Distribución municipal de la incidencia de los tumores más frecuentes en un área de elevada mortalidad por cáncer / Municipal distribution of the incidence of the most common tumours in an area with high cancer mortality

Objetivo: Describir los patrones de distribución geográfica de la incidencia municipal de los tumores más frecuentes en la provincia de Huelva y compararla con la estimada para el conjunto de España. Método: Se calcularon los riesgos relativos (RR) usando el modelo condicional autorregresivo propuesto por Besag, York y Mollié mediante la herramienta INLA, para los años 2007-2011, de las siguientes localizaciones: colon, recto y ano en hombres y en mujeres; tráquea, bronquios y pulmón, próstata y vejiga en hombres; y mama en mujeres. Estos RR se representaron en mapas de coropletas y de isopletas (mediante interpolación por kriging). Resultados: Los RR para cáncer de vejiga en hombres fueron superiores a 1 en todos los municipios, siendo sus intervalos de credibilidad superiores a la unidad en cuatro municipios, destacando la capital con 1,56 (intervalo de credibilidad al 95%:1,30-1,67). Para el cáncer de próstata, las probabilidades a posteriori en 68 de los 79 municipios quedaron por debajo de 0,1. Para el cáncer de pulmón, nueve municipios mostraron intervalos de credibilidad por debajo de la unidad, casi todos en la zona oriental. En las mujeres, los RR para cáncer de mama fueron significativamente superiores en la zona de la capital. Finalmente, las tasas de incidencia provincial de Huelva muestran en general valores próximos a las estimadas para el conjunto de España, destacando las diferencias en cáncer de vejiga en hombres (35% superior) y en cáncer de próstata (30% inferior). Conclusiones: En la provincia de Huelva existe una distribución espacial municipal de la incidencia de cáncer con unos patrones bien definidos para algunas localizaciones tumorales concretas, presentando en general unas tasas de incidencia cercanas a las del territorio nacional (AU)

Objective: To describe the geographic distribution patterns of the municipal incidence of the most common tumours in the Huelva province (Spain) as compared to the estimated incidence for all of Spain. Methods: Relative risk (RR) was computed based on the conditional autoregressive model proposed by Besag, York and Mollié by applying the INLA tool to the cancer data for 2007-2011 for the following tumour locations: colon, rectum and anus (men and women); trachea, bronchia, and lungs, prostate and bladder in men; and breasts in women. The RR was presented in in choropleth and isopleth (with kriging interpolation) risk maps. Results: RR for bladder cancer in men was greater than 1.0 in all municipalities, with confidence intervals over 1.0 in four municipalities; Madrid having a 1.56 RR (95%CI 1.30-1.67). For prostate cancer, a posteriori probabilities were below 0.1 in 68 of the 79 municipalities. For lung cancer, nine municipalities had confidence limits below 1.0, almost all of them in western Spain. For women, the RR for breast cancer was significantly higher in the capital of province area. The cancer incidence rates for the Huelva province were, in general, similar to those estimated for Spain, standing out bladder cancer in men (35% higher) and prostate cancer (30% lower). Conclusions: In the Huelva province, there is a geographical municipal distribution of cancer incidence with well-defined patterns for some specific tumour locations, with overall incidence rates very similar to those in the rest of Spain (AU)

[Municipal distribution of the incidence of the most common tumours in an area with high cancer mortality]. / Distribución municipal de la incidencia de los tumores más frecuentes en un área de elevada mortalidad por cáncer.

OBJECTIVE: To describe the geographic distribution patterns of the municipal incidence of the most common tumours in the Huelva province (Spain) as compared to the estimated incidence for all of Spain. METHODS: Relative risk (RR) was computed based on the conditional autoregressive model proposed by Besag, York and Mollié by applying the INLA tool to the cancer data for 2007-2011 for the following tumour locations: colon, rectum and anus (men and women); trachea, bronchia, and lungs, prostate and bladder in men; and breasts in women. The RR was presented in in choropleth and isopleth (with kriging interpolation) risk maps. RESULTS: RR for bladder cancer in men was greater than 1.0 in all municipalities, with confidence intervals over 1.0 in four municipalities; Madrid having a 1.56 RR (95%CI 1.30-1.67). For prostate cancer, a posteriori probabilities were below 0.1 in 68 of the 79 municipalities. For lung cancer, nine municipalities had confidence limits below 1.0, almost all of them in western Spain. For women, the RR for breast cancer was significantly higher in the capital of province area. The cancer incidence rates for the Huelva province were, in general, similar to those estimated for Spain, standing out bladder cancer in men (35% higher) and prostate cancer (30% lower). CONCLUSIONS: In the Huelva province, there is a geographical municipal distribution of cancer incidence with well-defined patterns for some specific tumour locations, with overall incidence rates very similar to those in the rest of Spain.

JAK/STAT and Hox Dynamic Interactions in an Organogenetic Gene Cascade.

Organogenesis is controlled by gene networks activated by upstream selector genes. During development the gene network is activated stepwise, with a sequential deployment of successive transcription factors and signalling molecules that modify the interaction of the elements of the network as the organ forms. Very little is known about the steps leading from the early specification of the cells that form the organ primordium to the moment when a robust gene network is in place. Here we study in detail how a Hox protein induces during early embryogenesis a simple organogenetic cascade that matures into a complex gene network through the activation of feedback and feed forward interaction loops. To address how the network organization changes during development and how the target genes integrate the genetic information it provides, we analyze in Drosophila the induction of posterior spiracle organogenesis by the Hox gene Abdominal-B (Abd-B). Initially, Abd-B activates in the spiracle primordium a cascade of transcription factors and signalling molecules including the JAK/STAT signalling pathway. We find that at later stages STAT activity feeds back directly into Abd-B, initiating the transformation of the Hox cascade into a gene-network. Focusing on crumbs, a spiracle downstream target gene of Abd-B, we analyze how a modular cis regulatory element integrates the dynamic network information set by Abd-B and the JAK/STAT signalling pathway during development. We describe how a Hox induced genetic cascade transforms into a robust gene network during organogenesis due to the repeated interaction of Abd-B and one of its targets, the JAK/STAT signalling cascade. Our results show that in this network STAT functions not just as a direct transcription factor, but also acts as a "counter-repressor", uncovering a novel mode for STAT directed transcriptional regulation.

Antagonism versus cooperativity with TALE cofactors at the base of the functional diversification of Hox protein function.

Extradenticle (Exd) and Homothorax (Hth) function as positive transcriptional cofactors of Hox proteins, helping them to bind specifically their direct targets. The posterior Hox protein Abdominal-B (Abd-B) does not require Exd/Hth to bind DNA; and, during embryogenesis, Abd-B represses hth and exd transcription. Here we show that this repression is necessary for Abd-B function, as maintained Exd/Hth expression results in transformations similar to those observed in loss-of-function Abd-B mutants. We characterize the cis regulatory module directly regulated by Abd-B in the empty spiracles gene and show that the Exd/Hth complex interferes with Abd-B binding to this enhancer. Our results suggest that this novel Exd/Hth function does not require the complex to bind DNA and may be mediated by direct Exd/Hth binding to the Abd-B homeodomain. Thus, in some instances, the main positive cofactor complex for anterior Hox proteins can act as a negative factor for the posterior Hox protein Abd-B. This antagonistic interaction uncovers an alternative way in which MEIS and PBC cofactors can modulate Abd-B like posterior Hox genes during development.

Genetic control of morphogenesis - Hox induced organogenesis of the posterior spiracles.

The posterior spiracle has become one of the best systems to study how Hox genes control morphogenesis. Interaction of Abdominal-B (ABD-B) with dorso ventral and intrasegmental positional information leads to the local activation of ABD-B primary targets in the dorsal region of the eighth abdominal segment (A8). Primary targets pattern the spiracle subdividing it into two broad areas: external stigmatophore vs. internal spiracular chamber precursor cells. Primary targets then activate secondary targets and modulate the expression of signalling molecules in the spiracle primordium creating unique spiracle positional values. This genetic cascade activates the realisator genes that modulate the cell behaviours causing invagination, elongation and cell rearrangements responsible for spiracle morphogenesis. The spiracle realisators that have been identified to date correspond to cell adhesion proteins, cytoskeleton regulators and cell polarity molecules. Interestingly, these realisators localise to different apico-basal locations in the cell (RhoGEF apical, Crumbs subapical, E-cadherin in the adherens junction, RhoGAP basolateral). Therefore, the Hox anterior-posterior code is converted in the cell into apico-basal information required to implement the posterior spiracle morphogenetic program. We believe this may be a common characteristic for Hox induced organogenesis.

Plasticity of Drosophila Stat DNA binding shows an evolutionary basis for Stat transcription factor preferences.

In vertebrates, seven signal transducer and activator of transcription (STAT) proteins bind to palindromic sites separated by spacers of two or three nucleotides (STAT1), four nucleotides (STAT6) or three nucleotides (STAT2 to STAT5a/b). This diversity of binding sites provides specificity to counter semiredundancy and was thought to be a recent evolutionary acquisition. Here, we examine the natural DNA-binding sites of the single Drosophila Stat and show that this is not the case. Rather, Drosophila Stat92E is able to bind to and activate target gene expression through both 3n and 4n spaced sites. Our experiments indicate that Stat92E has a higher binding affinity for 3n sites than for 4n sites and suggest that the levels of target gene expression can be modulated by insertion and/or deletion of single bases. Our results indicate that the ancestral STAT protein had the capacity to bind to 3n and 4n sites and that specific STAT binding preferences evolved with the radiation of the vertebrate STAT family.

Coordinated control of cell adhesion, polarity, and cytoskeleton underlies Hox-induced organogenesis in Drosophila.

BACKGROUND: Hox genes control animal body plans by directing the morphogenesis of segment-specific structures. As transcription factors, HOX proteins achieve this through the activation of downstream target genes. Much research has been devoted to the search for these targets and the characterization of their roles in organogenesis. This has shown that the direct targets of Hox activation are often transcription factors or signaling molecules, which form hierarchical genetic networks directing the morphogenesis of particular organs. Importantly, very few of the direct Hox targets known are "realizator" genes involved directly in the cellular processes of organogenesis. RESULTS: Here, we describe for the first time a complete network linking the Hox gene Abdominal-B to the realizator genes it controls during the organogenesis of the external respiratory organ of the larva. In this process, Abdominal-B induces the expression of four intermediate signaling molecules and transcription factors, and this expression results in the mosaic activation of several realizator genes. The ABD-B spiracle realizators include at least five cell-adhesion proteins, cell-polarity proteins, and GAP and GEF cytoskeleton regulators. Simultaneous ectopic expression of the Abd-B downstream targets can induce spiracle-like structure formation in the absence of ABD-B protein. CONCLUSION: Hox realizators include cytoskeletal regulators and molecules required for the apico-basal cell organization. HOX-coordinated activation of these realizators in mosaic patterns confers to the organ primordium its assembling properties. We propose that during animal development, Hox-controlled genetic cascades coordinate the local cell-specific behaviors that result in organogenesis of segment-specific structures.