Thomas J. Gardner

Arsenal Biosciences (United States)

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David A. Scheinberg

Cornell University

Megan M. Dacek

Kettering University

Christopher M. Bourne

University of Pennsylvania

Domenico Tortorella

Icahn School of Medicine at Mount Sinai

Keifer G. Kurtz

Kettering University

Kristen Vogt

Tri-Institutional PhD Program in Chemical Biology

Broderick C. Corless

Kettering University

Derek S. Tan

Memorial Sloan Kettering Cancer Center

Patrick Wallisch

Memorial Sloan Kettering Cancer Center

Stephanie Pierre

Kettering University

Cooperative Institutions

Icahn School of Medicine at Mount Sinai

Arsenal Biosciences (United States)

Memorial Sloan Kettering Cancer Center

Cornell University

Kettering University

Weill Cornell Medicine

University of Colorado Anschutz Medical Campus

University of Colorado Denver

Rockefeller University

University of California, San Francisco

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Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection

Immunity (2016)

Nicholas S. Heaton Natasha Moshkina Romain Fenouil Thomas J. Gardner Sebastián Aguirre

Proteostasis

Antibody-dependent enhancement

10.1016/j.immuni.2016.01.016

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Citations (1)

A TCR mimic CAR T cell specific for NDC80 is broadly reactive with solid tumors and hematologic malignancies

Blood (2022)

Martin G. Klatt Tao Dao Zhiyuan Yang Jianying Liu Sung Soo Mun

Druggability

10.1182/blood.2021012882

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Citations (17)

A Simple System of Replicated Recirculating Experimental Streams

Journal of Freshwater Ecology (1990)

William J. Matthews Frances P. Gelwick Thomas J. Gardner

ABSTRACT A system of recirculating artificial streams is described that has low initial cost and operating expense and operates efficiently over long periods of time. Although individual stream units are large enough to accommodate minnows and crayfish, they are sufficiently compact that replication with up to 12 streams is possible in a relatively small laboratory. The system is simple in design, with no moving parts (except pumps) and no costly flow meters or regulating devices. Replication of stream units is facilitated by depending on inlet ports of fixed size, full-capacity operation of pumps, and uniform diameters of distribution systems. A basic stream tank unit is described in detail, with techniques for combining up to 12 units for water-exchange and inflow-outflow of water in different experimental applications. We have operated the system for almost a year with very little cost or repair. Substrates incubated in the laboratory streams readily grow an algal flora similar to that of nearby natural streams, and fish, crayfish and snails exhibit normal activities in the streams. Total cost for construction of a 12-stream system was less than $3,500 U.S.

Inflow

Replication

Outflow

10.1080/02705060.1990.9665260

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Citations (7)

Data from Host Interactions with Engineered T-cell Micropharmacies

Christopher M. Bourne Patrick Wallisch Megan M. Dacek Thomas J. Gardner Stephanie Pierre

<div>Abstract<p>Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with a killing mechanism orthogonal to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Herein, we expanded the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with T-cell receptor (TCR)–engineered T cells. We demonstrate that SEAKER cells localized specifically to tumors, and activated bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells were efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.</p></div>

Adoptive Cell Transfer

Cancer Immunotherapy

10.1158/2326-6066.c.6750021.v1

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Microbial Use of Leaf Litter in Prairie Streams

Journal of the North American Benthological Society (1992)

Brian H. Hill Thomas J. Gardner O. F. Ekisola Geoffrey M. Henebry

Mass loss and microbial oxygen consumption on decaying leaves from five species of gallery forest trees were measured in six prairie streams (three perennial, three intermittent) ranging in size from 2nd to 4th order. Leaf decay was monitored for 56 d in late fall and early winter 1987-1988. Mass loss was greatest for bois d'arc (Maclura pomifera), followed by hackberry (Celtis laevigata), cottonwood (Populus deltoides), elm (Ulmus rubra), and Shumard oak (Quercus shumaraii). Breakdown rates in the six streams fell into two groups: decay in 3rd-order intermittent, 3rd-order perennial, and 4th-order perennial streams all exhibited faster breakdown rates than the 2nd-order intermittent 2nd-order perennial, and 4th-order intermittent streams. These differences appear to be related to stream order and hydrologic regime. Microbial respiration was strongly correlated with mass loss for the first 28 d. This period of rapid mass loss from the leaf litter was followed by a period in which mass loss and respiration were poorly correlated. Respiration was greatest on bois d'arc and hackberry, followed by cottonwood, elm, and oak. Microbial respiration accounted for 10% to 66% of the mass loss from the decaying leaves. Overall, leaf species seemed to be the most important factor controlling breakdown rates, followed by stream order and hydrologic regime.

Litter

Perennial stream

Plant litter

10.2307/1467878

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Citations (23)

Development of a novel autoantibody assay for autoimmune gastritis in type 1 diabetic individuals

Diabetes/Metabolism Research and Reviews (2011)

Janet M. Wenzlau Thomas J. Gardner Lisa M. Frisch Howard W. Davidson John C. Hutton

Abstract Background Autoimmune atrophic body gastritis (ABG) and pernicious anaemia are prototypical, organ‐specific autoimmune diseases whose prevalence in the general population is 2.0 vs 2 and 0.15–1%, respectively. The incidence of disease increases with age and is frequently associated with other autoimmune disorders such as type 1 diabetes mellitus (T1DM). Early diagnosis of ABG/pernicious anaemia is essential for the prevention and/or treatment before manifestations of chronic disease become irreversible. Parietal cell autoantibody detection via enzyme‐linked immunosorbent assay is currently the most widely used biomarker of disease with diagnosis confirmed by subsequent immunohistochemistry via biopsy. Methods To improve the assay we designed a specific, molecularly defined radioimmunoprecipitation assay for early detection of ABG, targeting its major antigen, the gastric H + /K + ATPase 4A subunit ATP4A. Results The major antigenic domain in ATP4A was tested against a panel of sera from new onset patients with T1DM which tested positive for the gold standard T1DM autoantibodies (IAA, IA2A, GAD65A, and ZnT8A). Significant immunoreactivity to ATP4A was measured (25%) while 6% of first‐degree relatives of subjects with T1DM who were sero‐negative for T1DM autoantigens were positive for ATP4A autoantibodies. ATP4A antibody prevalence increased with age of onset of T1DM, which is atypical of other T1DM autoantibodies. Immunoreactivity to ATP4A, unlike that of T1DM antigens, demonstrates a significant gender bias in newly diagnosed individuals with T1DM. Conclusion Although the utility of the assay as a biomarker for T1DM is likely limited, it may serve as an improved indicator of ABG. Copyright © 2011 John Wiley & Sons, Ltd.

Autoimmune Gastritis

Pernicious anaemia

Atrophic gastritis

10.1002/dmrr.1267

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Citations (17)

Development of a p-Hydroxybenzyl-Alcohol-Linked Glutamate Prodrug for Activation by Pseudomonas Carboxypeptidase G2

Organic Letters (2023)

J. Peter Lee Broderick C. Corless Thomas J. Gardner David A. Scheinberg Derek S. Tan

Directed enzyme–prodrug therapies used for targeted drug delivery require prodrugs that are chemically stable and processed efficiently by the activating enzyme. We recently reported the development of AMS-6-Glu (2), a glutamate-masked version of the cytotoxic natural product 5′-O-sulfamoyladenosine (AMS, 1) that can be activated by Pseudomonas carboxypeptidase G2 (CPG2). Herein, we report the development of a second-generation prodrug, AMS-5′-PHOBA-Glu (5), that undergoes cleavage by CPG2 with >160-fold higher efficiency. Use of a p-hydroxybenzyl alcohol (PHOBA) self-immolative linker overcame unexpected chemical instability observed with a conventional p-aminobenzyl alchohol (PABA) linker.

Linker

Cleavage (geology)

Nitroreductase

Natural product

10.1021/acs.orglett.3c02130

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Citations (1)

Criminal Law: Principles and Cases

Thomas J. Gardner Terry M. Anderson

This highly accessible text provides a comprehensive introduction to all aspects of criminal law. Gardner and Anderson illuminate what is prescribed criminal behavior by discussing and citing criminal law without employing extensive cases. Using a strong pedagogical framework, this book aids the student in comprehending complex topics in a methodical manner.

Criminal procedure

Criminal investigation

Source

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Citations (4)

Novel antigens in type 1 diabetes: The importance of ZnT8

Current Diabetes Reports (2009)

Janet M. Wenzlau Lisa M. Frisch Thomas J. Gardner Suparna A. Sarkar John C. Hutton

Pathogenesis

10.1007/s11892-009-0019-4

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Citations (61)

Human cytomegalovirus gH stability and trafficking are regulated by ER-associated degradation and transmembrane architecture

Scientific Reports (2016)

Thomas J. Gardner Rosmel E. Hernandez Vanessa M. Noriega Domenico Tortorella

The prototypic betaherpesvirus human cytomegalovirus (CMV) establishes life-long persistence within its human host. While benign in healthy individuals, CMV poses a significant threat to the immune compromised, including transplant recipients and neonates. The CMV glycoprotein complex gH/gL/gO mediates infection of fibroblasts, and together with the gH/gL/UL128/130/131 a pentameric complex permits infection of epithelial, endothethial, and myeloid cells. Given the central role of the gH/gL complex during infection, we were interested in studying cellular trafficking of the gH/gL complex through generation of human cells that stably express gH and gL. When expressed alone, CMV gH and gL were degraded through the ER-associated degradation (ERAD) pathway. However, co-expression of these proteins stabilized the polypeptides and enhanced their cell-surface expression. To further define regulatory factors involved in gH/gL trafficking, a CMV gH chimera in which the gH transmembrane and cytoplasmic tail were replaced with that of human CD4 protein permitted cell surface gH expression in absence of gL. We thus demonstrate the ability of distinct cellular processes to regulate the trafficking of viral glycoproteins. Collectively, the data provide insight into the processing and trafficking requirements of CMV envelope protein complexes and provide an example of the co-opting of cellular processes by CMV.

Endoplasmic-reticulum-associated protein degradation

10.1038/srep23692

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Citations (10)