Little evidence for association between the TGFBR1*6A variant and colorectal cancer: a family-based association study on non-syndromic family members from Australia and Spain.

Genome-wide linkage studies have identified the 9q22 chromosomal region as linked with colorectal cancer (CRC) predisposition. A candidate gene in this region is transforming growth factor beta receptor 1 (TGFBR1). Investigation of TGFBR1 has focused on the common genetic variant rs11466445, a short exonic deletion of nine base pairs which results in truncation of a stretch of nine alanine residues to six alanine residues in the gene product. While the six alanine (*6A) allele has been reported to be associated with increased risk of CRC in some population based study groups this association remains the subject of robust debate. To date, reports have been limited to population-based case-control association studies, or case-control studies of CRC families selecting one affected individual per family. No study has yet taken advantage of all the genetic information provided by multiplex CRC families. Methods: We have tested for an association between rs11466445 and risk of CRC using several family-based statistical tests in a new study group comprising members of non-syndromic high risk CRC families sourced from three familial cancer centres, two in Australia and one in Spain. Results: We report a finding of a nominally significant result using the pedigree-based association test approach (PBAT; p = 0.028), while other family-based tests were non-significant, but with a p-value < 0.10 in each instance. These other tests included the Generalised Disequilibrium Test (GDT; p = 0.085), parent of origin GDT Generalised Disequilibrium Test (GDT-PO; p = 0.081) and empirical Family-Based Association Test (FBAT; p = 0.096, additive model). Related-person case-control testing using the 'More Powerful' Quasi-Likelihood Score Test did not provide any evidence for association (M-QL5; p = 0.41). Conclusions: After conservatively taking into account considerations for multiple hypothesis testing, we find little evidence for an association between the TGFBR1*6A allele and CRC risk in these families. The weak support for an increase in risk in CRC predisposed families is in agreement with recent meta-analyses of case-control studies, which estimate only a modest increase in sporadic CRC risk among 6*A allele carriers.

Molecular Interactions of Prodiginines with the BH3 Domain of Anti-Apoptotic Bcl-2 Family Members.

Prodigiosin and obatoclax, members of the prodiginines family, are small molecules with anti-cancer properties that are currently under preclinical and clinical trials. The molecular target(s) of these agents, however, is an open question. Combining experimental and computational techniques we find that prodigiosin binds to the BH3 domain in some BCL-2 protein families, which play an important role in the apoptotic programmed cell death. In particular, our results indicate a large affinity of prodigiosin for MCL-1, an anti-apoptotic member of the BCL-2 family. In melanoma cells, we demonstrate that prodigiosin activates the mitochondrial apoptotic pathway by disrupting MCL-1/BAK complexes. Computer simulations with the PELE software allow the description of the induced fit process, obtaining a detailed atomic view of the molecular interactions. These results provide new data to understand the mechanism of action of these molecules, and assist in the development of more specific inhibitors of anti-apoptotic BCL-2 proteins.

Identification of potential small molecule binding pockets on Rho family GTPases

Rho GTPases are conformational switches that control a wide variety of signaling pathways critical for eukaryotic cell development and proliferation. They represent attractive targets for drug design as their aberrant function and deregulated activity is associated with many human diseases including cancer. Extensive high-resolution structures (.100) and recent mutagenesis studies have laid the foundation for the design of new structure-based chemotherapeutic strategies. Although the inhibition of Rho signaling with drug-like compounds is an active area of current research, very little attention has been devoted to directly inhibiting Rho by targeting potential allosteric non-nucleotide binding sites. By avoiding the nucleotide binding site, compounds may minimize the potential for undesirable off-target interactions with other ubiquitous GTP and ATP binding proteins. Here we describe the application of molecular dynamics simulations, principal component analysis, sequence conservation analysis, and ensemble small-molecule fragment mapping to provide an extensive mapping of potential small-molecule binding pockets on Rho family members. Characterized sites include novel pockets in the vicinity of the conformationaly responsive switch regions as well as distal sites that appear to be related to the conformations of the nucleotide binding region. Furthermore the use of accelerated molecular dynamics simulation, an advanced sampling method that extends the accessible time-scale of conventional simulations, is found to enhance the characterization of novel binding sites when conformational changes are important for the protein mechanism.

DIC.CAT. Dona, immigració i ciutadania: les dones marrquines com a generadores de ciutadania a Catalunya

DIC.CAT es centra en les contribucions a la ciutadania que realitzen les dones immigrants marroquines, sobre les quals recauen forts estereotips i imatges que, sovint, les vinculen a la passivitat i a la submissió. Partint d'aquest fet, el projecte analitza el paper d'aquetes dones com a generadores de noves formes de ciutadania a Catalunya, a partir de les seves accions en les esferes pública i privada. El projecte contribueix, d'una banda a ampliar el coneixement teòric sobre la noció de ciutadania, incorporant la dimensió del gènere i partint de la realitat multicultural actual; i de l'altra a aprofundir sobre el rol que estan exercint les doens marroquines estudiades, com agents actius de xsocialització i generadores de canvis en els formes d'exercir la ciutadania en la societat catalana. Destaquen les accions que desenvolupen des de la seva quotidianitat en relació a aspectes com el procés de reagrupació, la incorporació al mercat laboral, la transmissio de valores dins la familia, la relació amb la comunitat d'origen, les motivacions, aspiracions o els projectes professionals i personals propis. Alhora, el projecte vincula aquestes accions amb les que desenvolupen des dels espais públics en els que participen, especialment dins l'àmbit associatiu.

MYADM regulates Rac1 targeting to ordered membranes required for cell spreading and migration

Membrane organization into condensed domains or rafts provides molecular platforms for selective recruitment of proteins. Cell migration is a general process that requires spatiotemporal targeting of Rac1 to membrane rafts. The protein machinery responsible for making rafts competent to recruit Rac1 remains elusive. Some members of the MAL family of proteins are involved in specialized processes dependent on this type of membrane. Because condensed membrane domains are a general feature of the plasma membrane of all mammalian cells, we hypothesized that MAL family members with ubiquitous expression and plasma membrane distribution could be involved in the organization of membranes for cell migration. We show that myeloid-associated differentiation marker (MYADM), a protein with unique features within the MAL family, colocalizes with Rac1 in membrane protrusions at the cell surface and distributes in condensed membranes. MYADM knockdown (KD) cells had altered membrane condensation and showed deficient incorporation of Rac1 to membrane raft fractions and, similar to Rac1 KD cells, exhibited reduced cell spreading and migration. Results of rescue-of-function experiments by expression of MYADM or active Rac1L61 in cells knocked down for Rac1 or MYADM, respectively, are consistent with the idea that MYADM and Rac1 act on parallel pathways that lead to similar functional outcomes.

Who Cares? A comparison of informal and formal care provision in Spain, England and the USA

This paper investigates the prevalence of incapacity in performing daily activities and the associations between household composition and availability of family members and receipt of care among older adults with functioning problems in Spain, England and the United States of America (USA). We examine how living arrangements, marital status, child availability, limitations in functioning ability, age and gender affect the probability of receiving formal care and informal care from household members and from others in three countries with different family structures, living arrangements and policies supporting care of the incapacitated. Data sources include the 2006 Survey of Health, Ageing and Retirement in Europe for Spain, the third wave of the English Longitudinal Study of Ageing (2006), and the eighth wave of the USA Health and Retirement Study (2006). Logistic and multinomial logistic regressions are used to estimate the probability of receiving care and the sources of care among persons age 50 and older. The percentage of people with functional limitations receiving care is higher in Spain. More care comes from outside the household in the USA and England than in Spain. The use of formal care among the incapacitated is lowest in the USA and highest in Spain.

Oral findings in Midline Syndrome: a case report and literature review

We describe a female patient with a midline syndrome. The patient presents agenesis of the corpus callosum, encephalocele, iris coloboma, hypertelorism, submucosal cleft palate and dental anomalies. Despite being very characteristic, her phenotypical traits do not coincide exactly with those reported to date in the literature. The karyotype and the molecular cytogenetic study do not show mutations. We identify the presence of dental anomalies in the mother and other family members, not being identified MSX1 and PAX9 mutations that could the related with their etiology. Despite the fact that dental agenesis has been related to a large number of other malformation syndromes and congenital conditions, dental anomalies have only rarely been mentioned when reporting midline syndromes. These dental phenotypical traits, present in the patient and her family, could be considered part of the midline syndrome in carriers as well as in the patients.

N-myc controls proliferation, morphogenesis, and patterning of the inner ear

Myc family members play crucial roles in regulating cell proliferation, size, and differentiation during organogenesis. Both N-myc and c-myc are expressed throughout inner ear development. To address their function in the mouse inner ear, we generated mice with conditional deletions in either N-myc or c-myc. Loss of c-myc in the inner ear causes no apparent defects, whereas inactivation of N-myc results in reduced growth caused by a lack of proliferation. Reciprocally, the misexpression of N-myc in the inner ear increases proliferation. Morphogenesis of the inner ear in N-myc mouse mutants is severely disturbed, including loss of the lateral canal, fusion of the cochlea with the sacculus and utriculus, and stunted outgrowth of the cochlea. Mutant cochleas are characterized by an increased number of cells exiting the cell cycle that express the cyclin-dependent kinase inhibitor p27Kip1 and lack cyclin D1, both of which control the postmitotic state of hair cells. Analysis of different molecular markers in N-myc mutant ears reveals the development of a rudimentary organ of Corti containing hair cells and the underlying supporting cells. Differentiated cells, however, fail to form the highly ordered structure characteristic for the organ of Corti but appear as rows or clusters with an excess number of hair cells. The Kölliker's organ, a transient structure neighboring the organ of Corti and a potential source of ectopic hair cells, is absent in the mutant ears. Collectively, our data suggest that N-myc regulates growth, morphogenesis, and pattern formation during the development of the inner ear.

Abuelos contemporáneos : ¿dónde está el límite?

En la sociedad actual están aconteciendo una serie de cambios en la estructura de lafamilia, en su ciclo y evolución, en los roles tradicionales, en la aparición de nuevosroles y en las relaciones intergeneracionales. Esta situación cambiante afecta al rol deabuelo y abuela y, en la actualidad, nadie cuestionará la importancia que estánadquiriendo los abuelos/as en las relaciones familiares, ya que el número de personasque llegan a ser abuelos/as aumenta, así como también crece el número de años quelos abuelos/as pueden compartir con sus nietos. Estos cambios han hecho que lafigura de los abuelos/as recupere su importancia dentro de la familia y adquiera unnotable protagonismo y una valiosa función social produciéndose una mayorintegración de los abuelos/as en la familia. En esta nueva situación social y familiarresulta especialmente importante el estudio de las características del rol de abuelo/aactual y de la relación y actividades que comparte con su nieto/a. Con estainvestigación se pretende examinar la relación abuelo nieto en la infancia, desde laperspectiva de los abuelos/as así como las repercuciones del cuidado de los nietos enla salud de éstos

An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: gefitinib (Iressatrade mark)-induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review)

Intrinsic resistance to the epidermal growth factor receptor (EGFR; HER1) tyrosine kinase inhibitor (TKI) gefitinib, and more generally to EGFR TKIs, is a common phenomenon in breast cancer. The availability of molecular criteria for predicting sensitivity to EGFR-TKIs is, therefore, the most relevant issue for their correct use and for planning future research. Though it appears that in non-small-cell lung cancer (NSCLC) response to gefitinib is directly related to the occurrence of specific mutations in the EGFR TK domain, breast cancer patients cannot be selected for treatment with gefitinib on the same basis as such EGFR mutations have beenreported neither in primary breast carcinomas nor in several breast cancer cell lines. Alternatively, there is a generalagreement on the hypothesis that the occurrence of molecular alterations that activate transduction pathways downstreamof EGFR (i.e., MEK1/MEK2 - ERK1/2 MAPK and PI-3'K - AKT growth/survival signaling cascades) significantly affect the response to EGFR TKIs in breast carcinomas. However,there are no studies so far addressing a role of EGF-related ligands as intrinsic breast cancer cell modulators of EGFR TKIefficacy. We recently monitored gene expression profiles andsub-cellular localization of HER-1/-2/-3/-4 related ligands (i.e., EGF, amphiregulin, transforming growth factor-α, ß-cellulin,epiregulin and neuregulins) prior to and after gefitinib treatment in a panel of human breast cancer cell lines. First, gefitinibinduced changes in the endogenous levels of EGF-related ligands correlated with the natural degree of breast cancer cellsensitivity to gefitinib. While breast cancer cells intrinsically resistant to gefitinib (IC50 ≥15 μM) markedly up-regulated(up to 600 times) the expression of genes codifying for HERspecific ligands, a significant down-regulation (up to 106 times)of HER ligand gene transcription was found in breast cancer cells intrinsically sensitive to gefitinib (IC50 ≤1 μM). Second,loss of HER1 function differentially regulated the nuclear trafficking of HER-related ligands. While gefitinib treatment induced an active import and nuclear accumulation of the HER ligand NRG in intrinsically gefitinib-resistant breastcancer cells, an active export and nuclear loss of NRG was observed in intrinsically gefitinib-sensitive breast cancer cells.In summary, through in vitro and pharmacodynamic studies we have learned that, besides mutations in the HER1 gene,oncogenic changes downstream of HER1 are the key players regulating gefitinib efficacy in breast cancer cells. It now appears that pharmacological inhibition of HER1 functionalso leads to striking changes in both the gene expression and the nucleo-cytoplasmic trafficking of HER-specific ligands,and that this response correlates with the intrinsic degree of breast cancer sensitivity to the EGFR TKI gefitinib. Therelevance of this previously unrecognized intracrine feedback to gefitinib warrants further studies as cancer cells could bypassthe antiproliferative effects of HER1-targeted therapeutics without a need for the overexpression and/or activation of other HER family members and/or the activation of HER-driven downstream signaling cascades

Chemokines induce axon outgrowth downstream of Hepatocyte Growth Factor and TCF/β-catenin signaling

Axon morphogenesis is a complex process regulated by a variety of secreted molecules, including morphogens and growth factors, resulting in the establishment of the neuronal circuitry. Our previous work demonstrated that growth factors [Neurotrophins (NT) and Hepatocyte Growth Factor (HGF)] signal through β-catenin during axon morphogenesis. HGF signaling promotes axon outgrowth and branching by inducing β-catenin phosphorylation at Y142 and transcriptional regulation of T-Cell Factor (TCF) target genes. Here, we asked which genes are regulated by HGF signaling during axon morphogenesis. An array screening indicated that HGF signaling elevates the expression of chemokines of the CC and CXC families. In line with this, CCL7, CCL20, and CXCL2 significantly increase axon outgrowth in hippocampal neurons. Experiments using blocking antibodies and chemokine receptor antagonists demonstrate that chemokines act downstream of HGF signaling during axon morphogenesis. In addition, qPCR data demonstrates that CXCL2 and CCL5 expression is stimulated by HGF through Met/b-catenin/TCF pathway. These results identify CC family members and CXCL2 chemokines as novel regulators of axon morphogenesis downstream of HGF signaling.

A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion

Deletions in the 2p16.3 region that includes the neurexin (NRXN1) gene are associated with intellectual disability and various psychiatric disorders, in particular, autism and schizophrenia. We present three unrelated patients, two adults and one child, in whom we identified an intragenic 2p16.3 deletion within the NRXN1 gene using an oligonucleotide comparative genomic hybridization array. The three patients presented dual diagnosis that consisted of mild intellectual disability and autism and bipolar disorder. Also, they all shared a dysmorphic phenotype characterized by a long face, deep set eyes, and prominent premaxilla. Genetic analysis of family members showed two inherited deletions. A comprehensive neuropsychological examination of the 2p16.3 deletion carriers revealed the same phenotype, characterized by anxiety disorder, borderline intelligence, and dysexecutive syndrome. The cognitive pattern of dysexecutive syndrome with poor working memory and reduced attention switching, mental flexibility, and verbal fluency was the same than those of the adult probands. We suggest that in addition to intellectual disability and psychiatric disease, NRXN1 deletion is a risk factor for a characteristic cognitive and dysmorphic profile. The new cognitive phenotype found in the 2p16.3 deletion carriers suggests that 2p16.3 deletions might have a wide variable expressivity instead of incomplete penetrance

Acción educativa para la prevención y el tratamiento de la neglicencia parental en el barrio de Can Rull del municipio de Sabadell

Este trabajo se inscribe en el ámbito de la prevención de la negligencia parental. Basado en un proceso teórico-práctico, el programa de intervención está sujeto a la línea de los programas de formación de padres, por lo que sigue una dinámica psico-educativa y comunitaria. Para la realización del trabajo se ha partido de la idea que la familia es la base del desarrollo personal de los humanos y que el buen desarrollo de los menores dependerá en gran parte de las relaciones intrafamiliares. Se establece como objetivo principal ofrecer un servicio específico, estable y continuo, vinculado a los servicios de atención a la infancia y a la familia, que trabaje con el fin de conseguir un cambio conductual en aquellas familias en las que se presente una dinámica parental negligente. La metodología utilizada ha combinado diferentes técnicas de investigación. Para el trabajo de documentación se ha realizado una búsqueda bibliográfica alrededor del concepto de negligencia parental, se han analizado las acciones que se llevan a cabo a nivel institucional y se ha establecido el marco conceptual en el que se incluye tanto los aspectos legal de las diferentes áreas de la administración como aquellos conceptos que forman la estructura de una intervención en el ámbito de la infancia y la familia. También se ha tenido en cuenta la comunicación directa con algunos profesionales del ámbito social, sanitario y educativo como parte importante y determinante del proceso de ejecución del programa. El diseño del programa sigue la metodología del planeamiento estratégico e incluye un diagnóstico preliminar, un plan de acción detallado de las diferentes fases de implementación de la propuesta de intervención, la previsión de mecanismos de evaluación y un presupuesto detallado. En la primera parte del trabajo se refleja la gravedad y el impacto que tiene la negligencia parental en nuestra sociedad, observando la evolución histórica del concepto y la visualización de la problemática a la que va asociado. También se expone la necesidad de crear programas destinados a trabajar esta problemática y una revisión del marco legal que regula la atención a la infancia por parte de las administraciones públicas. En una segunda parte, se propone un programa específico destinado a trabajar la negligencia parental desde una perspectiva de reeducación y cambio conductual. Este proyecto de intervención se ubica en el barrio de Can Rull en Sabadell, del cual se detallan sus especificidades socioeconómicas y su realidad institucional.

Valoració de la qualitat de vida dels familiars de pacients amb fibromiàlgia

Fonament i objectiu: La Fibromiàlgia (FM) és una malaltia reumàtica caracteritzada per dolor generalitzat, que afecta a un tant per cent elevat de la població general , majoritàriament dones i d’etiologia desconeguda, i que pensem que no afecta tan sols als qui la pateixen, sinó que també als seus familiars. En aquest estudi s’han avaluat diferents variables com l’impacte emocional, la vida social, aspectes econòmics i laborals i altres activitats en familiars de primer grau de pacients amb FM. L’objectiu principal és determinar quin és el grau d’afectació negativa en la seva qualitat de vida. Material i mètodes: Es va fer un estudi observacional clínic a un grup de 27 familiars de 1er grau que convivien a la mateixa casa que els respectius afectats per FM. Se’ls va passar un qüestionari ad- hoc de 16 preguntes tancades, basades en estudis previs , i també una entrevista oberta amb l’objectiu de reforçar les dades estadístiques. Les entrevistes es varen fer a la Unitat de Fibromiàlgia de l’Hospital Santa Maria de Lleida. Resultats: Es va entrevistar a 27 familiars, 85’2 % homes, la majoria de entre 51 – 70 anys (63%). El 85’2 % eren casats, amb estudis primaris el 59’3% i el 88% tenien coneixements sobre la malaltia del familiar afectat. El percentatge de familiars que van opinar que hi havia una minva del grau de felicitats amb la malaltia era del 74’1%. El 85% no havia pensat mai en trencar la relació familiar. El 70% referien canvis en la vida social i relacional arrel del diagnòstic de FM , un 88’9% havien tingut que augmentar l’ajut en tasques domèstiques i el 70’4% patien efectes econòmics negatius arrel de la malaltia. La relació sexual es va veure afectada en un 85% dels casos, en canvi no es varen veure alteracions del son ni de la percepció de salut. Conclusions: El fet de conviure amb una persona afectada de FM suposa pèrdua del grau de felicitat i canvis en la vida social, relacional i sexual amb empitjorament del nivell econòmic.

Abuelos contemporáneos : ¿dónde está el límite?

En la sociedad actual están aconteciendo una serie de cambios en la estructura de la familia, en su ciclo y evolución, en los roles tradicionales, en la aparición de nuevos roles y en las relaciones intergeneracionales. Esta situación cambiante afecta al rol de abuelo y abuela y, en la actualidad, nadie cuestionará la importancia que están adquiriendo los abuelos/as en las relaciones familiares, ya que el número de personas que llegan a ser abuelos/as aumenta, así como también crece el número de años que los abuelos/as pueden compartir con sus nietos. Estos cambios han hecho que la figura de los abuelos/as recupere su importancia dentro de la familia y adquiera un notable protagonismo y una valiosa función social produciéndose una mayor integración de los abuelos/as en la familia. En esta nueva situación social y familiarresulta especialmente importante el estudio de las características del rol de abuelo/a actual y de la relación y actividades que comparte con su nieto/a. Con esta investigación se pretende examinar la relación abuelo nieto en la infancia, desde la perspectiva de los abuelos/as así como las repercuciones del cuidado de los nietos enla salud de éstos