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

Variational methods with coupled Gaussian functions for Bose-Einstein condensates with long-range interactions. II. Applications

Bose-Einstein condensates with an attractive 1/r interaction and with dipole-dipole interaction are investigated in the framework of the Gaussian variational ansatz introduced by S. Rau, J. Main, and G. Wunner [Phys. Rev. A, submitted]. We demonstrate that the method of coupled Gaussian wave packets is a full-fledged alternative to direct numerical solutions of the Gross-Pitaevskii equation, or even superior in that coupled Gaussians are capable of producing both, stable and unstable states of the Gross-Pitaevskii equation, and thus of giving access to yet unexplored regions of the space of solutions of the Gross-Pitaevskii equation. As an alternative to numerical solutions of the Bogoliubov-de Gennes equations, the stability of the stationary condensate wave functions is investigated by analyzing the stability properties of the dynamical equations of motion for the Gaussian variational parameters in the local vicinity of the stationary fixed points. For blood-cell-shaped dipolar condensates it is shown that on the route to collapse the condensate passes through a pitchfork bifurcation, where the ground state itself turns unstable, before it finally vanishes in a tangent bifurcation.Comment: 14 pages, 14 figures, submitted to Phys. Rev. A, some equations correcte

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.

Expression of ISG15, UBE1L and MX2 in white blood cells of early pregnant and bred-nonpregnant dairy cows

Abstract only availableIdentifying pregnant and nonpregnant cows shortly after insemination can improve reproductive efficiency in dairy cows if resynchronization is practiced on nonpregnant cows. Bovine Interferon Stimulated Gene Product 15 (ISG15), Bovine Ubiquitin-Activating E1-Like (UBE1L) Enzyme and MX2 are produced in response to conceptus-dervied interferon-τ. The objective was to determine the level of these mRNA in pregnant and bred-nonpregnant Holstein cows (n=14). We hypothesized that the amount of ISG15, UBE1L and MX2 mRNA would increase between d 14 to 20 in pregnant cows but not increase in bred-nonpregnant cows. Cows were synchronized to estrus and inseminated (d 0). Blood samples were collected on d 14, 16, 18 and 20 following insemination. Pregnancy status was determined at approximately 30 and 60 d after insemination. RNA was isolated, reverse transcribed into cDNA and amplified using quantitative RTPCR. Six cows were nonpregnant (open) and eight cows were pregnant on d 30. On d 60, four of the pregnant cows remained pregnant (pregnant-pregnant) and four were found open (aborted; pregnant-open). mRNA data were expressed as fold increase above control and relative to cyclophilin. A status by day interaction was detected for ISG15 (P<.001) and MX2 (P<.02). The interaction was not significant for UBE1L. Mean ISG15 and mean MX2 remained low for open cows, but increased markedly on d 18 and 20 in pregnant-pregnant cows. Pregnant-open cows either had low levels of ISG15 and MX2 or underwent an increase in ISG15 and MX2 on d 18 and 20. We conclude that ISG15, UBE1L and MX2 are differentially regulated in dairy cows during pregnancy recognition. ISG15 and MX2 mRNA expression could be used as an indicator of early pregnancy. Cows that abort their pregnancy after d 28 (pregnant-open) have abnormal ISG15 and MX2 mRNA expression between d 14 to 20.F.B. Miller Undergraduate Research Program in Animal Science