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Biomedical subjects

J P McLaughlin

Publications and source records attributed to J P McLaughlin.

At least 19 recordsLinked to original sources
PubMed2001

Retrospective assessment of historic radon concentrations in Norwegian dwellings by measuring glass implanted Po-210--an international field intercomparison.

The first Norwegian study of historic radon concentrations in 17 dwellings in the high radon areas in Norway has been conducted as part of an international field intercomparison during 1998. The retrospective radon concentration is estimated via measurements of Po-210, the long-lived decay product of Rn-222 implanted in glass surfaces of objects like pictures, mirrors, cabinet-glass, etc. the method called 'surface trap'. Three different surface trap techniques to assess the implanted Po-210 activity and two different procedures to estimate retro radon from Po-210 data were used. The Po-210 and the retrospectively estimated radon results agree reasonably well over a wide range of concentrations. Historic radon concentrations were also estimated from analysis of a smaller number of 'volume trap' samples (pieces of spongy materials), and the results compared to those from 'surface traps'. The retro radon results correlate with contemporary radon results with a correlation coefficient of 0.877. To evaluate uncertainty in Po-210 measurements due to varying position on the glass a study of spatial homogeneity of three sample glasses was conducted and variations between 12% and 18% were found.

Air Pollution, Indoor↗
PubMed2001

Correlation of 210Po implanted in glass with radon gas exposure: sensitivity analysis of critical parameters using a Monte-Carlo approach.

In recent years, 210Po implanted in glass artefacts has been used as an indicator of the mean radon gas concentration in dwellings in the past. Glass artefacts have been selected in many dwellings and the alpha-recoil implanted 210Po concentration has been measured using various techniques. Some of these retrospective techniques use a model to estimate the retrospective radon gas on the basis of this surface 210Po activity. The accumulation of 210Po on glass surfaces is determined by the deposition regime over the exposure period. The 210Po activity is determined not only by the radon progeny deposition velocities, but by other room parameters such as ventilation rate, aerosol conditions and the surface to volume ratio of the room. Up to now in using room models, a nominal or 'base-case' scenario is used, i.e. a single value is chosen for each input parameter. In this paper a Monte-Carlo analysis is presented in which a probability distribution for each parameter is chosen, based on measurements quoted in the literature. A 210Po surface activity is calculated using a single value drawn from each of the parameter distributions using a pseudo-random number generator. This process is repeated n times (up to 20,000), producing n independent scenarios with corresponding 210Po values. This process permits a sensitivity analysis to be carried out to see the effect of changes in inputs on the model output.

Aerosols↗
PubMed2001

Integrated natural radiation exposure studies in stable Yugoslav rural communities.

The results of field investigations of natural radiation exposures of the general population in two stable rural communities in Yugoslavia are presented. The principal emphasis was on exposures to contemporary indoor radon, but measurements of external penetrating radiation absorbed dose rates in air were carried out in the majority of cases. In addition, in a limited number of dwellings, measurements of thoron gas concentrations were made. By means of making a series of sequential 3-month radon measurements, both seasonal variations and annual average radon levels in the dwellings were determined. Using passive alpha track detectors, individual radon and thoron indoor concentrations as high as 9591 Bq m(-3) and 709 Bq m(-3), respectively, were detected while absorbed dose rates in air in the dwellings as high as 430 nGy h(-1) were recorded. On the basis of these different types of measurements, assessments could be made of the integrated natural radiation exposures being received by the populations. In addition to contemporary radon measurements, retrospective radon exposure assessments in most of the dwellings were made on the basis of measurements of 210Po concentrations in both surface (glass) traps and in volume (porous materials) traps. A description is given of the sampling strategies and protocols used in this field work. It is shown that at least one stable rural community receiving high natural radiation exposures, has been clearly identified and plans for future health investigations of the population there are outlined.

Air Pollutants, Radioactive↗
PubMed2001

Field experience with volume traps for assessing retrospective radon exposures.

Approximately 200 volume traps were retrieved from dwellings in various radon prone areas in Europe. They were analysed for the purpose of retrospective radon assessment. Emphasis is put on specific problems encountered when using field samples as opposed to laboratory exposed samples. It was seen that in very dusty circumstances, direct penetration of radon decay products from the outside to the centre of the volume traps calls for extra caution. Rinsing the samples is proposed as a solution and was tested in field and laboratory conditions, showing good results. An attempt was made to give an assessment of the achievable accuracy of the method. Where possible, the volume trap retrospective results were compared with contemporary measurements or to retrospective results from surface traps. The overall impression is that although volume traps are sometimes hard to find in the field, the high reliability of the results makes it well worth the effort.

Air Pollutants, Radioactive↗
PubMed2001

Tyrosine phosphorylation of the mu-opioid receptor regulates agonist intrinsic efficacy.

The mu-opioid receptor (MOR) contains four highly conserved cytoplasmic tyrosine residues that may serve to regulate receptor activity. For Xenopus laevis oocytes coexpressing the rat MOR and the heteromultimeric potassium channel, K(IR)3.1/3.2, pretreatment with insulin produced both a 40% suppression in the basal channel conductance and potentiation of response to the mu-opioid agonist [D-Ala(2),methyl-Phe(4),Gly(5)-ol]enkephalin (DAMGO) to 155% of matched, untreated control cells. Insulin-induced potentiation of the DAMGO response was concentration-dependent and reversed after 1 h. Insulin pretreatment increased the maximal effect of DAMGO, but did not change its EC(50) value. Potentiation of the DAMGO response did not result from a recruitment of MOR to the cell surface, as measured by specific binding of the opioid peptide antagonist [(3)H]d-Phe((3)H)-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH(2) (cyclic) to whole-oocytes, but instead the potentiation was probably caused by an increase in intrinsic efficacy of G protein coupling. The involvement of tyrosine residues on the putative intracellular loops of the MOR was demonstrated with four point-mutated receptors, replacing tyrosine with phenylalanine to create MOR(Y96F), MOR(Y106F), MOR(Y166F), and MOR(Y336F). None of these mutations significantly altered the EC(50) value for DAMGO compared with wild-type MOR, and insulin pretreatment still potentiated the effect of 1 microM DAMGO in oocytes containing either MOR(Y96F) or MOR(Y336F) to 137 +/- 10 and 124 +/- 8%, respectively. However, insulin did not significantly potentiate the DAMGO response with oocytes containing either MOR(Y106F) or MOR(Y166F), suggesting that these two sites were responsible for the insulin-induced opioid potentiation. The tyrosine-kinase inhibitors genistein (100 microM) or K-252a (20 microM) did not block the insulin-induced potentiation of the DAMGO response, but coincubation of insulin with either the MAP kinase inhibitor PD98,059 (20 microM) or phosphatase inhibitor orthovanadate (30 microM) completely blocked the potentiation. The results suggest the hypothesis that the potentiation was caused by dephosphorylation of the two tyrosines in MOR. To test this hypothesis, we measured the recovery rates after insulin treatment. As predicted, tyrosine kinase inhibition by K-252a significantly slowed the reversal and phosphatase inhibition by orthovanadate significantly accelerated the recovery. These findings support a rapid modulatory role for insulin on opioid signal transduction, possibly through the dephosphorylation of the MOR at tyrosines 106 and 166 by an insulin-activated MAP kinase/protein tyrosine phosphatase cascade. We conclude that tyrosine phosphorylation of the mu-opioid receptor regulates receptor-G protein coupling efficacy.

Animals↗
PubMed2000

Tyrosine phosphorylation of the kappa -opioid receptor regulates agonist efficacy.

To explore the role of highly conserved tyrosine residues in the putative cytoplasmic domains of the seven-transmembrane G protein-coupled opioid receptors, we expressed the rat kappa-opioid receptor (KOR) in Xenopus oocytes and then activated the intrinsic insulin receptor tyrosine kinase. KOR activation by the agonist produced a strong increase in potassium current through coexpressed G protein-gated inwardly rectifying potassium channels (K(IR)3). Brief pretreatment with insulin caused a 60% potentiation of the KOR-activated response. The insulin-induced increase in kappa-opioid response was blocked by the tyrosine kinase inhibitor genistein. In contrast, insulin had no effect on the basal activity of K(IR)3, suggesting that KOR is the target of the tyrosine kinase cascade. Mutation of tyrosine residues to phenylalanines in either the first or second intracellular loop of KOR to produce KOR(Y87F) and KOR(Y157F) had no effect on either the potency or maximal effect of. However, neither KOR(Y87F)- nor KOR(Y157F)-mediated responses were potentiated by insulin treatment. Insulin pretreatment shifted the dose-response curve for activation of KOR by increasing the maximal response without changing the EC(50) value for. These results suggest that insulin increases the efficacy of KOR activation by phosphorylating two tyrosine residues in the first and second intracellular loops of the receptor. Thus, tyrosine phosphorylation may provide an important mechanism for modulation of G protein-coupled receptor signaling.

Amino Acid Sequence↗
PubMed2000

Partial opioids. Medications for the treatment of pain and drug abuse.

Pentazocine and cyclazocine are two benzomorphans that were synthesized by the late Sydney Archer in 1962. These benzomorphans were synthesized as part of an effort to develop analgesics with little or no abuse potential. Pentazocine is used as an analgesic, often in individuals who have sever pain or in those who have drug-abuse problems. Cyclazocine is a low-liability analgesic and potential therapeutic for the treatment of drug abuse. The risk of drug dependence is lower with the benzomorphans, which usually act as partial agonists at the mu opioid receptor and as kappa agonists. In an attempt to synthesize analogs of cyclazocine with increased bioavailability and varying kappa agonist and partial mu agonist properties, a series of 8-amino derivatives of cyclazocine were synthesized. These compounds were characterized in radioligand binding assays for their affinity and selectivity for the mu, delta, and kappa opioid receptors. Mouse antinociceptive tests were used to characterize the agonist and antagonist properties of each compound at the mu, delta and kappa receptors.

Analgesics↗
PubMed1999

Genetic alteration of phospholipase C beta3 expression modulates behavioral and cellular responses to mu opioids.

Morphine and other micro opioids regulate a number of intracellular signaling pathways, including the one mediated by phospholipase C (PLC). By studying PLC beta3-deficient mice, we have established a strong link between PLC and mu opioid-mediated responses at both the behavioral and cellular levels. Mice lacking PLC beta3, when compared with the wild type, exhibited up to a 10-fold decrease in the ED(50) value for morphine in producing antinociception. The reduced ED(50) value was unlikely a result of changes in opioid receptor number or affinity because no differences were found in whole-brain B(max) and K(d) values for mu, kappa, and delta opioid receptors between wild-type and PLC beta3-null mice. We also found that opioid regulation of voltage-sensitive Ca(2+) channels in primary sensory neurons (dorsal root ganglion) was different between the two genotypes. Consistent with the behavioral findings, the specific mu agonist [D-Ala(2),(Me)Phe(4),Gly(ol)(5)]enkephalin (DAMGO) induced a greater whole-cell current reduction in a greater proportion of neurons isolated from the PLC beta3-null mice than from the wild type. In addition, reconstitution of recombinant PLC protein back into PLC beta3-deficient dorsal root ganglion neurons reduced DAMGO responses to those of wild-type neurons. In neurons of both genotypes, activation of protein kinase C with phorbol esters markedly reduced DAMGO-mediated Ca(2+) current reduction. These data demonstrate that PLC beta3 constitutes a significant pathway involved in negative modulation of mu opioid responses, perhaps via protein kinase C, and suggests the possibility that differences in opioid sensitivity among individuals could be, in part, because of genetic factors.

Animals↗
PubMed1999

Nitrocinnamoyl and chlorocinnamoyl derivatives of dihydrocodeinone: in vivo and in vitro characterization of mu-selective agonist and antagonist activity.

Two 14beta-p-nitrocinnamoyl derivatives of dihydrocodeinone, 14beta-(p-nitrocinnamoylamino)-7,8-dihydrocodeinone (CACO) and N-cyclopropylmethylnor-14beta-(p-nitrocinnamoylamino)- 7, 8-dihydrocodeinone (N-CPM-CACO), and the corresponding chlorocinnamoylamino analogs, 14beta-(p-chlorocinnamoylamino)-7, 8-dihydrocodeinone (CAM) and N-cyclopropylmethylnor-14beta-(p-chlorocinnamoylamino) -7, 8-dihydrocodeinone (MC-CAM), were tested in opioid receptor binding assays and the mouse tail-flick test to characterize the opioid affinity, selectivity, and antinociceptive properties of these compounds. In competition binding assays, all four compounds bound to the mu opioid receptor with high affinity. When bovine striatal membranes were incubated with any of the four dihydrocodeinones, binding to the mu receptor was inhibited in a concentration-dependent, wash-resistant manner. Saturation binding experiments demonstrated that the wash-resistant inhibition of mu binding was due to a decrease in the Bmax value for the binding of the mu-selective peptide [3H][D-Ala2, MePhe4,Gly(ol)5] enkephalin and not a change in the Kd value, suggesting an irreversible interaction of the compounds with the mu receptor. In the mouse 55 degrees C warm water tail-flick test, both CACO and N-CPM-CACO acted as short-term mu-selective agonists when administered by i. c.v. injection, whereas CAM and MC-CAM produced no measurable antinociception at doses up to 30 nmol. Pretreatment of mice for 24 h with any of the four dihydrocodeinone derivatives produced a dose-dependent antagonism of antinociception mediated by the mu but not the delta or kappa receptors. Long-term antagonism of morphine-induced antinociception lasted for at least 48 h after i.c. v. administration. Finally, shifts in the morphine dose-response lines after 24-h pretreatment with the four dihydrocodeinone compounds suggest that the nitrocinnamoylamino derivatives may produce a greater magnitude long-term antagonism of morphine-induced antinociception than the chlorocinnamoylamino analogs.

Analgesics, Opioid↗
PubMed1997

14 beta-Chlorocinnamoylamino derivatives of metopon: long-term mu-opioid receptor antagonists.

The affinity, selectivity and antinociceptive properties of 5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7,8-dihydromorphinone (MET-Cl-CAMO) and N-cyclopropyl-methyl-5 beta-methyl-14 beta-(p-chlorocinnamoylamino)-7, 8-dihydronormorphinone (N-CPM-MET-Cl-CAMO) for the multiple opioid receptors were characterized. In competition binding assays using bovine striatal membranes, both compounds inhibited the binding of 0.25 nM [3H][D-Ala2, (Me)-Phe4,Gly(ol)5]enkephalin (DAMGO) with IC 50 values of less than 2 nM. Preincubation of membranes with MET-CI-CAMO and N-CPM-MET-Cl-CAMO produced a concentration-dependent, wash-resistant inhibition of mu-opioid receptor binding. Saturation binding experiments with N-CPM-MET-Cl-CAMO showed a reduction in the number of mu-opioid binding sites without a change in affinity. In the mouse 55 degrees C warm-water tail-flick assay, neither MET-Cl-CAMO nor N-CPM-MET-Cl-CAMO at doses up to 100 nmol produced antinociception after intracerebroventricular administration, but morphine-induced antinociception was antagonized in a time- and dose-dependent manner by both compounds. The antagonism produced by 1 nmol of either MET-Cl-CAMO or N-CPM-MET-Cl-CAMO reached a maximal effect after 24 h, and lasted up to 48 h. Analgesia mediated by delta- or kappa-opioids was not altered by either compound. In summary, the data suggest that MET-Cl-CAMO and N-CPM-MET-Cl-CAMO are long-term, mu-opioid receptor antagonists, devoid of agonist properties in the mouse tail-flick assay, and that N-CPM-MET-Cl-CAMO may produce its antagonistic effects by binding irreversibly to the mu-opioid receptor.

Analgesics↗
PubMed1997

Therapeutic antitumor response after immunization with an admixture of recombinant vaccinia viruses expressing a modified MUC1 gene and the murine T-cell costimulatory molecule B7.

Tumor-associated antigens have considerable promise not only as diagnostic or prognostic markers but also as targets for active or passive immunotherapy. DF3/MUC1 is a tumor-associated antigen that is overexpressed with an abnormal glycosylation pattern in breast, ovarian, lung, and pancreatic cancers. The major extracellular portion of MUC1 is composed of tandem repeat units of 20 amino acids. Recombinant vaccinia viruses encoding mucin molecules have been constructed by several groups. However, these recombinants have met with limited success in protecting animals from MUC1-expressing tumors because of the vaccinia genome being subject to high-frequency homologous recombination, therefore being unstable in expression of the tandem repeats. In light of these studies, two concurrent strategies were used to improve immune responses to MUC1: a recombinant vaccinia virus was constructed containing a modified "mini" MUC1 gene containing only 10 tandem repeat sequences to minimize vaccinia-mediated rearrangement (designated rV-MUC1); and an admixture was used containing rV-MUC1 and a recombinant vaccinia virus containing the gene for the murine T-cell costimulatory molecule B7-1 (rV-B7). The rV-MUC1 gene product maintained a consistent molecular weight throughout several passages, indicating stability of the inserted gene. Mice inoculated with rV-MUC1 demonstrated MUC1-specific cytolytic responses that were further enhanced by admixture with rV-B7. In a MUC1-expressing pulmonary metastases prevention model, mice inoculated two times with rV-MUC1 were protected from the establishment of metastases. No additive effect on antitumor immunity (> 90% with rV-MUC1 alone) was observed in mice primed with an admixture of rV-MUC1 and rV-B7 and boosted with rV-MUC1. When rV-MUC1 was used to treat established MUC1 positive metastases, however, three administrations of rV-MUC1 were not sufficient to confer antitumor effects. In contrast, when tumor-bearing mice were primed with an admixture of rV-MUC1 and rV-B7, followed by two boosts with rV-MUC1, there was a significant reduction in pulmonary metastases (p = < 0.0001), which correlated to 100% survival. Coexpression of the B7 molecule, although not necessary for the induction of an immune response of sufficient magnitude to prevent MUC1 tumors, was thus essential in a treatment setting.

Animals↗
PubMed1997

Adoptive immunotherapy as an in vivo model to explore antitumor mechanisms induced by a recombinant anticancer vaccine.

We have described previously the construction, generation, and in vivo biologic consequences of a recombinant vaccinia virus containing the human CEA gene (rV-CEA) in an experimental murine colon carcinoma model. Immunization of C57BL/6 mice with rV-CEA led to antigen-specific inhibition of tumor growth in both prophylactic and therapeutic settings. Although such antitumor effects were correlated with the induction of CEA-specific T-cell responses, their exact contribution in the tumor rejection mechanism remained unclear. In this study, we examined the mechanism of action of rV-CEA, with emphasis on definition of the immune cells important for such antitumor effects. To that end, a cellular adoptive transfer model was established in vivo, which allowed specific functional analysis of donor-derived immune cells in naive, sublethally irradiated, tumor-bearing recipients. Splenocytes from rV-CEA-immunized donors expressed strong antitumor activity in such tumor-bearing recipients, whereas nonimmune donor cells did not. Depletion of immune T cells before cellular transfer abolished the antitumor response. Moreover, depletion of CD8+ T cells before transfer resulted in the loss of antitumor activity, despite the presence of CD4+ T cells. In contrast, antitumor activity was demonstrable with CD8-containing, CD4-depleted effectors, although it was not as effective as with both T-cell subpopulations combined. Finally, in beta 2-microglobulin/CD8+ T-cell-deficient mice, rV-CEA immunization exerted only partial antitumor protection, compared with the immune-competent controls. Overall, we demonstrated that (a) antitumor activity induced by rV-CEA was essentially mediated by CD8+ effectors; and (b) the combination of both CD8+ and CD4+ lymphocytes led to maximal antitumor therapeutic effects, suggesting an important helper or immunoregulatory contribution of the CD4+ subset. Thus, adoptive cellular transfer strategies may have implications for both the study of recombinant anticancer vaccines and the development of potential clinical applications for cancer immunotherapy.

Adenocarcinoma↗
PubMed1997

Immunization with a syngeneic tumor infected with recombinant vaccinia virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) induces tumor regression and long-lasting systemic immunity.

A recombinant vaccinia virus encoding the gene for granulocyte-macrophage colony-stimulating factor (rV-GM-CSF) was used to infect the poorly immunogenic murine colon adenocarcinoma cell line, MC-38. Infection of MC-38 tumor cells with rV-GM-CSF completely suppressed the growth of the MC-38 primary tumors, whereas progressively growing tumors were formed in mice injected with MC-38 cells infected with wild type V-Wyeth. Irradiation of the recipient B6 mice before implantation of rV-GM-CSF-infected tumor cells resulted in the development of progressively growing tumors. Moreover, in vivo T-cell depletion studies revealed that growth suppression of the rV-GM-CSF-infected tumor cells was dependent on the presence of both CD4+ and CD8+ T-cell subsets. Subsequent studies established that this immunity was long-lasting and antigen specific, as demonstrated by the protection of rV-GM-CSF-immunized mice from MC-38 tumor challenge but not from challenge with another syngeneic tumor cell type. No such effects were observed when MC-38 tumor cells were infected with recombinant vaccinia viruses expressing interleukin (IL)-2 or IL-6. The results demonstrate that paracrine release of biologically active murine GM-CSF by tumor cells infected with rV-GM-CSF enhances the intrinsic immunogenicity of a poorly immunogenic murine tumor. Presumably the augmentation of tumor immunogenicity induces an antigen-specific T-cell-dependent antitumor response that prevents the formation of primary tumors and protects mice from tumor challenge. Thus in this experimental model, GM-CSF functions as a highly effective vaccine adjuvant.

Adenocarcinoma↗
PubMed1996

Improved immunotherapy of a recombinant carcinoembryonic antigen vaccinia vaccine when given in combination with interleukin-2.

Interleukin-2 (IL-2) has been an effective immune modulator in several active-specific immunotherapy experimental protocols using either viral or oncolysate-based vaccines. In this report, data indicate that IL-2 administration can appreciably augment the therapeutic effect of a single immunization of a recombinant vaccinia virus-carcinoembryonic antigen (rV-CEA) vaccine using a CEA-expressing syngeneic experimental murine model system. A single rV-CEA immunization of C57BL/6 mice bearing palpable CEA-positive colon adenocarcinoma tumors results in complete tumor regression in approximately 20% of the mice. The addition of a course of low-dose IL-2 results in complete tumor regression in 60-70% of the mice. Moreover, the combination of rV-CEA and IL-2 induces systemic immunity, which protects those tumor-free mice from subsequent rechallenge with the CEA-expressing tumor cells. No such tumor regression or protection was observed in those mice immunized with the wild-type vaccinia vaccine (V-Wyeth) alone or with IL-2 administration alone. Cellular immune assays revealed that the addition of IL-2 to rV-CEA immunization significantly increased the CEA-specific T-cell proliferative responses as well as the cytolytic T-cell responses when compared with rV-CEA immunization alone. The enhanced CEA-specific immune response, coupled with the improved experimental therapeutic outcome following IL-2 administration, suggests that treatment with that cytokine may effectively substitute for multiple rV-CEA immunizations in active-specific immunotherapy clinical protocols directed at CEA-expressing tumors.

Adjuvants, Immunologic↗
PubMed1995

Metopon and two unique derivatives: affinity and selectivity for the multiple opioid receptors.

5 beta-Methyl-7,8-dihydromorphinone (metopon), an isomer [6aS-(6a alpha,9a alpha, 10 beta)13aS]-1,10-methano-4-hydroxy-11-methyl- 6,6a,8,9,10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]isoquinoline- 7-(9aH)-one (compound 1) derived from a photochemical rearrangement of 5 beta-methylmorphinone, and [6aS-(6a alpha,9a alpha,10 beta)13aS]-1,10-methano-4-hydroxy-11-methyl- 6,6a,8,9, 10,11,12,13-octahydro-[1]-benzopyrano[4,3,e]-14 beta- (p-nitrocinnamoylamino) isoquinoline-7-(9aH)-one (compound 2) were characterized for opioid receptor affinity, selectivity and analgesic properties. In competition binding assays using bovine striatal membranes, the three compounds inhibited the binding of 0.25 nM [3H][D-Ala2,(Me)-Phe4,Gly(ol)5]enkephalin (DAMGO), a mu-selective peptide, with IC50 values less than 5 nM. All three compounds exhibited lower affinity for delta- and kappa-opioid receptors. In the mouse 55 degrees C warm-water tail-flick assay, both metopon and compound 1 displayed antinociception that lasted for 60 min after i.c.v. injection. Morphine sulfate, metopon and compound 1 produced 50% antinociception with i.c.v. doses of 0.83, 2.0 and 4.0 nmol, respectively. The mu-selective, irreversible opioid receptor antagonist beta-funaltrexamine blocked antinociception induced by metopon and compound 1, while delta- and kappa-opioid receptor selective antagonists did not effect antinociception. These findings demonstrate metopon and its isomer bound with high affinity to the mu-opioid receptor and produced antinociception through this receptor.

Analgesics, Opioid↗
PubMed1995

Admixture of a recombinant vaccinia virus containing the gene for the costimulatory molecule B7 and a recombinant vaccinia virus containing a tumor-associated antigen gene results in enhanced specific T-cell responses and antitumor immunity.

At least two signals are required for the activation of naive T cells by antigen-bearing target cells: an antigen-specific signal, delivered through the T-cell receptor, and a costimulatory signal delivered through the T-cell surface molecule CD28 by its natural ligand B7-1. The immunological benefit of coexpression of B7 with target antigen has been demonstrated with the use of several retroviral systems to transfect antigen-bearing cells. Although engineering recombinant constructs with genes for two or more antigens can mediate the dual expression of those antigens, disadvantages of this approach include the time for construction of each desirable combination and the inability to control differential expression levels of each gene product. An alternative approach would utilize separate constructs that could be admixed appropriately before administration. In this report we describe the functional consequences of the admixture of recombinant vaccinia murine B7-1 (rV-B7) to recombinant vaccinia expressing the human carcinoembryonic antigen gene (rV-CEA). Coinfection of cells resulted in high levels of cell surface expression of both the CEA and B7 molecules. Immunization of mice with various ratios (1:3, 1:1, 3:1) of rV-CEA and rV-B7 demonstrated that an admixture of rV-CEA and rV-B7 at a 3:1 ratio resulted in the generation of optimal CEA-specific T-cell responses. Next, we examined the efficacy of this admixture on antitumor activity. Typically, injection of murine carcinoma cells expressing CEA leads to the death of the host. One immunization of C57BL/6 mice with rV-CEA:rV-B7 (3:1) resulted in no tumor establishment. In contrast, administration of rV-CEA or rV-B7 alone had little or no antitumor effects. These studies demonstrate the advantages of the use of recombinant vaccinia viruses to deliver B7 molecules in combination with a tumor-associated antigen. The availability of the rV-B7 single construct and the ability to alter the B7 ratio could also have potential utility when coinfecting rV-B7 with recombinant vaccinia viruses containing genes for infectious agents or other tumor-associated antigen genes.

Animals↗
PubMed1992

The roles of handedness and stimulus asymmetry in aesthetic preference.

When some pictures are mirror reversed, aesthetic evaluations of them change dramatically. Stimulus features that may be important in contributing to this effect are: (a) location of areas of principal interest or weight in the picture space, (b) cues that suggest a direction of motion within the picture. Dextrals and inverted sinistrals preferred paintings with cues suggesting motion proceeding from left to right over their mirror-reversed versions and also preferred those with weight concentrated in the left portions of the picture space. The explanation that best fits these data is that preference is promoted when the picture content encourages attention to its rightmost portions, thus placing a majority of the picture in the left visual field where it is directly processed by the right hemisphere.

Adult↗