To identify therapeutic opportunities for oncolytic viral therapy, we conducted genome-wide RNAi screens to search for host factors that modulate rhabdoviral oncolysis. Our screens uncovered the endoplasmic reticulum (ER) stress response pathways as important modulators of rhabdovirus-mediated cytotoxicity. Further investigation revealed an unconventional mechanism whereby ER stress response inhibition preconditioned cancer cells, which sensitized them to caspase-2-dependent apoptosis induced by a subsequent rhabdovirus infection. Importantly, this mechanism was tumor cell specific, selectively increasing potency of the oncolytic virus by up to 10,000-fold. In vivo studies using a small molecule inhibitor of IRE1α showed dramatically improved oncolytic efficacy in resistant tumor models. Our study demonstrates proof of concept for using functional genomics to improve biotherapeutic agents for cancer.
Pubmed ID: 22014571 RIS Download
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View all literature mentionsConfocal microscopy can improve conventional fluorescence images by recording fluorescence generated from the focal plane within the sample, while rejecting all other light coming from above or below the focal plane. The efficient point-scan/pinhole-detection confocal optics of the FluoView systems virtually eliminate out of focus light to produce high-contrast images with superb resolution. The FluoView systems are fully integrated workstations that incorporate user-friendly image acquisition and image analysis software with high-resolution confocal optics that require no user alignment. An , Windows-based graphic user interface allows new users to quickly generate images in various scan modes, such as XY, XZ, XT, XYZ, XYT, and XYZT. Standard image formats, including TIFF and AVI, permit easy, direct export of FluoView images to off-line analysis packages. XY scanning is performed with a pair of galvanometric mirrors, yielding a wide scanning range to cover up to a field number of 20. The optical zoom (up to 10x magnification) can be performed by narrowing the scanning range while maintaining the maximum pixel resolution of up to 2048 x 2048 pixels.
View all literature mentionsConfocal microscopy can improve conventional fluorescence images by recording fluorescence generated from the focal plane within the sample, while rejecting all other light coming from above or below the focal plane. The efficient point-scan/pinhole-detection confocal optics of the FluoView systems virtually eliminate out of focus light to produce high-contrast images with superb resolution. The FluoView systems are fully integrated workstations that incorporate user-friendly image acquisition and image analysis software with high-resolution confocal optics that require no user alignment. An , Windows-based graphic user interface allows new users to quickly generate images in various scan modes, such as XY, XZ, XT, XYZ, XYT, and XYZT. Standard image formats, including TIFF and AVI, permit easy, direct export of FluoView images to off-line analysis packages. XY scanning is performed with a pair of galvanometric mirrors, yielding a wide scanning range to cover up to a field number of 20. The optical zoom (up to 10x magnification) can be performed by narrowing the scanning range while maintaining the maximum pixel resolution of up to 2048 x 2048 pixels.
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