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

Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy

Melanoma is the most fatal skin cancer. In the early stages, it can be safely treated with surgery alone. However, since 2011, there has been an important revolution in the treatment of melanoma with new effective treatments. Targeted therapy and immunotherapy with checkpoint inhibitors have changed the history of this disease. To date, more than half of advanced melanoma patients are alive at 5 years; despite this breakthrough, approximately half of the patients still do not respond to treatment. For these reasons, new therapeutic strategies are required to expand the number of patients who can benefit from immunotherapy or combination with targeted therapy. Current research aims at preventing primary and acquired resistance, which are both responsible for treatment failure in about 50% of patients. This could increase the effectiveness of available drugs and allow for the evaluation of new combinations and new targets. The main pathways and molecules under study are the IDO inhibitor, TLR9 agonist, STING, LAG-3, TIM-3, HDAC inhibitors, pegylated IL-2 (NKTR-214), GITR, and adenosine pathway inhibitors, among others (there are currently about 3000 trials that are evaluating immunotherapeutic combinations in different tumors). Other promising strategies are cancer vaccines and oncolytic viruses. Another approach is to isolate and remove immune cells (DCs, T cells, and NK cells) from the patient’s blood or tumor infiltrates, add specific gene fragments, expand them in culture with growth factors, and re-inoculate into the same patient. TILs, TCR gene transfer, and CAR-T therapy follow this approach. In this article, we give an overview over the current status of melanoma therapies, the clinical rationale for choosing treatments, and the new immunotherapy approaches

Probability of Detection Study for Visual Inspection of Steel Bridges: Volume 1—Executive Summary

An inspector’s ability to correctly identify surface and internal defects in steel bridge components is critical to protecting public safety. Ensuring that inspectors are properly trained and adequately equipped to detect these defects in locations that are difficult to access and/or in unfavorable environmental conditions must be a high priority. While the Federal Highway Administration and individual state departments of transportation have guidelines for inspector qualifications, trainings, and certifications, there is very little emphasis placed on evaluating or “testing” a given inspector’s capability to characterize detect defects in the field. As a result, there is also very little if any data on how well a given inspector actually performs or the variability which can be expected between various inspectors. This comprehensive Probability of Detection (POD) study was conducted to establish the ability of an inspector with the current required training to locate cracks in steel bridge components using typical visual inspection techniques

Synthesis of 5,6-Diaminoacenaphthylene by Reduction of Sterically Crowded Nitro Groups with Sodium Dithionite

5,6-Diaminoacenaphthylene was synthesized in four steps from acenaphthene. This seemingly simple molecule provides unique synthetic challenges because it is relatively difficult to reduce the nitro groups and the molecule contains a particularly reactive double bond. It was determined that the only feasible sequence for the synthesis was to nitrate acenaphthene, then brominate, eliminate, and finally selectively reduce. Several reduction methods were attempted before finding one that would completely reduce both nitro groups while leaving the double bond intact

Adaptive radiation along a deeply conserved genetic line of least resistance in \u3cem\u3eAnolis\u3c/em\u3e lizards

On microevolutionary timescales, adaptive evolution depends upon both natural selection and the underlying genetic architecture of traits under selection, which may constrain evolutionary outcomes. Whether such genetic constraints shape phenotypic diversity over macroevolutionary timescales is more controversial, however. One key prediction is that genetic constraints should bias the early stages of species divergence along “genetic lines of least resistance” defined by the genetic (co)variance matrix, G. This bias is expected to erode over time as species means and G matrices diverge, allowing phenotypes to evolve away from the major axis of variation. We tested for evidence of this signal in West Indian Anolis lizards, an iconic example of adaptive radiation. We found that the major axis of morphological evolution was well aligned with a major axis of genetic variance shared by all species despite separation times of 20–40 million years, suggesting that divergence occurred along a conserved genetic line of least resistance. Further, this signal persisted even as G itself evolved, apparently because the largest evolutionary changes in G were themselves aligned with the line of genetic least resistance. Our results demonstrate that the signature of genetic constraint may persist over much longer timescales than previously appreciated, even in the presence of evolving genetic architecture. This pattern may have arisen either because pervasive constraints have biased the course of adaptive evolution or because the G matrix itself has been shaped by selection to conform to the adaptive landscape

Synthesis of porous high-temperature superconductors via a melamine formaldehyde sacrificial template

Nanostructured high-temperature superconductors YBa(2)Cu(3)O(6+δ) and Bi(2)Sr(2)CaCu(2)O(8+δ) were synthesised using a melamine formaldehyde sponge as a sacrificial template, via three solution-based approaches. In the case of YBa(2)Cu(3)O(6+δ), a modified Pechini method produced a material with a superconducting transition at 92 K and a specific surface area of 4.22 m(2) g(−1). Further analysis with Hg porosimetry determined that the sponge exhibited a porosity of 82%. In the case of Bi(2)Sr(2)CaCu(2)O(8+δ), this method produced a material that exhibited superconductivity at 86 K with a specific surface area of 9.62 m(2) g(−1). Hg-porosimetry determined that the BSCCO sponge exhibited a porosity of 78%

Bio-GO-SHIP: the time is right to establish global repeat sections of ocean biology

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Clayton, S., Alexander, H., Graff, J. R., Poulton, N. J., Thompson, L. R., Benway, H., Boss, E., & Martiny, A. Bio-GO-SHIP: the time is right to establish global repeat sections of ocean biology. Frontiers in Marine Science, 8, (2022): 767443, https://doi.org/10.3389/fmars.2021.767443.In this article, we present Bio-GO-SHIP, a new ocean observing program that will incorporate sustained and consistent global biological ocean observations into the Global Ocean Ship-based Hydrographic Investigations Program (GO-SHIP). The goal of Bio-GO-SHIP is to produce systematic and consistent biological observations during global ocean repeat hydrographic surveys, with a particular focus on the planktonic ecosystem. Ocean plankton are an essential component of the earth climate system, form the base of the oceanic food web and thereby play an important role in influencing food security and contributing to the Blue Economy. Despite its importance, ocean biology is largely under-sampled in time and space compared to physical and chemical properties. This lack of information hampers our ability to understand the role of plankton in regulating biogeochemical processes and fueling higher trophic levels, now and in future ocean conditions. Traditionally, many of the methods used to quantify biological and ecosystem essential ocean variables (EOVs), measures that provide valuable information on the ecosystem, have been expensive and labor- and time-intensive, limiting their large-scale deployment. In the last two decades, new technologies have been developed and matured, making it possible to greatly expand our biological ocean observing capacity. These technologies, including cell imaging, bio-optical sensors and 'omic tools, can be combined to provide overlapping measurements of key biological and ecosystem EOVs. New developments in data management and open sharing can facilitate meaningful synthesis and integration with concurrent physical and chemical data. Here we outline how Bio-GO-SHIP leverages these technological advances to greatly expand our knowledge and understanding of the constituents and function of the global ocean plankton ecosystem.The Bio-GO-SHIP pilot program was funded under the National Oceanographic Partnership Program as an inter-agency partnership between NOAA and NASA, with the US Integrated Ocean Observing System and NOAA's Global Ocean Monitoring and Observing program (HA, SC, JG, AM, and NP). HA was supported by a WHOI Independent Research and Development award. AM was supported by funding from NSF OCE-1848576 and 1948842 and NASA 80NSSC21K1654. JG was funded by NASA from grants 80NSSC17K0568 and NNX15AAF30G. LT was supported by award NA06OAR4320264 06111039 to the Northern Gulf Institute by NOAA's Office of Oceanic and Atmospheric Research, U.S. Department of Commerce

In Vivo Role of Neutrophil Extracellular Traps in Antiphospholipid Antibody–Mediated Venous Thrombosis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136296/1/art39938_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136296/2/art39938.pd