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71 results on '"Jessen, Bart"'

51. Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

Author

Chen, Shihao, primary, Lee, Li-Fen, additional, Fisher, Timothy S., additional, Jessen, Bart, additional, Elliott, Mark, additional, Evering, Winston, additional, Logronio, Kathryn, additional, Tu, Guang Huan, additional, Tsaparikos, Konstantinos, additional, Li, Xiaoai, additional, Wang, Hui, additional, Ying, Chi, additional, Xiong, Mengli, additional, VanArsdale, Todd, additional, and Lin, John C., additional

Published
2015
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61. Pharmacologic properties of AG-012986, a pan-cyclin-dependent kinase inhibitor with antitumor efficacy

Author

Zhang, Cathy, primary, Lundgren, Karen, additional, Yan, Zhengming, additional, Arango, Maria E., additional, Price, Sharon, additional, Huber, Andrea, additional, Higgins, Joseph, additional, Troche, Gabriel, additional, Skaptason, Judith, additional, Koudriakova, Tatiana, additional, Nonomiya, Jim, additional, Yang, Michelle, additional, O'Connor, Patrick, additional, Bender, Steve, additional, Los, Gerrit, additional, Lewis, Cristina, additional, and Jessen, Bart, additional

Published
2008
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69. Off-target immune cell toxicity caused by AG-012986, a pan-CDK inhibitor, is associated with inhibition of p38 MAPK phosphorylation.

Author

Lee, Dong U. and Jessen, Bart

Abstract

AG-012986 is a pan-CDK (cyclin-dependent kinase) inhibitor that has in vitro and in vivo antitumor properties but was stopped in development due in part to rapid bone-marrow-independent white blood cell toxicity in preclinical studies and the potential for acute and delayed immunosuppression in humans. Because peripheral lymphocytes are largely nonproliferating, it was hypothesized the toxicity of AG-012986 was due to an off-target mechanism and not driven by the intended pharmacology. We show the toxicity mechanism in primary human immune cells is caspase driven. T-cells treated with AG-012986 and acutely stimulated through the T-cell receptor exhibited decreased toxicity while still maintaining cell division inhibition. This indicated that the pharmacology of AG-012986 functioned as expected but the toxicity had now been decoupled through activation. Induced phosphorylation of p38 and IL-2 production was impaired with AG-012986. Thus, AG-012986 could cause apoptosis of T-cells by targeting upstream kinases in the p38 Mitogen-activated protein kinase (MAPK) pathway and impairing cellular survival. © 2012 Wiley Periodicals, Inc. J Biochem Mol Toxicol 26:101-108 2012; View this article online at . DOI 10.1002/jbt.20415 [ABSTRACT FROM AUTHOR]

Published
2012
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71. Lysosome Impairment, Phagocytosis Inhibition and Retinopathy.

Author

Shuyan Lu, Sokolowski, Sharon A., Blasi, Eileen, and Jessen, Bart

Abstract

Retina is a highly compact neural structure composed of distinct layers. The retinal pigmented epithelium (RPE) is the pigmented cell layer just outside the neurosensory and serves a number of crucial metabolic functions including the phagocytosis and removal of shed photoreceptor cell outer segments. Drugs with a basic moiety can accumulate in the lysososme and disturb lysosome function including phagocytosis, which will retard the clearance of outer segments and ultimately induce retinopathy. To test this hypothesis we chose a compound that contains a basic moiety and induced retinopathy in long term in vivo studies in rats In vitro assays including viability, LC-3 staining, and phagocytosis were conducted using the human retinal pigmented epithelium cell line ARPE-19. These studies showed that this compound caused cellular vacuolation and dose dependent cytotoxicity that was related to the initial cell number and dosing volume, indicating an accumulation effect. This compound also decreased phagocytosis function of ARPE-19, and induced accumulation of LC-3, suggesting a blockage of the autophagy process. EM analysis of eyes taken from an in vivo study showed the presence of large phagolysosomes, supporting the hypothesis of impairment of lysosome function as a mechanism for retinal toxicity. Twenty three proprietary compounds for which the in vivo effects on the retina were known were tested in a phagocytosis assay to examine the prevalence of this cellular mechanism in retinal toxicity. A correlation amongst the physiochemical properties, in vitro lysosomal pathway effects, and in vivo retinal effects was established. This data reveals the importance of physiochemical properties and lysosome accumulation as a common mechanism for drug induced retinopathy and demonstrates the potential usefulness of in vitro screening in predicting this liability. [ABSTRACT FROM AUTHOR]

Published
2010
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