Therapeutic Targeting of ATP7B in Ovarian Carcinoma.

PURPOSE: Resistance to platinum chemotherapy remains a significant problem in ovarian carcinoma. Here, we examined the biological mechanisms and therapeutic potential of targeting a critical platinum resistance gene, ATP7B, using both in vitro and in vivo models. EXPERIMENTAL DESIGN: Expression of ATP7A and ATP7B was examined in ovarian cancer cell lines by real-time reverse transcription-PCR and Western blot analysis. ATP7A and ATP7B gene silencing was achieved with targeted small interfering RNA (siRNA) and its effects on cell viability and DNA adduct formation were examined. For in vivo therapy experiments, siRNA was incorporated into the neutral nanoliposome 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC). RESULTS: ATP7A and ATP7B genes were expressed at higher levels in platinum-resistant cells compared with sensitive cells; however, only differences in ATP7B reached statistical significance. ATP7A gene silencing had no significant effect on the sensitivity of resistant cells to cisplatin, but ATP7B silencing resulted in 2.5-fold reduction of cisplatin IC(50) levels and increased DNA adduct formation in cisplatin-resistant cells (A2780-CP20 and RMG2). Cisplatin was found to bind to the NH(2)-terminal copper-binding domain of ATP7B, which might be a contributing factor to cisplatin resistance. For in vivo therapy experiments, ATP7B siRNA was incorporated into DOPC and was highly effective in reducing tumor growth in combination with cisplatin (70-88% reduction in both models compared with controls). This reduction in tumor growth was accompanied by reduced proliferation, increased tumor cell apoptosis, and reduced angiogenesis. CONCLUSION: These data provide a new understanding of cisplatin resistance in cancer cells and may have implications for therapeutic reversal of drug resistance

Topographic and stochastic influences on pāhoehoe lava lobe emplacement

A detailed understanding of pāhoehoe emplacement is necessary for developing accurate models of flow field development, assessing hazards, and interpreting the significance of lava morphology on Earth and other planetary surfaces. Active pāhoehoe lobes on Kīlauea Volcano, Hawai'i, were examined on 21–26 February 2006 using oblique time series stereo-photogrammetry and differential global positioning system measurements. During this time, the local discharge rate for peripheral lava lobes was generally constant at 0.0061±0.0019 m3/s, but the areal coverage rate of the lobes exhibited a periodic increase every 4.13±0.64 min. This periodicity is attributed to the time required for the pressure within the liquid lava core to exceed the cooling-induced strength of its margins. The pāhoehoe flow advanced through a series of down-slope and cross-slope breakouts, which began as ∼0.2-m-thick units (i.e., toes) that coalesced and inflated to become approximately meter-thick lobes. The lobes were thickest above the lowest points of the initial topography and above shallow to reverse-facing slopes, defined relative to the local flow direction. The flow path was typically controlled by high-standing topography, with the zone directly adjacent to the final lobe margin having an average relief that was a few centimeters higher than the lava-inundated region. This suggests that toe-scale topography can, at least temporarily, exert strong controls on pāhoehoe flow paths by impeding the lateral spreading of the lobe. Observed cycles of enhanced areal spreading and inflated lobe morphology are also explored using a model that considers the statistical likelihood of sequential breakouts from active flow margins and the effects of topographic barriers