Characterization of STAT3 activation and expression in canine and human osteosarcoma

Abstract Background Dysregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a key participant in tumor cell survival, proliferation, and metastasis and is often correlated with a more malignant tumor phenotype. STAT3 phosphorylation has been demonstrated in a subset of human osteosarcoma (OSA) tissues and cell lines. OSA in the canine population is known to exhibit a similar clinical behavior and molecular biology when compared to its human counterpart, and is often used as a model for preclinical testing of novel therapeutics. The purpose of this study was to investigate the potential role of STAT3 in canine and human OSA, and to evaluate the biologic activity of a novel small molecule STAT3 inhibitor. Methods To examine STAT3 and Src expression in OSA, we performed Western blotting and RT-PCR. OSA cells were treated with either STAT3 siRNA or small molecule Src (SU6656) or STAT3 (LLL3) inhibitors and cell proliferation (CyQUANT), caspase 3/7 activity (ELISA), apoptosis (Western blotting for PARP cleavage) and/or viability (Wst-1) were determined. Additionally, STAT3 DNA binding after treatment was determined using EMSA. Expression of STAT3 targets after treatment was demonstrated with Western blotting, RT-PCR, or gel zymography. Results Our data demonstrate that constitutive activation of STAT3 is present in a subset of canine OSA tumors and human and canine cell lines, but not normal canine osteoblasts. In both canine and human OSA cell lines, downregulation of STAT3 activity through inhibition of upstream Src family kinases using SU6656, inhibition of STAT3 DNA binding and transcriptional activities using LLL3, or modulation of STAT3 expression using siRNA, all resulted in decreased cell proliferation and viability, ultimately inducing caspase-3/7 mediated apoptosis in treated cells. Furthermore, inhibition of either Src or STAT3 activity downregulated the expression of survivin, VEGF, and MMP2, all known transcriptional targets of STAT3. Conclusion These data suggest that STAT3 activation contributes to the survival and proliferation of human and canine OSA cells, thereby providing a potentially promising target for therapeutic intervention. Future investigational trials of LLL3 in dogs with spontaneous OSA will help to more accurately define the role of STAT3 in the clinical setting.</p

The High Resolution Imaging Science Experiment (HiRISE) during MRO’s Primary Science Phase (PSP)

The High Resolution Imaging Science Experiment (HiRISE) on the Mars Reconnaissance Orbiter (MRO) acquired 8 terapixels of data in 9137 images of Mars between October 2006 and December 2008, covering ~0.55% of the surface. Images are typically 5–6 km wide with 3-color coverage over the central 20% of the swath, and their scales usually range from 25 to 60 cm/pixel. Nine hundred and sixty stereo pairs were acquired and more than 50 digital terrain models (DTMs) completed; these data have led to some of the most significant science results. New methods to measure and correct distortions due to pointing jitter facilitate topographic and change-detection studies at sub-meter scales. Recent results address Noachian bedrock stratigraphy, fluvially deposited fans in craters and in or near Valles Marineris, groundwater flow in fractures and porous media, quasi-periodic layering in polar and non-polar deposits, tectonic history of west Candor Chasma, geometry of clay-rich deposits near and within Mawrth Vallis, dynamics of flood lavas in the Cerberus Palus region, evidence for pyroclastic deposits, columnar jointing in lava flows, recent collapse pits, evidence for water in well-preserved impact craters, newly discovered large rayed craters, and glacial and periglacial processes. Of particular interest are ongoing processes such as those driven by the wind, impact cratering, avalanches of dust and/or frost, relatively bright deposits on steep gullied slopes, and the dynamic seasonal processes over polar regions. HiRISE has acquired hundreds of large images of past, present and potential future landing sites and has contributed to scientific and engineering studies of those sites. Warming the focal-plane electronics prior to imaging has mitigated an instrument anomaly that produces bad data under cold operating conditions