Harnessing autophagy to overcome mitogen‐activated protein kinase kinase inhibitor‐induced resistance in metastatic melanoma

Background Patients with malignant melanoma often relapse after treatment with BRAF and/or mitogen‐activated protein kinase kinase (MEK) inhibitors (MEKi) owing to development of drug resistance. Objectives To establish the temporal pattern of CD271 regulation during development of resistance by melanoma to trametinib, and determine the association between development of resistance to trametinib and induction of prosurvival autophagy. Methods Immunohistochemistry for CD271 and p62 was performed on human naevi and primary malignant melanoma tumours. Western blotting was used to analyse expression of CD271, p62 and LC3 in melanoma subpopulations. Flow cytometry and immunofluorescence microscopy was used to evaluate trametinib‐induced cell death and CD271 expression. MTS viability assays and zebrafish xenografts were used to evaluate the effect of CD271 and autophagy modulation on trametinib‐resistant melanoma cell survival and invasion, respectively. Results CD271 and autophagic signalling are increased in stage III primary melanomas vs. benign naevi. In vitro studies demonstrate MEKi of BRAF‐mutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271‐expressing subpopulations. Trametinib‐induced CD271 reduced autophagic flux, leading to activation of prosurvival autophagy and development of MEKi resistance. Treatment of CD271‐expressing melanoma subpopulations with RNA interference and small‐molecule inhibitors to CD271 reduced the development of MEKi resistance, while clinically applicable autophagy modulatory agents – including Δ9‐tetrahydrocannabinol and Vps34 – reduced survival of MEKi‐resistant melanoma cells. Combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKi‐resistant cells in an in vivo zebrafish xenograft. Conclusions These results highlight a novel mechanism of MEKi‐induced drug resistance and suggest that targeting autophagy may be a translatable approach to resensitize drug‐resistant melanoma cells to the cytotoxic effects of MEKi

The Axiverse Extended: Vacuum Destabilisation, Early Dark Energy and Cosmological Collapse

A model is presented in the philosophy of the "String Axiverse" of Arvanitaki et al (arXiv:0905.4720v2 [hep-th]) that incorporates a coupling of ultralight axions to their corresponding moduli through the mass term. The light fields roll in their potentials at late times and contribute to the dark sector energy densities in the cosmological expansion. The addition of a coupling and extra field greatly enrich the possible phenomenology of the axiverse. There are a number of interesting phases where the axion and modulus components behave as Dark Matter or Dark Energy and can have considerable and distinct effects on the expansion history of the universe by modifying the equation of state in the past or causing possible future collapse of the universe. In future such a coupling may help to alleviate fine tuning problems for cosmological axions. We motivate and present the model, and briefly explore its cosmological consequences numerically.Comment: 13 pages, 17 figures, published in PRD. v3: corrected SUSY interpretation of axion potential scal

Do Perceptions of Ballot Secrecy Influence Turnout? Results from a Field Experiment

Although the secret ballot has long been secured as a legal matter in the United States, formal secrecy protections are not equivalent to convincing citizens that they may vote privately and without fear of reprisal. We present survey evidence that those who have not previously voted are particularly likely to voice doubts about the secrecy of the voting process. We then report results from a field experiment where we provided registered voters with information about ballot secrecy protections prior to the 2010 general election. We find that these letters increased turnout for registered citizens without records of previous turnout, but did not appear to influence the behavior of citizens who had previously voted. These results suggest that although the secret ballot is a long-standing institution in the United States, providing basic information about ballot secrecy can affect the decision to participate to an important degree.

Sexual Attraction Toward Clients, Use of Supervision, and Prior Training: A Qualitative Study of Predoctoral Psychology Interns

Interviews were conducted with 13 predoctoral psychology interns about an experience of sexual attraction toward a client, use of supervision to address the sexual attraction, and prior training regarding sexual attraction. Results indicated that sexual attraction to clients consisted of physical and interpersonal aspects. Therapists believed they were more invested and attentive than usual to clients to whom they were sexually attracted, and they indicated that sexual attraction created distance, distraction, and loss of objectivity. In terms of supervision, only half of the participants disclosed their sexual attraction to supervisors, and supervisors seldom initiated the discussion. Furthermore, trainees found it helpful when supervisors normalized the sexual attraction and provided the opportunity to explore feelings in supervision. Finally, trainees believed their training programs did not adequately address therapist sexual attraction

Shock and Release Temperatures in Molybdenum

Shock and release temperatures in Mo were calculated, taking account of heating from plastic flow predicted using the Steinberg-Guinan model. Plastic flow was calculated self-consistently with the shock jump conditions: this is necessary for a rigorous estimate of the locus of shock states accessible. The temperatures obtained were significantly higher than predicted assuming ideal hydrodynamic loading. The temperatures were compared with surface emission spectrometry measurements for Mo shocked to around 60GPa and then released into vacuum or into a LiF window. Shock loading was induced by the impact of a planar projectile, accelerated by high explosive or in a gas gun. Surface velocimetry showed an elastic wave at the start of release from the shocked state; the amplitude of the elastic wave matched the prediction to around 10%, indicating that the predicted flow stress in the shocked state was reasonable. The measured temperatures were consistent with the simulations, indicating that the fraction of plastic work converted to heat was in the range 70-100% for these loading conditions