Toward an Epigenetic View of Our Musical Mind

We are transient beings, in a world of constantly changing culture. At home in the fields of Art and Science, seemingly capable of magnificent abstractions, humans have an intense need to externalize their insights. Music is an art and a highly transmissible cultural product, but we still have an incomplete understanding of how our musical experience shapes and is vividly retained within our brain, and how it affects our behavior. However, the developing field of social epigenetics is now helping us to describe how communication and emotion, prime hallmarks of music, can be linked to a transmissible, biochemical change

Differentiated thyroid cancer: role of the lymph node dissection

Il cancro della tiroide è la più comune neplasia maligna endocrina con la più alta mortalità. La tiroidectomia totale è il trattamento primario per pazienti con cancro differenziato della tiroide (DTC) e si è dimostrata efficace e sicura. L’estensione della dissezione linfonodale rimane controversa tra esperti nel campo.Questa controversia persiste largamente anche per la mancanza di uno studio prospettico controllato randomizzato che riconosca come la dissezione linfonodale centrale (CLND) per cancro papillare della tiroide (PTC) conferisca alla tiroidectomia totale un aumentato rischio di ipoparatiroidismo e di lesione ricorrenziale permanente. Secondo la Consensus Conference del UEC’s Club la dissezione radicale terapeutica modificata del collo (MRND) dovrebbe essere eseguita solo in pazienti con evidenza di coinvolgimento lonfonodale neoplastico multiplo. Sebbene la dissezione linfonodale centrale possa aumentare il rischio di ipoparatiroidismo e di lesione del ricorrente a confronto con la tiroidectomia totale senza CLND, essa può ridurre le metastasi da PTC e probabilmente migliorare la sopravvivenza specifica della malattia. Offre inoltre un’alternativa sufficiente alla dissezione radicale profilattica modificata del collo. La dissezione linfonodale centrale selettiva deve essere eseguita da mani esperte, in pazienti ad alto rischio (maggiori di 50 anni, larga diffusione del tumore intra o extratiroidea), con l’estensione alle stazioni II-III-IV in caso di coinvolgimento linfonodale singolo in esse

Androgen Receptor Activity Is Affected by Both Nuclear Matrix Localization and the Phosphorylation Status of the Heterogeneous Nuclear Ribonucleoprotein K in Anti-Androgen-Treated LNCaP Cells

<div><p>The androgen receptor (AR) plays a central role in the development and progression of prostate cancer (PCa) and anti-androgen therapy is a standard treatment. Unfortunately, after a few years, the majority of patients progress, developing androgen-independent PCa. AR-driven gene transcription recruits a large number of co-activator/co-repressor complexes; among these, the heterogeneous nuclear ribonucleoprotein K (hnRNP K) directly interacts with and regulates the AR translational apparatus. Here we examined AR and hnRNP K expression in response to the treatment of LNCaP cells with anti-androgen cyproterone acetate (CPA) or bicalutamide (BIC). AR and hnRNP K modulation and compartmentalization were studied by Western blot and confocal microscopy. Phosphate-affinity gel electrophoresis was employed to examine how anti-androgens modified hnRNP K phosphorylation. 10⁻⁶M CPA significantly stimulated LNCaP proliferation, whereas for 10⁻⁴M CPA or 10⁻⁵M BIC an antagonistic effect was observed. After anti-androgen treatment, AR expression was remarkably down-regulated within both the cytoplasm and the nucleus; however, when CPA had an agonist activity, the AR associated with the nuclear matrix (NM) increased approximately 2.5 times. This increase was synchronous with a higher PSA expression, indicating that the NM-associated AR represents the active complex. After BIC treatment, hnRNP K expression was significantly lower in the NM, the protein was hypophosphorylated and the co-localization of AR and hnRNP K decreased. In contrast, CPA as an agonist caused hnRNP K hyperphosphorylation and an increase in the co-localization of two proteins. These findings demonstrate that, in vitro, there is a strong relationship between NM-associated AR and both cell viability and PSA levels, indicating that AR transcriptional activity is critically dependent on its subnuclear localization. Moreover, the agonistic/antagonistic activity of anti-androgens is associated with modifications in hnRNP K phosphorylation, indicating an involvement of this protein in the AR transcriptional activity and likely in the onset of the androgen-independent phenotype.</p></div

The phosphorylation status of hnRNP K changes after anti–androgen exposure.

<p>NMs extracted from LNCaP untreated cells grown in presence of 0.1(A, D), cells treated with 10⁻⁵M BIC (B, E) and cells treated with 10⁻⁶M CPA (C, F). The samples were separated by conventional 2D-PAGE (A, B, C) or 2D-phosphate-affinity-PAGE (D, E, F), as reported in the Materials and Methods section, and probed with the anti-hnRNP K antibody. Magnified sections of the hnRNP K detection region are shown. The arrowheads indicate the various protein isoforms. The colors in the histograms correspond to the isoforms present in cells after the different treatments. In (D, E, F), dotted squares surround the spots belonging to the four spliced forms (iso1, iso2, iso3 and iso4); the numbers that identify the spots are the same used by Kimura <i>et al </i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079212#pone.0079212-Kimura1" target="_blank">[15]</a>. The histograms represent the relative amount (RA) of the hnRNP K spots marked with arrowheads in (A, B, C) and of the phosphorylated spots present in spliced isoform 1, 2, 3 in (D, E, F). The colors in the histograms correspond to spots. hK, hnRNP K; hK phiso, hnRNP K phosphorylated isoforms.</p

LNCaP cell proliferation in the presence of increasing concentrations of BIC or CPA.

<p>LNCaP cells were grown with 0.1-androgen under study. The effects were significant (P<0.01) for all concentrations ≥10⁻⁶M and for all times reported, except for 10⁻⁵M CPA for 48 h. Data are presented as percentage of the absorbance of BIC or CPA treated cells with respect to controls. The bars represent the mean ± SD of three independent experiments, each performed 10 times.</p

AR and hnRNP K are differently distributed in the NM after anti-androgen treatments.

<p>(A) Confocal microscopy analysis clearly shows that in the absence (−) of DHT, the AR is not localized in the NM, whereas in the presence (+) of 0.1 nM DHT, the AR is distributed both in the periphery and in inner punctuate sites. HnRNP K staining is independent of DHT and is present in the internal NM. After exposure of cells grown in presence of 0.1 nM DHT to 10⁻⁵M BIC, both AR and hnRNP K show a very weak diffuse fluorescence pattern. Treatment with 10⁻⁶M CPA gives rise to a strong increase in AR fluorescence. NMs were immunostained with anti-lamin B (blue), anti-AR (red) and anti–hnRNP K (green) antibodies. (B) Scatterplots show the quantification analysis of AR/hnRNP K co-localization. M1 corresponds to the fraction of AR overlapping hnRNP K, and M2 indicates the fraction of hnRNP K overlapping AR; R is Pearson’s coefficient. The horizontal lines indicate the mean values from 20–23 fields (160–190 total cells) replicated in two different experiments; *P<0.02. (C) Frequency distribution of the size of the punctuate sites, corresponding to AR (upper panel) and hnRNP K (lower panel), grouped in intervals of 0.003 µm³. The ordinates are the mean ± SE. The red curves representing BIC treatment are significantly different from control (+DHT; green curves P = 0.01). The blue curves correspond to CPA treatment. Representative projections of image stacks utilized to calculate the size of punctuate sites are reported. hK, hnRNP K. The bars correspond to 10 µm in (A) and 5 µm in (C).</p

The PI3K/Akt inhibitor Wortmannin modifies hnRNP K phosphorylation status.

<p>LNCaP cells grown in presence of 0.1(A–D) control (E–H) Wortmannin treated cells. Magnified sections of 2D-PAGE stained with SYPRO Ruby (A, E) or Pro-Q Diamond, that selectively stains only phosphoproteins (B, F), are shown. The boxes mark the phosphorylated hnRNP K isoforms. After Wortmannin treatment a marked decrease in some hnRNP K isoforms and the loss of the more acidic spots are evident. The hnRNP K spots separated by 2D-PAGE (C, G) or 2D-phosphate-affinity-PAGE (D, H) and probed with anti-hnRNP K antibody are also reported. The arrowheads in C, G and the numbers in D, H indicate the different protein isoforms as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0079212#pone-0079212-g004" target="_blank">Figure 4</a>. hK, hnRNP K.</p

doi:10.1155/2010/263914 Review Article Inflammation, HIF-1, and the Epigenetics That Follows

Copyright © 2010 Claudio Brigati et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We summarize recent findings linking inflammatory hypoxia to chromatin modifications, in particular to repressive histone signatures. We focus on the role of Hypoxia-Induced Factor-1 in promoting the activity of specific histone demethylases thus deeply modifying chromatin configuration. The consequences of these changes are depicted in terms of gene expression and cellular phenotypes. We finally integrate available data to introduce novel speculations on the relationship between inflammation, histones, and DNA function and integrity. 1