Osteosarcoma is the most commonly occurring bone cancer in children and adolescents. Unfortunately, treatment failures are common due to the development of chemoresistance, for which the underlying molecular mechanisms remain unclear. In this study, we implicate the DNA-binding protein HMGB1, which also exerts immunoregulatory effects in its secreted form, in the development of drug resistance in osteosarcoma. Anticancer agents including doxorubicin, cisplatin, and methotrexate each induced HMGB1 upregulation in human osteosarcoma cells, and RNA interference-mediated knockdown of HMGB1 restored the chemosensitivity of osteosarcoma cells in vivo and in vitro. Mechanistic investigation revealed that HMGB1 increased drug resistance by inducing autophagy, an intracellular self-defense mechanism known to confer drug resistance. We found that HMGB1 bound to the autophagy regulator Beclin1 and regulated the formation of the Beclin1-PI3KC3 [PI3KC3, phosphatidylinositol 3-kinase class 3] complex that facilitates autophagic progression. In addition, we found that interaction between HMGB1 and Beclin1 relied upon the autophagic complex ULK1-mAtg13-FIP200. Therefore, through its role as a regulator of autophagy, HMGB1 is a critical factor in the development of chemoresistance, and it offers a novel target for improving osteosarcoma therapy. Cancer Res; 72(1); 230-8. Ó2011 AACR.

A unique dataset obtained with combinations of minisodars and 915-MHz wind profilers at the Atmospheric Boundary Layer Experiments (ABLE) facility in Kansas was used to examine the detailed characteristics of the nocturnal low-level jet (LLJ). In contrast to instruments used in earlier studies, the ABLE instruments provide hourly, high-resolution vertical profiles of wind velocity from just above the surface to approximately 2 km above ground level (AGL). Furthermore, the 6-yr span of the dataset allowed the examination of interannual variability in jet properties with improved statistical reliability. It was found that LLJs occurred during 63% of the nighttime periods sampled. Although most of the observed jets were southerly, a substantial fraction (28%) was northerly. Wind maxima occurred most frequently at 200-400 m AGL, though some jets were found as low as 50 m, and the strongest jets tended to occur above 300 m. Comparison of LLJ heights at three locations within the ABLE domain and at one location outside the domain suggests that the jet is equipotential rather than terrain following. The occurrence of southerly LLJ varied annually in a way that suggests a connection between the tendency for jet formation and the large-scale circulation patterns associated with El Niño and La Niña, as well as with the Pacific decadal oscillation. Frequent and strong southerly jets that transport moisture downstream do not necessarily lead to more precipitation locally, however.

No abstract