Identificació de noves dianes terapèutiques en neoplàsies limfoides

El limfoma de cèl•lules de mantell (LCM) és un limfoma de cèl•lules B incurable que presenta sobreexpressió de ciclina D1. Això fa necessari el desenvolupament de noves teràpies. Els gens supressors de tumors estan alterats en càncer pel silenciament epigenètic aberrant, com a conseqüència de la desacetilació de les histones dels seus promotors. Els inhibidors de les desacetilases d'histones (HDACi) són nous compostos amb resultats prometedors per al tractament de tumors. L'objectiu principal, i que ha durat 7 mesos, va ser analitzar l'activitat antitumoral de l'àcid hidroxàmic suberoilanílid (SAHA, vorinostat), un HDACi en fase d'assajos clínics per al tractament de varis tumors, en cèl•lules de LCM. Es va analitzar la sensibilitat al SAHA (Merck Pharmaceuticals) en nou línies cel•lulars humanes de LCM, que es diferenciaven en les alteracions genètiques, les característiques replicatives i la sensibilitat als fàrmacs; i cèl•lules primàries de 6 pacients. El SAHA va presentar un efecte citotòxic heterogeni amb DL50 (Dosi Letal 50) de 3.25 μM a &25 μM amb 24 d'incubació. Aquest efecte citotòxic s'incrementava notablement després de 48 hores d'incubació assolint una DL50 de 0.34 a 5.69 μM. Cal destacar que 5 dels 6 casos de les mostres primàries de LCM van mostrar una elevada sensibilitat (DL50 & 8.07 μM). A nivell mecanistic, el SAHA va augmentar l'acetilació de les histones H3 i H4, i va disminuir els nivells de proteïna de la ciclina D1 i c-Flip. La citometria de flux i els anàlisis per Western Blot van posar de manifest que l'efecte citotòxic del SAHA es dóna a través de l'activació de la via mitocondrial de mort cel•lular i la cascada de caspases. El SAHA indueix l'expressió transcripcional de la proteïna proapoptòtica Bmf. Aquests resultats suggereixen que el SAHA podria ser una nova teràpia prometedora per al tractament del LCM.

Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications

Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications.

Directional and fluctuating asymmetry in finger and a-b ridge counts in psychosis: a case-control study

Background: Several studies have reported alterations in finger and a-b ridge counts, and theirderived measures of asymmetry, in schizophrenia compared to controls. Because ridges are fully formed by the end of the second trimester, they may provide clues to disturbed early development. The aim of this study was to assess these measures in a sample of patients with psychosis and normal controls.Methods: Individuals with psychosis (n = 240), and normal controls (n = 228) were drawn from a catchment-area case-control study. Differences in finger and a-b ridge count and Fluctuating Asymmetry were assessed in three group comparisons (non-affective psychosis versus controls; affective psychosis versus controls; non-affective psychosis versus affective psychosis). The analyses were performed separately for males and females. Results: There were no significant group differences for finger nor a-b ridge counts. While there were no group difference for Directional Asymmetry, for Fluctuating Asymmetry measures men with non-affective psychosis had significantly higher fluctuating asymmetry of the index finger ridge count (a) when compared to controls (FA-correlation score, p = 0.02), and (b) when compared to affective psychosis (adjusted FA-difference score, p = 0.04). Conclusion: Overall, measures of finger and a-b ridge counts, and their derived measures of directional and fluctuating asymmetry were not prominent features of psychosis in this sample. While directional asymmetry in cerebral morphology is reduced in schizophrenia, this is not reflected in dermatoglyphic variables.