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Biomedical subjects

E J Roy

Publications and source records attributed to E J Roy.

At least 19 recordsLinked to original sources
PubMed1998

Targeting T cells against brain tumors with a bispecific ligand-antibody conjugate.

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.

Animals↗
PubMed1997

Folate receptors as potential therapeutic targets in choroid plexus tumors of SV40 transgenic mice.

A high affinity folate receptor is expressed in some human cancers, including choroid plexus tumors and ependymomas, and has been suggested as a target for therapeutics. In this report, the expression of folate receptors in an SV40 large T antigen transgenic mouse (SV11) was investigated. SV11 mice develop choroid plexus tumors, a property that may be related to the observation that SV40 has been isolated from human choroid plexus tumors and ependymomas. We report that SV11 choroid plexus tumors contain a high affinity folate receptor (KD of 1 nM), detectable by 125I-folate autoradiography and immunohistochemistry. Western blot analysis indicated an apparent molecular weight of 38 kDa. RT-PCR revealed the presence of transcripts for both alpha and beta isoforms of the folate receptor. Brain parenchyma has undetectable folate receptor, but normal choroid plexus has substantial levels (as does human choroid plexus). The folate receptors of the tumor are accessible from the bloodstream whereas those of the normal choroid plexus are not. Thus SV11 transgenic mice should be useful for evaluating therapeutic targeting of high affinity folate receptors, both for efficacy of specific agents and possible side effects.

Animals↗
PubMed1997

Long-term adrenalectomy can decrease or increase hippocampal dentate gyrus volumes.

Male and female Long-Evans adult rats were adrenalectomized and sacrificed 6 weeks later to determine whether dentate gyrus damage would differ in females and males. A subset of adrenalectomized rats of both sexes had significantly reduced dentate gyrus volumes compared to the same sex SHAM operated rats. The remainder of the male and female adrenalectomized rats which did not have clear dentate gyrus damage had significantly larger dentate gyrus volumes compared to the same sex SHAM rats. The dentate gyrus volumes of all adrenalectomized rats were significantly correlated with two indices of residual hormonal levels (Na+/K+ ratios and body weight gain 6 weeks after surgery), indicating that endogenous corticosterone levels may be a determining factor in the response of the dentate gyrus to adrenalectomy. These dentate gyrus volumetric changes could not be attributed to tissue shrinkage as there were no changes in CA3 volumes in any of the groups. These results suggest that long-term adrenalectomy can result in either increased or decreased dentate gyrus volumes and that the adrenal steroid levels of each individual adrenalectomized rat may be the factor determining the direction of the dentate gyrus volumetric response.

Adrenal Glands↗
PubMed1995

Conjugates of folate and anti-T-cell-receptor antibodies specifically target folate-receptor-positive tumor cells for lysis.

High-affinity folate receptors (FRs) are expressed at elevated levels on many human tumors. Bispecific antibodies that bind the FR and the T-cell receptor (TCR) mediate lysis of these tumor cells by cytotoxic T lymphocytes. In this report, conjugates that consist of folate covalently linked to anti-TCR antibodies are shown to be potent in mediating lysis of tumor cells that express either the alpha or beta isoform of the FR. Intact antibodies with an average of five folate per molecule exhibited high affinity for FR+ tumor cells but did not bind to FR- tumor cells. Lysis of FR+ cell lines could be detected at concentrations as low as 1 pM (approximately 0.1 ng/ml), which was 1/1000th the concentration required to detect binding to the FR+ cells. Various FR+ mouse tumor cell lines could be targeted with each of three different anti-TCR antibodies that were tested as conjugates. The antibodies included 1B2, a clonotypic antibody specific for the cytotoxic T cell clone 2C; KJ16, an anti-V beta 8 antibody; and 2C11, an anti-CD3 antibody. These antibodies differ in affinities by up to 100-fold, yet the cytolytic capabilities of the folate/antibody conjugates differed by no more than 10-fold. The reduced size (in comparison with bispecific antibodies) and high affinity of folate conjugates suggest that they may be useful as immunotherapeutic agents in targeting tumors that express folate receptors.

Animals↗
PubMed1995

Dentate gyrus destruction and spatial learning impairment after corticosteroid removal in young and middle-aged rats.

We investigated the functional and behavioral implications of chronic corticosteroid removal in young and middle-aged rats. Prepubertal and 13-month-old rats were adrenalectomized (ADX) or sham operated (SHAM). The young ADX rats were divided further into three groups: ADX with no hormone replacement, ADX given corticosterone chronically, (chCORT), and ADX given corticosterone acutely at the time of Morris water maze testing (acCORT). All rats were run on the Morris water maze 12 weeks after surgery. They were then sacrificed and the brains were removed for histological analysis. The results showed that prolonged corticosteroid absence caused major damage to the dentate gyrus and learning impairment on the Morris water maze. The chCORT rats had little dentate gyrus cell loss and were as efficient as the controls in Morris water maze performance, whereas the acCORT rats had dentate gyrus cell loss and were impaired in the spatial acquisition task. Furthermore, exogenously administered corticosterone had an interactive effect on ADX rats. Water maze performance was improved in dentate gyrus damaged rats (acCORT) compared to ADX rats not given corticosterone, whereas ADX rats with very little dentate gyrus damage (chCORT) did not exhibit better water maze performance relative to controls. Middle-aged ADX rats lost cells only in the dorsal blade of the dentate gyrus but they did not show a learning impairment in the Morris water maze relative to the middle-aged controls. These results indicate that corticosteroids are trophic for the dentate gyrus, that mature granule cells are less affected by adrenalectomy, that corticosteroid absence is responsible for some water maze impairment in ADX rats, but that in addition to corticosteroid absence, a substantial amount of dentate gyrus damage is necessary to impair spatial learning.

Adrenal Cortex Hormones↗
PubMed1993

Juvenile desipramine reduces adult sensitivity to imipramine in two behavioral tests.

The behavioral effects of adult imipramine administration were examined in female rats treated with desipramine as juveniles (JDES), treated with saline as juveniles (JSAL), and untreated as juveniles (JUNT). In the forced swimming test, the juvenile groups displayed similar behavioral effects of imipramine when administered short term following a pretest forced swimming exposure. Similar effects of imipramine were observed when administered long term prior to the only test exposure. When rats were not given a pretest forced swimming test exposure, short-term imipramine had no effect on JDES rats but did influence JSAL and JUNT rats. In the open-field test, short- and long-term imipramine treatment affected the behavior of JUNT and JSAL rats. Short-term imipramine treatment influenced open-field behavior of JDES animals, but long-term imipramine treatment had no effect. These results suggest that JDES treatment may permanently alter the neural mechanism underlying the behavioral effects of antidepressant treatment.

Animals↗
PubMed1993

Selective loss of hippocampal granule cells following adrenalectomy: implications for spatial memory.

We examined the effects of long-term adrenalectomy (ADX) on hippocampal anatomy and behavioral learning in two spatial memory tasks. We assessed damage throughout the hippocampus by stereological analysis of the dentate gyrus and Ammon's horn. Rats were ADX or sham operated, and then tested in the Morris water maze 12 weeks after surgery, followed by testing on an eight-arm, alternating-baited radial maze at 22 weeks postsurgery. Animals were killed 7 1/2 months after surgery. ADX rats had selective volume reduction in the dentate gyrus with no changes in pyramidal regions CA1, CA2, CA3, or CA4. Dentate gyrus damage in some cases occurred throughout the entire rostrocaudal extent of the hippocampus. Analysis of corticosterone serum levels, serum Na+/K+ ratios, and body weight gain suggested that individual differences in dentate gyrus damage appear to be due to incomplete adrenalectomies or remaining ectopic tissue. ADX rats were able to learn in both the Morris water maze and eight-arm radial maze, even when the dentate gyrus was severely damaged (80% volume reduction). However, in the Morris water maze, the ADX rats' learning rate was significantly slower compared to controls. There was no difference between ADX and controls during reversal in either task. These data indicate that damage to the dentate gyrus following long-term ADX is severe enough to cause learning impairment in selected learning tasks. Such damage is restricted to the dentate gyrus and can occur throughout the rostrocaudal regions of the hippocampus.

Adrenalectomy↗
PubMed1990

Characterization of a protein that appears in the nervous system of the moth Manduca sexta coincident with neuronal death.

Two-dimensional gel electrophoresis was used to locate potential neuronal death-related proteins in the moth Manduca sexta. Protein patterns of ganglia of pharate adult moths (taken prior to adult ecdysis) compared with protein patterns of one-day-old adults revealed reproducible changes in protein patterns. An acidic protein of approximately 40,000 Da was present in all samples from adult moths undergoing neuronal death and essentially absent from pharate adult samples.

Aging↗
PubMed1990

Individual variations in hippocampal dentate degeneration following adrenalectomy.

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.

Adrenal Glands↗
PubMed1990

Estradiol in the striatum: effects on behavior and dopamine receptors but no evidence for membrane steroid receptors.

Estradiol was applied directly to the striatum of ovariectomized female rats by a unilateral intracerebral cannula for three hr or four days. Following four days of estradiol treatment, rats increased the number of rotations in the direction away from the side of the hormone treatment. Cholesterol-treated animals did not change their rotational behavior. Dopamine receptors were assayed in the same animals by autoradiography; D2 receptors increased on the hormone-treated side relative to the untreated side after four days of treatment, only in the lateral striatum. D1 dopamine receptors did not change. The D2:D1 receptor ratio was related to the direction of rotation. Measurements of membrane fluidity with a fluorescent probe revealed no effect of estradiol on striatal membrane fluidity. Membrane proteins were labeled with estrogen agonist and antagonist affinity labels and analyzed by gel electrophoresis, but no saturable membrane binding sites were detected. The results indicate that estradiol acts directly in the striatum to affect behavior and dopamine receptors, but the neurochemical mechanisms remain to be determined.

Animals↗
PubMed1990

Modulation by norepinephrine of neural responses to estradiol.

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.

Adrenergic Antagonists↗
PubMed1989

Social stimuli augment estrogen receptor binding in preoptic area of female prairie voles.

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.

Animals↗
PubMed1989

Direct effects of ovarian hormones on antidepressant binding sites.

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.

Animals↗
PubMed1988

Retention of masculine sexual behavior following castration in male B6D2F1 mice.

The reduction of masculine sexual behavior following castration varies widely among genotypes. In contrast to the loss of sexual behavior by castrated males of other strains, males of the B6D2F1 genotype retain the ejaculatory reflex for many weeks after castration. The present study examined this retention phenomenon. Masculine sexual behaviors were measured before and after castration or sham operation in male C57BL/6J, DBA/2J, and B6D2F1 mice. Castrated C57BL/6J and DBA/2J males showed a rapid decline in copulatory behavior. In contrast, 30% of the B6D2F1 males continued to ejaculate 25 weeks after castration. Regardless of whether or not sexual behaviors were retained, levels of plasma testosterone and hypothalamic nuclear estrogen receptors were reduced by castration. These results suggest that the intra- and inter-strain differences in the retention of sexual behavior following castration are not due to differences in levels of steroid hormones. Further, some B6D2F1 males retain the ability to copulate in the absence of gonadal hormone levels required for the maintenance of sexual behavior in other genotypes.

Animals↗
PubMed1987

Endogenous aldosterone and corticosterone in brain cell nuclei of adrenal-intact rats: regional distribution and effects of physiological variations in serum steroids.

In vivo brain uptake of labeled aldosterone (ALD) and corticosterone (CORT) in adrenalectomized (ADX) rats indicates a strong cell-nuclear localization of both hormones, predominantly in the hippocampus. The primarily limbic concentration of these hormones is also supported by in vitro assays of ALD and CORT binding in cytosol from ADX rats. However, assays of binding in tissues from ADX rats often fail to account for the normal competition of assorted corticosteroids for binding sites in the adrenal-intact subject. Because the binding affinity of corticoid receptors for CORT is greater than, or equivalent to that for ALD, and plasma concentrations of CORT exceed ALD levels, it is possible that ALD is not actually concentrated by brain cell-nuclei in the normal, adrenal-intact subject. Moreover, description of the brain's in vivo regional uptake of ALD or CORT in ADX rats may reflect labeling of heterogeneous binding sites by the single corticosteroid ligand ([3H]ALD or [3H]CORT) under investigation. Research using subcellular fractionation and radioimmunoassay (RIA) has demonstrated the presence of endogenously secreted CORT in brain cell nuclei of adrenal-intact rats, and confirmed the principally limbic localization of endogenous CORT in the brain. In the present study, subcellular fractionation and RIA were employed to determine whether endogenously secreted ALD is concentrated by cell nuclei of the brain in adrenal-intact rats, and to assess the regional variation in the brain's cell-nuclear uptake of endogenously secreted ALD. Cell-nuclear CORT levels were also measured in this experiment to assess the possible competition between ALD and CORT for brain cell-nuclear uptake. Circadian rhythms, stress and dietary sodium were utilized in this study to induce physiological variations in serum ALD and CORT. Endogenous ALD was found in the nuclear fraction of all brain tissues tested, indicating that ALD is bound and translocated to brain cell nuclei in the presence of normal corticosteroid competition. However, brain cell-nuclear ALD appeared not to vary as a function of physiological variation in serum ALD, suggesting that the receptor population was saturated under most normal circumstances. Unexpectedly, the highest cell-nuclear concentrations of endogenous ALD were found in the hypothalamus, rather than hippocampus. This finding suggests that the predominantly hippocampal localization of ALD observed in previous in vivo autoradiographic studies may have provided an inaccurate profile of the loci of ALD action in brain by failing to control for competitive binding by other corticosteroids in the adrenal-intact preparation.

Adrenalectomy↗
PubMed1987

Effective intervals for the administration of estradiol pulses and the induction of sexual behavior in female rats.

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.

Animals↗
PubMed1987

Asymmetry in responsiveness of the hypothalamus of the female rat to estradiol.

Asymmetry of function is an increasingly general principle of neuroanatomy, and right-left asymmetry has been observed in some neuroendocrine functions. We report that the right side of the hypothalamus of female rats is more responsive to estradiol than the left side of the hypothalamus for the induction of sexual receptivity. These results are consistent with previous suggestions that the left side of the hypothalamus is more sensitive to the defemininizing actions of neonatal hormones.

Animals↗