The small molecule SI113 synergizes with mitotic spindle poisons in arresting the growth of human glioblastoma multiforme

Glioblastoma multiforme (GBM) is the deadliest brain tumor. State-of-art GBM therapy often fails to ensure control of a disease characterized by high frequency of recurrences and progression. In search for novel therapeutic approaches, we assayed the effect of compounds from a cancer drug library on the ADF GBM cell line, establishing their elevated sensitivity to mitotic spindle poisons. Our previous work showed that the effectiveness of the spindle poison paclitaxel in inhibiting cancer cell growth was dependent on the expression of RANBP1, a regulatory target of the serine/threonine kinase SGK1. Recently, we developed the small molecule SI113 to inhibit SGK1 activity. Therefore, we explored the outcome of the association between SI113 and selected spindle poisons, finding that these drugs generated a synergistic cytotoxic effect in GBM cells, drastically reducing their viability and clonogenic capabilities in vitro, as well as inhibiting tumor growth in vivo. We also defined the molecular bases of such a synergistic effect. Because SI113 displays low systemic toxicity, yet strong activity in potentiating the effect of radiotherapy in GBM cells, we believe that this drug could be a strong candidate for clinical trials, with the aim to add it to the current GBM therapeutic approaches

Diversity of experimentation by farmers engaged in agroecology

International audienceAbstractAgroecology questions the production of generic knowledge. Rather than searching for the best practices for large-scale transfer, it would be more efficient to help farmers find their own solutions. A promising activity for farmers is experimentation because it answers their needs and helps them learn. However, how agroecological practices are tested by farmers in their own experiments is still poorly known. In this study, we examined the short-term experimental activity, i.e., experiments carried out at a yearly scale in pre-defined fields. Seventeen farmers in south eastern France were surveyed. The farmers practiced conventional or organic farming and cultivated either arable or market garden crops. Experiments on agroecological practices were characterized, located along a timeline, and discussed with them. To conduct the interviews with the farmers, each experiment was described in three stages: (1) designing the experiment, (2) managing it in real time, and (3) evaluating the results of the experiment. The data collected in the interviews were first analyzed to build a descriptive framework of farmers’ experiments, after which hierarchical cluster analysis was used to analyze the diversity of the farmers’ experiments. Here, we propose for the first time a generic framework to describe farmers’ experiments at a short time scale based on the consistency between the Design, Management, and Evaluation stages. We used the framework to characterize the diversity of farmers’ experiments and identified four clusters. The originality of this work is both building a descriptive framework resulting from in-depth analyses of farmers’ discourse and using statistical tools to identify and interpret the groups of experiments. Our results provide a better understanding of farmers’ experiments and suggest tools and methods to help them experiment, a major challenge in the promotion of a large-scale agroecological transition

Capillaroscopic evidence of microvascular damage in volleyball players

Volleyball players experience repetitive stress that involves their hands and, in particular, their fingers. Literature reports that repetitive trauma can lead to local vascular abnormalities, such as reduced capillarization and lower resting blood flow. These anomalies could be related to the presence of dysfunctional endothelium. The aim of this study is to correlate the capillaroscopic findings by nailfold video capillaroscopy (NVC) to volleyball practice in order to early detect possible anomalies and perform an adequate follow-up to avoid damages that could negatively affect sport practice and the players’ health status. In this study, 38 subjects were enrolled, 19 volleyball players and 19 healthy non-players as a comparison group. In almost all the players, we found capillaroscopic alterations of the “aspecific pattern” type without substantial gender differences. We may assume that the repeated traumas involving players’ fingers can negatively modify their microcirculation. Based on these observations, it could be a desirable clinical practice to screen professional volleyball players with NVC in order to implement preventive strategies aimed at protecting the health of athletes

SGK1 affects RAN/RANBP1/RANGAP1 via SP1 to play a critical role in pre-miRNA nuclear export: a new route of epigenomic regulation.

The serum- and glucocorticoid-regulated kinase (SGK1) controls cell transformation and tumor progression. SGK1 affects mitotic stability by regulating the expression of RANBP1/RAN. Here, we demonstrate that SGK1 fluctuations indirectly modify the maturation of pre-miRNAs, by modulating the equilibrium of the RAN/RANBP1/RANGAP1 axis, the main regulator of nucleo-cytoplasmic transport. The levels of pre-miRNAs and mature miRNAs were assessed by qRT-PCR, in total extracts and after differential nuclear/cytoplasmic extraction. RANBP1 expression is the limiting step in the regulation of SGK1-SP1 dependent nuclear export. These results were validated in unrelated tumor models and primary human fibroblasts and corroborated in tumor-engrafted nude mice. The levels of pri-miRNAs, DROSHA, DICER and the compartmental distribution of XPO5 were documented. Experiments using RANGTP conformational antibodies confirmed that SGK1, through RANBP1, decreases the level of the GTP-bound state of RAN. This novel mechanism may play a role in the epigenomic regulation of cell physiology and fate