Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

No abstract

Redox reactions pervade living cells. They are central to both anabolic and catabolic metabolism. The ability to maintain redox balance is therefore vital to all organisms. Various regulatory sensors continually monitor the redox state of the internal and external environments and control the processes that work to maintain redox homeostasis. In response to redox imbalance, new metabolic pathways are initiated, the repair or bypassing of damaged cellular components is coordinated and systems that protect the cell from further damage are induced. Advances in biochemical analyses are revealing a range of elegant solutions that have evolved to allow bacteria to sense different redox signals.

Nitric oxide (NO) is a signalling and defence molecule of major importance in biology. The flavohaemoglobin Hmp of Escherichia coli is involved in protective responses to NO. Because hmp gene transcription is repressed by the O(2)-responsive regulator FNR, we investigated whether FNR also senses NO. The [4Fe-4S](2+) cluster of FNR is oxygen labile and controls protein dimerization and site-specific DNA binding. NO reacts anaerobically with the Fe-S cluster of purified FNR, generating spectral changes consistent with formation of a dinitrosyl-iron-cysteine complex. NO-inactivated FNR can be reconstituted, suggesting physiological relevance. FNR binds at an FNR box within the hmp promoter (P(hmp)). FNR samples inactivated by either O(2) or NO bind specifically to P(hmp), but with lower affinity. Dose-dependent up-regulation of P(hmp) in vivo by NO concentrations of pathophysiological relevance is abolished by fnr mutation, and NO also modulates expression from model FNR-regulated promoters. Thus, FNR can respond to not only O(2), but also NO, with major implications for global gene regulation in bacteria. We propose an NO-mediated mechanism of hmp regulation by which E.coli responds to NO challenge.

How do individuals remember feedback that is inconsistent or negative? According to the inconsistency-negativity resolution model, individuals are motivated to reduce uncertainty and resolve inconsistency even when threat to self is potential. They more deeply process and better remember negative self- than other-referent information. According to the inconsistency-negativity neglect model, individuals are motivated to protect the self against threat. They engage in more shallow processing and remember less negative self- than other-referent information. Participants read and recalled either self- or other-referent mixed-valence information. The neglect model was supported in personality and minimal feedback settings. A chronometric exploration of processing mechanisms and the ruling out of a retrieval interference account clarified aspects of the model. Individuals are hypersensitive to threat potential: They will protect the self against even hypothetical threat.