Novel mechanisms of resistance to vemurafenib in melanoma – V600E B-Raf reversion and switching VEGF-A splice isoform expression

Targeting activating mutations in the proto-oncogene B-Raf, in melanoma, has led to increases in progression free survival. Treatment with vemurafenib, which inhibits the most common activating-mutated form of B-Raf (B-RafV600E), eventually results in resistance to therapy. VEGF-A is the principal driver of angiogenesis in primary and metastatic lesions. The bioactivity of VEGF-A is dependent upon alternative RNA splicing and pro-angiogenic isoforms of VEGF-A are upregulated in many disease states dependent upon angiogenesis, including cancers. Using techniques including RT-PCR, Western blotting, ELISA and luciferase reporter assays, the effect of vemurafenib on proliferation, ERK1/2 phosphorylation and the levels of pro- and anti-angiogenic VEGF-A isoforms was investigated in melanoma cell types expressing either wild-type B-Raf or B-RafV600E, including a primary melanoma culture derived from a highly vascularised and active nodule taken from a patient with a V600E mutant melanoma. The primary melanoma culture was characterised and found to have reverted to wild-type B-Raf. In B-RafV600E A375 cells ERK1/2 phosphorylation, pro-angiogenic VEGF-A mRNA, total VEGF-A protein expression and VEGF-A 3’UTR activity were all decreased in a concentration-dependent manner by vemurafenib. Conversely vemurafenib treatment of wild-type B-Raf cells significantly increased ERK1/2 phosphorylation, pro-angiogenic VEGF-A mRNA and total VEGF-A expression in a concentration-dependent manner. A switch to pro-angiogenic VEGF-A isoforms, with a concomitant upregulation of expression by increasing VEGF-A mRNA stability, may be an additional oncogenic and pathological mechanism in B-RafV600E melanomas, which promotes tumor-associated angiogenesis and melanoma-genesis. We have also identified the genetic reversal of B-RafV600E to wild-type in an active melanoma nodule taken from a V600E-positive patient and continued vemurafenib treatment for this patient is likely to have had a detrimental effect by promoting B-RafWT activity

Evaluation of a cognitive skills programme for male prisoners – exploring treatment effectiveness

Aim: The current study provides an evaluation of a cognitive skills programme (Enhanced Thinking Skills) with adult prisoners. Method: A pre and post treatment-only design with 171 male prisoners, using self-report psychometric measures. Results: Significant differences were found in the direction expected. Clinical recovery using stringent methods was not indicated, although improvement/partial response was across a number of domains. Originality: This study represents the first prison study to distinguish between levels of positive change. It questions previous interpretations of treatment outcome. Implications for practice: Expectations for treatment outcome for short term interventions should be more realistic; Cognitive skills programmes may be best considered as precursors to longer term therapies; Treatment outcome should focus on improvement and not recovery

Garden and landscape-scale correlates of moths of differing conservation status: significant effects of urbanization and habitat diversity

Moths are abundant and ubiquitous in vegetated terrestrial environments and are pollinators, important herbivores of wild plants, and food for birds, bats and rodents. In recent years, many once abundant and widespread species have shown sharp declines that have been cited by some as indicative of a widespread insect biodiversity crisis. Likely causes of these declines include agricultural intensification, light pollution, climate change, and urbanization; however, the real underlying cause(s) is still open to conjecture. We used data collected from the citizen science Garden Moth Scheme (GMS) to explore the spatial association between the abundance of 195 widespread British species of moth, and garden habitat and landscape features, to see if spatial habitat and landscape associations varied for species of differing conservation status. We found that associations with habitat and landscape composition were species-specific, but that there were consistent trends in species richness and total moth abundance. Gardens with more diverse and extensive microhabitats were associated with higher species richness and moth abundance; gardens near to the coast were associated with higher richness and moth abundance; and gardens in more urbanized locations were associated with lower species richness and moth abundance. The same trends were also found for species classified as increasing, declining and vulnerable under IUCN (World Conservation Union) criteria

Women’s experiences of menopause at work and performance management

Presenting findings from our global evidence review of menopause transition and economic participation emboldened us to establish a menopause policy at the university where we all worked at the time. Our report was published in July 2017 and the policy was in place by November that year. Our critical reflection on this activism focuses on issues that are not commonly recognized around such interventions, and which we ourselves have only been able to acknowledge through engaged action. Challenges remain in normalizing menopause in organizations, specifically around gendered ageism and performance management. In drawing on Meyerson and Kolb’s framework for understanding gender in organizations, we highlight how policies are both vital and yet insufficient in and of themselves in revising the dominant discourse around menopause at work. At the same time, we highlight the importance and shortcomings of academic activism within these processes

d-Cystine di(m)ethyl ester reverses the deleterious effects of morphine on ventilation and arterial blood gas chemistry while promoting antinociception

We have identified thiolesters that reverse the negative effects of opioids on breathing without compromising antinociception. Here we report the effects of d-cystine diethyl ester (d-cystine diEE) or d-cystine dimethyl ester (d-cystine diME) on morphine-induced changes in ventilation, arterial-blood gas chemistry, A-a gradient (index of gas-exchange in the lungs) and antinociception in freely moving rats. Injection of morphine (10 mg/kg, IV) elicited negative effects on breathing (e.g., depression of tidal volume, minute ventilation, peak inspiratory flow, and inspiratory drive). Subsequent injection of d-cystine diEE (500 μmol/kg, IV) elicited an immediate and sustained reversal of these effects of morphine. Injection of morphine (10 mg/kg, IV) also elicited pronounced decreases in arterial blood pH, pO2 and sO2 accompanied by pronounced increases in pCO2 (all indicative of a decrease in ventilatory drive) and A-a gradient (mismatch in ventilation-perfusion in the lungs). These effects of morphine were reversed in an immediate and sustained fashion by d-cystine diME (500 μmol/kg, IV). Finally, the duration of morphine (5 and 10 mg/kg, IV) antinociception was augmented by d-cystine diEE. d-cystine diEE and d-cystine diME may be clinically useful agents that can effectively reverse the negative effects of morphine on breathing and gas-exchange in the lungs while promoting antinociception. Our study suggests that the d-cystine thiolesters are able to differentially modulate the intracellular signaling cascades that mediate morphine-induced ventilatory depression as opposed to those that mediate morphine-induced antinociception and sedation

Hypoxia releases S-nitrosocysteine from carotid body glomus cells—relevance to expression of the hypoxic ventilatory response

We have provided indirect pharmacological evidence that hypoxia may trigger release of the S-nitrosothiol, S-nitroso-L-cysteine (L-CSNO), from primary carotid body glomus cells (PGCs) of rats that then activates chemosensory afferents of the carotid sinus nerve to elicit the hypoxic ventilatory response (HVR). The objective of this study was to provide direct evidence, using our capacitive S-nitrosothiol sensor, that L-CSNO is stored and released from PGCs extracted from male Sprague Dawley rat carotid bodies, and thus further pharmacological evidence for the role of S-nitrosothiols in mediating the HVR. Key findings of this study were that 1) lysates of PGCs contained an S-nitrosothiol with physico-chemical properties similar to L-CSNO rather than S-nitroso-L-glutathione (L-GSNO), 2) exposure of PGCs to a hypoxic challenge caused a significant increase in S-nitrosothiol concentrations in the perfusate to levels approaching 100 fM via mechanisms that required extracellular Ca2+, 3) the dose-dependent increases in minute ventilation elicited by arterial injections of L-CSNO and L-GSNO were likely due to activation of small diameter unmyelinated C-fiber carotid body chemoafferents, 4) L-CSNO, but not L-GSNO, responses were markedly reduced in rats receiving continuous infusion (10 μmol/kg/min, IV) of both S-methyl-L-cysteine (L-SMC) and S-ethyl-L-cysteine (L-SEC), 5) ventilatory responses to hypoxic gas challenge (10% O2, 90% N2) were also due to the activation of small diameter unmyelinated C-fiber carotid body chemoafferents, and 6) the HVR was markedly diminished in rats receiving L-SMC plus L-SEC. This data provides evidence that rat PGCs synthesize an S-nitrosothiol with similar properties to L-CSNO that is released in an extracellular Ca2+-dependent manner by hypoxia

Measurements from the RV Ronald H. Brown and related platforms as part of the Atlantic Tradewind Ocean-Atmosphere Mesoscale Interaction Campaign (ATOMIC)

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Quinn, P. K., Thompson, E. J., Coffman, D. J., Baidar, S., Bariteau, L., Bates, T. S., Bigorre, S., Brewer, A., de Boer, G., de Szoeke, S. P., Drushka, K., Foltz, G. R., Intrieri, J., Iyer, S., Fairall, C. W., Gaston, C. J., Jansen, F., Johnson, J. E., Krueger, O. O., Marchbanks, R. D., Moran, K. P., Noone, D., Pezoa, S., Pincus, R., Plueddemann, A. J., Poehlker, M. L., Poeschl, U., Melendez, E. Q., Royer, H. M., Szczodrak, M., Thomson, J., Upchurch, L. M., Zhang, C., Zhang, D., & Zuidema, P. Measurements from the RV Ronald H. Brown and related platforms as part of the Atlantic Tradewind Ocean-Atmosphere Mesoscale Interaction Campaign (ATOMIC). Earth System Science Data, 13(4), (2021): 1759-1790, https://doi.org/10.5194/essd-13-1759-2021.The Atlantic Tradewind Ocean-Atmosphere Mesoscale Interaction Campaign (ATOMIC) took place from 7 January to 11 July 2020 in the tropical North Atlantic between the eastern edge of Barbados and 51∘ W, the longitude of the Northwest Tropical Atlantic Station (NTAS) mooring. Measurements were made to gather information on shallow atmospheric convection, the effects of aerosols and clouds on the ocean surface energy budget, and mesoscale oceanic processes. Multiple platforms were deployed during ATOMIC including the NOAA RV Ronald H. Brown (RHB) (7 January to 13 February) and WP-3D Orion (P-3) aircraft (17 January to 10 February), the University of Colorado's Robust Autonomous Aerial Vehicle-Endurant Nimble (RAAVEN) uncrewed aerial system (UAS) (24 January to 15 February), NOAA- and NASA-sponsored Saildrones (12 January to 11 July), and Surface Velocity Program Salinity (SVPS) surface ocean drifters (23 January to 29 April). The RV Ronald H. Brown conducted in situ and remote sensing measurements of oceanic and atmospheric properties with an emphasis on mesoscale oceanic–atmospheric coupling and aerosol–cloud interactions. In addition, the ship served as a launching pad for Wave Gliders, Surface Wave Instrument Floats with Tracking (SWIFTs), and radiosondes. Details of measurements made from the RV Ronald H. Brown, ship-deployed assets, and other platforms closely coordinated with the ship during ATOMIC are provided here. These platforms include Saildrone 1064 and the RAAVEN UAS as well as the Barbados Cloud Observatory (BCO) and Barbados Atmospheric Chemistry Observatory (BACO). Inter-platform comparisons are presented to assess consistency in the data sets. Data sets from the RV Ronald H. Brown and deployed assets have been quality controlled and are publicly available at NOAA's National Centers for Environmental Information (NCEI) data archive (https://www.ncei.noaa.gov/archive/accession/ATOMIC-2020, last access: 2 April 2021). Point-of-contact information and links to individual data sets with digital object identifiers (DOIs) are provided herein.NOAA's Climate Variability and Predictability Program provided funding under NOAA CVP NA19OAR4310379, GC19-301, and GC19-305. The Joint Institute for the Study of the Atmosphere and Ocean (JISAO) supported this study under NOAA cooperative agreement NA15OAR4320063. Additional support was provided by the NOAA's Uncrewed Aircraft Systems (UAS) Program Office, NOAA's Physical Sciences Laboratory, and NOAA AOML's Physical Oceanography Division. The NTAS project is funded by the NOAA's Global Ocean Monitoring and Observing Program (CPO FundRef number 100007298), through the Cooperative Institute for the North Atlantic Region (CINAR) under cooperative agreement NA14OAR4320158

Tropical secondary forest regeneration conserves high levels of avian phylogenetic diversity

Secondary forests are promoted as having pivotal roles in reversing the tropical extinction crisis. While secondary forests recover carbon and species over time, a key question is whether phylogenetic diversity—the total evolutionary history across all species within a community—also recovers. Conserving phylogenetic diversity protects unique phenotypic and ecological traits, and benefits ecosystem functioning and stability. We examined the extent to which avian phylogenetic diversity recovers in secondary forests in the Colombian Chocó-Andes. sesPD, a measure of phylogenetic richness corrected for species richness, recovered to old-growth forest levels after ~ 30 years, while sesMPD, a measure of the phylogenetic distance between individuals in a community, recovered to old-growth levels even within young secondary forest. Mean evolutionary distinctiveness also recovered rapidly in secondary forest communities. Our results suggest that secondary forests can play a vital role in conserving distinct evolutionary lineages and high levels of evolutionary history. Focusing conservation and carbon-based payments for ecosystem services on secondary forest recovery and their subsequent protection thus represent a good use of scarce conservation resources

Estimating Mass Properties of Dinosaurs Using Laser Imaging and 3D Computer Modelling

Body mass reconstructions of extinct vertebrates are most robust when complete to near-complete skeletons allow the reconstruction of either physical or digital models. Digital models are most efficient in terms of time and cost, and provide the facility to infinitely modify model properties non-destructively, such that sensitivity analyses can be conducted to quantify the effect of the many unknown parameters involved in reconstructions of extinct animals. In this study we use laser scanning (LiDAR) and computer modelling methods to create a range of 3D mass models of five specimens of non-avian dinosaur; two near-complete specimens of Tyrannosaurus rex, the most complete specimens of Acrocanthosaurus atokensis and Strutiomimum sedens, and a near-complete skeleton of a sub-adult Edmontosaurus annectens. LiDAR scanning allows a full mounted skeleton to be imaged resulting in a detailed 3D model in which each bone retains its spatial position and articulation. This provides a high resolution skeletal framework around which the body cavity and internal organs such as lungs and air sacs can be reconstructed. This has allowed calculation of body segment masses, centres of mass and moments or inertia for each animal. However, any soft tissue reconstruction of an extinct taxon inevitably represents a best estimate model with an unknown level of accuracy. We have therefore conducted an extensive sensitivity analysis in which the volumes of body segments and respiratory organs were varied in an attempt to constrain the likely maximum plausible range of mass parameters for each animal. Our results provide wide ranges in actual mass and inertial values, emphasizing the high level of uncertainty inevitable in such reconstructions. However, our sensitivity analysis consistently places the centre of mass well below and in front of hip joint in each animal, regardless of the chosen combination of body and respiratory structure volumes. These results emphasize that future biomechanical assessments of extinct taxa should be preceded by a detailed investigation of the plausible range of mass properties, in which sensitivity analyses are used to identify a suite of possible values to be tested as inputs in analytical models