BackgroundPatients diagnosed with metastatic cancer have almost uniformly poor prognoses. The treatments available for patients with disseminated disease are usually not curative and have side effects that limit the therapy that can be given. A treatment that is selectively toxic to tumors would maximize the beneficial effects of therapy and minimize side effects, potentially enabling effective treatment to be administered.Methods and FindingsWe postulated that the tumor-tropic property of stem cells or progenitor cells could be exploited to selectively deliver a therapeutic gene to metastatic solid tumors, and that expression of an appropriate transgene at tumor loci might mediate cures of metastatic disease. To test this hypothesis, we injected HB1.F3.C1 cells transduced to express an enzyme that efficiently activates the anti-cancer prodrug CPT-11 intravenously into mice bearing disseminated neuroblastoma tumors. The HB1.F3.C1 cells migrated selectively to tumor sites regardless of the size or anatomical location of the tumors. Mice were then treated systemically with CPT-11, and the efficacy of treatment was monitored. Mice treated with the combination of HB1.F3.C1 cells expressing the CPT-11-activating enzyme and this prodrug produced tumor-free survival of 100% of the mice for >6 months (P<0.001 compared to control groups).ConclusionsThe novel and significant finding of this study is that it may be possible to exploit the tumor-tropic property of stem or progenitor cells to mediate effective, tumor-selective therapy for metastatic tumors, for which no tolerated curative treatments are currently available.
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. Dynamic properties of pheromone plumes are behaviorally important in some moths for inducing upwind flight, but little is known about the time-dependent properties of odor transduction or the mechanisms that limit receptor dynamic sensitivity. We stimulated male antennae of two moth species, Cadra cautella and Spodoptera exigua, with pheromone plumes in a wind tunnel while recording electroantennograms (EAG) and concentration of a surrogate plume (propylene, which mimics a pheromone plume) using a photoionization detector (PID). Turbulent plumes were produced by mechanical baffles, creating broad frequency range dynamic concentration changes at the antennae. Frequency response functions and coherence functions between PID and EAG signals were used to measure the dynamic responses of the two species to pheromone blends and individual components. A single time constant filter fitted the responses of both species, but S. exigua was about three times faster than C. cautella. Responses to individual pheromone components were significantly different in S. exigua but not in C. cautella. We also fitted the data with a simple blockstructured nonlinear cascade. This supported the simple filter model but also suggested that the response saturates at an early stage of chemotransduction.
Abstract. Airborne pheromone plumes in wind comprise filaments of odour interspersed with gaps of clean air. When flying moths intercept a filament, they have a tendency to surge upwind momentarily, and then fly crosswind until another filament is intercepted. Thus, the moment-to-moment contact with pheromone mediates the shape of a flight track along the plume. Within some range of favourable interception rates, flight tracks become straighter and are headed more due upwind. However, as the rate of interception increases, there comes a point at which the moth should not be able to discern discreet filaments but, rather, should perceive a`fused signal'. At the extreme, homogeneous clouds of pheromone inhibit upwind progress by representative tortricids. In a wind tunnel, Cadra cautella (Walker) (Lepidoptera: Pyralidae) were presented with 10 ms pulses of pheromone at a repetition rate of 5, 10, 17 and 25/s and a continuous, internally turbulent plume. Pulse size and concentrations were verified with a miniature photoionization detector sampling surrogate odour, propylene, at 100 Hz. Male moths maintain upwind progress even at plumes of 25 filaments/s. Furthermore, moths exhibited greater velocities and headings more due upwind at 17 and 25 Hz than at the lower frequencies or with the continuous plume. It is hypothesized that either C. cautella possesses a versatile sensory system that allows the resolution of these rapidly pulsed pheromone plumes, or that this species does not require à flickering' signal to fly upwind.
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