Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats were trained to asymptotic performance in an 8-arm radial maze. They then received chronic intraventricular infusion of either artificial CSF or the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5- phosphonopentanoic acid (AP5), at a concentration (30 mM) that has been shown previously to prevent the induction of long-term potentiation in the dentate gyrus of the hippocampus in vivo. Subsequently the rats received another 9 trials in the maze in a quasi-random order, 3 uninterrupted trials, and another 6 trials each with mid-trial delays of 5, 20 or 60 min during which the animals were placed in their home cage. The mean number of errors for the AP5 rats did not differ significantly from that of the controls in the uninterrupted trials throughout the experiment, nor did it differ from that of the controls in any of the 3 delayed trials when these were first introduced. However, the control animals performed better at the longer delays when these were introduced for the second time, whilst there was no such improvement (but rather a deterioration) for the AP5 animals. The impairment of performance in the AP5 rats during the second block of delayed trials was significant, and independent of the length of the delay. These results show that NMDA receptor blockade does not impair working memory in the radial maze per se, but that it does prevent an improvement of working memory persistence with further training.
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PMID:Effects of intraventricular infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 on spatial memory of rats in a radial arm maze. 135 Apr 49

The behavioral consequences of the central administration of corticotropin releasing hormone (CRH) in rhesus monkeys was determined using food-maintained behavior. Acute doses of CRH (0.003 ng/kg-10 micrograms/kg, i.c.v.), decreased responding for food in a dose- and time-related manner. With intermediate doses, responding occurred at a high rate until food was delivered, and then abruptly ceased for several minutes. Previous studies have attributed similar effects to the noxious properties of certain drugs. Acute doses had no effect on home cage food consumption, body weight, or responding for food on subsequent days. When CRH was given repeatedly for several days, its behavioral suppressant effects increased. Home cage food intake, body weight, and subsequent responding for food decreased for up to 6 weeks before returning to normal. These results suggest that sustained elevations in central levels of CRH can result in a sensitization to its anorexigenic effects, an effect that has not been reported in other species. Because hyperaroused clinical states such as depression and anorexia nervosa are characterized biochemically by hypercortisolism and elevated CRH in CSF, these anorexigenic effects may corroborate a potential role for CRH in affective disorders.
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PMID:Corticotropin releasing hormone produces profound anorexigenic effects in the rhesus monkey. 204 89

Two groups of vervet monkeys were fed, on alternate days, either before or after a morning observation period. This enabled us to determine changes in behavior when the animals were fed a nutritionally balanced breakfast of monkey chow. Feeding did not alter the proportion of behaviors that were social or non-social, but had a marked effect on individual behaviors. Feeding increased active behaviors among the adult animals except for the vervets who were lowest in the social hierarchy in each cage. For some of the individual behaviors that were altered by feeding, the changes were most marked early on in the observation period, when the animals were still feeding. Other behavioral changes were seen only later in the observation period, a time course consistent with a food-mediated change in brain biochemistry. A parallel biochemical experiment showed that feeding decreased the levels of tryptophan and 5-hydroxyindoleacetic acid in the CSF. Our data indicate that feeding can influence both brain biochemistry and behavior. The behavioral changes may be influenced by social and psychological factors as well as changes in brain biochemistry.
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PMID:The effect of breakfast on social behavior and brain amine metabolism in vervet monkeys. 335 16

Studies on the influence of substances on the central nervous system and on the function of the blood-CSF-barrier made long-term cannulation of the CSF compartment interesting. This study was to test, whether a permanent CSF-drainage from any point of the subarachnoid space was possible with modified "tissue cages" (Guyton 1963). For that purpose a steel wire cage and a teflon cage were implanted subarachnoidally into beagle dogs. The two cages stopped draining on the second and on the third day respectively. Histological examination showed, that, because of the strong reaction of animal tissue to implanted material, direct cannulation of the CSF compartment does not seem feasible. In the second part the "Manuilov-system" was modified. An indwelling guiding tube was implanted and fixed with a horseshoe shaped plate to the occipital bone. Puncture can be made on the awake dog without local anaesthetic and produces samples of 1.5 to 2.0 ml CSF for up to 30 days without complications.
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PMID:Problems of long-term cannulation of cisterna magna and subarachnoid space in the conscious dog.--Technical note--. 714 4

Strain differences in temperament and physiology have been reported for several animal species, but nonhuman primates have not been well studied in this regard. We assessed behavioral and physiology in Chinese-Indian hybrid (n = 13) and Indian-origin (n = 29) nursery-reared rhesus monkey infants. Previous data indicate that Chinese-origin and Chinese-Indian hybrid rhesus exhibit more aggression directed toward humans and conspecifics and are more irritable in response to neonatal assessment procedures than are Indian-derived rhesus. In addition, in rhesus adults, low levels of cerebrospinal fluid 5-HIAA have been correlated with impulsivity, aggressive behavior, and diminished social competence. We therefore hypothesized that hybrid infants would exhibit more behavioral and adrenocortical reactivity in the home cage and during social separations, would be less sociable in their peer groups, and would exhibit lower CSF 5-HIAA levels than Indian-derived monkeys. Blood and cerebrospinal fluid samples were obtained on Days, 14, 30, 60, 90, 120, and 150 of life, and prior to and during social separations at 6 months of age. Behavioral observations were conducted in the home cage and during the separation condition. No differences in behavior were observed between hybrid and Indian-derived animals in the home cage. Indian-derived and hybrid infants exhibited diverging patterns of behavioral reactivity across the 4 weeks of the repetitive social-separation procedure, and during reunion periods. Although plasma cortisol levels were sensitive to the testing conditions, no group differences were observed. CSF 5-HIAA declined over time for all monkeys, and hybrid animals exhibited significantly lower 5-HIAA levels than Indian monkeys beginning at 6 months of age. These findings are consistent with the known behavioral and physiological characteristics of Chinese-origin adult rhesus.
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PMID:Behavioral and physiological characteristics of Indian and Chinese-Indian hybrid rhesus macaque infants. 922 16

Cancer cells genetically modified to secrete immunoregulatory cytokines offer great promise for human cancer treatment as tumor vaccines. However, in preclinical animal studies, large established cancer burdens have appeared difficult to eradicate with such vaccines. For example, lethally-irradiated GM-CSF-secreting CT26 colon carcinoma cell vaccine therapy tends to cure only animals bearing 1 x 10(5) wild-type CT26 cells or less. For many human cancers, antineoplastic chemotherapy can often significantly reduce systemic cancer burdens. Unfortunately, for most advanced metastatic solid organ cancers, such as cancers of the breast, colon, and prostate, antineoplastic drug treatments generally fail to effect cancer cures. Treatment regimens combining genetically-modified cancer cell vaccine therapy and antineoplastic chemotherapy have the potential to increase advanced cancer cure rates if antineoplastic drugs and drug combinations that do not inhibit vaccine-induced immune responses can be identified. To assess the potential immunomodulatory properties of commonly-used antineoplastic drugs that might be used in combination with cancer vaccine treatments, we studied the effects of the drugs on antitumor immune responses manifest by animals receiving lethally-irradiated GM-CSF-secreting CT26 cell vaccines. Immunomodulatory properties of the antineoplastic drugs were evaluated i) by monitoring drug effects on the generation of tumor-specific CD8+ cytotoxic T-lymphocytes (CTLs) in response to GM-CSF-secreting CT26 vaccine administration, ii) by determining drug effects on the resistance of vaccinated animals to subsequent challenge with lethal inoculac of CT26 cells, and iii) by evaluating combination drug and vaccine treatment efficacy against established CT26 tumors. Using this approach, doxorubicin was found to possess apparent immunostimulatory activities, depending on the dose and schedule of administration, while cyclophosphamide appeared immunosuppressive. The different immunomodulatory properties of doxorubicin and cyclophosphamide may be clinically relevant: combination doxorubicin and vaccine treatment of established CT26 cancers increased cure rates over that achieved with either agent alone, while combination cyclophosphamide and vaccine treatment of animals carrying CT26 tumors was no better in curing the animals than drug treatment alone.
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PMID:Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines. 945

We explored the potential therapeutic benefit of introducing GM-CSF, IFN-gamma or a combination of both factors into CT26 tumor cells. CT26 cells secreting either GM-CSF or IFN-gamma exhibited delayed tumorigenicity; however, cells expressing both GM-CSF and IFN-gamma did not form tumors. Even when wild type CT26 cells were introduced into a distant site of mice that had been inoculated with CT26/GM-CSF/IFN-gamma cells, no tumors were generated. Furthermore, when we injected GM-CSF + IFN-gamma cells into animals bearing established tumors, the tumors were either rejected or their development was delayed, suggesting that synergistic effects were induced against these tumors via a systemic immune response. Histopathological examination of the tumors injected with cells expressing GM-CSF and IFN-gamma combined showed necrosis and few signs of malignancy. The growth of tumors from mice treated with CT26/GM-CSF/IFN-gamma cells exhibited a delay in tumor formation and no effects were seen in athymic nude mice, which are deficient in T lymphocytes, or in splenectomized nude mice, which are deficient in natural killer (NK) cells, respectively. Our data indicate a dual role for T and NK cells in mediating the anti-tumor activity of this therapy. Our results suggest that transduction of tumor cells with both GM-CSF + IFN-gamma results in a powerful synergistic effect of the 2 cytokines that is of greater therapeutic benefit than transduction with either cytokine alone.
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PMID:Synergistic anti-tumor effects with co-expression of GM-CSF and IFN-gamma in murine tumors. 971 62

The specific aim of this study was to examine the prophylactic as well as the therapeutic efficacies of irradiated mouse CT26 colon cancer cells, infected with recombinant adenoviruses harboring cDNAs specific for granulocyte macrophage-colony-stimulating factor (GM-CSF), interferon (IFN-gamma) and monocyte chemotactic protein1 (MCP-1). Results showed that tumor cells secrete the respective cytokines for several days after infection and subsequent irradiation. Vaccination with irradiated GM-CSF-secreting CT26 cells protected 90% of syngeneic mice challenged with live parental cells. On the other hand, vaccination with irradiated IFNgamma or MCP-1-secreting CT26 cells totally failed to protect mice from tumor development after challenge with parental cells. None of the tumor-free mice initially vaccinated with irradiated GM-CSF-producing CT26 cells developed tumor upon repeated challenge with parental cells during the entire observation period. The establishment of specific and long-lasting antitumor immunity following vaccination with GM-CSF-producing tumor cells requires the simultaneous presence of GM-CSF and tumor antigen at the vaccine site. Depletion of CD8+ cells, but not CD4+ cells, blocked the vaccine efficacy of GM-CSF-producing tumor cells. Subcutaneous injection of irradiated GM-CSF-producing CT26 cells also effectively prevented the growth of a small load of parental tumor that was implanted 3 days earlier or the development of metastatic foci in the lung from intravenously injected parental cells either 7 days before or 3 days after vaccination. Our data thus show that, in these experimental tumor models, subcutaneous injection of irradiated tumor cells adenovirally, transduced with the GM-CSF gene leads not only to prevention of growth of subsequently implanted tumor but also to elimination of pre-existing and metastatic tumors.
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PMID:Irradiated tumor cells adenovirally engineered to secrete granulocyte/macrophage-colony-stimulating factor establish antitumor immunity and eliminate pre-existing tumors in syngeneic mice. 976 15

The characterization of tumor-associated antigens recognized by cellular or humoral effectors of the immune system has opened new perspectives for cancer therapy. Several categories of cancer-associated antigens have been described as targets for cytotoxic T lymphocytes (CTLs) in vitro and in vivo: "cancer-testis" (CT) antigens expressed in different tumors and normal testis, melanocyte differentiation antigens, point mutations of normal genes, antigens that are overexpressed in malignant tissues, and viral antigens. Clinical studies using peptides derived from these antigens have been initiated to induce specific CTL responses in vivo. Immunological and clinical parameters for the assessment of peptide-specific reactions have been defined, i.e., induction of delayed-type hypersensitivity (DTH), CTL, autoimmune, and tumor regression responses. Preliminary results demonstrate that tumor-associated peptides alone elicit specific DTH and CTL responses leading to tumor regression after intradermal injection. GM-CSF was proved to be effective in enhancing peptide-specific immune reactions by amplification of dermal peptide-presenting dendritic cells. Long-lasting complete tumor regressions have been observed after induction of CTLs by peptide immunization. However, in a few cases where there was disease progression after initial tumor response, loss of either the tumor antigen targeted by CTLs or of the presenting MHC class I molecule was detected as the mechanism of immune escape under immunization in vivo. Based on these observations, cytokines to enhance antigen and MHC class I expression in vivo are being evaluated to prevent immunoselection. Recently, a strategy utilizing spontaneous antibody responses to tumor-associated antigens (SEREX) has led to the identification of a new CT antigen, NY-ESO-1. In a melanoma patient with high titer antibody against NY-ESO-1, strong HLA-A2-restricted CTL reactivity against the same antigen was also found. Clinical studies involving tumor antigens that induce both antibody and CTL responses will show whether these are better candidates for immunotherapy of cancer.
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PMID:Strategies for the development of vaccines to treat breast cancer. 992 50

Anti-idiotype antibody, 11D10 mimics biologically and antigenically a distinct and specific epitope of the high molecular weight human milk fat globule (HMFG), a cancer-associated antigen present in over 90% of breast tumor samples. To augment the immunogenicity of 11D10 without the aid of a carrier protein or adjuvant, we made a chimeric 11D10-GM-CSF fusion protein for use as a vaccine. An expression plasmid for 11D10 was made by ligation of the DNA sequences of the 11D10 light-chain variable region upstream of the human kappa constant region. The heavy-chain plasmid carrying GM-CSF was made by ligation of the heavy-chain variable region sequences upstream of the human gamma1 constant region CH1 fused to the DNA fragment encoding the mature GM-CSF peptide 3' to the CH3 exon. NS1 plasmacytoma cells were transfected with the light and heavy-chain vectors by electroporation. Fusion protein secreted in the culture medium was purified and was characterized by gel electrophoresis as well as by determination of the biological activity of the fused GM-CSF. In nonreducing SDS-polyacrylamide gels, a single band approximately 200 Kd reacted with anti-human kappa, anti-human lambda1 and anti-GM-CSF antibodies. In reducing polyacrylamide gels, a approximately 74 kd protein reacted with anti-human lambda1 and anti-GM-CSF antibodies. The fusion protein induced proliferation of GM-CSF dependent NFS-60 cells. These results suggest that the protein is a chimeric anti-idiotype antibody consisting of 11D10 variable domains, human kappa and lambda1 constant domains and that the GM-CSF moiety fused to the constant region lambda1 is biologically active.
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PMID:Construction and characterization of a chimeric fusion protein consisting of an anti-idiotype antibody mimicking a breast cancer-associated antigen and the cytokine GM-CSF. 1038 19


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