Bespoken Nanoceria : An Effective Treatment in Experimental Hepatocellular Carcinoma

Despite the availability of new-generation drugs, hepatocellular carcinoma (HCC) is still the third most frequent cause of cancer-related deaths worldwide. Cerium oxide nanoparticles (CeONPs) have emerged as an antioxidant agent in experimental liver disease because of their antioxidant, anti-inflammatory, and antisteatotic properties. In the present study, we aimed to elucidate the potential of CeONPs as therapeutic agents in HCC. HCC was induced in 110 Wistar rats by intraperitoneal administration of diethylnitrosamine for 16 weeks. Animals were treated with vehicle or CeONPs at weeks 16 and 17. At the eighteenth week, nanoceria biodistribution was assessed by mass spectrometry (MS). The effect of CeONPs on tumor progression and animal survival was investigated. Hepatic tissue MS-based phosphoproteomics as well as analysis of principal lipid components were performed. The intracellular uptake of CeONPs by human ex vivo perfused livers and human hepatocytes was analyzed. Nanoceria was mainly accumulated in the liver, where it reduced macrophage infiltration and inflammatory gene expression. Nanoceria treatment increased liver apoptotic activity, while proliferation was attenuated. Phosphoproteomic analysis revealed that CeONPs affected the phosphorylation of proteins mainly related to cell adhesion and RNA splicing. CeONPs decreased phosphatidylcholine-derived arachidonic acid and reverted the HCC-induced increase of linoleic acid in several lipid components. Furthermore, CeONPs reduced serum alpha-protein levels and improved the survival of HCC rats. Nanoceria uptake by ex vivo perfused human livers and in vitro human hepatocytes was also demonstrated. These data indicate that CeONPs partially revert the cellular mechanisms involved in tumor progression and significantly increase survival in HCC rats, suggesting that they could be effective in patients with HCC

Small-mammals from the Middle Pleistocene layers of the Sima del Elefante (Sierra de Atapuerca, Burgos, northwestern Spain)

The Sima del Elefante site, located in the Sierra de Atapuerca (Burgos, Spain), is an important Pleistocene archaeopalaeontological locality that has been excavated every year since 1996. At least two main infill phases have been identified: a first (TELRU) early Pleistocene phase that has provided a rich faunal assemblage, various stone tools and the earliest human remains from western Europe; and a second phase (TEURU) attributed to the Middle Pleistocene. In this paper, for the first time we present a description of the TEURU small-mammal assemblage and its subsequent biochronological, palaeoenvironmental and palaeoclimatic implications. The small-mammal assemblage is highly diverse and comprises at least 17 species: 3 insectivores (cf. Erinaceus sp., Crocidura sp. and Sorex sp.); 4 chiropters (Rhinolophus ferrumequinum, Rhinolophus gr. euryale-mehelyi, Myotis gr. Myotisoxygnathus and Miniopteurs schreibersii); 9 rodents (Myodes glareolus, Microtus arvalis, Microtus agrestis, Iberomys brecciensis, Terricola cf. atapuerquensis, Arvicola sp., Apodemus sylvaticus, Eliomys quercinus and Allocricetus bursae) and 1 lagomorph (Oryctolagus sp.). Such an association suggests a late Middle Pleistocene age (ca. 250-350 ka), a patchy landscape dominated by humid meadows and woodland areas, and mild climatic conditions. These results are compared with other proxies, such as the herpetofauna, malacofauna, large-mammals and charcoals, providing a new scenario for the climatic and environmental conditions that prevailed during the latest Middle Pleistocene in the Sierra de Atapuerca