Intrinsic or acquired resistance to the HER2-targeted therapy trastuzumab is a clinical concern in the treatment of patients with HER2-over-expressing metastatic breast cancers. We demonstrate here that multiple models of intrinsic and acquired resistance exhibit increased phosphorylation of p38 MAPK. Kinase inhibition of p38 rescued trastuzumab sensitivity in cells with acquired resistance. In addition, knockdown of p38 increased sensitivity to trastuzumab in an intrinsically resistant cell line. We previously reported that expression of growth differentiation factor 15 (GDF15) is increased in trastuzumab-resistant HER2-overexpressing breast cancer cells. In this study, we found that exogenous GDF15 or stable overexpression of GDF15 stimulated p38 phosphorylation in HER2-positive cells, suggesting a possible mechanism by which p38 is activated in resistant cells. GDF15 stable clones showed significantly increased invasiveness, which was rescued by p38 kinase inhibition, suggesting that p38 plays a role in the pro-invasive phenotype conferred by GDF15. Importantly, immunohistochemical analysis of a breast tumor tissue array indicated a significant (p=0.0053) correlation between HER2 and phosphorylated p38 specifically in GDF15-positive tissues. Our results suggest that p38 signaling drives trastuzumab resistance and invasiveness in HER2-overexpressing breast cancer. Upstream growth factor signals that have previously been implicated in trastuzumab resistance, such as GDF15, may contribute to the increased phosphorylation of p38 found in resistant cells.
Climate often regulates different aspects of the life cycle and activity of amphibians. Climatic seasonality may impose severe restrictions on breeding patterns of directdeveloping terraranan frogs. We studied the influence of abiotic cues on calling activity of males of the direct-developing frog Oreobates discoidalis in the Yungas forests of north-western Argentina. Vocalization activity and daily emission pattern of the vocal repertoire were registered with a frog-logger, and climatic variables were registered with a data logger. We sampled two reproductive seasons from 2010 to 2011. We used ordinal logistic regression to evaluate the relationship between independent climatic variables and the intensity of calling activity. The calling season of males of O. discoidalis was triggered by the first rainfall of the aestival season. The species could be defined as crepuscular -nocturnal with a calling activity peak at dusk. Sporadic calling activity during day time was associated with conditions of high humidity and rainfall. Both the emission and the intensity of the advertisement call activity were influenced by time of the day, high levels of relative air humidity and presence of rainfall; air temperature was not a determinant factor in the calling activity of this frog species. Territorial calls were strongly associated with full chorus activity that could be associated with a mechanism of inter-male spacing.
El presente trabajo estudia la dieta de una población de Leptodactylus ocellatus de los Humedales de Zonda, San Juan, al oeste de Argentina. Se analizaron 35 estómagos, las presas fueron clasificadas y los individuos se midieron en ancho y largo para calcular su volumen con la fórmula de la esfera elipsoide; además, se estimó la frecuencia de ocurrencia y abundancia. Se calcularon índices de diversidad, de similitud, amplitud de nicho e importancia relativa (IRI). Los presas mas importantes fueron: Hymenoptera, Anura, Coleoptera. Las presas con mayor porcentaje de presencia fueron los Hymenoptera Formicidae que representaron el 22,4%. No se encontró una relación significativa entre el ancho de la boca del depredador y el tamaño medio de la presa. La dieta observada en ambos sexos resultó similar.
The American bullfrog Lithobates catesbeianus has been introduced around the world, with invasive populations reported from almost all South American countries. A population of this species was introduced in the Calingasta department of San Juan province, which is an arid environment in western Argentina. This work provides information on the dietary composition of an invasive population of L. catesbeianus, and compares the degree of dietary overlap between adults and juveniles. Stomach contents of 169 bullfrogs (82 adults and 87 juveniles) were analysed. Adults consumed 40 prey taxa and Hymenoptera (Insecta) was the most numerous prey item (41.8%), followed by Araneae (13.6%) and Aeglidae (13.4%). Juveniles consumed 29 prey taxa and Hymenoptera constituted the highest percentage in prey number (77.2%). The trophic overlap niche index at the same level shows a value of 0.64 overlap in dietary community between adults and juveniles of this bullfrog. Aeglidae was volumetrically the most important trophic item (25.4%), followed by Anura (25.02%). Our results showed that cannibalism in bullfrogs is more common than the consumption of native anurans, coinciding with that reported in other populations of introduced bullfrogs. The high similarity in the diets of both size classes and the association between the size of the predator and prey suggest that the impact caused by bullfrogs throughout their ontogeny is high and probably has an impact on their prey. Freshwater crabs are the main items in the diet of Lithobates catesbeianus in other introduced populations and are usually the most conspicuous at our study site. The crabs in freshwater ecosystems are part of the lowest trophic level in the food chain. The major threats to the southern region's freshwater crabs include deforestation, farming and exotic species. Lithobates catesbeianus has a generalist diet and high overlap between adults and juveniles.
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