Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer

Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-k B transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evi-dence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer.

Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer

Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel þ androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-k B transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44 þ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44 þ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evi-dence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer.

Absolute and relative deprivation and the measurement of poverty

This paper develops the link between poverty and inequality by focussing on a class of poverty indices (some of them well-known) which aggregate normative concerns for absolute and relative deprivation. The indices are distinguished by a parameter that captures the ethical sensitivity of poverty measurement to ``exclusion'' or ``relative-deprivation'' aversion. We also show how the indices can be readily used to predict the impact of growth on poverty. An illustration using LIS data finds that he United States show more relative deprivation than Denmark and Belgium whatever the percentiles considered, but that overall deprivation comparisons of the four countries considered will generally necessarily depend on the intensity of the ethical concern for relative deprivation. The impact of growth on poverty is also seen to depend on the presence of and on the attention granted to concerns over relative deprivation. }

Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-Binding Motif

The androgen receptor (AR) is a ligand-activated transcription factor that is essential for prostate cancer development. It is activated by androgens through its ligand-binding domain (LBD), which consists predominantly of 11 α-helices. Upon ligand binding, the last helix is reorganized to an agonist conformation termed activator function-2 (AF-2) for coactivator binding. Several coactivators bind to the AF-2 pocket through conserved LXXLL or FXXLF sequences to enhance the activity of the receptor. Recently, a small compound-binding surface adjacent to AF-2 has been identified as an allosteric modulator of the AF-2 activity and is termed binding function-3 (BF-3). However, the role of BF-3 in vivo is currently unknown, and little is understood about what proteins can bind to it. Here we demonstrate that a duplicated GARRPR motif at the N terminus of the cochaperone Bag-1L functions through the BF-3 pocket. These findings are supported by the fact that a selective BF-3 inhibitor or mutations within the BF-3 pocket abolish the interaction between the GARRPR motif(s) and the BF-3. Conversely, amino acid exchanges in the two GARRPR motifs of Bag-1L can impair the interaction between Bag-1L and AR without altering the ability of Bag-1L to bind to chromatin. Furthermore, the mutant Bag-1L increases androgen-dependent activation of a subset of AR targets in a genome-wide transcriptome analysis, demonstrating a repressive function of the GARRPR/BF-3 interaction. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the AR.

Allosteric conversation in the androgen receptor ligand-binding domain surfaces

Androgen receptor (AR) is a major therapeutic target that plays pivotal roles in prostate cancer (PCa) and androgen insensitivity syndromes. We previously proposed that compounds recruited to ligand-binding domain (LBD) surfaces could regulate AR activity in hormone-refractory PCa and discovered several surface modulators of AR function. Surprisingly, the most effective compounds bound preferentially to a surface of unknown function [binding function 3 (BF-3)] instead of the coactivator-binding site [activation function 2 (AF-2)]. Different BF-3 mutations have been identified in PCa or androgen insensitivity syndrome patients, and they can strongly affect AR activity. Further, comparison of AR x-ray structures with and without bound ligands at BF-3 and AF-2 showed structural coupling between both pockets. Here, we combine experimental evidence and molecular dynamic simulations to investigate whether BF-3 mutations affect AR LBD function and dynamics possibly via allosteric conversation between surface sites. Our data indicate that AF-2 conformation is indeed closely coupled to BF-3 and provide mechanistic proof of their structural interconnection. BF-3 mutations may function as allosteric elicitors, probably shifting the AR LBD conformational ensemble toward conformations that alter AF-2 propensity to reorganize into subpockets that accommodate N-terminal domain and coactivator peptides. The induced conformation may result in either increased or decreased AR activity. Activating BF-3 mutations also favor the formation of another pocket (BF-4) in the vicinity of AF-2 and BF-3, which we also previously identified as a hot spot for a small compound. We discuss the possibility that BF-3 may be a protein-docking site that binds to the N-terminal domain and corepressors. AR surface sites are attractive pharmacological targets to develop allosteric modulators that might be alternative lead compounds for drug design.

Expressional regulation of key hepatic enzymes of intermediary metabolism in European seabass (Dicentrarchus labrax) during food deprivation and refeeding

We hypothesized that the analysis of mRNA level and activity of key enzymes in amino acid and carbohydrate metabolism in a feeding/fasting/refeeding setting could improve our understanding of how a carnivorous fish, like the European seabass (Dicentrarchus labrax), responds to changes in dietary intake at the hepatic level. To this end cDNA fragments encoding genes for cytosolic and mitochondrial alanine aminotransferase (cALT; mALT), pyruvate kinase (PK), glucose 6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) were cloned and sequenced. Measurement of mRNA levels through quantitative real-time PCR performed in livers of fasted seabass revealed a significant increase in cALT (8.5-fold induction)while promoting a drastic 45-fold down-regulation of PK in relation to the levels found in fed seabass. These observations were corroborated by enzyme activity meaning that during food deprivation an increase in the capacity of pyruvate generation happened via alanine to offset the reduction in pyruvate derived via glycolysis. After a 3-day refeeding period cALT returned to control levels while PK was not able to rebound. No alterations were detected in the expression levels of G6PDH while 6PGDH was revealed to be more sensitive specially to fasting, as confirmed by a significant 5.7-fold decrease in mRNA levels with no recovery after refeeding. Our results indicate that in early stages of refeeding, the liver prioritized the restoration of systemic normoglycemia and replenishment of hepatic glycogen. In a later stage, once regular feeding is re-established, dietary fuel may then be channeled to glycolysis and de novo lipogenesis.

Expressional regulation of key hepatic enzymes of intermediary metabolism in European seabass (Dicentrarchus labrax) during food deprivation and refeeding

We hypothesized that the analysis of mRNA level and activity of key enzymes in amino acid and carbohydrate metabolism in a feeding/fasting/refeeding setting could improve our understanding of how a carnivorous fish, like the European seabass (Dicentrarchus labrax), responds to changes in dietary intake at the hepatic level. To this end cDNA fragments encoding genes for cytosolic and mitochondrial alanine aminotransferase (cALT; mALT), pyruvate kinase (PK), glucose 6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) were cloned and sequenced. Measurement of mRNA levels through quantitative real-time PCR performed in livers of fasted seabass revealed a significant increase in cALT (8.5-fold induction)while promoting a drastic 45-fold down-regulation of PK in relation to the levels found in fed seabass. These observations were corroborated by enzyme activity meaning that during food deprivation an increase in the capacity of pyruvate generation happened via alanine to offset the reduction in pyruvate derived via glycolysis. After a 3-day refeeding period cALT returned to control levels while PK was not able to rebound. No alterations were detected in the expression levels of G6PDH while 6PGDH was revealed to be more sensitive specially to fasting, as confirmed by a significant 5.7-fold decrease in mRNA levels with no recovery after refeeding. Our results indicate that in early stages of refeeding, the liver prioritized the restoration of systemic normoglycemia and replenishment of hepatic glycogen. In a later stage, once regular feeding is re-established, dietary fuel may then be channeled to glycolysis and de novo lipogenesis.

An Atkinson-Gini family of social evaluation functions

We investigate the properties of a family of social evaluation functions and inequality indices which merge the features of the family of Atkinson (1970) and S-Gini (Donaldson and Weymark (1980, 1983), Yitzhaki (1983) and Kakwani (1980)) indices. Income inequality aversion is captured by decreasing marginal utilities, and aversion to rank inequality is captured by rank-dependent ethical weights, thus providing an ethically-flexible dual basis for the assessment of inequality and equity. These ocial evaluation functions can be interpreted as average utility corrected for the illfare of relative deprivation. They can alternatively be understood as averages of altruistic well-being in a population. They moreover have a simple graphical interpretation.

Caracterización de la privación y de la pobreza en Catalunya

Este trabajo contribuye a la escasa literatura sobre la evaluación multidimensional del nivel de bienestar de los individuos más desfavorecidos de nuestra sociedad. Se distingue claramente entre pobreza monetaria y privación multidimensional, para proceder entonces a su cuantificación y caracterización empleando una base de datos nueva (PaD) para Cataluña y utilizando, por vez primera, una metodología que nos permite considerar de forma conjunta la pobreza y la privación. Nuestros resultados empíricos deberían informar a la política social. Aportamos evidencia nueva sobre viejas y nuevas relaciones entre situaciones de desventaja económica y características de los individuos, algunas de las cuales invitan a reconsiderar viejas concepciones. This paper contributes to the scarce literature on the multidimensional assessment of the well-being of the worse off individuals. We document and characterise monetary poverty and multidimensional deprivation using a new database (PaD) for Catalonia. The econometric methodology we employ allows for a join analysis of poverty and deprivation, which has not been seen before. Our empirical findings should be informative for social policy. We provide new evidence on old and new relations between situations of economic disadvantage and individual characteristics, some of which invite to reconsider old conceptions.

Gestión de cambios y proyectos

Moltes inversions corporatives actuals són destinades a la millora de la gestió del canvi. Aquestes inversions són motivades per una carència històrica entre el conjunt recursos humans i les noves tecnologies tal com va reflexar l'estudi del MIT en 1992. L’objectiu del projecte és analitzar la gestió del canvi i projectes des d’un put de vista poc conegut per els enginyers. Direcció de l'equip humà, Procés de qualitat industrial, Programació extrema, Anàlisi de la cobertura dels Sistemes d’informació d’una companyia segons la seva estructura i estratègia empresarial, El mercat i les seves forces competitives, el retorn de la inversió, el cicle PDCA d’un projecte d’inversió, entre d’altres.

Taxes de reincidència 2006 de justícia juvenil: actualització de la taxa de reincidència dels joves sotmesos a mesures de llibertat vigilada i internament en centre

L’estudi actualitza les taxes de reincidència dels menors sotmesos a una mesura d’internament o de llibertat vigilada que van ser publicades a la recerca “La reincidència en el delicte en la justícia de menors” l’any 2005. Si en aquell estudi es recollien per primer cop dades sobre la reincidència dels joves infractors que havien entrat en el circuit de la justícia de menors després de la posada en marxa de la Llei Orgànica 5/2000, de 12 de gener, reguladora de la responsabilitat penal dels menors (LORPM), en aquest s’actualitzen les dades pel col•lectiu de joves que van ser sotmesos a mesures de llibertat vigilada i internament i que les van finalitzar durant l’any 2003. Es fa un seguiment als joves fins a finals del 2006 per saber si han reincidit. També s’ha seguit als joves que hagin arribat a la majoria d’edat per saber si han entrat novament en el sistema d’execució penal, en aquest cas sentenciat al compliment d’una mesura penal alternativa, o a una mesura de privació de llibertat. L’estudi pretén iniciar una sèrie que permeti comparar els resultats anualment, de manera que puguem veure l’evolució de l’execució penal juvenil en algunes de les variables estudiades.

Taxes de reincidència 2007 de justícia juvenil Actualització de la taxa de reincidència dels joves sotmesos a mesures de llibertat vigilada i internament en centre

L’estudi actualitza les taxes de reincidència dels menors sotmesos a una mesura d’internament o de llibertat vigilada que van ser publicades a la recerca “La reincidència en el delicte en la justícia de menors” finalitzada l’any 2005 i que van iniciar la sèrie. Aquesta recerca ja és la tercera del mateix tipus i en aquest cas estudia els joves que van finalitzar una mesura de llibertat vigilada i d’internament l’any 2004 i els segueix fins el 31 de desembre de 2007, per saber si han comès un nou delicte que hagi estat detectat per la Xarxa d’execució penal, tant de joves com d’adults. S’ha estudiat tota la població de joves desinternats de centres (N=169 subjectes l’any 2004). En el cas de llibertat vigilada, del total de joves que finalitzaren mesura l’any 2004 (N= 718), s’ha fet una mostra de 558 subjectes (interval de confiança:95,5%; marge d’error±2;p=q=50). Els resultats en llibertat vigilada apunten un descens significatiu en la taxa de reincidència, que ha passat del 31,9% al 2005 al 22,0% el 2007. En canvi en internament la fluctuació de la taxa no dona diferències significatives tot i que el 2005 era del 62,8%, va augmentar al 66,9% el 2006 i ha tornat a baixar al 56,2% l’any 2007. L’estudi permet comparar de forma seriada ja tres anys d’evolució de la taxa de reincidència juvenil després de la posada en marxa de la Llei Orgànica 5/2000, de 12 de gener, reguladora de la responsabilitat penal dels menors (LORPM).

Tasas de reincidencia 2007 de justicia juvenil: actualización de la tasa de reincidencia de los jóvenes sometidos a medidas de libertad vigilada y internamiento en centro

El estudio actualiza las tasas de reincidencia que se publicaron en 2005 en la investigación “La reincidencia en el delito en la justicia de menores”, relativas al colectivo de jóvenes que finalizaron medidas de libertad vigilada e internamiento durante el año 2004. Para ello se ha realizado un seguimiento de estos sujetos hasta finales de 2007. Este es ya el tercer estudio que se realiza de forma seriada sobre esta materia, y permite comparar los tres años de evolución de la tasa de reincidencia juvenil tras la puesta en marcha de la Ley Orgánica 5/2000, reguladora de la responsabilidad penal de los menores.

La llibertat vigilada: pena accessòria o mesura de seguretat contra els condemnats per delictes sexuals i delictes de terrorisme

La llibertat vigilada s'incorpora al Codi penal com una mesura de seguretat a imposar a subjectes plenament responsables que hagin estat condemnats per delictes contra la llibertat i indemnitat sexual i per terrorisme, el compliment de la mateixa tindrà lloc una vegada que hagin complert la pena privativa de llibertat