Epigenetics of human cutaneous melanoma: setting the stage for new therapeutic strategies

Cutaneous melanoma is a very aggressive neoplasia of melanocytic origin with constantly growing incidence and mortality rates world-wide. Epigenetic modifications (i.e., alterations of genomic DNA methylation patterns, of post-translational modifications of histones, and of microRNA profiles) have been recently identified as playing an important role in melanoma development and progression by affecting key cellular pathways such as cell cycle regulation, cell signalling, differentiation, DNA repair, apoptosis, invasion and immune recognition. In this scenario, pharmacologic inhibition of DNA methyltransferases and/or of histone deacetylases were demonstrated to efficiently restore the expression of aberrantly-silenced genes, thus re-establishing pathway functions. In light of the pleiotropic activities of epigenetic drugs, their use alone or in combination therapies is being strongly suggested, and a particular clinical benefit might be expected from their synergistic activities with chemo-, radio-, and immuno-therapeutic approaches in melanoma patients. On this path, an important improvement would possibly derive from the development of new generation epigenetic drugs characterized by much reduced systemic toxicities, higher bioavailability, and more specific epigenetic effects

Signal assessment in Photinus greeni fireflies

In Photinus fireflies, flying males emit bioluminescent courtship signals to which conspecific females selectively respond. Previous work has examined variation in male signals and female preference in firefly species with either single-pulse or multiple-pulse male signals. Little, however, is known about Photinus species such as Photinus greeni in which males emit paired pulses. We first examined variation in male P. greeni signals. Using playback experiments, in lab and in the field, we then independently manipulated male pulse duration and inter-pulse interval (IPI) to examine female P. greeni signal assessment. Early in the season when the sex ratio was male biased, we examined morphological and behavioral correlates of male mating success in competitive courtships. We hypothesized that if females assess male IPI for species recognition then (a) females should prefer mean male IPIs and (b) female responsiveness to male signals with different IPIs should be independent of female body condition. We found that females were most responsive to signals with mean male IPIs and that body condition did not affect female responsiveness to signals with differing IPI but did affect female responsiveness to signals with differing pulse duration. Across the range of male pulse durations and IPIs seen in the field, females responded less to male signals with different IPI. In competitive courtships, males that flashed at a high rate and elicited more female responses were more likely to mate. These data support our hypothesis that female P. greeni assess male IPI primarily for species recognition and suggest that male pulse duration and flash rate may be indicators of male quality

Male courtship signals and female signal assessment in Photinus greeni fireflies

The evolutionary dynamic of courtship signaling systems is driven by the interaction between male trait distributions and female preferences. This interaction is complex because females may choose mates based on multiple components of male signals, and female preference functions may vary depending on mate availability, female reproductive state, and environmental conditions. In Photinus fireflies (Coleoptera: Lampyridae), flying males emit bioluminescent flash signals to locate sedentary females, which reply selectively to attractive male flash signals with their own response flash. In this study, we first examined temporal variation in the paired-pulse flash patterns produced by Photinus greeni males in the field and found significant among-male variation (∼70% of total variation) in interpulse intervals (IPIs). There was no significant relationship between male IPI and spermatophore size, suggesting that P. greeni male courtship signals do not provide females with reliable indicators of male material resources. In laboratory playback experiments, we presented P. greeni females with simulated flash signals to assess how IPI and pulse duration independently affected the likelihood of female flash response. We also examined the effects of female body mass and time during the mating season on female preference functions, hypothesizing that females would be less discriminating when they were heavier (more fecund) and when mate availability declined. We found that P. greeni females discriminated among signals within their species' range based primarily on flash pattern IPI. Neither the time during the mating season nor female weight altered female preference functions for IPI, although season did influence female response to pulse duration. These results reveal that P. greeni females discriminate among conspecific males based primarily on male IPIs, the same signal character previously shown to be important for firefly species recognition. Field playback experiments indicated that female responsiveness peaked near the average IPI given by males at different ambient temperatures, suggesting that fireflies exhibit temperature coupling similar to that seen in many acoustically signaling animals. Copyright 2006.bioluminescence; mate choice; multiple cues; preference functions; sexual selection; temperature coupling

Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs

ObjectiveTo investigate the risk of developing lower intestinal perforations (LIPs) in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ).MethodsIn 13 310 patients with RA observed in the German biologics register Rheumatoid Arthritis: Observation of Biologic Therapy, 141 serious gastrointestinal events possibly associated with perforations were reported until 31 October 2015. All events were validated independently by two physicians, blinded for treatment exposure.Results37 LIPs (32 in the colon/sigma) were observed in 53 972 patient years (PYs). Only two patients had a history of diverticulitis (one in TCZ). Age, current/cumulative glucocorticoids and non-steroidal anti-inflammatory drugs were significantly associated with the risk of LIP. The crude incidence rate of LIP was significantly increased in TCZ (2.7/1000 PYs) as compared with all other treatments (0.2−0.6/1000 PYs). The adjusted HR (ref: conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs)) in TCZ was 4.48 (95% CI 2.0 to 10.0), in tumour necrosis factor-α inhibitor (TNFi) 1.04 (0.5 to 2.3) and in other biologic DMARDs 0.33 (0.1 to 1.4). 4/11 patients treated with TCZ presented without typical symptoms of LIP (acute abdomen, severe pain). Only one patient had highly elevated C reactive protein (CRP). One quarter of patients died within 30 days after LIP (9/37), 5/11 under TCZ, 2/13 under TNFi and 2/11 under csDMARD treatment.ConclusionsThe incidence rates of LIP under TCZ found in this real world study are in line with those seen in randomised controlled trials of TCZ and higher than in all other DMARD treatments. To ensure safe use of TCZ in daily practice, physicians and patients should be aware that, under TCZ, LIP may occur with mild symptoms only and without CRP elevation.</jats:sec