How does the identification of the regulation of DRAK2 by COX-2 further our understanding of the role of COX-2 in cancer? One of the most consistent observations about COX-2 in cancer is its contribution in vivo to the risk of systemic metastases (Tomozawa et al, 2000; Yao et al, 2004) . This fact likely explains the impaired survival observed in individuals whose tumours express COX-2 (Sheehan et al, 1999) . Previous observations about the effects of DAP kinase (the best-characterised member of the kinase family to which DRAK2 belongs) in cancer cells may provide a unifying explanation, linking the ability of this DAP kinase to regulate apoptosis to a suppression of metastatic potential (Inbal et al, 1997) . The most plausible explanation is that the enhanced cell survival conferred by DRAK2 silencing (by COX-2) provide a resistance to various forms of cell death and possibly crucially to anoikis (matrix detachment-induced cell death) (Hofmann et al, 2007) , the form of cell death that may be the most important in deciding the viability of circulating tumour cells and their ability to form distant metastases. Rooting human parechovirus evolution in time BACKGROUND: The Picornaviridae family contains a number of important pathogenic viruses, among which the recently reclassified human parechoviruses (HPeVs). These viruses are widespread and can be grouped in several types. Understanding the evolutionary history of HPeV could answer questions such as how long the circulating lineages last shared a common ancestor and how the evolution of this viral species is shaped by its population dynamics. Using both strict and relaxed clock Bayesian phylogenetics we investigated 1) the substitutions rates of the structural P1 and capsid VP1 regions and 2) evolutionary timescale of currently circulating HPeV lineages. RESULTS: Our estimates reveal that human parechoviruses exhibit high substitution rates for both structural P1 and capsid VP1 regions, respectively 2.21 × 10(-3 )(0.48 – 4.21 × 10(-3)) and 2.79 × 10(-3 )(2.05 – 3.66 × 10(-3)) substitutions per site per year. These are within the range estimated for other picornaviruses. By employing a constant population size coalescent prior, the date of the most recent common ancestor was estimated to be at around 1600 (1427–1733). In addition, by looking at the frequency of synonymous and non-synonymous substitutions within the VP1 gene we show that purifying selection constitutes the dominating evolutionary force leading to strong amino acid conservation. CONCLUSION: In conclusion, our estimates provide a timescale for the evolution of HPeVs and suggest that genetic diversity of current circulating HPeV types has arisen about 400 years ago. Parechoviruses belong to the Picornaviridae family which includes other pathogenic viruses such as foot-and-mouth disease virus (FMDV), hepatitis A virus, enteroviruses and rhinoviruses [1, 2] . The Parechovirus genus includes two species: human parechoviruses (HPeV) and the zoonotic Ljungan virus. HPeV are non-enveloped pathogens with a single-stranded genomic RNA of positive polarity with around 7.400 nucleotides organized into a single long open reading frame in between a 5'UTR and 3'UTR. The open reading frame can be divided into three main regions: P1 (encoding capsid proteins VP0, VP3, VP1), P2 (nonstructural proteins) and P3 (nonstructural proteins, including the viral RNA polymerase) [2] [3] [4] . In HPeV, out of the three capsid proteins that constitute the monomeric units of the viral icosahedric-shaped capsid [3] , VP1 protein plays a crucial role in cell entry via interaction of an Arg-Gly-Asp (RGD) triplet with integrins on the cell surface [5] . However, some HPeVs (among which the type 3 strains) lack the RGD motif in VP1, and their mode of cell recognition and entry is less clear [6] . Typing of HPeV is based on the VP1 sequence providing a reliable locus to type all the identified HPeV strains as described for enteroviruses by Oberste et al [7] . As a result, the majority of HPeV available nucleotide data concerns the VP1 gene.