83 research outputs found
Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer.
Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer
Electrochemical methods for speciation of trace elements in marine waters. Dynamic aspects
The contribution of electrochemical methods
to the knowledge of dynamic speciation of toxic trace elements in marine waters is critically reviewed. Due to the importance
of dynamic considerations in the interpretation of the electrochemical signal, the principles and recent developments of kinetic features in the interconversion of metal complex species will be presented. As dynamic electrochemical
methods, only stripping techniques (anodic stripping voltammetry and stripping chronopotentiometry) will be used because they are the most important for the
determination of trace elements. Competitive ligand ex- change-adsorptive cathodic stripping voltammetry, which should be considered an equilibrium technique rather than a dynamic method, will be also discussed because the complexing parameters may be affected by some kinetic limitations if equilibrium before analysis is not attained and/or the flux of the adsorbed complex is in fluenced by the lability of the natural complexes in the water sample. For a correct data interpretation and system characterization the comparison of results obtained from different techniques seems essential in the articulation of a serious discussion of their meaning
The malignant phenotype in breast cancer is driven by eIF4A1-mediated changes in the translational landscape
Human mRNA DeXD/H-box helicases are ubiquitous molecular motors that are required for the majority of cellular processes that involve RNA metabolism. One of the most abundant is eIF4A, which is required during the initiation phase of protein synthesis to unwind regions of highly structured mRNA that would otherwise impede the scanning ribosome. Dysregulation of protein synthesis is associated with tumorigenesis, but little is known about the detailed relationships between RNA helicase function and the malignant phenotype in solid malignancies. Therefore, immunohistochemical analysis was performed on over 3000 breast tumors to investigate the relationship among expression of eIF4A1, the helicase-modulating proteins eIF4B, eIF4E and PDCD4, and clinical outcome. We found eIF4A1, eIF4B and eIF4E to be independent predictors of poor outcome in ER-negative disease, while in contrast, the eIF4A1 inhibitor PDCD4 was related to improved outcome in ER-positive breast cancer. Consistent with these data, modulation of eIF4A1, eIF4B and PCDC4 expression in cultured MCF7 cells all restricted breast cancer cell growth and cycling. The eIF4A1-dependent translatome of MCF7 cells was defined by polysome profiling, and was shown to be highly enriched for several classes of oncogenic genes, including G-protein constituents, cyclins and protein kinases, and for mRNAs with G/C-rich 5′UTRs with potential to form G-quadruplexes and with 3′UTRs containing microRNA target sites. Overall, our data show that dysregulation of mRNA unwinding contributes to the malignant phenotype in breast cancer via preferential translation of a class of genes involved in pro-oncogenic signaling at numerous levels. Furthermore, immunohistochemical tests are promising biomarkers for tumors sensitive to anti-helicase therapies
Mergers & Acquisitions in European banking : higher productivity or better synergy among business lines ?
Finding the right compromise between productivity and environmental efficiency on high input tropical dairy farms: A case study
International audienceThis study focused on the trade-off between milk production and its environmental impact on greenhouse gas (GHG) emissions and nitrogen surplus in a high input tropical system. We first identified the objectives of the three main stakeholders in the dairy sector (farmers, a milk cooperative and environmentalists). The main aim of the farmers and cooperative's scenarios was to increase milk production without additional environmental deterioration but with the possibility of increasing the inputs for the cooperative. The environmentalist's objective was to reduce environmental deterioration. Second, we designed a sustainable intensification scenario combining maximization of milk production and minimization of environmental impacts. Third, the objectives for reducing the eco-inefficiency of dairy systems in Reunion Island were incorporated in a framework for activity analysis, which was used to model a technological approach with desirable and undesirable outputs. Of the four scenarios, the sustainable intensification scenario produced the best results, with a potential decrease of 238 g CO2-e per liter of milk (i.e. a reduction of 13.93% compared to the current level) and a potential 7.72 L increase in milk produced for each kg of nitrogen surplus (i.e. an increase of 16.45% compared to the current level). These results were based on the best practices observed in Reunion Island and optimized manure management, crop–livestock interactions, and production processes. Our results also showed that frontier efficiency analysis can shed new light on the challenge of developing sustainable intensification in high input tropical dairy systems
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