1,615 publications from this institution
<p>PDF file, 282K, Presence of aberrant mitotic figures in engrafted OVA1X tumors analyzed by co-immunostaining with anti-H3S10ph, anti-tubulin. Chromosomes were labeled with DAPI.</p>
<p>Expression of let-7c (A) and miR-29c (B) miRNAs was evaluated in Karpas1718 parental and resistant lines by real time PCR upon previous exposure to DMSO (control, grey), decitabine (100nM, yellow) or tazemetostat (5µM, red). RQ values calculated by the DDCt method, RNU6 was used as housekeeping miRNA. Data derived from three independent experiments.</p>
Tax auditing parameters have been largely overlooked by the literature as policy-making instruments of any relevance; however, enforcement strategies are critical elements of the tax burden. In this paper we show that, in a federal framework, tax auditing policies can serve as additional tools for regional interaction. We examine the presence of this interaction by adopting a spatial econometric approach. We employ a time-space recursive model that accounts for sluggish adjustment in auditing policies and obtain results that are congruent with standard theory, corroborating the presence of horizontal competition between regions in their tax auditing policies. We also find that once regional governments acquire legal power, the opaque competition in enforcement policies disappears apparently switching to a more transparent competition in statutory tax parameters.
AbstractThe disruption of genomic DNA methylation patterns was the first epigeneticabnormality to be described in human cancer. This imbalance involves thepromoter CpG island hypermethylation of tumor-suppressor genes, causingtranscriptional repression, and global genomic hypomethylation, leading tochromosomal instability and reactivation of endoparasitic sequences. Therelationship between DNA methylation and histone modifications was initiallydescribed in the context of the inactivation of female X chromosomes and of thedemonstration of strong interactions between the DNA methylation machinery andchromatin modifiers. The repression of tumor-suppressor genes by promoterhypermethylation was also found to be associated with a specific histonemodification index. However, this jigsaw was missing a piece: a global view of howthe histone modification landscape was distorted in cancer cells. We have recentlydiscovered this piece of the puzzle, demonstrating that the association betweenDNA methylation and histone modification aberrations in cancer also occurs at theglobal level. In human and mouse tumors, histone H4 undergoes a loss ofmonoacetylated and trimethylated lysines 16 and 20, respectively. Mostimportantly, these alterations occur within the context of the repetitive DNAsequences that also become hypomethylated in transformed cells. The globalalterations of histone acetylation status suggest novel pathways by which histoneacetyltransferases (HATs), histone methyltransferases (HMTs), and histonedeacetylases (HDACs) may play roles as tumor-suppressor genes or oncogenes. Inthis regard, we have shown how the generation of particular fusion proteinsinvolving HATs in leukemias is associated with an erasure of the monoacetylatedlysine 16-H4 marker, whilst the loss of trimethylation at lysine 20-H4 disruptsheterochromatic domains and may reduce the response to DNA damage of cancercells.
The INK4a/ARF locus encodes two distinct tumor suppressors, p16INK4a and p14ARF. Although the contribution of p16INK4a to human tumorigenesis through point mutation, deletion, and hypermethylation has been widely documented, little is known about specific p14ARF lesions and their consequences. Recent data indicate that p14ARF suffers inactivation by promoter hypermethylation in colorectal cancer cells. Because it is known that p14ARF prevents MDM2 nucleocytoplasmic shuttling and thus stabilizes p53 by attenuating MDM2-mediated degradation, we studied the relationship of p14ARF epigenetic silencing to the expression and localization of MDM2 and p53. Cancer cell lines with an unmethylated p14ARF promoter showed strong nuclear expression of MDM2, whereas in a colorectal cell line with p14ARF hypermethylation-associated inactivation, MDM2 protein was also seen in the cytosol. Treatment with the demethylating agent 5-aza-2'-deoxycytidine was able to reinternalize MDM2 to the nucleus, and p53 expression was restored. No apparent changes in retinoblastoma localization were observed. We also studied the profile of p14ARF promoter hypermethylation in an extensive collection of 559 human primary tumors of different cell types, observing that in colorectal, gastric, renal, esophageal, and endometrial neoplasms and gliomas, aberrant methylation of p14ARF was a relatively common epigenetic event. MDM2 expression patterns revealed that lack of p14ARF promoter hypermethylation was associated with tumors showing exclusive nuclear MDM2 staining, whereas MDM2 cytosolic staining was frequently observed in neoplasms with aberrant p14ARF methylation. Taken together, these data support that epigenetic silencing of p14ARF by promoter hypermethylation is a key mechanism in the disturbance of the MDM2 nuclear localization in human cancer.
