Browsing by Author "Tatter, Stephen B."

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    Immersion Bioprinting of Tumor Organoids in Multi-Well Plates for Increasing Chemotherapy Screening Throughput
    Maloney, Erin; Clark, Casey; Sivakumar, Hemamylammal; Yoo, KyungMin; Aleman, Julio; Rajan, Shiny A. P.; Forsythe, Steven; Mazzocchi, Andrea R.; Laxton, Adrian W.; Tatter, Stephen B.; Strowd, Roy E.; Votanopoulos, Konstantinos I.; Skardal, Aleksander (MDPI, 2020-02-18)
    The current drug development pipeline takes approximately fifteen years and $2.6 billion to get a new drug to market. Typically, drugs are tested on two-dimensional (2D) cell cultures and animal models to estimate their efficacy before reaching human trials. However, these models are often not representative of the human body. The 2D culture changes the morphology and physiology of cells, and animal models often have a vastly different anatomy and physiology than humans. The use of bioengineered human cell-based organoids may increase the probability of success during human trials by providing human-specific preclinical data. They could also be deployed for personalized medicine diagnostics to optimize therapies in diseases such as cancer. However, one limitation in employing organoids in drug screening has been the difficulty in creating large numbers of homogeneous organoids in form factors compatible with high-throughput screening (e.g., 96- and 384-well plates). Bioprinting can be used to scale up deposition of such organoids and tissue constructs. Unfortunately, it has been challenging to 3D print hydrogel bioinks into small-sized wells due to well–bioink interactions that can result in bioinks spreading out and wetting the well surface instead of maintaining a spherical form. Here, we demonstrate an immersion printing technique to bioprint tissue organoids in 96-well plates to increase the throughput of 3D drug screening. A hydrogel bioink comprised of hyaluronic acid and collagen is bioprinted into a viscous gelatin bath, which blocks the bioink from interacting with the well walls and provides support to maintain a spherical form. This method was validated using several cancerous cell lines, and then applied to patient-derived glioblastoma (GBM) and sarcoma biospecimens for drug screening.
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    Phase I trial of convection-enhanced delivery of IL13RA2 and EPHA2 receptor targeted cytotoxins in dogs with spontaneous intracranial gliomas
    Rossmeisl, John H. Jr.; Herpai, Denise; Quigley, Mindy; Cecere, Thomas E.; Robertson, John L.; D'Agostino, Ralph B.; Hinckley, Jonathan; Tatter, Stephen B.; Dickinson, Peter J.; Debinski, Waldemar (2021-03)
    Background. The interleukin-13 receptor alpha 2 (IL13RA2) and ephrin type A receptor 2 (EPHA2) are attractive therapeutic targets, being expressed in similar to 90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met with technical barriers associated with the convection-enhanced delivery (CED) method. In this study, IL-13 mutant and ephrin A1 (EFNA1)-based bacterial cytotoxins targeted to IL13RA2 and EPHA2 receptors, respectively, were administered locoregionally by CED to dogs with intracranial gliomas to evaluate their safety and preliminary efficacy. Methods. In this phase I, 3 + 3 dose escalation trial, cytotoxins were infused by CED in 17 dogs with gliomas expressing IL13RA2 or EPHA2 receptors. CED was performed using a shape-fitting therapeutic planning algorithm, reflux-preventing catheters, and real-time intraoperative MRI monitoring. The primary endpoint was to determine the maximum tolerated dose of the cytotoxic cocktail in dogs with gliomas. Results. Consistent intratumoral delivery of the cytotoxic cocktail was achieved, with a median target coverage of 70% (range, 40-94%). Cytotoxins were well tolerated over a dose range of 0.012-1.278 mu g/mL delivered to the target volume (median, 0.099 mu g/mL), with no dose limiting toxicities observed. Objective tumor responses, up to 94% tumor volume reduction, were observed in 50% (8/16) of dogs, including at least one dog in each dosing cohort >0.05 mu g/mL. Conclusions. This study provides preclinical data fundamental to the translation of this multireceptor targeted therapeutic approach to the human clinic.
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    Sub-second Dopamine and Serotonin Signaling in Human Striatum during Perceptual Decision-Making
    Bang, Dan; Kishida, Kenneth T.; Lohrenz, Terry; Tatter, Stephen B.; Fleming, Stephen M.; Montague, P. Read (CellPress, 2020-12-09)
    Recent animal research indicates that dopamine and serotonin, neuromodulators traditionally linked to appetitive and aversive processes, are also involved in sensory inference and decisions based on such inference. We tested this hypothesis in humans by monitoring sub-second striatal dopamine and serotonin signaling during a visual motion discrimination task that separates sensory uncertainty from decision difficulty in a factorial design. Caudate nucleus recordings (n = 4) revealed multi-scale encoding: in three participants, serotonin tracked sensory uncertainty, and, in one participant, both dopamine and serotonin tracked deviations from expected trial transitions within our factorial design. Putamen recordings (n = 1) supported a cognitionaction separation between caudate nucleus and putamen—a striatal sub-division unique to primates—with both dopamine and serotonin tracking decision times. These first-of-their-kind observations in the human brain reveal a role for sub-second dopamine and serotonin signaling in non-reward-based aspects of cognition and action.
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    Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward
    Kishida, Kenneth T.; Sáez, Ignacio; Lohrenz, Terry; Witcher, Mark R.; Tatter, Stephen B.; White, Jason P.; Ellis, Thomas L.; Phillips, Paul E. M.; Montague, P. Read; Laxton, Adrian W. (NAS, 2016-01-05)
    In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson’s disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson’s disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.