Neuroimaging studies suggest that a fronto-parietal network is activated when we expect visual information to appear at a specific spatial location. Here we examined whether a similar network is involved for auditory stimuli. We used sparse fMRI to infer brain activation while participants performed analogous visual and auditory tasks. On some trials, participants were asked to discriminate the elevation of a peripheral target. On other trials, participants made a nonspatial judgment. We contrasted trials where the participants expected a peripheral spatial target to those where they were cued to expect a central target. Crucially, our statistical analyses were based on trials where stimuli were anticipated but not presented, allowing us to directly infer perceptual orienting independent of perceptual processing. This is the first neuroimaging study to use an orthogonal-cuing paradigm (with cues predicting azimuth and responses involving elevation discrimination). This aspect of our paradigm is important, as behavioral cueing effects in audition are classically only observed when participants are asked to make spatial judgments. We observed similar fronto-parietal activation for both vision and audition. In a second experiment that controlled for stimulus properties and task difficulty, participants made spatial and temporal discriminations about musical instruments. We found that the pattern of brain activation for spatial selection of auditory stimuli was remarkably similar to what we found in our first experiment. Collectively, these results suggest that the neural mechanisms supporting spatial attention are largely similar across both visual and auditory modalities.
Introduction
Defects in the apoptosis pathway limit the effectiveness of radiation in non-small cell lung cancer (NSCLC) therapy. BV6 is an antagonist of cIAP1 and XIAP, members of the inhibitors of apoptosis (IAP) family. We investigated the potential of BV6 to sensitize NSCLC cell lines to radiation.
Methods
HCC193 and H460 lung cancer cell lines were treated with BV6 to investigate the effects of drug administration on cell proliferation, apoptosis, inhibition of XIAP and cIAP1, and radiosensitivity. Subsequent immunoblotting and Hoechst staining were utilized to determine the role of apoptosis in radiosensitization. Finally, the pathway of apoptosis was characterized by western blot analysis for cleaved caspase-8 and cleaved caspase-9, and ELISA assays for TNF-α.
Results
HCC193 was found to be more sensitive than H460 to BV6-induced apoptosis in a concentration-dependent and time-dependent manner. BV6 significantly sensitized both cell lines to radiation (HCC193—DER=1.38, p<0.05 at 1μM BV6; H460—DER=1.42, p<0.05 at 5μM BV6), but a higher concentration of and longer incubation time with BV6 was necessary for H460 cells. The BV6-induced radiosensitization of HCC193 favored the extrinsic pathway of apoptosis, while that of H460 favored the intrinsic pathway.
Conclusions
BV6, an IAP antagonist, significantly enhanced the radiosensitization of HCC193 and H460 cells in vitro. More research is warranted to test the mechanism of action of BV6, and to assess its potential in vivo and in the clinical setting.
Lung cancer is the leading cause of cancer-related death in the United States despite recent advances in our understanding of this challenging disease. An animal model for high-throughput screening of therapeutic agents for advanced lung cancer could help promote the development of more successful treatment interventions. To develop our orthotopic lung cancer model, luciferase-expressing A549 cancer cells were injected into the mediastinum of athymic nude mice. To determine whether the model would allow easy monitoring of response to therapeutic interventions, tumors were treated with 30 mg/kg Paclitaxel or were irradiated with 5 fractions of 2 Gy, and tumor burden was monitored using bioluminescence imaging. Evidence of radiation-induced lung injury was assessed using immunohistochemical staining for phospho-Smad2/3 and cleaved caspase-3. We found that tumor implantation recapitulated advanced human lung cancer as evidenced by tumor establishment and proliferation within the mediastinum. The tumor responded to Paclitaxel or radiation as shown by decreased tumor bioluminescence and improved overall survival. Immunohistochemistry revealed increased phospho-Smad2/3 and cleaved caspase-3 in irradiated lungs, consistent with radiation-induced lung injury. This orthotopic lung cancer model may help provide a method to assess therapeutic interventions in a preclinical setting that recapitulates locally advanced lung cancer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.