The common biology of cancer and ageing

At first glance, cancer and ageing would seem to be unlikely bedfellows. Yet the origins for this improbable union can actually be traced back to a sequence of tragic--and some say unethical--events that unfolded more than half a century ago. Here we review the series of key observations that has led to a complex but growing convergence between our understanding of the biology of ageing and the mechanisms that underlie cancer.     

Biological activity of phenolic lipids

Phenolic lipids are a very diversified group of compounds derived from mono and dihydroxyphenols, i.e., phenol, catechol, resorcinol, and hydroquinone. Due to their strong amphiphilic character, these compounds can incorporate into erythrocytes and liposomal membranes. In this review, the antioxidant, antigenotoxic, and cytostatic activities of resorcinolic and other phenolic lipids are described. The ability of these compounds to inhibit bacterial, fungal, protozoan and parasite growth seems to depend on their interaction with proteins and/or on their membrane-disturbing properties.     

Homing endonucleases: from basics to therapeutic applications

Homing endonucleases (HE) are double-stranded DNAses that target large recognition sites (12–40 bp). HE-encoding sequences are usually embedded in either introns or inteins. Their recognition sites are extremely rare, with none or only a few of these sites present in a mammalian-sized genome. However, these enzymes, unlike standard restriction endonucleases, tolerate some sequence degeneracy within their recognition sequence. Several members of this enzyme family have been used as templates to engineer tools to cleave DNA sequences that differ from their original wild-type targets. These custom HEs can be used to stimulate double-strand break homologous recombination in cells, to induce the repair of defective genes with very low toxicity levels. The use of tailored HEs opens up new possibilities for gene therapy in patients with monogenic diseases that can be treated ex vivo. This review provides an overview of recent advances in this field.     

RACK1 depletion in a mouse model causes lethality, pigmentation deficits and reduction in protein synthesis efficiency

The receptor for activated C-kinase 1 (RACK1) is a conserved structural protein of 40S ribosomes. Strikingly, deletion of RACK1 in yeast homolog Asc1 is not lethal. Mammalian RACK1 also interacts with many nonribosomal proteins, hinting at several extraribosomal functions. A knockout mouse for RACK1 has not previously been described. We produced the first RACK1 mutant mouse, in which both alleles of RACK1 gene are defective in RACK1 expression (ΔF/ΔF), in a pure C57 Black/6 background. In a sample of 287 pups, we observed no ΔF/ΔF mice (72 expected). Dissection and genotyping of embryos at various stages showed that lethality occurs at gastrulation. Heterozygotes (ΔF/+) have skin pigmentation defects with a white belly spot and hypopigmented tail and paws. ΔF/+ have a transient growth deficit (shown by measuring pup size at P11). The pigmentation deficit is partly reverted by p53 deletion, whereas the lethality is not. ΔF/+ livers have mild accumulation of inactive 80S ribosomal subunits by polysomal profile analysis. In ΔF/+ fibroblasts, protein synthesis response to extracellular and pharmacological stimuli is reduced. These results highlight the role of RACK1 as a ribosomal protein converging signaling to the translational apparatus.     

Population ecology and reproduction of the Mexican mud turtle ( Kinosternon integrum ) in Tonatico Estado De México

Ecological data directly from the field are important in understanding the life history strategies of kinosternid species in the tropics. Herein we summarize the basic population ecology and life history of Kinosternon integrum in the municipality of Tonatico (southeastern Estado de México, México). From October 2003 to November 2004, we marked a total of 204 turtles and recaptured 118 of them. Mean population size using the Jolly-Seber model was 197 (95% CI 128–416) individuals, with a sex ratio of 1:1.7, biased to females. Males were larger than females in carapace length and plastron length. The reproductive season starts in late June and finishes in late October. The smallest female with oviductal eggs was 122 mm in carapace length. Mean clutch size was 4 eggs ( s = 1.77, range 1–8) and was significantly and positively related to body size. Mean egg length was 30.43 mm ( s = 2.24, range 23.92–35.96), mean width was 16.35 mm ( s = 1.01, range 12.99–18.30), and mean weight was 5.14 g ( s = 0.60, range 3.41–6.57). Mean egg length was significantly and inversely related to clutch size. Relative clutch mass (reproductive effort) was 0.043 ( s = 0.017, range 0.017–0.071), which is the smallest value reported for the genus Kinosternon. Additionally, there was no evidence of a pelvic restriction on egg size in this population. This is the first study that documents basic population ecology and reproductive characteristics for a single population of the most widespread freshwater turtle in Mexico.     

TNF-α modulates the migratory response of mesenchymal stem cells to TRAIL

The number of circulating mesenchymal stem cells (MSC), analyzed after acute myocardial infarction (AMI), was lower in AMI patients who developed heart failure (HF) in the follow-up. Conversely, the circulating levels of tumor necrosis factor (TNF)-α, and osteoprotegerin (OPG) were higher in AMI patients who developed HF with respect to the patients who did not develop HF. In vitro exposure to TNF-α enhanced the migration of MSC in response to TNF-related apoptosis-inducing ligand (TRAIL) and significantly increased the release of OPG by endothelial cells. On the contrary, OPG dose-dependently neutralized the in vitro pro-migratory activity of TRAIL. Thus, TNF-α exhibits opposite effects on MSC migration driven by TRAIL: it is capable of potentiating MSC migration as well as of inhibiting MSC migration as an indirect consequence of OPG induction, which might result in a suboptimal recruitment of circulating MSC after AMI in those patients who develop HF in the follow-up.     

A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition

Disruption of histone acetylation patterns is a common feature of cancer cells, but very little is known about its genetic basis. We have identified truncating mutations in one of the primary human histone deacetylases, HDAC2, in sporadic carcinomas with microsatellite instability and in tumors arising in individuals with hereditary nonpolyposis colorectal cancer syndrome. The presence of the HDAC2 frameshift mutation causes a loss of HDAC2 protein expression and enzymatic activity and renders these cells more resistant to the usual antiproliferative and proapoptotic effects of histone deacetylase inhibitors. As such drugs may serve as therapeutic agents for cancer, our findings support the use of HDAC2 mutational status in future pharmacogenetic treatment of these individuals.