Allelic variant at −79 (C>T) in CDKN1B (p27Kip1) confers an increased risk of thyroid cancer and alters mRNA levels

The aim of this study is to assess if common genetic variants located in the CDKN1B locus, coding for the cell cycle inhibitor p27Kip1, are involved in thyroid cancer susceptibility. Based on the literature and functional predictions, we selected three polymorphisms within the CDKN1B gene (rs2066827 (T326G, V109G), rs34330 (−79C>T) and rs36228499 (−838C>A)) to perform the first case–control study in thyroid cancer involving this locus. We had 649 Spanish patients with sporadic thyroid cancer and 385 healthy representative controls available. Luciferase reporter gene assays, real-time quantitative reverse transcription-PCR and immunoblot experiments were carried out to demonstrate the putative effect of the associated variant. The polymorphism rs34330 (−79C>T) was identified as a risk factor for developing the follicular variant of papillary thyroid carcinoma (FVPTC), fitting a recessive model (odds ratio=2.12; 95% confidence interval=1.09–4.15; P value=0.023). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27Kip1 promoter (P value T (rs34330) variant as a novel mechanism underlying p27Kip1 downregulation

Correction: An epistatic interaction between the PAX8 and STK17B genes in papillary thyroid cancer susceptibility

El artículo original ha sido publicado: Landa I, Boullosa C, Inglada-Pe´rez L, Sastre-Perona A, Pastor S, et al. (2013) An Epistatic Interaction between the PAX8 and STK17B Genes in Papillary Thyroid Cancer Susceptibility. PLoS ONE 8(9): e74765. doi:10.1371/journal.pone.0074765

The Variant rs1867277 in FOXE1 Gene Confers Thyroid Cancer Susceptibility through the Recruitment of USF1/USF2 Transcription Factors

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30–1.70; P = 5.9×10−9). Functional assays of rs1867277 (NM_004473.3:c.−283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era

Advances in Thyroid Carcinoma

“Thyroid cancer” encompasses a heterogeneous group of tumors that range from the predominant papillary thyroid cancer (PTC) subtype, which shows excellent survival rates, to the poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) forms, accounting for most of the disease-related morbidity and mortality [...

Los Albers en Teotihuacán. El arte abstracto visto desde el entendimiento de la ciudad precolombina

Las ciudades prehispánicas de Mesoamérica han sido objeto de estudio para muchos historiadores y arqueólogos europeos. Una de las ciudades que menos información ofrece y que a la vez mejor representa la monumentalidad presente en las zonas arqueológicas de América es la ciudad de Teotihuacán. En este trabajo se analizan los aspectos que originan la legibilidad del concepto del espacio de las ciudades mesoamericanas fundamentadas en una visión abierta del espacio. Para ello, se estudian las características arquitectónicas y urbanísticas de las urbes precolombinas y los elementos que componen la ciudad de Teotihuacán. Se evidencia el hecho de que el urbanismo mesoamericano no responde únicamente a unas demandas prácticas y funcionales. El espacio urbano se encuentra ligado a un orden cosmológico basado en el universo, los movimientos cíclicos de los astros y la ubicación de los elementos físico-naturales del paisaje. La ciudad, por los mencionados principios de composición y ordenación espacial, inspiró al artista alemán de la Bauhaus Josef Albers. Mediante estudios sobre la observación del color y sus interacciones, realizó la serie de pinturas Homenaje al cuadrado, que se apoya en principios urbanísticos mesoamericanos como la cuadrilateralidad. De este modo, la obra se transforma en una representación abstracta de los conjuntos ceremoniales teotihuacanos

Non-destructive measurement techniques for taper equation development: a study case in the Spanish Northern Iberian Range

In recent years, the technology for measuring the diameter and height of standing trees has improved significantly. These enhancements allow estimation of the volume of standing trees using stem taper equations, which traditionally have been constructed with data from felled trees, in an accurate and economically feasible way. A nondestructive method was evaluated with data from 38 pines and was validated with data from another 38 pines, both in the Northern Iberian Range (Spain). The electronic dendrometer Criterion RD1000 (Laser Technology Inc.) and the laser hypsometer TruPulse (Laser Technology Inc.) were used due to their accuracy and interoperability. The methodology was valid (unbiased and precise) measuring from a distance similar to the height of the tree. In this distance, statistical criteria and plots based on the residuals showed no clear advantage in volume estimation with models fitted with data from destructive methods against models fitted with data from the proposed non-destructive technique. This methodology can be considered useful for individual volume estimation and for developing taper equations

Multiple ETS Factors Participate in the Transcriptional Control of TERT Mutant Promoter in Thyroid Cancers

Hotspot mutations in the TERT (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. TERT promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transformation specific”) family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the TERT mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact TERT expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing TERT transcription in the absence of TPMs. Taken together, our results show a more complex scenario of TERT regulation in thyroid cancers compared with other lineages and suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need for a more comprehensive understanding of the mechanisms of TERT deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies

An epistatic interaction between the PAX8 and STK17B genes in papillary thyroid cancer susceptibility

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.Papillary Thyroid Cancer (PTC) is a heterogeneous and complex disease; susceptibility to PTC is influenced by the joint effects of multiple common, low-penetrance genes, although relatively few have been identified to date. Here we applied a rigorous combined approach to assess both the individual and epistatic contributions of genetic factors to PTC susceptibility, based on one of the largest series of thyroid cancer cases described to date. In addition to identifying the involvement of TSHR variation in classic PTC, our pioneer study of epistasis revealed a significant interaction between variants in STK17B and PAX8. The interaction was detected by MD-MBR (p = 0.00010) and confirmed by other methods, and then replicated in a second independent series of patients (MD-MBR p = 0.017). Furthermore, we demonstrated an inverse correlation between expression of PAX8 and STK17B in a set of cell lines derived from human thyroid carcinomas. Overall, our work sheds additional light on the genetic basis of thyroid cancer susceptibility, and suggests a new direction for the exploration of the inherited genetic contribution to disease using association studies. © 2013 Landa et al.This work was supported by Grants from the Fondo de Investigaciones Sanitarias (FIS) project PI11/01359 (to MR), the Red Temática de Investigación Cooperativa en Cáncer, the Instituto de Salud Carlos III, RD12/0030/0060 (to PS), RD12/0036/0050 (to NM) and S2011/BMD-2328 TIRONET from the Comunidad de Madrid (to MR and PS), and European Regional Development Fund. IL is supported by FIS grant FI07/00326; CB is supported by the FPI grant BES-2008-006332; LI-P is supported by Centro de Investigación Biomédica en Red de Enfermedades Raras, and AS-P is a predoctoral fellows of the FPU program (MICINN) respectively. SR-LL is a postdoctoral fellow of the FIS (contract # CD05-0055). RDU is supported by project BIO2009-12458 from the Spanish Ministry of Economy and Innovation. RM, SP and AV are supported by the Generalitat de Catalunya, CIRIT (2009SGR-725).Peer Reviewe

Thyroid cancer GWAS identifies 10q26.12 and 6q14.1 as novel susceptibility loci and reveals genetic heterogeneity among populations

et al.Thyroid cancer is the most heritable cancer of all those not displaying typical Mendelian inheritance. However, most of the genetic factors that would explain the high heritability remain unknown. Our aim was to identify additional common genetic variants associated with susceptibility to this disease. In order to do so, we performed a genome-wide association study in a series of 398 cases and 502 controls from Spain, followed by a replication in four well-defined Southern European case-control collections contributing a total of 1,422 cases and 1,908 controls. The association between the variation at the 9q22 locus near FOXE1 and thyroid cancer risk was consistent across all series, with several SNPs identified (rs7028661: OR = 1.64, p = 1.0 × 10−22, rs7037324: OR = 1.54, p = 1.2 × 10−17). Moreover, the rare alleles of three SNPs (rs2997312, rs10788123 and rs1254167) at 10q26.12 showed suggestive evidence of association with higher risk of the disease (OR = 1.35, p = 1.2 × 10−04, OR = 1.26, p = 5.2 × 10−04 and OR = 1.38, p = 5.9 × 10−05, respectively). Finally, the rare allele of rs4075570 at 6q14.1 conferred protection in the series studied (OR = 0.82, p = 2.0 × 10−04). This study suggests that heterogeneity in genetic susceptibility between populations is a key feature to take into account when exploring genetic risk factors related to this disease.The authors thank the Spanish National Genotyping Center (CEGEN) for its support in this study. Grant sponsor: Fondo de Investigaciones Sanitarias (FIS); Grant numbers: PI11/01359 (to M.R.), PI13/01136 (to A.C.), PI12/00749 (to J.C.- T.); Grant sponsor: Comunidad de Madrid (to P.S., M.R. and A.C.); Grant number: S2011/BMD-2328 TIRONET; Grant sponsor: “La Caixa”/CNIO International PhD Program (to V.M.) and Centro de Investigación Biomédica en Red de Enfermedades Raras (to L.I.-P. and R.C.).Peer reviewe

An enhanced integrity multisensor Fusion for a reliable seamless navigation.

Since its first applications in the late 20th century, GNSS technology has been deployed by the world’s technologically advanced countries in multiple fields, from fleet monitoring to sport-related topics. This massive deployment has led to new use cases that may not have been expected during the definition of said technology. Different error sources, such as interferences, jamming, signal attenuation due to indoor or urban canyon navigation, and signal-blocking objects may degrade the performance of GNSS-based navigation. Thus, standalone GNSS systems may not fulfil all the requirements a certain scenario might ask for. This has resulted in the research of alternative or supplementary methods to solve the aforementioned issues, such as multisensor navigation. This has become one of the main alternatives to GNSS standalone navigation, as it has been shown in the literature that it can result in an improvement in navigation in terms of availability or continuity, for example. Human-life involvement and high-cost freight transportation, among other factors, have attracted the attention of the users to the definition of a measure of trust that is placed in the correctness of the information supplied by the navigation systems; also called integrity. This concept is employed, among others, to enable the system to detect if it is trustable for navigation, provide warnings, and even act consequently. In this dissertation, we analyze, first, the design of an online multisensory navigation algorithm as a solution to the issues GNSS suffers especially in urban and indoor environments. Moreover, a two-stage integrity-ensuring method is analyzed, being this second algorithm a tailored complementary feature of the proposed navigation one.Desde sus primeras aplicaciones a fines del siglo XX, la tecnología GNSS ha sido implementada por los países tecnológicamente avanzados del mundo en múltiples campos, desde la monitorización de flotas hasta temas relacionados con el deporte. Este despliegue masivo ha dado lugar a nuevos casos de uso no contemplados durante la definición de dicha tecnología. Diferentes fuentes de error, como interferencias, atenuación de la señal debido a la navegación en interiores o en cañones urbanos y objetos que bloquean la señal pueden degradar el rendimiento de la navegación basada en GNSS. Por lo tanto, es posible que los sistemas basados únicamente en GNSS no cumplan con todos los requisitos que podría solicitar un determinado escenario. Esto ha dado lugar a la investigación de métodos alternativos o complementarios para solucionar los problemas antes mencionados, como la navegación multisensor. Ésta se ha convertido en una de las principales alternativas a la navegación autónoma GNSS, ya que se ha demostrado en la literatura que puede resultar en una mejora en la navegación en términos de disponibilidad o continuidad, por ejemplo. La afectación de la vida humana y el transporte de carga de alto costo, entre otros factores, han llamado la atención de los usuarios sobre la definición de una medida de confianza que se deposita en la exactitud de la información suministrada por los sistemas de navegación; también llamada integridad. Este concepto se emplea, entre otros, para que el sistema detecte si es fiable para la navegación, emita avisos e incluso actúe en consecuencia. En esta tesis analizamos, en primer lugar, el diseño de un algoritmo de navegación multisensorial online como solución a los problemas que sufre el GNSS especialmente en entornos urbanos e interiores. Además, se analiza un método de aseguramiento de la integridad en dos etapas, siendo este segundo algoritmo una característica complementaria a la medida del de navegación propuesto