Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways

Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAFV600E have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAFV600E inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells, although combination with other kinase inhibitors may be needed in some of the more aggressive tumors initially resistant to apoptosis

Translating land cover/land use classifications to habitat taxonomies for landscape monitoring: A Mediterranean assessment

Periodic monitoring of biodiversity changes at a landscape scale constitutes a key issue for conservation managers. Earth observation (EO) data offer a potential solution, through direct or indirect mapping of species or habitats. Most national and international programs rely on the use of land cover (LC) and/or land use (LU) classification systems. Yet, these are not as clearly relatable to biodiversity in comparison to habitat classifications, and provide less scope for monitoring. While a conversion from LC/LU classification to habitat classification can be of great utility, differences in definitions and criteria have so far limited the establishment of a unified approach for such translation between these two classification systems. Focusing on five Mediterranean NATURA 2000 sites, this paper considers the scope for three of the most commonly used global LC/LU taxonomies—CORINE Land Cover, the Food and Agricultural Organisation (FAO) land cover classification system (LCCS) and the International Geosphere-Biosphere Programme to be translated to habitat taxonomies. Through both quantitative and expert knowledge based qualitative analysis of selected taxonomies, FAO-LCCS turns out to be the best candidate to cope with the complexity of habitat description and provides a framework for EO and in situ data integration for habitat mapping, reducing uncertainties and class overlaps and bridging the gap between LC/LU and habitats domains for landscape monitoring—a major issue for conservation. This study also highlights the need to modify the FAO-LCCS hierarchical class description process to permit the addition of attributes based on class-specific expert knowledge to select multi-temporal (seasonal) EO data and improve classification. An application of LC/LU to habitat mapping is provided for a coastal Natura 2000 site with high classification accuracy as a result

An Open-Label Study of Risperidone in the Improvement of Quality of Life and Treatment of Symptoms of Violent and Self-Injurious Behaviour in Adults with Intellectual Disability

Background We examined the benefits of risperidone, including quality of life (QoL), in the treatment of violent and self-injurious behaviour in adults with moderate, severe or profound intellectual disability. Methods Twenty-four participants received open-label, oral, flexible-dose risperidone of 0.5–6 mg/day for 12 weeks. Efficacy was measured primarily using the Aberrant Behaviour Checklist (ABC) and secondarily using validated measures of depression, autism, QoL and global condition. Safety and tolerability were also assessed. Results Total ABC significantly improved from baseline by week 1. This improvement was maintained throughout the study (final visit, P < 0.001). Secondary efficacy measures were also improved with risperidone, including QoL measures (final visit: home life, P < 0.001; activity, P = 0.002; skills, P = 0.014). Risperidone was generally well tolerated, with no unexpected adverse events. Conclusions In this open-label trial, risperidone was efficacious and well tolerated for managing violent and self-injurious behaviour and improving QoL in adults with moderate, severe or profound intellectual disabilit