Edward Roy - Academia.edu (original) (raw)

Papers by Edward Roy

Brain Research Bulletin, Feb 1, 1989

Tricyclic antidepressants such as imipramine interact with a membrane binding site associated wit... more Tricyclic antidepressants such as imipramine interact with a membrane binding site associated with the uptake of serotonin. Ovarian hormones estradiol and progesterone were found to affect the concentration and affinity of imipramine binding sites in the hypothalamus but not the cortex of female rats. In vivo and in vitro, estradiol increased the amount of imipramine binding at physiological concentrations; at high concentrations estradiol decreased imipramine binding. Ovariectomy (OVX) had no effect on imipramine binding, consonant with the biphasic dose-response relationship for estradiol. The effects of progesterone were dependent upon the concentration of estradiol. Effects of physiological concentrations of both estradiol and progesterone on imipramine binding in an isolated membrane preparation suggest that the hormones are affecting this aspect of serotonergic neuronal function by nongenomic mechanisms.

Biotechnology Progress, Apr 4, 2003

Neuroendocrinology, 1986

High-affinity progestin binding sites were found in the brain and pituitary of the female South A... more High-affinity progestin binding sites were found in the brain and pituitary of the female South African clawed frog, Xenopus laevis. Cytosol progestin receptors in the hypothalamus-preoptic area and pituitary were increased in number by estradiol treatment in ovariectomized frogs. The telencephalon also contained high-affinity binding sites, but the concentration was not affected by estrogen priming. Autoradiographic analysis of the distribution of the synthetic progestin 3H-R5020 revealed some lightly labeled cells in the anterior preoptic area and ventral infundibulum of ovariectomized animals. After estrogen priming, many heavily labeled cells were observed in the following areas: ventrolateral striatum and amygdala, anterior preoptic area, ventral infundibular nucleus, laminar nucleus of the torus semicircularis, and anterior pituitary. The areas in which dense accumulations of 3H-R5020 labeled cells were found after estrogen treatment are a subset of areas known to contain estrogen binding sites. The induction of progestin receptors by estradiol may be related to the requirement for both estrogen and progestin to elicit female sexual behavior in this species.

Neuroscience Letters, Oct 1, 2005

Hormones and Behavior, Jun 1, 1985

Intact male rats were tested on two successive weekly tests with females to determine their level... more Intact male rats were tested on two successive weekly tests with females to determine their level of sexual activity. Nuclear estrogen receptor content was measured in specific brain regions of individual sexually responsive and sexually nonresponsive males. Sexually nonresponsive male rats had significantly reduced nuclear estrogen receptor levels in the preoptic area compared to sexually responsive males. Sexually active males did not differ from inactive males in nuclear estrogen receptors in the medialbasal hypothalamus.

Brain Research, Mar 1, 1985

Endocrinology, May 1, 1979

Estradiol treatment of ovariectomized-adrenalectomized rats produced an increase in cytosol proge... more Estradiol treatment of ovariectomized-adrenalectomized rats produced an increase in cytosol progestin binding in the hypothalamus-preoptic area (HPOA), pituitary, and uterus. In the HPOA and pituitary, this induction of progestin receptors by estradiol was inhibited by the antiestrogen CI-628 under a variety of dose and time conditions. In the uterus, inhibition of the full effect of estradiol on progestin binding was observed after 3 days of injection of antiestrogen and estradiol. In the absence of estradiol, the antiestrogen produced a slight induction of progestin receptors in the HPOA and pituitary and a substantial induction of progestin receptors in the uterus. The results suggest that the induction of progestin receptors could be a key intermediate step in some behavioral and neuroendocrine actions of estradiol.

Molecular Therapy, Oct 1, 2018

Immunology, Aug 13, 2020

Chimeric antigen receptors (CARs) have shown remarkable promise in treating hematological maligna... more Chimeric antigen receptors (CARs) have shown remarkable promise in treating hematological malignancies, especially those expressing CD19 antigen. On the other hand, identification and efficacy of CARs against antigens in solid cancers has remained a significant challenge. Defects in glycosylation in solid cancers are common, and can result in formation of cell surface-expressed neoantigens that are aberrantly glycosylated. Here, we focused on antigens that result from defects in O-linked glycosylation, leading to formation of unique antigens that possess an N-acetyl-galactosamine linked to a serine or threonine residue on a surface-expressed protein (also called Tn antigen), instead of extended glycosylation patterns. 237 is a mouse monoclonal antibody that was generated by a mouse immunized with cells of a spontaneous murine cancer, and that binds to a Tn-antigen linked to the mouse protein, OTS8. Previously, we showed that a CAR generated from the 237 single chain variable fragment (scFv) recognized, with low affinity, the human cell line Jurkat. More recently, we demonstrated that the 237 CAR could eradicate established Jurkat leukemia in a mouse model. Here, we used structure-guided directed evolution to engineer the binding site of 237 to bind to multiple Tn linked antigens, including MUC1, with higher affinity. CARs containing these engineered scFv variants recognized a panel of glycosylation-defective mouse and human cancer cell lines more effectively than the wild-type 237 CAR, with no activity toward cell lines lacking these defects. Cancer cell lines lacking MUC1 were also effectively recognized by the engineered variants, indicating their broadened specificity toward multiple Tn-linked antigens. Consistent with this finding, the CAR variants also demonstrated greater sensitivity toward several Tn-linked human peptides. To extend these studies, we are currently developing additional mouse models to study the efficacy of the engineered 237 CARs in the control of solid tumors. In summary, we developed efficient chimeric antigen receptors that recognize multiple, cancer-associated Tn linked antigens, based on a single antibody scaffold. We believe that their specific recognition of Tn antigen, together with broadened peptide-backbone reactivity, holds promise for cancer-specific recognition yet minimal antigen escape against tumors with defects in O-linked glycosylation, because cancer-specific Tn-linked epitopes on several independent proteins can be simultaneously targeted. Citation Format: Preeti Sharma, Venkata VVR Marada, Monika Kizerwetter, Claire P. Schane, Yanran He, Steven P. Wolf, Karin Schreiber, Edward J. Roy, Henrik Clausen, Hans Schreiber, David M. Kranz. Engineering chimeric antigen receptors for adoptive T cell therapy of cancers that express the Tn antigen [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3238.

Life Sciences, Feb 1, 1986

Chronic treatment with the antidepressant imipramine (IMI) leads to accumulation of imipramine&am... more Chronic treatment with the antidepressant imipramine (IMI) leads to accumulation of imipramine's major metabolite desmethylimipramine (DMI) in the brain. Juvenile, young and middle-aged female rats, as well as juvenile and young male rats were treated chronically with imipramine (14 days) and analyzed 24 hours later for levels of IMI and DMI in the hypothalamus-preoptic area (HPA) and serum. Older animals of both sexes showed higher levels of DMI than juvenile animals, in both the HPA and serum. Females also had higher DMI levels than males at comparable ages. Analysis of IMI and DMI levels at intervals after a single imipramine injection suggested that the initial metabolism of imipramine is slower in older animals and in females (compared to males). The results indicate that age and gender alter the initial metabolism of imipramine, leading to enhanced accumulation of metabolites during chronic treatment in older animals and in female rats, compared to younger rats and males, respectively.

Neuroendocrinology, 1990

Pharmacological studies have suggested that neurotransmitter activity impinging on steroid-concen... more Pharmacological studies have suggested that neurotransmitter activity impinging on steroid-concentrating cells can affect the steroid receptor system within those cells, modifying behavioral responses to the hormone. The present experiments revealed that the alpha 1-noradrenergic antagonist prazosin, administered to ovariectomized rats at the time of each of two pulses of estradiol, inhibited the appearance of sexual receptivity. Prazosin also substantially reduced the levels of estrogen receptors within hypothalamic cell nuclei following an injection of estradiol. Manipulation of noradrenergic inputs into the hypothalamus by lesioning brain stem norepinephrine cell groups with 6-hydroxydopamine (6OHDA) also reduced the level of nuclear estrogen receptors following an injection of estradiol. Although this effect of 6OHDA lesions was observed in two separate experiments, in other experiments 6OHDA had no effect on estrogen receptors. In some instances, there was a positive correlation between nuclear estrogen receptor levels in the hypothalamus and the levels of norepinephrine. The results are consistent with the hypothesis that brain stem inputs to the hypothalamus are able to modulate neural responses to steroids and specifically that noradrenergic inputs are able to modulate neural responses to estradiol. However, there are additional undiscovered variables that preclude statements of a simple relationship between norepinephrine levels and estrogen receptor levels.

Science Translational Medicine, Jul 21, 2021

Activation of the unfolded protein response induces regression of estrogen receptor α–positive br... more Activation of the unfolded protein response induces regression of estrogen receptor α–positive breast cancer xenografts in mice.

Physiology & Behavior, 1987

The interval between two pulses of estradiol was varied and subsequent progesterone-facilitated f... more The interval between two pulses of estradiol was varied and subsequent progesterone-facilitated female sexual behavior was observed. The total dose of estradiol (2 micrograms free estradiol) has been shown previously to elicit little receptivity when administered in a single pulse. In the present study, two pulses of 1.0 microgram free estradiol separated by anywhere from 3-36 hours induced high levels of progesterone-facilitated receptivity when observed 18 hours after the second estrogen pulse. Various intervals between the second estrogen pulse and the time of testing were also evaluated. Female rats tested at 18, 24 and 36 hours after the second estrogen pulse (plus progesterone) were highly receptive. These results raise new possibilities about the time course of cellular events underlying the estrogen induction of feminine sexual behavior.

International Journal of Cancer, May 29, 1998

High-affinity receptors expressed on the surface of some tumors can be exploited by chemically co... more High-affinity receptors expressed on the surface of some tumors can be exploited by chemically conjugating the ligand for the receptor and an antibody against immune effector cells, thus redirecting their cytolytic potential against the tumor. Ovarian carcinomas and some brain tumors express the high-affinity folate receptor (FR). In this report, a transgenic mouse model that generates endogenously arising choroid plexus tumors was used to show that folate/anti-T-cell receptor antibody conjugates can direct infiltration of T cells into solid brain tumor masses. An engineered single-chain Fv form of the anti-T-cell receptor antibody KJ16 was conjugated with folate, to produce a bispecific agent that was substantially smaller than most previously characterized bispecific antibodies. Folate conjugation to the antibody increased T-cell infiltration into the tumors by 10- to 20-fold, and significantly prolonged survival of the mice.

Nuclear Instruments and Methods in Physics Research, Mar 1, 2009

Behavioral and Neural Biology, Nov 1, 1990

Corticosterone appears to have two markedly different effects on cells of the hippocampus in rats... more Corticosterone appears to have two markedly different effects on cells of the hippocampus in rats. On one hand, elevated levels of corticosterone contribute to the degeneration of pyramidal cells. On the other hand, elimination of corticosterone by adrenalectomy may cause degeneration of dentate granule cells (Sloviter, Valiquette, Abrams, Ronk, Sollas, Paul, & Neubort, 1989). However, the latter response is variable. Low levels of corticoids from accessory adrenal tissue not consistently detectable by radioimmunoassay may provide sufficient hormone to maintain granule cell viability. We describe simple measures that predict which individual adrenalectomized rats have degeneration of the granule cell layer. Body weight gain after adrenalectomy is positively correlated with granule cell layer area at sacrifice 3 months after surgery. Also, short-term loss of body weight when saline drinking water is replaced with tap water predicts the degree of degeneration of the granule cell layer. These observations may aid further study of this striking effect of adrenal hormones on brain anatomy.

European Journal of Pharmacology, Nov 1, 1984

Brain Research, 1989

In female prairie voles ovarian estrogen secretion is stimulated by exposure to males. The presen... more In female prairie voles ovarian estrogen secretion is stimulated by exposure to males. The present study determined that social stimuli can also enhance the neural response to estrogen. Ovariectomized female voles given a fixed amount of estradiol and exposed to males had higher levels of estrogen receptor binding in cell nuclei in the preoptic area than did females given estrogen and not exposed to males.

International Journal of Cancer, Sep 24, 1999

A variety of immunological approaches to cancer treatment are currently being explored. These inc... more A variety of immunological approaches to cancer treatment are currently being explored. These include strategies designed to enhance or redirect the activity of T cells against tumors. Bispecific antibodies comprise a class of agents capable of redirecting T cells by binding to a tumor antigen and the T-cell receptor (TCR). In vivo pre-clinical testing of bispecific antibodies against human tumors has to date been limited to the use of immunodeficient mice that receive the bispecific agent, activated human effector T cells, and human tumor cells. In this report, we show that TCR transgenic/RAG-1 knockout mice (TCR/RAG) serve as a unique model allowing endogenous T cells to be redirected against transplanted human tumors. The findings show that TCR/RAG mice (i) accepted transplants of human tumors, including the folate-receptor-positive tumor line KB; (ii) contained endogenous cytotoxic T lymphocytes that could be activated in vivo with an antigenic peptide recognized by the transgenic TCR; (iii) rejected human tumors after treatment with the activating peptide and bispecific agents that contained folic acid co-valently linked to an anti-TCR antibody. Successful rejection was achieved with folate conjugates of Fab or scFv fragments. Treatment with activating agents and bispecific conjugates resulted in the complete eradication of freshly transplanted tumors as well as significantly prolonging the survival of mice bearing established solid tumors. Our results highlight the importance of including T-cell-activating modalities in combination with bispecific antibodies. Additionally, we introduce a system that allows endogenous T cells to be redirected against human tumor xenografts and in which the T cells may be followed in vivo by use of a clonotypic marker.

Tumor Biology, Aug 13, 2020

There is an urgent need to develop new therapeutic or lifestyle strategies for treating ovarian c... more There is an urgent need to develop new therapeutic or lifestyle strategies for treating ovarian cancer due to its high mortality and recurrence rate. In this regard, we found that cholesterol appears to be clinically important for ovarian cancer survival, highlighting it and its metabolism as potential therapeutic targets for improving the lifespan of patients. In a cohort of 153 patients, we found high total cholesterol or high LDL cholesterol was associated with high tumor grade, which in turn was associated with poor survival. Additionally, patients prescribed cholesterol lowering drugs such as statins, cholesterol absorption inhibitors or fiber were associated with significantly improved overall survival. We did not observe significant differences between statins and other cholesterol lowering drugs, indicating the effects observed were most likely due to cholesterol lowering rather than other unintended pharmacologic properties of statins. Cytochrome P450 enzymes catalyze the first steps in cholesterol metabolism pathways. Among them, CYP27A1 is highly expressed in myeloid cells and oxidizes cholesterol into 27-hydroxychoelsterol (27HC), which is the most abundant oxysterol and an endogenous signaling molecule. Analysis of publicly available databases indicated that low tumoral CYP27A1 expression was associated with better progression-free survival and overall survival. Conversely, high tumoral CYP7B1 expression, the enzyme that metabolites 27HC, was associated with improved progression-free survival. Therefore, we hypothesized that CYP27A1/27HC might be mediating the effects of cholesterol on cancer survival. Indeed, we found ovarian tumors failed to grow in CYP27A1−/− mice, eventually completely regressing, while treatment with exogenous 27HC was able to sustain tumor growth in CYP27A1−/− mice, indicating that CYP27A1/27HC are important for ovarian cancer progression. Analysis of tumors and lymphoid tissues suggested that 27HC was associated with compromised immunosurveillance. Specifically, CYP27A1/27HC-axis altered the recruitment of 1) monocytic-MDSCs, an immunosuppressive subtype of myeloid cells, 2) antigen-presenting myeloid cells, and 3) CD4+ T cells. Thus, the CYP27A1/27HC-axis presents an alternative path for cancer associated immunosuppression, offering a potentially novel therapeutic target. We tested the therapeutic utility of targeting this axis and found that a small molecule CYP27A1 inhibitor significantly improved the efficacy of anti-PDL1 checkpoint inhibition in a preclinical model. Collectively, our data suggest that cholesterol/27HC-axis modulates the ovarian tumor microenvironment and promotes cancer progression, revealing a novel therapeutic target for the treatment of ovarian cancer. Supported by: NIH R01CA234025 (E.R.N.), a Cancer Scholars for Translational and Applied Research (C*STAR) Award (S.H.) and NIH T32EB019944 (S.H.). Citation Format: Sisi He, Georgina Cheng, Edward Roy, Marta Spain, Ronald Kimball, Nikolas Snyder, Melina Salgado, Debby Vannoy, Betsy Barnick, Liqian Ma, Varsha Vembar, Anna Vardanyan, Amy Baek, Joanna Burdette, Erik R. Nelson. Cholesterol and its metabolism impact ovarian cancer progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2821.