New developments in the treatment of metastatic melanoma – role of dabrafenib–trametinib combination therapy

Development of selective inhibitors of BRAF has improved the survival of patients with BRAF-mutant melanoma. The progression-free survival after treatment with a BRAF inhibitor is modest, however, and BRAF inhibitors induce cutaneous toxicity, likely due to paradoxical activation of the mitogen-activated protein kinase pathway. Combining selective BRAF and MEK inhibition, such as the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, has been shown to improve the response rate and progression-free survival in patients with advanced melanoma while significantly alleviating the paradoxical activation of mitogen-activated protein kinase. This combination treatment results in a reduction in skin toxicity relative to that seen with a BRAF inhibitor alone; however, addition of the MEK inhibitor adds other toxicities, such as pyrexia and gastrointestinal or ocular toxicity. While combined BRAF–MEK inhibition appears primed to become a standard molecular approach for BRAF-mutant melanoma, the utility of the combination has to be considered in the rapidly changing landscape of immunotherapeutics, such as immune checkpoint blockade using anti-cytotoxic T lymphocyte antigen-4 and anti-programmed death-1/programmed death-L1 antibodies. Here we review the development of the dabrafenib plus trametinib combination, the characteristics of each drug and the combination, and the role of this combination in the management of patients with BRAF-mutant melanoma

Impact of MAPK Pathway Activation in BRAFV600 Melanoma on T Cell and Dendritic Cell Function

Constitutive upregulation of the MAPK pathway by a BRAFV600 mutation occurs in about half of melanomas. This leads to increased oncogenic properties such as tumor cell invasion, metastatic potential, and resistance to apoptosis. Blockade of the MAPK pathway with highly specific kinase inhibitors induces unprecedented tumor response rates in patients with advanced BRAFV600 mutant melanoma. Immune checkpoint blockade with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 and programed death-1/PD-L1 has also demonstrated striking anti-tumor activity in patients with advanced melanoma. Tumor responses are likely limited by multiple additional layers of immune suppression in the tumor microenvironment. There is emerging preclinical and clinical evidence suggesting that MAPK inhibition has a beneficial effect on the immunosuppressive tumor microenvironment, providing a strong rationale for combined immunotherapy and MAPK pathway inhibition in melanoma. The T cell response has been the main focus in the studies reported to date. Since dendritic cells (DCs) are important in the induction of tumor-specific T cell responses, the impact of MAPK pathway activation in melanoma on DC function is critical for the melanoma directed immune response. BRAFV600E melanoma cells modulate DCs through the MAPK pathway because its blockade in melanoma cells can reverse suppression of DC function. As both MEK/BRAF inhibition and immune checkpoint blockade have recently taken center stage in the treatment of melanoma, a deeper understanding of how MAPK pathway inhibition affects the tumor immune response is needed

Single-cell transcriptomics : a high-resolution avenue for plant functional genomics

Plant function is the result of the concerted action of single cells in different tissues. Advances in RNA-seq technologies and tissue processing allow us now to capture transcriptional changes at single-cell resolution. The incredible potential of single-cell RNA-seq lies in the novel ability to study and exploit regulatory processes in complex tissues based on the behaviour of single cells. Importantly, the independence from reporter lines allows the analysis of any given tissue in any plant. While there are challenges associated with the handling and analysis of complex datasets, the opportunities are unique to generate knowledge of tissue functions in unprecedented detail and to facilitate the application of such information by mapping cellular functions and interactions in a plant cell atlas. [Abstract copyright: Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.

Bayesian detection of unmodeled bursts of gravitational waves

The data analysis problem of coherently searching for unmodeled gravitational-wave bursts in the data generated by a global network of gravitational-wave observatories has been at the center of research for almost two decades. As data from these detectors is starting to be analyzed, a renewed interest in this problem has been sparked. A Bayesian approach to the problem of coherently searching for gravitational wave bursts with a network of ground-based interferometers is here presented. We demonstrate how to systematically incorporate prior information on the burst signal and its source into the analysis. This information may range from the very minimal, such as best-guess durations, bandwidths, or polarization content, to complete prior knowledge of the signal waveforms and the distribution of sources through spacetime. We show that this comprehensive Bayesian formulation contains several previously proposed detection statistics as special limiting cases, and demonstrate that it outperforms them.Comment: 18 pages, 3 figures, revisions based on referee comment

Measurements of branching fraction ratios and CP-asymmetries in suppressed B^- -> D(-> K^+ pi^-)K^- and B^- -> D(-> K^+ pi^-)pi^- decays

We report the first reconstruction in hadron collisions of the suppressed decays B^- -> D(-> K^+ pi^-)K^- and B^- -> D(-> K^+ pi^-)pi^-, sensitive to the CKM phase gamma, using data from 7 fb^-1 of integrated luminosity collected by the CDF II detector at the Tevatron collider. We reconstruct a signal for the B^- -> D(-> K^+ pi^-)K^- suppressed mode with a significance of 3.2 standard deviations, and measure the ratios of the suppressed to favored branching fractions R(K) = [22.0 \pm 8.6(stat)\pm 2.6(syst)]\times 10^-3, R^+(K) = [42.6\pm 13.7(stat)\pm 2.8(syst)]\times 10^-3, R^-(K)= [3.8\pm 10.3(stat)\pm 2.7(syst]\times 10^-3, as well as the direct CP-violating asymmetry A(K) = -0.82\pm 0.44(stat)\pm 0.09(syst) of this mode. Corresponding quantities for B^- -> D(-> K^+ pi^-)pi^- decay are also reported.Comment: 8 pages, 1 figure, accepted by Phys.Rev.D Rapid Communications for Publicatio

Scientific Potential of Einstein Telescope

Einstein gravitational-wave Telescope (ET) is a design study funded by the European Commission to explore the technological challenges of and scientific benefits from building a third generation gravitational wave detector. The three-year study, which concluded earlier this year, has formulated the conceptual design of an observatory that can support the implementation of new technology for the next two to three decades. The goal of this talk is to introduce the audience to the overall aims and objectives of the project and to enumerate ET's potential to influence our understanding of fundamental physics, astrophysics and cosmology.Comment: Conforms to conference proceedings, several author names correcte

Scientific Objectives of Einstein Telescope

The advanced interferometer network will herald a new era in observational astronomy. There is a very strong science case to go beyond the advanced detector network and build detectors that operate in a frequency range from 1 Hz-10 kHz, with sensitivity a factor ten better in amplitude. Such detectors will be able to probe a range of topics in nuclear physics, astronomy, cosmology and fundamental physics, providing insights into many unsolved problems in these areas.Comment: 18 pages, 4 figures, Plenary talk given at Amaldi Meeting, July 201