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2. GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

Author

Takahashi, Keigo, primary, Rensing, Nicholas R, additional, Eultgen, Elizabeth M, additional, Wang, Sophie H, additional, Nelvagal, Hemanth R, additional, Le, Steven Q, additional, Roberts, Marie S, additional, Doray, Balraj, additional, Han, Edward, additional, Dickson, Patricia, additional, Wong, Michael, additional, Sands, Mark S, additional, and Cooper, Jonathan D, additional

Published
2024
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7. Supplementary Data from Acquired Resistance to Combination Treatment with Temozolomide and ABT-888 Is Mediated by Both Base Excision Repair and Homologous Recombination DNA Repair Pathways

Author

Liu, Xuesong, primary, Han, Edward K., primary, Anderson, Mark, primary, Shi, Yan, primary, Semizarov, Dimitri, primary, Wang, Gang, primary, McGonigal, Thomas, primary, Roberts, Lisa, primary, Lasko, Loren, primary, Palma, Joann, primary, Zhu, Gui-dong, primary, Penning, Thomas, primary, Rosenberg, Saul, primary, Giranda, Vincent L., primary, Luo, Yan, primary, Leverson, Joel, primary, Johnson, Eric F., primary, and Shoemaker, Alexander R., primary

Published
2023
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8. Data from Acquired Resistance to Combination Treatment with Temozolomide and ABT-888 Is Mediated by Both Base Excision Repair and Homologous Recombination DNA Repair Pathways

Author

Liu, Xuesong, primary, Han, Edward K., primary, Anderson, Mark, primary, Shi, Yan, primary, Semizarov, Dimitri, primary, Wang, Gang, primary, McGonigal, Thomas, primary, Roberts, Lisa, primary, Lasko, Loren, primary, Palma, Joann, primary, Zhu, Gui-dong, primary, Penning, Thomas, primary, Rosenberg, Saul, primary, Giranda, Vincent L., primary, Luo, Yan, primary, Leverson, Joel, primary, Johnson, Eric F., primary, and Shoemaker, Alexander R., primary

Published
2023
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15. sj-docx-1-tej-10.1177_20417314211027714 – Supplemental material for Development of a Bioartificial Vascular Pancreas

Author

Han, Edward X, Wang, Juan, Kural, Mehmet, Jiang, Bo, Leiby, Katherine L, Chowdhury, Nazar, Tellides, George, Kibbey, Richard G, Lawson, Jeffrey H, and Niklason, Laura E

Subjects
110599 Dentistry not elsewhere classified, FOS: Clinical medicine, FOS: Biological sciences, 69999 Biological Sciences not elsewhere classified
Abstract

Supplemental material, sj-docx-1-tej-10.1177_20417314211027714 for Development of a Bioartificial Vascular Pancreas by Edward X Han, Juan Wang, Mehmet Kural, Bo Jiang, Katherine L Leiby, Nazar Chowdhury, George Tellides, Richard G Kibbey, Jeffrey H Lawson and Laura E Niklason in Journal of Tissue Engineering

Published
2021
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16. Development of a Bioartificial Vascular Pancreas

Author

Han, Edward X, primary, Wang, Juan, additional, Kural, Mehmet, additional, Jiang, Bo, additional, Leiby, Katherine L, additional, Chowdhury, Nazar, additional, Tellides, George, additional, Kibbey, Richard G, additional, Lawson, Jeffrey H, additional, and Niklason, Laura E, additional

Published
2021
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17. Chemical mutagenesis of a GPCR ligand: Detoxifying “inflammo-attraction” to direct therapeutic stem cell migration

Author

Lee, Jean-Pyo, primary, Zhang, Runquan, additional, Yan, Maocai, additional, Duggineni, Srinivas, additional, Wakeman, Dustin R., additional, Niles, Walter L., additional, Feng, Yongmei, additional, Chen, Justin, additional, Hamblin, Milton H., additional, Han, Edward B., additional, Gonzalez, Rodolfo, additional, Fang, Xiao, additional, Zhu, Yinsong, additional, Wang, Juan, additional, Xu, Yan, additional, Wenger, David A., additional, Seyfried, Thomas N., additional, An, Jing, additional, Sidman, Richard L., additional, Huang, Ziwei, additional, and Snyder, Evan Y., additional

Published
2020
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22. Organ‐on‐a‐Chip: Ex vivo Dynamics of Human Glioblastoma Cells in a Microvasculature‐on‐a‐Chip System Correlates with Tumor Heterogeneity and Subtypes (Adv. Sci. 8/2019)

Author

Xiao, Yang, primary, Kim, Dongjoo, additional, Dura, Burak, additional, Zhang, Kerou, additional, Yan, Runchen, additional, Li, Huamin, additional, Han, Edward, additional, Ip, Joshua, additional, Zou, Pan, additional, Liu, Jun, additional, Chen, Ann Tai, additional, Vortmeyer, Alexander O., additional, Zhou, Jiangbing, additional, and Fan, Rong, additional

Published
2019
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25. Ex vivo Dynamics of Human Glioblastoma Cells in a Microvasculature‐on‐a‐Chip System Correlates with Tumor Heterogeneity and Subtypes

Author

Xiao, Yang, primary, Kim, Dongjoo, additional, Dura, Burak, additional, Zhang, Kerou, additional, Yan, Runchen, additional, Li, Huamin, additional, Han, Edward, additional, Ip, Joshua, additional, Zou, Pan, additional, Liu, Jun, additional, Chen, Ann Tai, additional, Vortmeyer, Alexander O., additional, Zhou, Jiangbing, additional, and Fan, Rong, additional

Published
2019
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26. Chemical mutagenesis of a GPCR ligand: Detoxifying "inflammo-attraction" to direct therapeutic stem cell migration.

Author

Jean-Pyo Lee, Runquan Zhang, Maocai Yan, Duggineni, Srinivas, Wakeman, Dustin R., Niles, Walter L., Yongmei Feng, Chen, Justin, Hamblin, Milton H., Han, Edward B., Gonzalez, Rodolfo, Xiao Fang, Yinsong Zhu, Juan Wang, Yan Xu, Wenger, David A., Seyfried, Thomas N., Jing An, Sidman, Richard L., and Ziwei Huang

Subjects
CELL migration, CHEMICAL mutagenesis, STEM cells, NEURAL stem cells, G protein coupled receptors
Abstract

A transplanted stem cell's engagement with a pathologic niche is the first step in its restoring homeostasis to that site. Inflammatory chemokines are constitutively produced in such a niche; their binding to receptors on the stem cell helps direct that cell's "pathotropism." Neural stem cells (NSCs), which express CXCR4, migrate to sites of CNS injury or degeneration in part because astrocytes and vasculature produce the inflammatory chemokine CXCL12. Binding of CXCL12 to CXCR4 (a G protein-coupled receptor, GPCR) triggers repair processes within the NSC. Although a tool directing NSCs to where needed has been long-sought, one would not inject this chemokine in vivo because undesirable inflammation also follows CXCL12-CXCR4 coupling. Alternatively, we chemically "mutated" CXCL12, creating a CXCR4 agonist that contained a strong pure binding motif linked to a signaling motif devoid of sequences responsible for synthetic functions. This synthetic dual-moity CXCR4 agonist not only elicited more extensive and persistent human NSC migration and distribution than did native CXCL 12, but induced no host inflammation (or other adverse effects); rather, there was predominantly reparative gene expression. When coadministered with transplanted human induced pluripotent stem cell-derived hNSCs in a mouse model of a prototypical neurodegenerative disease, the agonist enhanced migration, dissemination, and integration of donor-derived cells into the diseased cerebral cortex (including as electrophysiologically-active cortical neurons) where their secreted cross-corrective enzyme mediated a therapeutic impact unachieved by cells alone. Such a "designer" cytokine receptor-agonist peptide illustrates that treatments can be controlled and optimized by exploiting fundamental stem cell properties (e.g., "inflammo-attraction"). [ABSTRACT FROM AUTHOR]

Published
2020
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27. Ex vivo dynamics of human glioblastoma cells in a microvasculature-on-a-chip system correlates with tumor heterogeneity and subtypes

Author

Xiao, Yang, primary, Kim, Dongjoo, additional, Dura, Burak, additional, Zhang, Kerou, additional, Yan, Runchen, additional, Li, Huamin, additional, Han, Edward, additional, Ip, Joshua, additional, Zou, Pan, additional, Liu, Jun, additional, Chen, Ann Tai, additional, Vortmeyer, Alexander O., additional, Zhou, Jiangbing, additional, and Fan, Rong, additional

Published
2018
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29. Structure-based Design of Pyridone–Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition

Author

Reich, Siegfried H., primary, Sprengeler, Paul A., additional, Chiang, Gary G., additional, Appleman, James R., additional, Chen, Joan, additional, Clarine, Jeff, additional, Eam, Boreth, additional, Ernst, Justin T., additional, Han, Qing, additional, Goel, Vikas K., additional, Han, Edward Z. R., additional, Huang, Vera, additional, Hung, Ivy N. J., additional, Jemison, Adrianna, additional, Jessen, Katti A., additional, Molter, Jolene, additional, Murphy, Douglas, additional, Neal, Melissa, additional, Parker, Gregory S., additional, Shaghafi, Michael, additional, Sperry, Samuel, additional, Staunton, Jocelyn, additional, Stumpf, Craig R., additional, Thompson, Peggy A., additional, Tran, Chinh, additional, Webber, Stephen E., additional, Wegerski, Christopher J., additional, Zheng, Hong, additional, and Webster, Kevin R., additional

Published
2018
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30. Attacking cancer with a prodrug-doped cellular Trojan Horse

Author

Heinelt Martina, Milton Yuka, Safaee Helia, Karp Jeffrey, Brennen Nate, Denmeade Samuel, Isaacs John, Rosen David Marc, Bhowmick Neil, Musabeyezu Juliet, Levy Oren, Han Edward, Ngai Jessica, Wang Hao, and Ranganath Sudhir

Subjects
Histology, Chemistry, Biomedical Engineering, Cancer research, medicine, Trojan horse, Cancer, Bioengineering, Prodrug, medicine.disease, Biotechnology
Published
2016

33. ABBV-399, a c-Met Antibody–Drug Conjugate that Targets Both MET–Amplified and c-Met–Overexpressing Tumors, Irrespective of MET Pathway Dependence

Author

Wang, Jieyi, primary, Anderson, Mark G., additional, Oleksijew, Anatol, additional, Vaidya, Kedar S., additional, Boghaert, Erwin R., additional, Tucker, Lora, additional, Zhang, Qian, additional, Han, Edward K., additional, Palma, Joann P., additional, Naumovski, Louie, additional, and Reilly, Edward B., additional

Published
2017
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34. A Small-Molecule Screen for Enhanced Homing of Systemically Infused Cells

Author

Harvard University--MIT Division of Health Sciences and Technology, Karp, Jeffrey Michael, Levy, Oren, Mortensen, Luke J., Boquet, Gerald, Tong, Zhixiang, Perrault, Christelle, Benhamou, Brigitte, Zhang, Jidong, Stratton, Tara, Han, Edward, Safaee, Helia, Musabeyezu, Juliet, Yang, Zijiang, Multon, Marie-Christine, Rothblatt, Jonathan, Deleuze, Jean-Francois, Lin, Charles P., Harvard University--MIT Division of Health Sciences and Technology, Karp, Jeffrey Michael, Levy, Oren, Mortensen, Luke J., Boquet, Gerald, Tong, Zhixiang, Perrault, Christelle, Benhamou, Brigitte, Zhang, Jidong, Stratton, Tara, Han, Edward, Safaee, Helia, Musabeyezu, Juliet, Yang, Zijiang, Multon, Marie-Christine, Rothblatt, Jonathan, Deleuze, Jean-Francois, and Lin, Charles P.

Abstract

Poor homing of systemically infused cells to disease sites may limit the success of exogenous cell-based therapy. In this study, we screened 9,000 signal-transduction modulators to identify hits that increase mesenchymal stromal cell (MSC) surface expression of homing ligands that bind to intercellular adhesion molecule 1 (ICAM-1), such as CD11a. Pretreatment of MSCs with Ro-31-8425, an identified hit from this screen, increased MSC firm adhesion to an ICAM-1-coated substrate in vitro and enabled targeted delivery of systemically administered MSCs to inflamed sites in vivo in a CD11a- (and other ICAM-1-binding domains)-dependent manner. This resulted in a heightened anti-inflammatory response. This represents a new strategy for engineering cell homing to enhance therapeutic efficacy and validates CD11a and ICAM-1 as potential targets. Altogether, this multi-step screening process may significantly improve clinical outcomes of cell-based therapies., Sanofi Aventis (Firm) (Research Grant), National Institutes of Health (U.S.) (Grant HL095722)

Published
2016

35. Abstract 2067: Attacking prostate cancer with a prodrug-doped cellular Trojan horse

Author

Brennen, Nathaniel, primary, Levy, Oren, additional, Han, Edward, additional, Rosen, David Marc, additional, Musabeyezu, Juliet, additional, Safaee, Helia, additional, Ranganath, Sudhir, additional, Ngai, Jessica, additional, Heinelt, Martina, additional, Billett, Sandrine, additional, Bhowmick, Neil, additional, Denmeade, Samuel, additional, Karp, Jeffrey, additional, and Isaacs, John, additional

Published
2016
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39. A Small-Molecule Screen for Enhanced Homing of Systemically Infused Cells

Author

Levy, Oren, primary, Mortensen, Luke J., additional, Boquet, Gerald, additional, Tong, Zhixiang, additional, Perrault, Christelle, additional, Benhamou, Brigitte, additional, Zhang, Jidong, additional, Stratton, Tara, additional, Han, Edward, additional, Safaee, Helia, additional, Musabeyezu, Juliet, additional, Yang, Zijiang, additional, Multon, Marie-Christine, additional, Rothblatt, Jonathan, additional, Deleuze, Jean-Francois, additional, Lin, Charles P., additional, and Karp, Jeffrey M., additional

Published
2015
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40. GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice.

Author

Takahashi K, Rensing NR, Eultgen EM, Wang SH, Nelvagal HR, Le SQ, Roberts MS, Doray B, Han EB, Dickson PI, Wong M, Sands MS, and Cooper JD

Abstract

GABAergic interneuron deficits have been implicated in the epileptogenesis of multiple neurological diseases. While epileptic seizures are a key clinical hallmark of CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), the etiology of these seizures remains elusive. Given that Cln2 R207X/R207X mice display fatal spontaneous seizures and an early loss of several cortical interneuron populations, we hypothesized that those two events might be causally related. To address this hypothesis, we first generated an inducible transgenic mouse expressing lysosomal membrane-tethered TPP1 (TPP1LAMP1) on the Cln2 R207X/R207X genetic background to study the cell-autonomous effects of cell-type-specific TPP1 deficiency. We crossed the TPP1LAMP1 mice with Vgat-Cre mice to introduce interneuron-specific TPP1 deficiency. Vgat-Cre ; TPP1LAMP1 mice displayed storage material accumulation in several interneuron populations both in cortex and striatum, and increased susceptibility to die after PTZ-induced seizures. Secondly, to test the role of GABAergic interneuron activity in seizure progression, we selectively activated these cells in Cln2 R207X/R207X mice using Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) in in Vgat-Cre : Cln2 R207X/R207X mice. EEG monitoring revealed that DREADD-mediated activation of interneurons via chronic deschloroclozapine administration accelerated the onset of spontaneous seizures and seizure-associated death in Vgat-Cre : Cln2 R207X/R207X mice, suggesting that modulating interneuron activity can exert influence over epileptiform abnormalities in CLN2 disease. Taken together, these results provide new mechanistic insights into the underlying etiology of seizures and premature death that characterize CLN2 disease.

Published
2024
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41. Functionally distinct dopamine domains in the hippocampus.

Author

Mehra M, Molina G, Islam MT, Dhanerawala ZM, Bano E, and Han EB

Abstract

Numerous studies have identified dopamine signaling in the hippocampus as necessary for certain types of learning and memory. Since dopamine in the striatum is strongly tied to rewards, dopamine in the hippocampus is thought to reinforce reward learning. Despite the critical influence of dopamine on hippocampal function, little is known about dopamine release in the hippocampus or the specific ways dopamine can influence hippocampal function. Based on the functional complexity of hippocampal circuitry, we hypothesized the existence of multiple dopamine signaling domains. Using optical dopamine sensors, two-photon imaging, and head-fixed behaviors, we identified two functionally and spatially distinct dopamine domains in the hippocampus. The "superficial" domain (cell somata and apical dendrites) showed reward-related dopamine transients early in Pavlovian conditioning but were replaced by "deep" domain transients (basal dendritic layer) with experience. These two domains also play distinct roles in a hippocampal-dependent, goal-directed virtual reality task where mice use exploratory licks to discover the location of a hidden reward zone. Here, positive dopamine ramps appeared in the superficial domain as mice approached the reward zone, similar to those seen in the striatum. At the same time, the deep domain showed strong reward-related transients. These results reveal small-scale, anatomically segregated, dopamine domains in the hippocampus. Furthermore dopamine domain activity had temporal-specificity for different phases of behavior. Finally, the subcellular scale of dopamine domains suggests specialized postsynaptic pathways for processing and integrating functionally distinct dopaminergic influences.

Published
2024
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42. Rapid Screening of CAR T Cell Functional Improvement Strategies by Highly Multiplexed Single-Cell Secretomics.

Author

Slavkovic-Lukic D, Fioravanti J, Martín-Santos A, Han E, Zhou J, and Gattinoni L

Subjects
Treatment Outcome, Antigens, CD19, Immunotherapy, Adoptive methods, Receptors, Antigen, T-Cell, CD8-Positive T-Lymphocytes
Abstract

The functional fitness of CAR T cells plays a crucial role in determining their clinical efficacy. Several strategies are being explored to increase cellular fitness, but screening these approaches in vivo is expensive and time-consuming, limiting the number of strategies that can be tested at one time. The presence of polyfunctional CAR T cells has emerged as a critical parameter correlating with clinical responses. However, even sophisticated multiplexed secretomic assays often fail to detect differences in cytokine release due to the functional heterogeneity of CAR T cell products. Here, we describe a highly multiplexed single-cell secretomic assay based on the IsoLight platform to rapidly evaluate the impact of new pharmacologic or gene-engineering approaches aiming at improving CAR T cell function. As a key study, we focus on CD19-specific CAR CD8 + T cells modulated by miR-155 overexpression, but the protocol can be applied to characterize other functional immune cell modulation strategies., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Published
2024
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43. HIV vaccines induce CD8 + T cells with low antigen receptor sensitivity.

Author

Migueles SA, Nettere DM, Gavil NV, Wang LT, Toulmin SA, Kelly EP, Ward AJ, Lin S, Thompson SA, Peterson BA, Abdeen CS, Sclafani CR, Pryal PF, Leach BG, Ludwig AK, Rogan DC, Przygonska PA, Cattani A, Imamichi H, Sachs A, Cafri G, Huang NN, Patamawenu A, Liang CJ, Hallahan CW, Kambach DM, Han EX, Coupet T, Chen J, Moir SL, Chun TW, Coates EE, Ledgerwood J, Schmidt J, Taillandier-Coindard M, Michaux J, Pak H, Bassani-Sternberg M, Frahm N, McElrath MJ, and Connors M

Subjects
Humans, Clone Cells, Receptors, Antigen, T-Cell metabolism, AIDS Vaccines immunology, HIV Infections prevention & control, Cytotoxicity, Immunologic, T-Lymphocytes, Cytotoxic immunology, Cell Degranulation immunology
Abstract

Current HIV vaccines designed to stimulate CD8 + T cells have failed to induce immunologic control upon infection. The functions of vaccine-induced HIV-specific CD8 + T cells were investigated here in detail. Cytotoxic capacity was significantly lower than in HIV controllers and was not a consequence of low frequency or unaccumulated functional cytotoxic proteins. Low cytotoxic capacity was attributable to impaired degranulation in response to the low antigen levels present on HIV-infected targets. The vaccine-induced T cell receptor (TCR) repertoire was polyclonal and transduction of these TCRs conferred the same reduced functions. These results define a mechanism accounting for poor antiviral activity induced by these vaccines and suggest that an effective CD8 + T cell response may require a vaccination strategy that drives further TCR clonal selection.

Published
2023
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