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Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity [...]

Adaptation to hypoxia is mediated through a coordinated transcriptional response driven largely by hypoxia-inducible factor 1 (HIF-1). We used ChiP-chip and gene expression profiling to identify direct targets of HIF-1 transactivation on a genome-wide scale. Several hundred direct HIF-1 targets were identified and, as expected, were highly enriched for proteins that facilitate metabolic adaptation to hypoxia. Surprisingly, there was also striking enrichment for the family of 2-oxoglutarate dioxygenases, including the jumonji-domain histone demethylases. We demonstrate that these histone demethylases are direct HIF targets, and their up-regulation helps maintain epigenetic homeostasis under hypoxic conditions. These results suggest that the coordinated increase in expression of several oxygen-dependent enzymes by HIF may help compensate for decreased levels of oxygen under conditions of cellular hypoxia. ChIP-chip | hypoxia | jumonji protein | dioxygenase | epigenetics

Multiple receptor tyrosine kinases (RTKs), including PDGFR, have been validated as therapeutic targets in glioblastoma multiforme (GBM), yet inhibitors of RTKs have had limited clinical success. As various antiapoptotic mechanisms render GBM cells resistant to chemo- and radiotherapy, we hypothesized that these antiapoptotic mechanisms also confer resistance to RTK inhibition. We found that in vitro inhibition of PDGFR in human GBM cells initiated the intrinsic pathway of apoptosis, as evidenced by mitochondrial outer membrane permeabilization, but downstream caspase activation was blocked by inhibitor of apoptosis proteins (IAPs). Consistent with this, inhibition of PDGFR combined with small molecule inactivation of IAPs induced apoptosis in human GBM cells in vitro and had synergistic antitumor effects in orthotopic mouse models of GBM and in primary human GBM neurospheres. These results demonstrate that concomitant inhibition of IAPs can overcome resistance to RTK inhibitors in human malignant GBM cells, and suggest that blockade of IAPs has the potential to improve treatment outcomes in patients with GBM., Introduction The treatment of malignant gliomas remains one of the greatest challenges facing adult and pediatric oncologists today. At the most severe end of the spectrum is glioblastoma multiforme (GBM), [...]

Patel and Groen's notion that semiotic analysis is a framework rather than a theory for the study of diagnostic reasoning is flawed. Semiotics, particularly structural semantics is a well-established theory which deals with several variables. Based on semiotic constructs, a theory of expertise is proposed which could be supported by medical data. This theory is more comprehensive and indept than the one proposed by Patel and Groen.

Comparison of the propositional and semantic approaches to medical diagnostic thinking shows that the process of arriving at an accurate diagnosis involves the use of networks of semantic qualities culled from the signs and symptoms. Propositional methods embody the concept of causal networks whereas, structural semantics involves linear and vertical dimensions corresponding to the syntactic order of terms and logical levels of abstractions respectively. Successful diagnosis entails the use of diverse and pertinent set of semantic axes which leads to a deeper portrayal of the problem.

The deacetylation and repression of the activity of forkhead transcription factor - Foxo3a and other mammalian forkhead factors by the mammalian SIR2 ortholog SIRT1 is reported. The speculation over the down regulation of the two classes of damage - responsive mammalian factors, favoring longer life - span under specific environmental conditions is presented.