Tubulin inhibitors targeting the colchicine binding site: a perspective of privileged structures

The vital roles of microtubule in mitosis and cell division make it an attractive target for antitumor therapy. Colchicine binding site of tubulin is one of the most important pockets that have been focused on to design tubulin-destabilizing agents. Over the past few years, a large number of colchicine binding site inhibitors (CBSIs) have been developed inspired by natural products or synthetic origins, and many moieties frequently used in these CBSIs are structurally in common. In this review, we will classify the CBSIs into classical CBSIs and nonclassical CBSIs according to their spatial conformations and binding modes with tubulin, and highlight the privileged structures from these CBSIs in the development of tubulin inhibitors targeting the colchicine binding site

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study

Background: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced >= 1 treatment-emergent adverse event (TEAE), with = 3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients

Modelling Hot Spots of Soil Loss by Wind Erosion (SoLoWind) in Western Saxony, Germany

Land Degradation and Development published by John Wiley & Sons, Ltd. While it needs yet to be assessed whether or not wind erosion in Western Saxony is a major point of concern regarding land degradation and fertility, it has already been recognized that considerable off-site effects of wind erosion in the adjacent regions of Saxony-Anhalt and Brandenburg are connected to the spread of herbicides, pesticides and dust. So far, no wind erosion assessment for Western Saxony, Germany, exists. The wind erosion model previously applied for Germany (DIN standard 19706) is considering neither changes in wind direction over time nor influences of field size. This study aims to provide a first assessment of wind erosion for Western Saxony by extending the existing DIN model to a multidirectional model on soil loss by wind (SoLoWind) with new controlling factors (changing wind directions, soil cover, mean field length and mean protection zone) combined by fuzzy logic. SoLoWind is used for a local off-site effect evaluation in combination with high-resolution wind speed and wind direction data at a section of the highway A72. The model attributes 3·6% of the arable fields in Western Saxony to the very-high-wind erosion risk class. A relationship between larger fields (greater than 116 ha) and higher proportions (51·7%) of very-high-wind erosion risk can be observed. Sections of the highway A72 might be under high risk according to the modelled off-site effects of wind erosion. The presented applications showed the potential of SoLoWind to support and consult management for protection measures on a regional scale. © 2016 The Authors. Land Degradation and Development published by John Wiley & Sons, Ltd.The authors would like to thank Jürgen Heinrich and Gudrun Mayer for the technical revision of the model conception and the German Weather Service, the Saxon State Office for the Environment, Agriculture and Geology, the Saxon State Office for Road Construction and Traffic, the Saxon State Ministry of the Environment and Agriculture, the Saxon State Spatial Data and Land Survey Corporation, the Saxon Road Maintenance Depots, OpenStreetMap and the National Aeronautics and Space Administration for providing the datasets. We would also like to thank three anonymous reviewers for helpful comments.info:eu-repo/semantics/publishedVersio

Individual Actin Filaments in a Microfluidic Flow Reveal the Mechanism of ATP Hydrolysis and Give Insight Into the Properties of Profilin

A novel microfluidic approach allows the analysis of the dynamics of individual actin filaments, revealing both their local ADP/ADP-Pi-actin composition and that Pi release is a random mechanism

PAK1 Protein Expression in the Auditory Cortex of Schizophrenia Subjects

Deficits in auditory processing are among the best documented endophenotypes in schizophrenia, possibly due to loss of excitatory synaptic connections. Dendritic spines, the principal post-synaptic target of excitatory projections, are reduced in schizophrenia. p21-activated kinase 1 (PAK1) regulates both the actin cytoskeleton and dendritic spine density, and is a downstream effector of both kalirin and CDC42, both of which have altered expression in schizophrenia. This study sought to determine if there is decreased auditory cortex PAK1 protein expression in schizophrenia through the use of quantitative western blots of 25 schizophrenia subjects and matched controls. There was no significant change in PAK1 level detected in the schizophrenia subjects in our cohort. PAK1 protein levels within subject pairs correlated positively with prior measures of total kalirin protein in the same pairs. PAK1 level also correlated with levels of a marker of dendritic spines, spinophilin. These latter two findings suggest that the lack of change in PAK1 level in schizophrenia is not due to limited sensitivity of our assay to detect meaningful differences in PAK1 protein expression. Future studies are needed to evaluate whether alterations in PAK1 phosphorylation states, or alterations in protein expression of other members of the PAK family, are present in schizophrenia

Interactions between solidification and fluid flow. Effects on cast structures and segregations

Natural or forced fluid flow of the bulk melt can induce several changes in the solidification history of a casting : it may change the heat transfer conditions, the as-cast grain distribution, and the segregations. On the other hand, solidification can result in intense fluid flow due to natural solutal convection and in severe local segregations. The two following practical cases illustrate the variety and complexity of interactions between the fluid flow and the solidification of alloys : - the effects of the stirring of the bulk liquid on the formation of the equiaxed zone during the continuous casting of steels, - the formation of freckles and related segregations during the directional solidification of nickel-base alloys. Informations are given about, either new experimental observations, or up-dated physical and numerical models related to each case chosen here as examples. In the case of the influence of stirring on the formation of the equiaxed zone, emphasis is put on the importance of the interaction of the fluid flow with the dendrites in the columnar zone and in the stirred region itself. In the case of the freckles, evidence is brought forward that the dendritic nature and structure of the mushy zone are not the only causes of the dependence of the freckling on the heat transfer conditions during directional solidification

Étude de l'effet du mouvement relatif cristal/liquide sur la croissance d'un cristal dendritique dans un liquide en surfusion

Ce travail expérimental vise à mesurer l'impact du mouvement relatif solide / liquide sur la croissance de grains équiaxes en chute libre. Pour cela, nous avons développé un dispositif rendant possible le suivi tridimensionnel et in situ de cristaux équiaxes sédimentant dans un liquide surfondu. Les expériences ont été réalisées avec des solutions transparentes de chlorure d'ammonium - eau (NH4Cl-H2O). Chaque cristal est photographié simultanément dans 2 directions orthogonales tout au long de sa trajectoire. Il est ainsi possible d'observer la morphologie du grain, de mesurer sa taille puis d'en déduire des vitesses de croissance. Les résultats de cette étude montrent que les pointes croissent d'autant plus rapidement qu'elles sont exposées à la convection et que la vitesse relative du cristal par rapport au fluide environnant est élevée

Diagnostic environnemental d'un territoire français méditerranéen réalisé en combinant une démarche d'ACV orientée "territoire" et des outils SIG

International audienceAlthough LCA is product-oriented, recent proposals have been made to broaden its object of analysis by studying meso-level systems. This is even more interesting since LCA has been considered as a promising tool for the environmental assessment of territories (cities, districts, etc) compared to other methods. In order to remove the bottlenecks that arise when assessing territorial systems (i.e. functional unit definition, boundary selection, data collection and provision of indicators for local decision-making), we have adapted the LCA framework and created a new approach, called “territorial LCA”. This is a comprehensive method which provides two kinds of indicators, i.e. indicators of services provided by the territory (land use functions) and indicators of environmental impacts generated by the territory (unlike conventional LCA, for which provided services are used to define functional unit and the associated reference flow). “Territorial LCA” has been designed to meet the requirements of the European Directive (2001/42/EC) on Strategic Environmental Assessment of land planning policies. In this directive, two stages call for an environmental assessment, i.e. (i) provision of an environmental baseline of territories and (ii) comparison of land planning scenarios. This paper aims to validate the usefulness of territorial LCA for the first purpose (i.e. providing an environmental baseline of territories) as well as to emphasize the essential contributions brought by GIS (Geographic Information System) tools for this kind of assessment. The method relies on the implementation of territorial LCA on a French Mediterranean case study, i.e. a coastal area with municipalities and a harbour, as well as agricultural and industrial activities. The results highlight the strenghts of territorial LCA for assessing cumulative impacts, identifying transboundary impacts, prioritizing environmental issues, determining hotspot activities and assessing eco-efficiency. Furthermore, GIS tools have been mobilised to reinforce the overall approach. The combination of GIS and territorial LCA contributes to provide a comprehensive and understandable baseline. This approach proposes an original way to present results. It allows identifying main contributors to environmental impacts at a glance and makes easier the appropriation of results by stakeholders. Moreover, regional / local in-site impacts (i.e. impacts due to environmental flows occuring on the territory) can be mapped. Information on the location of in-site emissions of polluting substances can be cross-checked with data on sensitivity and vulnerabilty of the surrounding environment (e.g. proximity of water bodies or protected areas, population density, and so on). Environmental hotspots (sensitive areas located near in-site emissions) are thus identified and this paves the way for a deeper analysis of in-site impacts by taking into account spatial information. As a conclusion, combining territorial LCA and GIS contributes to enhance the communication of results and provides useful information that should be taken into account in the elaboration of land planning scenarios

Quantitative analysis by in situ synchrotron X-ray radiography of the evolution of the mushy zone in a fixed temperature gradient

International audienceThis paper deals with a series of experiments dedicated to the analysis of the time evolution of a mushy zone in a fixed temperature gradient, carried out on the BM05 beamline at the European Synchrotron Radiation Facility (ESRF) on Al-Cu alloy. Because most of phenomena involved in this evolution are dynamic, in situ and real time investigation is essential for conducting a thorough analysis as a function of time. Synchrotron X-ray radiography is a non-invasive visualization technique, perfectly suited to such a study since it is able to reveal the microstructural changes of the mushy zone during the holding stage, In addition, we extended our analysis by performing advanced image processing of synchrotron X-ray radiographs to characterize the solute distribution in the liquid phase. These measurements gave us crucial information for understanding the competition between the diffusion processes in the bulk and the mushy zone. Moreover, combining these data with mass balance equations at the two boundaries of the mushy zone enables us to demonstrate the major role of solute diffusion in the dynamics of the mushy zone, from the early instants to the final state of the holding stage