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

Subcutaneously administered methotrexate for rheumatoid arthritis, by prefilled syringes versus prefilled pens: patient preference and comparison of the self-injection experience

Winfried Demary,1 Holger Schwenke,2 Karin Rockwitz,3 Peter Kästner,4 Anke Liebhaber,5 Ulrich Schoo,6 Georg Hübner,7 Uwe Pichlmeier,8 Cécile Guimbal-Schmolck,8 Ulf Müller-Ladner9 1Private practice, Hildesheim, Germany; 2Private practice, Dresden, Germany; 3Private practice, Goslar, Germany; 4Outpatient Rheumatism Center, Erfurt, Germany; 5Private practice, Halle, Germany; 6Private practice, Rheine, Germany; 7Private practice, Lingen, Germany; 8medac GmbH, Hamburg, Germany; 9Department of Rheumatology and Clinical Immunology, Kerckhoff-Klinik GmbH, Bad Nauheim, Germany Purpose: This multicenter, randomized, crossover study compared preference, ease of use, acceptability, satisfaction, and safety of repeated subcutaneous (SC) self-administrations with prefilled pens and prefilled syringes delivering methotrexate (MTX), in patients with rheumatoid arthritis (RA).Patients and methods: The study (ClinicalTrials.gov number NCT01793259) enrolled 120 patients requiring initiation or intensification of MTX therapy for RA. Patients were randomized to receive the test drug, a prefilled pen (Metex® PEN/Metoject® PEN), or the reference drug, a prefilled syringe (Metex®/Metoject®), at doses of 15, 17.5, or 20 mg MTX SC once a week for 3 weeks. This was followed by receipt of the reference drug (prefilled syringe) or the test drug (prefilled pen) in a crossover design, with each patient serving as his/her own control. Questionnaires regarding patient preference, the Self-Injection Assessment Questionnaire (SIAQ), and diaries regarding local tolerability were used to document outcomes.Results: Overall patient preference for the MTX prefilled pen was 75% (P<0.0001). In a six-item questionnaire, 73% to 76% of the patients preferred the prefilled pen in relation to use, acceptability, and satisfaction, and 67% of the patients confirmed that it did not take much effort to overcome SC self-injection with the pen. The SIAQ showed no clinical differences, in any domain scores, between both devices. Overall patient attitude towards self-injection at baseline was positive, as was patient experience with both devices during the study. As well, 92% of physicians and study nurses indicated that they would recommend the MTX prefilled pen to patients for future MTX treatment. The formulations were generally well tolerated. Conclusion: SC self-injection of MTX with a prefilled pen was generally preferred, by patients with RA, over a prefilled syringe with regard to use, acceptability, and satisfaction. This is supported by the strong appreciation of their attending study nurses and physicians, for its convenience. Keywords: methotrexate, injection devic

A new beam polarimeter at COSY to search for electric dipole moments of charged particles

A calorimetric polarimeter based on inorganic LYSO scintillators is described. It has been designed for use in a storage ring to search for electric dipole moments (EDM) of charged particles such as the proton and deuteron. Its development and first use was on the Cooler Synchrotron (COSY) at the Forschungszentrum Jülich with 0.97 GeV/c polarized deuterons, a particle and energy suitable for an EDM search. The search requires a polarimeter with high efficiency, large analyzing power, and stable operating characteristics. With typical beam momenta of about 1 GeV/c, the scattering of protons or deuterons from a carbon target into forward angles becomes a nearly optimal choice of an analyzing reaction. The polarimeter described here consists of 52 LYSO detector modules, arranged in 4 symmetric blocks (up, down, left, right) for energy determination behind plastic scintillators for particle identification via energy loss. The commissioning results of the current setup demonstrate that the polarimeter is ready to be employed in a first direct measurement for an EDM on the deuteron, which is planned at COSY