melillo \n \t\t\t\t\t\t\t\t """ 5 => """ V Colantuoni \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "EMBO J" "fecha" => "1996" "volumen" => "15" "paginaInicial" => "25" ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib44" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ret oncogene signal transduction via a IRS-2/PI 3-kinase/PKB and a SHC/Grb-2 dependent pathway: possible implication for transforming activity in NIH3T3 cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ AM Hennige \n \t\t\t\t\t\t\t\t """ 1 => """ R Lammers \n \t\t\t\t\t\t\t\t """ 2 => """ D Arlt \n \t\t\t\t\t\t\t\t """ 3 => """ W Hoppner \n \t\t\t\t\t\t\t\t """ 4 => """ V Strack \n \t\t\t\t\t\t\t\t """ 5 => """ G Niederfellner \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Mol Cell Endocrinol" "fecha" => "2000" "volumen" => "167" "paginaInicial" => "76" ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib45" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The neuron-specific Rai (ShcC) adaptor protein inhibits apoptosis by coupling Ret to the phosphatidylinositol 3-kinase/Akt signaling pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ G Pelicci \n \t\t\t\t\t\t\t\t """ 1 => """ F Troglio \n \t\t\t\t\t\t\t\t """ 2 => """ A Bodini \n \t\t\t\t\t\t\t\t """ 3 => """ RM Melillo \n \t\t\t\t\t\t\t\t """ 4 => """ V Pettirossi \n \t\t\t\t\t\t\t\t """ 5 => """ L Coda \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Mol Cell Biol" "fecha" => "2002" "volumen" => "22" "paginaInicial" => "63" ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib46" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines for diagnosis and therapy of MEN type 1 and type 2" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:5 [ 0 => """ ML Brandi \n \t\t\t\t\t\t\t\t """ 1 => """ RF Gagel \n \t\t\t\t\t\t\t\t """ 2 => """ A Angeli \n \t\t\t\t\t\t\t\t """ 3 => """ JP Bilezikian \n \t\t\t\t\t\t\t\t """ 4 => """ P Beck-Peccoz \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2001" "volumen" => "86" "paginaInicial" => "71" ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib47" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship 1" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ L Yip \n \t\t\t\t\t\t\t\t """ 1 => """ GJ Cote \n \t\t\t\t\t\t\t\t """ 2 => """ SE Shapiro \n \t\t\t\t\t\t\t\t """ 3 => """ GD Ayers \n \t\t\t\t\t\t\t\t """ 4 => """ CE Herzog \n \t\t\t\t\t\t\t\t """ 5 => """ RV Sellin \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Arch Surg" "fecha" => "2003" "volumen" => "138" "paginaInicial" => "16" ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib48" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "[Proto-oncogene RET somatic mutations in medullary thyroid carcinoma]" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => """ M Wiench \n \t\t\t\t\t\t\t\t """ 1 => """ M Kwasniewski \n \t\t\t\t\t\t\t\t """ 2 => """ E Gubala \n \t\t\t\t\t\t\t\t """ 3 => """ Z Wygoda \n \t\t\t\t\t\t\t\t """ 4 => """ A Pawlaczek \n \t\t\t\t\t\t\t\t """ 5 => """ M Oczko \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Wiad Lek" "fecha" => "2001" "paginaInicial" => "415" "paginaFinal" => "421" ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib49" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Solution structure of all parallel G-quadruplex formed by the oncogene RET promoter sequence" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => """ X Tong \n \t\t\t\t\t\t\t\t """ 1 => """ W Lan \n \t\t\t\t\t\t\t\t """ 2 => """ X Zhang \n \t\t\t\t\t\t\t\t """ 3 => """ H Wu \n \t\t\t\t\t\t\t\t """ 4 => """ M Liu \n \t\t\t\t\t\t\t\t """ 5 => """ C Cao \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Nucleic Acids Res" "fecha" => "2011" "volumen" => "39" "paginaInicial" => "63" ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib50" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Novel molecular targeted therapies for refractory thyroid cancer" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => """ CA Perez \n \t\t\t\t\t\t\t\t """ 1 => """ ES Santos \n \t\t\t\t\t\t\t\t """ 2 => """ BA Arango \n \t\t\t\t\t\t\t\t """ 3 => """ LE Raez \n \t\t\t\t\t\t\t\t """ 4 => """ EE Cohen \n \t\t\t\t\t\t\t\t """ ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Nucleic Acids Res" "fecha" => "2011" "volumen" => "39" "paginaInicial" => "63" ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/18075932/00000067000000S1/v1_202212010649/S1807593222023985/v1_202212010649/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/18075932/00000067000000S1/v1_202212010649/S1807593222023985/v1_202212010649/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1807593222023985?idApp=UINPBA00004N" ]
Year/Month | Html | Total | |
---|---|---|---|
2024 November | 8 | 3 | 11 |
2024 October | 67 | 29 | 96 |
2024 September | 63 | 30 | 93 |
2024 August | 76 | 23 | 99 |
2024 July | 39 | 21 | 60 |
2024 June | 30 | 35 | 65 |
2024 May | 28 | 22 | 50 |
2024 April | 33 | 27 | 60 |
2024 March | 54 | 16 | 70 |
2024 February | 60 | 21 | 81 |
2024 January | 43 | 23 | 66 |
2023 December | 40 | 17 | 57 |
2023 November | 42 | 21 | 63 |
2023 October | 55 | 34 | 89 |
2023 September | 39 | 36 | 75 |
2023 August | 17 | 9 | 26 |
2023 July | 27 | 49 | 76 |
2023 June | 10 | 17 | 27 |
2023 May | 3 | 3 | 6 |
2023 April | 4 | 1 | 5 |
2023 March | 0 | 1 | 1 |
2023 February | 2 | 0 | 2 |
2023 January | 3 | 0 | 3 |
2022 December | 3 | 1 | 4 |