The Broad Stroke of Hsp90 Inhibitors: Painting over the RAF Inhibitor Paradox.

The novel Hsp90 inhibitor XL888 is undergoing clinical investigation for use in conjunction with the rapidly accelerated fibrosarcoma (RAF) kinase inhibitor vemurafenib to treat unresectable melanoma. The addition of XL888 to current regimens may serve an additional purpose by blocking the RAF inhibitor paradox. Such activity could reduce adverse events in patients and provide a biomarker for the successful inhibition of Hsp90 target proteins

Response and Resistance to Paradox-Breaking BRAF Inhibitor in Melanomas

FDA-approved BRAF inhibitors produce high response rates and improve overall survival in patients with BRAF V600E/K-mutant melanoma, but are linked to pathologies associated with paradoxical ERK1/2 activation in wild-type BRAF cells. To overcome this limitation, a next-generation paradox-breaking RAF inhibitor (PLX8394) has been designed. Here, we show that by using a quantitative reporter assay, PLX8394 rapidly suppressed ERK1/2 reporter activity and growth of mutant BRAF melanoma xenografts. Ex vivo treatment of xenografts and use of a patient-derived explant system (PDeX) revealed that PLX8394 suppressed ERK1/2 signaling and elicited apoptosis more effectively than the FDA-approved BRAF inhibitor, vemurafenib. Furthermore, PLX8394 was efficacious against vemurafenibresistant BRAF splice variant-expressing tumors and reduced splice variant homodimerization. Importantly, PLX8394 did not induce paradoxical activation of ERK1/2 in wild-type BRAF cell lines or PDeX. Continued in vivo dosing of xenografts with PLX8394 led to the development of acquired resistance via ERK1/2 reactivation through heterogeneous mechanisms; however, resistant cells were found to have differential sensitivity to ERK1/2 inhibitor. These findings highlight the efficacy of a paradox-breaking selective BRAF inhibitor and the use of PDeX system to test the efficacy of therapeutic agents. © 2017 American Association for Cancer Research

Correction to: Microbial communities associated with distance- and density-dependent seedling mortality in a tropical rainforest (Plant Ecology, (2020), 221, 1, (41-54), 10.1007/s11258-019-00989-y)

© 2020, Springer Nature B.V. The article entitled “Microbial communities associated with distance- and density-dependent seedling mortality in a tropical rainforest”, which is part of the special issue on “Applying microbial communities to improve restoration and conservation outcomes” was published prematurely in Volume 221, Issue 1, January 2020

Skeletal fluorosis from the point of view of an occupational exposure to fluorides in former Czechoslovakia

Electrolytic production of aluminium in former Czechoslovakia started in the year 1953 in the Žiar valley in the central Slovakia. However, till 1995 the hygienic conditions for health protection were not met in the factory. It underwent a reconstruction afterwards

The Impact of 3D Printing on Trade and FDI

This paper analyzes the effects of 3D printing technologies on the volume of trade and on the structure of FDI. A standard model with firm-specific heterogeneity generates three main predictions. First, 3D printers are introduced in areas with high economic activity that also face high transport costs. Second, technological progress related to 3D printing machines leads to a gradual replacement of FDI that relies on traditional production structures with FDI based on 3D printing techniques. At this stage international trade stays unaffected. Finally, at later stages, with 3D printing machines being widely used, further technological progress in 3D printing leads to a gradual replacement of international trade. Empirical evidence indicates that countries subject to higher transport costs and with high levels of economic activity are indeed among the ones that import more 3D printers. Anecdotal evidence also supports the second and third predictions of the model

Global Transcriptome and Deletome Profiles of Yeast Exposed to Transition Metals

A variety of pathologies are associated with exposure to supraphysiological concentrations of essential metals and to non-essential metals and metalloids. The molecular mechanisms linking metal exposure to human pathologies have not been clearly defined. To address these gaps in our understanding of the molecular biology of transition metals, the genomic effects of exposure to Group IB (copper, silver), IIB (zinc, cadmium, mercury), VIA (chromium), and VB (arsenic) elements on the yeast Saccharomyces cerevisiae were examined. Two comprehensive sets of metal-responsive genomic profiles were generated following exposure to equi-toxic concentrations of metal: one that provides information on the transcriptional changes associated with metal exposure (transcriptome), and a second that provides information on the relationship between the expression of ∼4,700 non-essential genes and sensitivity to metal exposure (deletome). Approximately 22% of the genome was affected by exposure to at least one metal. Principal component and cluster analyses suggest that the chemical properties of the metal are major determinants in defining the expression profile. Furthermore, cells may have developed common or convergent regulatory mechanisms to accommodate metal exposure. The transcriptome and deletome had 22 genes in common, however, comparison between Gene Ontology biological processes for the two gene sets revealed that metal stress adaptation and detoxification categories were commonly enriched. Analysis of the transcriptome and deletome identified several evolutionarily conserved, signal transduction pathways that may be involved in regulating the responses to metal exposure. In this study, we identified genes and cognate signaling pathways that respond to exposure to essential and non-essential metals. In addition, genes that are essential for survival in the presence of these metals were identified. This information will contribute to our understanding of the molecular mechanism by which organisms respond to metal stress, and could lead to an understanding of the connection between environmental stress and signal transduction pathways

Current Wildland Fire Patterns and Challenges in Europe: A Synthesis of National Perspectives

Changes in climate, land use, and land management impact the occurrence and severity of wildland fires in many parts of the world. This is particularly evident in Europe, where ongoing changes in land use have strongly modified fire patterns over the last decades. Although satellite data by the European Forest Fire Information System provide large-scale wildland fire statistics across European countries, there is still a crucial need to collect and summarize in-depth local analysis and understanding of the wildland fire condition and associated challenges across Europe. This article aims to provide a general overview of the current wildland fire patterns and challenges as perceived by national representatives, supplemented by national fire statistics (2009–2018) across Europe. For each of the 31 countries included, we present a perspective authored by scientists or practitioners from each respective country, representing a wide range of disciplines and cultural backgrounds. The authors were selected from members of the COST Action “Fire and the Earth System: Science & Society” funded by the European Commission with the aim to share knowledge and improve communication about wildland fire. Where relevant, a brief overview of key studies, particular wildland fire challenges a country is facing, and an overview of notable recent fire events are also presented. Key perceived challenges included (1) the lack of consistent and detailed records for wildland fire events, within and across countries, (2) an increase in wildland fires that pose a risk to properties and human life due to high population densities and sprawl into forested regions, and (3) the view that, irrespective of changes in management, climate change is likely to increase the frequency and impact of wildland fires in the coming decades. Addressing challenge (1) will not only be valuable in advancing national and pan-European wildland fire management strategies, but also in evaluating perceptions (2) and (3) against more robust quantitative evidence

Una rinnovata formazione civica per una societ\ue0 della convivenza

Innumerevoli sono i progetti, declinati prevalentemente sul piano dell\u2019apprendimento cognitivo, che puntano a creare simulazioni di situazioni di organizzazione della vita sociale, politica e istituzionale. E decisamente condivisibile \ue8 il loro obiettivo: promuovere l\u2019acquisizione delle abilit\ue0 della legalit\ue0. In ambito psicologico, tuttavia, questo aspetto non pu\uf2 esaurirsi nella sfera strettamente giuridica, n\ue9 nei limiti delle norme sociali attraverso le quali una collettivit\ue0 decide di autogovernarsi, bens\uec si concentra su quei fenomeni psicologici che hanno una ricaduta rilevante sul vivere comune. Pur riconoscendo l\u2019importanza delle regole in quanto punti di riferimento necessari e condivisi da una collettivit\ue0, questo saggio amplia il campo di ricerca analizzando i processi psicosociali che facilitano e rendono pi\uf9 efficace l\u2019interiorizzazione delle regole stesse. La questione ruota attorno al tema della formazione personale, declinata in senso civico, che oggi sembra aver subito un decadimento, sia rispetto alla sua espressione nell\u2019incontro e nello scambio quotidiano, sia in relazione alla sua trasmissibilit\ue0 intergenerazionale