Acquired resistance to oxaliplatin is not directly associated with increased resistance to DNA damage in SK-N-ASrOXALI4000, a newly established oxaliplatin-resistant sub-line of the neuroblastoma cell line SK-N-AS

The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin

Evaluation of Chlorpyrifos-Methyl and Chlorpyrifos-Methyl plus Methoprene as Protectants of Stored Corn: Small Bin Tests

Chlorpyrifos-methyl applied at 6 ppm and a combination of 6 ppm chlorpyrifos- methyl + 1 ppm methoprene were evaluated as protectants of stored corn (Zea mays L.) against a standard malathion application of 8 ppm and an untreated control. Corn was treated in October 1987, placed in 10-, 19-, and 76-bu bins, and infested at selected intervals with red flour beetle, Tribolium castaneum (Herbst); flat grain beetle, Cryptolestes pusillus (Schonherr); maize weevil, Sitophilus zeamais Motschulsky; and Indianmeal moth, Plodia interpunctella (Hiibner). Indianmeal moths did not establish populations on treated or untreated corn. Beetle populations in untreated controls were not abundant until June 1988 (8 mo after application). After 12 mo, red flour beetle and flat grain beetle populations were significantly greater in corn treated with malathion than in corn treated with either chlorpyrifos- methyl or chlorpyrifos-methyl + methoprene. Maize weevil populations were not significantly different among the three chemical treatments. Moisture content was not significantly different between treated and untreated corn or among the chemical treatments. Dockage and weight loss were significantly greater in untreated than in treated corn after 8 mo. After 12 mo, weight loss was significantly greater in malathion-treated corn than in corn treated with either chlorpyrifos-methyl or chlorpyrifos-methyl + methoprene. Insect population levels or insect damage did not differ significantly between the latter two treatments

Overview of the main achievements of the Ozone Climate Change Initiative Project

International audienceAtmospheric ozone is an Essential Climate Variable which impacts the radiation budget of the Earth, interacts with atmospheric dynamics and climate, and influences chemically other radiatively active species. As part of the Ozone Climate Change Initiative (Ozone_cci) project, a large number of ozone data sets have been generated from a full suite of atmospheric chemistry satellite missions. Following a first phase of 3 years during which new and improved algorithms and data products have been demonstrated and assessed against well-defined user requirements, the ongoing second phase of the Ozone_cci concentrates on extending and further improving these data sets with the ambition to realize the full potential of the existing archive of satellite ozone sensors. We present an overview of the main realizations of the project. This covers long-series of consistent ozone columns and profiles derived from nadir UV sensors and the thermal infrared IASI instrument. Also addressed is the generation of a large scale coherent data base of vertically resolved ozone measurements derived from a full suite of limb and occultation sensors, optimised for accuracy in a broad range of altitudes extending from the UT/LS to the mesosphere

Aurora kinases as targets in drug-resistant neuroblastoma cells

Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases