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Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype–phenotype correlation
Cornelis J. LipsI,
Corresponding author
lips05@zonnet.nl

Tel.: +31 703240428
, Koen M. DreijerinkI, Jo W. HöppenerII
I University Medical Center Utrecht, Department of Internal Medicine & Endocrinology, Utrecht, The Netherlands.
II University Medical Center Utrecht, Department of Metabolic & Endocrine Diseases, Utrecht, The Netherlands.
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Beyond inactivation of the <span class="elsevierStyleItalic">MEN1</span> gene&#44; additional mutations in other genes may be responsible for acceleration of tumor growth&#44; thus involving a process of multistep tumorigenesis&#46; Deregulation of normal neuroendocrine development&#47;differentiation can occur through a range of processes&#44; e&#46;g&#46; activation of the PI3K pathway leads to AKT phosphorylation&#44; triggering a downstream cascade of events&#46; Deregulation of this pathway can occur through several mechanisms&#58; 1&#41; gain of function by oncogenic mutations of PIK3&#59; 2&#41; loss of function of the tumor suppressor PTEN through gene deletion&#44; mutation&#44; micro-RNA expression&#44; or epigenetic silencing&#59; 3&#41; amplification or mutation of AKT isoforms&#59; 4&#41; upstream activation through RTK signalling&#59; 5&#41; downstream loss of the tumor suppressors p18 and p27&#59; 6&#41; increased RAS expression&#44; or activating mutations of RAF&#44; MEK&#44; or ERK&#44; which accelerate cell proliferation&#46; Opportunities for treatment are in blue&#46; NSAIDs &#61; non-steroidal anti-inflammatory drugs&#59; RTK &#61; receptor tyrosine kinase&#59; TZDs &#61; thiazolidinediones&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">&#8222;It is an old experience that through her errors&#44; Nature often grants us unexpected insights into her secrets which are otherwise a closed domain&#8220;&#44; William Harvey&#44; 1657&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">Multiple endocrine neoplasia type 1 &#40;MEN1&#41; is an inherited endocrine tumor syndrome&#44; characterized predominantly by tumors of the parathyroid glands&#44; gastroenteropancreatic tumors&#44; pituitary adenomas&#44; adrenal adenomas&#44; and neuroendocrine tumors of the thymus&#44; lungs or stomach&#46; MEN1 is caused by germline mutations of the <span class="elsevierStyleItalic">MEN1</span> tumor suppressor gene&#46; It appears that in the MEN1 syndrome&#44; clinical expression differs between families&#46; This may be the result of the specific <span class="elsevierStyleItalic">MEN1</span> gene mutation in a family &#40;genotype&#8211;phenotype correlation&#41;&#46; As a rule&#44; the development of a tumor depends on a series of genetic events &#40;multistep tumorigenesis&#41;&#46; Thus&#44; additional co-segregating modifying factors such as germline mutations in other genes are likely to play a role in the interfamilial variability of MEN 1&#46; Moreover&#44; clinical expression can also vary between individual members of the same family&#44; possibly because of additional genetic or epigenetic factors&#46; To date&#44; a clear correlation between genetic events and the variable clinical expression of MEN1 has not been established &#40;<a class="elsevierStyleCrossRefs" href="#bib1">1&#8211;5</a>&#41;&#46; Further understanding of the genetic aspects of MEN1 and the pathogenesis of MEN1-related tumors could enable more tailored clinical screening and treatment strategies&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">In this review&#44; we discuss recent reports on aberrant clinical expression of MEN1&#44; which may allow us a glimpse into the pathogenesis of this intriguing disorder&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">In 1903&#44; Erdheim described the case of an acromegalic patient with a pituitary adenoma and three enlarged parathyroid glands&#46; Fifty years later&#44; Underdahl et al&#46; reported eight patients with a syndrome of pituitary-&#44; parathyroid-&#44; and pancreatic islet adenomas&#46; In 1954&#44; Wermer found that the syndrome was transmitted as a dominant trait &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46; In 1968&#44; Steiner et al&#46; introduced the term &#8220;multiple endocrine neoplasia&#8221; &#40;MEN&#41; to describe disorders featuring combinations of endocrine tumors&#59; they designated the Wermer syndrome as MEN1 and the Sipple syndrome as MEN2&#46; Gorlin subdivided type 2 into A and B&#46; Then&#44; in 1975&#44; Khairi &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41; suggested that type 2B be called type 3&#59; however&#44; this was not generally accepted&#46; More recently&#44; in 2006&#44; families with multiple endocrine tumors but without <span class="elsevierStyleItalic">MEN1</span> or <span class="elsevierStyleItalic">RET</span> &#40;MEN2<span class="elsevierStyleItalic">&#41;</span> gene mutations were identified &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#41;&#46; This related syndrome is referred to as MEN4&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">DISCOVERY OF THE <span class="elsevierStyleItalic">MEN1</span> GENE</span><p id="para50" class="elsevierStylePara elsevierViewall">In positional cloning&#44; gene mapping precedes&#44; and eventually leads to&#44; gene identification&#46; The first step is mapping the gene to a specific chromosomal region by linkage analysis&#46; The second step is identifying the correct gene among all possible candidate genes within that particular chromosomal region&#46; After the gene has been identified&#44; it is possible to study its &#40;patho&#41;physiologic function&#46;</p><p id="para60" class="elsevierStylePara elsevierViewall">In 1996&#44; two groups independently identified the <span class="elsevierStyleItalic">MEN1</span> gene on chromosome 11q13 &#40;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#41;&#46; To date&#44; more than 1336 different <span class="elsevierStyleItalic">MEN1</span> gene mutations &#40;both germline and sporadic&#41; have been reported in the literature &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46; Most of these mutations are clearly inactivating&#44; in accordance with the notion that the <span class="elsevierStyleItalic">MEN1</span> gene is a tumor suppressor gene&#46; There are no mutational hot spots in the <span class="elsevierStyleItalic">MEN1</span> gene&#46;</p></span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">FUNCTION OF THE <span class="elsevierStyleItalic">MEN1</span>-GENE PRODUCT</span><p id="para70" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">MEN1</span> gene product&#44; menin&#44; functions as an adaptor protein that is involved in interactions with multiple protein partners&#46; <span class="elsevierStyleItalic">Men1</span> null mutant mice have indicated that menin is essential for viability &#40;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#41;&#46; Menin is involved in neuroendocrine cell development and function&#46; Later on&#44; it is active in many cellular processes&#44; including gene transcription regulation&#44; DNA replication&#44; DNA repair&#44; and signal transduction&#46;</p><p id="para80" class="elsevierStylePara elsevierViewall">Menin target genes that are important for development and proliferation&#44; including homeobox domain &#40;HOX&#41; genes&#44; the <span class="elsevierStyleItalic">CDKN2C</span> and <span class="elsevierStyleItalic">CDKN1B</span> cyclin-dependent kinase inhibiting genes&#44; the human telomerase &#40;<span class="elsevierStyleItalic">hTERT</span>&#41; gene&#44; and nuclear receptor target genes &#40;<a class="elsevierStyleCrossRefs" href="#bib12">12&#8211;15</a>&#41;&#46;</p><p id="para90" class="elsevierStylePara elsevierViewall">As a transcriptional co-regulator&#44; menin may function as a co-activator or co-repressor by recruiting histone-modifying enzymatic activity &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#41;&#46; As a co-activator&#44; menin is involved in the regulation of histone methylation by recruiting the mixed-lineage leukaemia &#40;MLL&#41; proteins MLL1 and MLL2 &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41;&#46; In this way&#44; menin can bind to nuclear receptors and activate nuclear receptor-mediated gene transcription &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#46; By tethering histone deacetylase activity to genes&#44; menin can serve as a repressor of transcription &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&#46;</p><p id="para100" class="elsevierStylePara elsevierViewall">In order to understand the role of menin as a tumor suppressor protein and as a co-factor of MLL fusion proteins&#44; the structural basis had to be revealed&#46; Recently&#44; the crystal structure of menin in <span class="elsevierStyleItalic">Nematostella vectensis</span> was reported &#40;<a class="elsevierStyleCrossRef" href="#bib19">19</a>&#41;&#46; Knowledge about the three-dimensional structure may elucidate the interactions essential to the function of menin&#46; It appears that the Leucine&#44; Leucine&#44; Tryptophan&#44; Leucine&#44; Leucine &#40;LLWLL&#41; amino acids nuclear receptor interaction motif of menin is well-conserved and is located in an alpha-helix&#46; In general&#44; modeling gene mutations into this structure will be helpful in determining the effects on protein function&#46; Inactivation of the <span class="elsevierStyleItalic">MEN1</span> gene results in predisposition to tumor formation &#40;see <a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#41;&#44; <a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia><elsevierMultimedia ident="tbl1"></elsevierMultimedia></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">ABERRANT CLINICAL EXPRESSION OF MEN1</span><p id="para110" class="elsevierStylePara elsevierViewall">A <span class="elsevierStyleItalic">MEN1</span> gene mutation may be completely detrimental to gene function&#46; It may also result in a protein product with some residual function&#46; An aberrant menin protein may be impaired in its function by several mechanisms&#58; menin can interact with many different proteins&#46; Possibly&#44; germline mutations in the <span class="elsevierStyleItalic">MEN1</span> gene selectively affect menin binding to its partners&#44; leading to distinct phenotypes&#46;</p><p id="para120" class="elsevierStylePara elsevierViewall">The type of missense mutation &#40;e&#46;g&#46; replacement of arginine with glycine&#41; may have a differential effect on the function of menin &#40;<a class="elsevierStyleCrossRef" href="#bib38">38</a>&#41;&#58; in-frame or missense mutations differ from frameshift&#47;nonsense mutations &#40;<a class="elsevierStyleCrossRef" href="#bib39">39</a>&#41;&#44; whereas missense and in-frame mutations may affect the interactions of a menin domain with transcription factors such as JunD&#44; Smad3 and NFkappaB and nuclear receptors &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#44; or impair sensitization to apoptosis from caspase-3&#44; p53 or p21 &#40;<a class="elsevierStyleCrossRef" href="#bib40">40</a>&#41;&#46; A <span class="elsevierStyleItalic">MEN1</span> gene missense mutation may result in protein instability&#44; and enhanced and early proteolytic degradation via the ubiquitin&#8211;proteasome pathway &#40;<a class="elsevierStyleCrossRef" href="#bib41">41</a>&#41;&#46;</p><p id="para130" class="elsevierStylePara elsevierViewall">It was generally assumed that&#44; in contrast to MEN2&#44; in MEN1 there is no clear genotype&#8211;phenotype correlation &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRefs" href="#bib3">3&#8211;5</a>&#41;&#46; However&#44; several reports challenge this assumption&#46;</p><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">Familial aberrant expression</span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">1&#46; MEN1 Burin</span><p id="para140" class="elsevierStylePara elsevierViewall">Four large kindreds from the Burin peninsula&#47;Fortune Bay area of Newfoundland with prominent features of prolactinomas&#44; in addition to carcinoids&#44; and parathyroid tumors &#40;referred to as MEN1Burin&#41; have been described&#44; and they show linkage to 11q13&#44; the same locus as that of MEN1&#46; Haplotype analysis with 16 polymorphic markers now reveals that representative affected individuals from all four families share a common haplotype over a 2&#46;5 Mb region&#46; A nonsense mutation in the <span class="elsevierStyleItalic">MEN1</span> gene has been found to be responsible for the disease in the affected members in all four of the MEN1-Burin families&#46; This suggests that either a common ancestral mutation in the <span class="elsevierStyleItalic">MEN1</span>-Burin gene or a modifying gene on 11q13 is responsible for this prolactinoma variant of MEN1 &#40;<a class="elsevierStyleCrossRefs" href="#bib42">42&#8211;45</a>&#41;&#46;</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">2&#46; Familiar isolated hyperparathyroidism and <span class="elsevierStyleItalic">MEN1</span> gene missense mutations</span><p id="para150" class="elsevierStylePara elsevierViewall">Familial isolated primary hyperparathyroidism &#40;FIHP&#41; is an autosomal dominant disorder that can represent an early stage of either MEN1 caused by an allelic variant of the <span class="elsevierStyleItalic">MEN1</span> gene&#44; or of hyperparathyroidism&#8211;jaw tumor &#40;HPT-JT&#41; syndromes&#59; alternatively&#44; the condition can be caused by an allelic variant of the hyperparathyroidism 2 &#40;<span class="elsevierStyleItalic">HRPT2</span>&#41; gene&#44; or caused by a mutation at another locus&#46; Interestingly&#44; the major proportion of <span class="elsevierStyleItalic">MEN1</span> gene germline mutations that have been found in FIHP are seemingly mild missense mutations or in-frame deletions &#40;<a class="elsevierStyleCrossRefs" href="#bib46">46&#8211;55</a>&#41;&#46; In MEN1&#44; roughly 80&#37; of patients harbor nonsense mutations&#46;</p></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">3&#46; Predominant mutations in MEN1 pancreatic neuroendocrine tumors</span><p id="para160" class="elsevierStylePara elsevierViewall">Schaaf performed mutation analysis of the <span class="elsevierStyleItalic">MEN1</span> gene in tumors from 306 patients with MEN1&#44; and found that patients with gastroenteropancreatic tumors more often had truncating mutations&#44; very probably leading to completely inactivated menin &#40;<a class="elsevierStyleCrossRef" href="#bib56">56</a>&#41;&#46;</p></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">4&#46; Mild&#47;late onset versus malignant phenotypes</span><p id="para170" class="elsevierStylePara elsevierViewall">To date&#44; several disease-related <span class="elsevierStyleItalic">MEN1</span> gene intron mutations have been reported&#46; These intron mutations may affect mRNA splicing and cause mild phenotypes&#44; with late&#44; and relatively low&#44; penetrance of the disease &#40;<a class="elsevierStyleCrossRefs" href="#bib57">57&#8211;59</a>&#41;&#46; However&#44; clinical expression at a young age may occur&#46; This may be explained by interpatient variations in gene transcription and translation of the <span class="elsevierStyleItalic">MEN1</span> gene&#46;</p><p id="para180" class="elsevierStylePara elsevierViewall">Two recent case reports described families with a high penetrance of malignant neuroendocrine tumors of the pancreas &#40;<a class="elsevierStyleCrossRef" href="#bib60">60</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib61">61</a>&#41;&#46; Both these families carried germline mutations that completely abolish menin function&#46;</p><p id="para190" class="elsevierStylePara elsevierViewall">The earliest manifestation of MEN1 was a pituitary adenoma in a 5-year-old boy who had a missense mutation leading to a H139D substitution in the <span class="elsevierStyleItalic">MEN1</span> protein &#40;<a class="elsevierStyleCrossRef" href="#bib62">62</a>&#41;&#46; Functional analysis of the mutant protein revealed severely reduced protein stability &#40;<a class="elsevierStyleCrossRef" href="#bib41">41</a>&#41;&#44; reduced binding to JunD &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#41;&#44; reduced binding to the estrogen receptor alpha and absent histone-methylation recruiting capacity&#46; Thus&#44; functional analysis of this potentially mild missense <span class="elsevierStyleItalic">MEN1</span> gene mutation shows that the protein product is&#44; in fact&#44; completely inactivated&#46;</p></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">5&#46; Metabolic effects of aberrant expression of the <span class="elsevierStyleItalic">MEN1</span> gene</span><p id="para200" class="elsevierStylePara elsevierViewall">In <span class="elsevierStyleItalic">MEN1</span> disease-gene carriers&#44; all vitamin D receptors &#40;VDRs&#41; and peroxisome proliferator-activated receptors &#40;PPARs&#41;-&#947; are expressed but are probably less activated because of impaired menin function&#46;</p><p id="para210" class="elsevierStylePara elsevierViewall">A&#46; PPAR&#947;2 is a transcription factor that plays a key role in adipocyte differentiation&#46; Polymorphisms in this gene may contribute to the variability in body mass index and insulin sensitivity in the general population&#46; PPAR&#947; is the receptor for the thiazolidinediones&#44; which act as PPAR&#947; agonists and lower the blood glucose levels in patients with type 2 diabetes mellitus by increasing insulin sensitivity&#46; Individuals with dominant-negative PPAR&#947; gene mutations manifest a syndrome that combines lipodystrophy with features of the metabolic syndrome&#44; including insulin resistance&#44; type 2 diabetes&#44; hepatic steatosis&#44; dyslipidemia&#44; hypertension and &#40;in women&#41; polycystic ovary syndrome&#46; In patients with MEN1&#44; decreased activation of PPAR may result in insulin resistance and weight gain &#40;<a class="elsevierStyleCrossRef" href="#bib63">63</a>&#41;&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">B&#46; Vitamin D receptors &#40;VDRs&#41; are found in a large number of tissues beyond the classic target tissues gut&#44; bone and kidney&#46; These tissues include endocrine glands such as pituitary&#44; parathyroid glands&#44; pancreatic islets&#44; etc&#46;</p><p id="para230" class="elsevierStylePara elsevierViewall">Louren&#231;o et al&#46; discussed the increased bone loss pattern found in patients with MEN1 compared with that of patients with sporadic primary HPT &#40;<a class="elsevierStyleCrossRef" href="#bib64">64</a>&#41;&#46; Besides increased bone loss&#44; resistance to vitamin D may be associated with insulin resistance and beta cell dysfunction&#44; leading to increased risk for type 2 diabetes in patients with MEN1 &#40;<a class="elsevierStyleCrossRef" href="#bib65">65</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib66">66</a>&#41;&#46;</p></span></span><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">Effect of gender</span><p id="para240" class="elsevierStylePara elsevierViewall">The prevalence and probability of pancreatic tumors among patients with MEN1 were higher in males than in females&#46; This difference was due to the differential occurrence of gastrinomas&#46; The prevalence and probability of developing pituitary adenomas were significantly greater in females&#46; Thymic tumors are found nearly exclusively in male MEN1 patients &#40;<a class="elsevierStyleCrossRef" href="#bib67">67</a>&#41;&#46;</p><p id="para250" class="elsevierStylePara elsevierViewall">The difference in clinical expression between the genders may be explained by the difference in transcription regulation of estrogen and androgen receptors&#46; Menin can act as a co-activator of nuclear hormone receptors including estrogen &#40;ER&#945;&#41; and possibly androgen &#40;AR&#41; receptors&#46; A defect in the <span class="elsevierStyleItalic">MEN1</span> gene&#44; together with gender-specific differences in concentrations of the hormones involved and tissue-specific distribution of their receptors&#44; may contribute to the observed gender-specific differences in prevalence of prolactinoma and gastrinoma&#46;</p></span><span id="cesec120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Additional genetic effects</span><span id="cesec130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">1&#46; Loss of heterozygosity&#59; the AIP gene</span><p id="para260" class="elsevierStylePara elsevierViewall">In accordance with the tumor suppressor function of menin&#44; MEN1-associated tumors exhibit loss of the wild-type allele&#46; This second hit occurs as a somatic mutation and often involves deletion of a larger chromosomal region containing multiple genes &#91;loss of heterozygosity &#40;LOH&#41;&#93;&#46;</p><p id="para270" class="elsevierStylePara elsevierViewall">The gene encoding the aryl hydrocarbon receptor interacting protein &#40;AIP&#41; is located on 11q13&#44; in the vicinity of the <span class="elsevierStyleItalic">MEN1</span> gene&#46; Recently&#44; it was found that inactivating mutations in the <span class="elsevierStyleItalic">AIP</span> gene are the underlying cause of low-penetrance pituitary adenoma predisposition&#46; The finding of a truncated gene and LOH indicates that <span class="elsevierStyleItalic">AIP</span> acts as a tumor suppressor gene &#40;<a class="elsevierStyleCrossRef" href="#bib68">68</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib69">69</a>&#41;&#46; In northern Finland&#44; <span class="elsevierStyleItalic">AIP</span>-germline mutations accounted for 16&#37; of cases of acromegaly in young patients&#46; The tumor suppressor genes <span class="elsevierStyleItalic">AIP</span> and <span class="elsevierStyleItalic">MEN1</span> are located 3 Mb apart&#46; Concomitant deletions of these genes may underlie predisposition to MEN1 and pituitary adenoma&#46; To what extent deletion of the <span class="elsevierStyleItalic">AIP</span> gene is present in MEN1 tumors has yet to be established&#46; Inactivation of this gene in animal models may reveal a potential causative role in MEN1-associated tumors&#46;</p></span><span id="cesec140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">2&#46; Genetic predisposition for other diseases</span><p id="para280" class="elsevierStylePara elsevierViewall">Genetic predisposition for other diseases may contribute to enhancement of tumor formation in patients with MEN1 &#40;<a class="elsevierStyleCrossRef" href="#bib70">70</a>&#41;&#46; For instance&#44; normally the vitamin D receptor on parathyroid cells inhibits production and release of parathyroid hormone &#40;PTH&#41;&#46; In families with inactivating mutations in the gene encoding VDR&#44; this is associated with end-organ resistance to calcitriol&#46;</p><p id="para290" class="elsevierStylePara elsevierViewall">In the parathyroid glands of patients with MEN1&#44; there exists a decreased activation of the VDR&#46; An additional defect in the VDR or calcium receptor may contribute to hyperactivity&#44; hyperplasia&#44; and adenoma &#40;<a class="elsevierStyleCrossRef" href="#bib71">71</a>&#41;&#46;</p></span><span id="cesec150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle160">3&#46; Additional&#44; somatic mutations involved in acceleration of tumor growth</span><span id="cesec160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle170">3a&#41;&#46; Data from other familial neuroendocrine tumor syndromes</span><p id="para300" class="elsevierStylePara elsevierViewall">How can we identify acquired mutations that are responsible for acceleration of tumor growth in MEN1&#63; Clues for modifier genes may be found in other familial neuroendocrine tumor syndromes such as MEN2 and MEN4 &#40;the latter is also referred to as MENX&#41;&#46; Which are their traditional pathogenetic pathways and are these involved in aberrant clinical MEN1 expression&#63; Overlap between MEN1 and MEN2 and additional genetic events have to be explored &#40;e&#46;g&#46; p18&#47;p27 knock-out mice develop both MEN1- and MEN2-associated tumors&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib72">72</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib73">73</a>&#41;&#46;</p><p id="para310" class="elsevierStylePara elsevierViewall">Phenotypic overlap between MEN1- and MEN2-like syndromes was identified in the rat and named MENX&#46; The syndrome is caused by a germline inactivating mutation in the <span class="elsevierStyleItalic">CDKN1B</span> gene encoding p27<span class="elsevierStyleSup">Kip1</span> &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#41;&#46; p27<span class="elsevierStyleSup">Kip1</span> has a key role in cell cycle regulation and is involved in differentiation&#44; apoptosis&#44; and angiogenesis&#46;</p><p id="para320" class="elsevierStylePara elsevierViewall">Subsequently&#44; germline mutations in the <span class="elsevierStyleItalic">CDKN1B</span> gene were identified in the germline of a MEN1-like family&#46; In these patients&#44; germline mutations of the <span class="elsevierStyleItalic">MEN1</span> gene could not be detected &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#41;&#46; However&#44; only the menin-coding region and splice junctions were analyzed&#46; The patients were also negative for <span class="elsevierStyleItalic">RET</span> gene mutations &#40;MEN2&#41;&#46; Mutations in <span class="elsevierStyleItalic">CDKN1B</span> and related genes&#44; but without <span class="elsevierStyleItalic">MEN1</span> gene mutations&#44; are a rare cause of MEN1-like phenotype &#40;<a class="elsevierStyleCrossRefs" href="#bib74">74&#8211;76</a>&#41;&#46; As a consequence of mutations in the p27 gene&#44; a novel human MEN syndrome was recognized and named MEN4&#46;</p><p id="para330" class="elsevierStylePara elsevierViewall">In mice&#44; the <span class="elsevierStyleItalic">Cdkn2c</span> gene encoding p18<span class="elsevierStyleSup">Ink4c</span> was shown to collaborate with menin in suppression of neuroendocrine tumor development &#40;<a class="elsevierStyleCrossRef" href="#bib77">77</a>&#41;&#46; Whether occurrence of somatic mutations in p18<span class="elsevierStyleSup">Ink4c</span> and&#47;or p27<span class="elsevierStyleSup">Kip1</span> accelerates tumor growth in human MEN1 tumors has yet to be established&#46; In transgenic MEN2 mice and human patients with MEN2&#44; inactivating mutations in p18 will promote tumor growth &#40;<a class="elsevierStyleCrossRef" href="#bib72">72</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib73">73</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib78">78</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib79">79</a>&#41;&#46; Reduced expression of <span class="elsevierStyleItalic">CDKN1B</span>&#44; but not <span class="elsevierStyleItalic">CDKN2C</span>&#44; has been observed in parathyroid adenomas from patients with MEN1&#46;</p></span><span id="cesec170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle180">3b&#41;&#46; Clues from sporadic parathyroid adenomas&#44; pituitary tumors&#44; and pancreatic NETs</span><span id="cesec180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle190">i&#41; Sporadic Parathyroid adenoma</span><p id="para340" class="elsevierStylePara elsevierViewall">A high rate of somatic <span class="elsevierStyleItalic">MEN1</span> gene mutations is seen in sporadic parathyroid adenomas&#46; There exists an interaction between menin and the transforming growth factor &#40;TGF&#41;-beta&#47;Smad signaling pathway&#46; <span class="elsevierStyleItalic">In vitro</span> experimentation has demonstrated that the presence of menin is required for TGF-beta to effectively inhibit parathyroid cell proliferation and PTH production &#40;<a class="elsevierStyleCrossRef" href="#bib80">80</a>&#41;&#46;</p></span><span id="cesec190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle200">ii&#41; Pituitary tumors</span><p id="para350" class="elsevierStylePara elsevierViewall">The pituitary tumor transforming gene &#40;PTTG&#59; securin&#41; was the first transforming gene found to be highly expressed in pituitary tumor cells&#44; and seems to play an important role in the process of oncogenesis&#46; Cell signaling abnormalities have been identified in pituitary tumors&#44; but their genetic basis is unknown&#46; Both Raf&#47;mitogen activated protein kinase kinase &#40;MEK&#41;&#47;extracellular signal-regulated kinase &#40;ERK&#41; and phosphoinositide 3-kinase&#40;PI3K&#41;&#47;Akt&#47;mammalian target of rapamycin &#40;mTOR&#41; pathways are over-expressed and&#47;or over-activated in pituitary tumors &#40;<a class="elsevierStyleCrossRef" href="#bib81">81</a>&#41;&#46; These pathways share a common root&#44; including initial activation by a tyrosine kinase receptor&#46;</p><p id="para360" class="elsevierStylePara elsevierViewall">Pit-1 is a direct transcriptional target of VDR&#46; Recruitment of histone deacetylase 1 is involved in the repressive effect of VDR on Pit-1 expression &#40;<a class="elsevierStyleCrossRef" href="#bib82">82</a>&#41;&#46;</p><p id="para370" class="elsevierStylePara elsevierViewall">There is a critical role for the growth factor activin in regulating inhibition of pituitary cell growth and Pit-1&#47;PRL expression through the Smads and menin &#40;<a class="elsevierStyleCrossRef" href="#bib83">83</a>&#41;&#46; Alterations in the activin&#47;TGF-beta downstream signaling pathways may be critical steps towards tumor formation and progression &#40;<a class="elsevierStyleCrossRef" href="#bib84">84</a>&#41;&#46; To date&#44; the occurrence of additional TGF-beta&#44; Pit-1&#44; PTTG&#44; or VDR mutations in MEN1-associated tumors has not been published&#46;</p></span><span id="cesec200" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle210">iii&#41; Pancreatic neuroendocrine tumors</span><p id="para380" class="elsevierStylePara elsevierViewall">In nonfamilial pancreatic neuroendocrine tumors &#40;PanNETs&#41; the most commonly mutated genes specify proteins implicated in chromatin remodeling&#58; 44&#37; of the tumors had somatic inactivating mutations in <span class="elsevierStyleItalic">MEN1&#46;</span> Clinically&#44; mutations in the <span class="elsevierStyleItalic">MEN1</span> gene were associated with better prognosis&#46; Also&#44; mutations in genes in the mTOR pathway were found in 14&#37; of the tumors&#44; a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors &#40;<a class="elsevierStyleCrossRef" href="#bib85">85</a>&#41;&#46;</p><p id="para390" class="elsevierStylePara elsevierViewall">Loss of menin expression is associated with over-expression of the Raf&#47;MEK&#47;ERK and P13K&#47;AKT&#47;mTOR pathways in pancreatic tumors &#40;<a class="elsevierStyleCrossRef" href="#bib34">34</a>&#41;&#46; Intact menin has an essential role in WNT&#47;&#946;-catenin signaling&#44; and inhibits mouse pancreatic islet tumor proliferation &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&#46; Menin regulates subcellular localization of &#946;-catenin via nuclear-cytoplasmic shuttling&#46; Loss of menin leads to Wnt&#47;&#946;-catenin signaling activation&#46; Expression of p27 was found to be repressed in pancreatic islet cell tumors &#40;<a class="elsevierStyleCrossRef" href="#bib86">86</a>&#41;&#46;</p></span></span><span id="cesec210" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle220">3c&#41; Pathways in multistep carcinogenesis</span><p id="para400" class="elsevierStylePara elsevierViewall">It appears that interaction of components of the PI3K&#47;AKT pathway is involved in neuroendocrine tumor formation &#40;<a class="elsevierStyleCrossRef" href="#bib87">87</a>&#41;&#44;&#40;<a class="elsevierStyleCrossRef" href="#bib88">88</a>&#41;&#46; Deregulation of the PI3K&#47;AKT pathway in neuroendocrine tumors can occur through a range of processes &#40;see <a class="elsevierStyleCrossRef" href="#fig2">Figure 2</a>&#41;&#44; including gain of function by oncogenic mutations of PI3K signalling&#44; loss of function of the tumor suppressor PTEN through gene deletion&#44; mutation&#44; micro-RNA expression or epigenetic silencing&#44; upstream activation through receptor tyrosine kinase &#40;RTK&#41; signaling&#44; and&#47;or downstream loss of the tumor suppressors p18 and p27&#46;</p><elsevierMultimedia ident="fig2"></elsevierMultimedia><p id="para410" class="elsevierStylePara elsevierViewall">A combination of a mutation in the <span class="elsevierStyleItalic">MEN1</span> disease gene with other specific mutations of genes in the PI3K&#47;AKT pathway may be associated with acceleration of tumor growth&#46;</p><p id="para420" class="elsevierStylePara elsevierViewall">In addition&#44; inactivated or absent menin promotes RAS expression&#59; activating mutations of RAF&#44; MEK&#44; or ERK may accelerate cell proliferation &#40;<a class="elsevierStyleCrossRef" href="#bib89">89</a>&#41;&#46;</p></span></span></span><span id="cesec220" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle230">Ecogenetic factors</span><p id="para430" class="elsevierStylePara elsevierViewall">Common environmental factors may interact with genetic predisposition to MEN1 and contribute to enhancement of tumor formation &#40;<a class="elsevierStyleCrossRef" href="#bib70">70</a>&#41;&#46; In the parathyroid glands of patients with MEN1&#44; a diet low in vitamin D or calcium may result in tumor growth&#46; In the lactotropic cells of the pituitary gland&#44; estrogenic or neuroleptic drugs may stimulate cell division&#46; In the gastrin-producing cells of the stomach&#44; presence of achlorhydria or use of histamine-H2 receptor or proton pump blockers may promote tumor growth &#40;<a class="elsevierStyleCrossRef" href="#bib90">90</a>&#41;&#46; Lifestyle factors such as smoking and exposure to radiation may have deleterious effects on menin function and tumor growth&#44; as with many types of cancer&#46;</p></span></span><span id="cesec230" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle240">CONCLUDING REMARKS</span><p id="para440" class="elsevierStylePara elsevierViewall">Careful observation of patients and collaboration between disciplines&#44; including molecular endocrinology&#44; has opened new directions in the management of MEN1 syndrome&#44; and has promoted development of novel target-directed therapy&#46; Since 1980&#44; life expectancy and quality of life have improved considerably&#46;</p><p id="para450" class="elsevierStylePara elsevierViewall">By contrast&#44; thymic tumors and duodenopancreatic tumors&#44; including nonsecreting pancreatic tumors increase the risk of death &#40;<a class="elsevierStyleCrossRef" href="#bib91">91</a>&#41;&#46; Rare&#44; but aggressive&#44; adrenal tumors may also cause early death&#46; In <span class="elsevierStyleItalic">MEN1</span> disease gene carriers in MEN1 families&#44; most deaths were related to the disease&#44; and probably resulted from additional mutations&#46;</p><p id="para460" class="elsevierStylePara elsevierViewall">It is possible that consecutive and specific pathogenetic pathways are involved in MEN1 tumor formation&#46; We presume that&#44; through the inherited germline mutation resulting in organ-specific cell division&#44; the patient is rendered vulnerable to additional&#44; somatic mutations in these organs&#46; These mutations may occur spontaneously or may be triggered by life style and&#47;or environment&#46; Predisposition and expression of other genetic diseases may also be involved&#46; A complex genotype&#8211;phenotype relationship may be present&#46; Unfortunately&#44; for the majority of the patients it is not currently possible to predict the course of the disease&#46;</p><p id="para470" class="elsevierStylePara elsevierViewall">Germline mutations that result in complete inactivation of the gene product apparently cause more severe disease&#46;</p><p id="para480" class="elsevierStylePara elsevierViewall">Consequently&#44; extensive periodical clinical examination has to be performed in all carriers of the <span class="elsevierStyleItalic">MEN1</span> disease gene&#46; In the near future&#44; tumor gene-expression profiles and high throughput sequencing may permit more insight into additional genetic and epigenetic events that cause progression of tumor development&#46; Functional analysis of <span class="elsevierStyleItalic">MEN1</span> gene mutations is sometimes required to study the true effect of the mutation&#46; In addition&#44; as already suggested by Sir William Harvey&#44; it is very helpful to investigate rare presentations of diseases &#40;<a class="elsevierStyleCrossRef" href="#bib92">92</a>&#41;&#46; Eventually&#44; this insight may allow target-directed and mutation-specific therapy&#46;</p></span></span>"
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          "titulo" => "KEYWORDS"
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        1 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
        ]
        2 => array:2 [
          "identificador" => "cesec20"
          "titulo" => "DISCOVERY OF THE MEN1 GENE"
        ]
        3 => array:2 [
          "identificador" => "cesec30"
          "titulo" => "FUNCTION OF THE MEN1-GENE PRODUCT"
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          "identificador" => "cesec40"
          "titulo" => "ABERRANT CLINICAL EXPRESSION OF MEN1"
          "secciones" => array:4 [
            0 => array:3 [
              "identificador" => "cesec50"
              "titulo" => "Familial aberrant expression"
              "secciones" => array:5 [
                0 => array:2 [
                  "identificador" => "cesec60"
                  "titulo" => "1&#46; MEN1 Burin"
                ]
                1 => array:2 [
                  "identificador" => "cesec70"
                  "titulo" => "2&#46; Familiar isolated hyperparathyroidism and MEN1 gene missense mutations"
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                  "identificador" => "cesec80"
                  "titulo" => "3&#46; Predominant mutations in MEN1 pancreatic neuroendocrine tumors"
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                  "titulo" => "4&#46; Mild&#47;late onset versus malignant phenotypes"
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                  "identificador" => "cesec100"
                  "titulo" => "5&#46; Metabolic effects of aberrant expression of the MEN1 gene"
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              "identificador" => "cesec110"
              "titulo" => "Effect of gender"
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              "identificador" => "cesec120"
              "titulo" => "Additional genetic effects"
              "secciones" => array:3 [
                0 => array:2 [
                  "identificador" => "cesec130"
                  "titulo" => "1&#46; Loss of heterozygosity&#59; the AIP gene"
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                  "identificador" => "cesec140"
                  "titulo" => "2&#46; Genetic predisposition for other diseases"
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                  "titulo" => "3&#46; Additional&#44; somatic mutations involved in acceleration of tumor growth"
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                    0 => array:2 [
                      "identificador" => "cesec160"
                      "titulo" => "3a&#41;&#46; Data from other familial neuroendocrine tumor syndromes"
                    ]
                    1 => array:3 [
                      "identificador" => "cesec170"
                      "titulo" => "3b&#41;&#46; Clues from sporadic parathyroid adenomas&#44; pituitary tumors&#44; and pancreatic NETs"
                      "secciones" => array:3 [
                        0 => array:2 [
                          "identificador" => "cesec180"
                          "titulo" => "i&#41; Sporadic Parathyroid adenoma"
                        ]
                        1 => array:2 [
                          "identificador" => "cesec190"
                          "titulo" => "ii&#41; Pituitary tumors"
                        ]
                        2 => array:2 [
                          "identificador" => "cesec200"
                          "titulo" => "iii&#41; Pancreatic neuroendocrine tumors"
                        ]
                      ]
                    ]
                    2 => array:2 [
                      "identificador" => "cesec210"
                      "titulo" => "3c&#41; Pathways in multistep carcinogenesis"
                    ]
                  ]
                ]
              ]
            ]
            3 => array:2 [
              "identificador" => "cesec220"
              "titulo" => "Ecogenetic factors"
            ]
          ]
        ]
        5 => array:2 [
          "identificador" => "cesec230"
          "titulo" => "CONCLUDING REMARKS"
        ]
        6 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "KEYWORDS"
          "identificador" => "xpalclavsec1581202"
          "palabras" => array:5 [
            0 => "Multiple Endocrine Neoplasia type 1"
            1 => "MEN1"
            2 => "Menin"
            3 => "Genotype&#8211;Phenotype Correlation"
            4 => "Clinical Expression"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:1 [
        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Multiple endocrine neoplasia type 1 is an inherited endocrine tumor syndrome&#44; predominantly characterized by tumors of the parathyroid glands&#44; gastroenteropancreatic tumors&#44; pituitary adenomas&#44; adrenal adenomas&#44; and neuroendocrine tumors of the thymus&#44; lungs or stomach&#46; Multiple endocrine neoplasia type 1 is caused by germline mutations of the multiple endocrine neoplasia type 1 tumor suppressor gene&#46; The initial germline mutation&#44; loss of the wild-type allele&#44; and modifying genetic and possibly epigenetic and environmental events eventually result in multiple endocrine neoplasia type 1 tumors&#46; Our understanding of the function of the multiple endocrine neoplasia type 1 gene product&#44; menin&#44; has increased significantly over the years&#46; However&#44; to date&#44; no clear genotype&#8211;phenotype correlation has been established&#46;</p><p id="spara50" class="elsevierStyleSimplePara elsevierViewall">In this review we discuss reports on exceptional clinical presentations of multiple endocrine neoplasia type 1&#44; which may provide more insight into the pathogenesis of this disorder and offer clues for a possible genotype&#8211;phenotype correlation&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:1 [
        "nota" => "<p class="elsevierStyleNotepara" id="cenpara20">No potential conflict of interest was reported&#46;</p> <p class="elsevierStyleNotepara" id="cenpara30">Lips CJ conceived and designed the study and was also responsible for the manuscript writing and preparation of figures and table&#46; Dreijerink KM searched the literature for important contents&#44; provided assistance to the manuscript writing and to the molecular aspects of the menin protein&#46; H&#246;ppener JW provided assistance to the study design&#44; manuscript writing and final version of the manuscript&#46;</p>"
      ]
    ]
    "multimedia" => array:3 [
      0 => array:7 [
        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 379
            "Ancho" => 661
            "Tamanyo" => 38237
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">In MEN1 tumors&#44; inactivating mutations in the <span class="elsevierStyleItalic">MEN1</span> gene result in alterations of histone protein modifications&#58; both deacetylation &#40;left&#41; and trimethylation &#40;right&#41; are repressed&#46; In this way&#44; the normal function of menin acting as co-repressor and co-activator of gene transcription is disabled&#46; Consequently&#44; the normal function of menin &#40;preservation of differentiation of the cell by modification of histone proteins and transcription of genes responsible for inhibition of cell division&#41; is defective&#46; Red arrows indicate inhibition of apoptosis&#44; cell differentiation&#44; DNA repair&#44; and endocrine metabolic functions&#44; whereas stimulators of cell division are indicated in green&#46; Opportunities for tumor treatment are indicated in blue&#46; E2 &#61; estradiol&#59; TZDs &#61; thiazolidinediones&#59; VDR &#61; Vitamin D receptor&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig2"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 549
            "Ancho" => 662
            "Tamanyo" => 38911
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Beyond inactivation of the <span class="elsevierStyleItalic">MEN1</span> gene&#44; additional mutations in other genes may be responsible for acceleration of tumor growth&#44; thus involving a process of multistep tumorigenesis&#46; Deregulation of normal neuroendocrine development&#47;differentiation can occur through a range of processes&#44; e&#46;g&#46; activation of the PI3K pathway leads to AKT phosphorylation&#44; triggering a downstream cascade of events&#46; Deregulation of this pathway can occur through several mechanisms&#58; 1&#41; gain of function by oncogenic mutations of PIK3&#59; 2&#41; loss of function of the tumor suppressor PTEN through gene deletion&#44; mutation&#44; micro-RNA expression&#44; or epigenetic silencing&#59; 3&#41; amplification or mutation of AKT isoforms&#59; 4&#41; upstream activation through RTK signalling&#59; 5&#41; downstream loss of the tumor suppressors p18 and p27&#59; 6&#41; increased RAS expression&#44; or activating mutations of RAF&#44; MEK&#44; or ERK&#44; which accelerate cell proliferation&#46; Opportunities for treatment are in blue&#46; NSAIDs &#61; non-steroidal anti-inflammatory drugs&#59; RTK &#61; receptor tyrosine kinase&#59; TZDs &#61; thiazolidinediones&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl1"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "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"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="top" scope="col">Protein&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col">Function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col">Reference&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></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="top"><span class="elsevierStyleBold">A Chromatin modification proteins</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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="top">HDAC1<a class="elsevierStyleCrossRef" href="#tfn1">&#8727;</a>&#41;&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="center" valign="top">Chromatin modification&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="center" valign="top">Kim et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&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="top">MLL&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="center" valign="top">Chromatin modification&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="center" valign="top">Yokoyama et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41;&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="top">MLL2&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="center" valign="top">Chromatin modification&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="center" valign="top">Hughes et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&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="top">mSin3A<a class="elsevierStyleCrossRef" href="#tfn1">&#8727;</a>&#41;&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="center" valign="top">Chromatin modification&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="center" valign="top">Kim et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&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="top">LEDGF&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="center" valign="top">Chromatin-associated&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="center" valign="top">Yokoyama et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#41;&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="top"><span class="elsevierStyleBold">B Transcription factors</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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="top">JunD&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="center" valign="top">Gene transcription&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="center" valign="top">Agarwal et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib21">21</a>&#41;&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="top">NF-&#954;B&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="center" valign="top">Gene transcription&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="center" valign="top">Heppner et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib22">22</a>&#41;&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="top">Pem&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="center" valign="top">Gene transcription&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="center" valign="top">Lemmens et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib23">23</a>&#41;&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="top">Smad&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="center" valign="top">Gene transcription&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="center" valign="top">Kaji et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib24">24</a>&#41;&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="top">TGF-&#946;&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="center" valign="top">Gene transcription&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="center" valign="top">Shattuck et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib25">25</a>&#41;&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="top">WNT&#47;&#946;-catenin<a class="elsevierStyleCrossRef" href="#tfn1">&#8727;</a>&#41;&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="center" valign="top">Gene transcription&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="center" valign="top">Chen et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&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="top">ER&#945;&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="center" valign="top">Gene transcription&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="center" valign="top">Dreijerink et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib27">27</a>&#41;&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="top">VDR&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="center" valign="top">Gene transcription&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="center" valign="top">Dreijerink et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib27">27</a>&#41;&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="top">PPAR&#947;&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="center" valign="top">Gene transcription&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="center" valign="top">Dreijerink et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib27">27</a>&#41;&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="top">FOXO1<a class="elsevierStyleCrossRef" href="#tfn1">&#8727;</a>&#41;&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="center" valign="top">Gene transcription&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="center" valign="top">Wuescher et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib28">28</a>&#41;&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="top"><span class="elsevierStyleBold">C DNA repair proteins</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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="top">RPA2&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="center" valign="top">DNA replication&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="center" valign="top">Sukhodolets et al&#46;&#40;<a class="elsevierStyleCrossRef" href="#bib29">29</a>&#41;&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="top">ASK&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="center" valign="top">Cell cycle regulation&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="center" valign="top">Schnepp et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib30">30</a>&#41;&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="top">CHES1&#40;FOXN3&#41;&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="center" valign="top">DNA repair&#47; Transcription&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="center" valign="top">Busygina et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib31">31</a>&#41;&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="top">FANCD2&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="center" valign="top">DNA repair&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="center" valign="top">Jin et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib32">32</a>&#41;&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
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="top">Vimentin&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="center" valign="top">Cytoplasmic&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="center" valign="top">Lopez-Egido et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib33">33</a>&#41;&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="top">AKT1&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="center" valign="top">Signal transduction&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="center" valign="top">Wang et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib34">34</a>&#41;&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="top">GFAP&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="center" valign="top">Cytoplasmic&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="center" valign="top">Lopez-Egido et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib33">33</a>&#41;&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="top">NM23&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="center" valign="top">GTP-ase&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="center" valign="top">Ohkura et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib35">35</a>&#41;&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="top">IQGAP1&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="center" valign="top">Cell adhesion&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="center" valign="top">Yan et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib36">36</a>&#41;&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="top">NMHC&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="center" valign="top">Myosin&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="center" valign="top">Obungu et al&#46; &#40;<a class="elsevierStyleCrossRef" href="#bib37">37</a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                          "etal" => true
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