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Biomedical subjects

M Roy

Publications and source records attributed to M Roy.

At least 19 recordsLinked to original sources
PubMed1995

Reaction of peripheral-blood lymphocytes to the human chorionic gonadotropin beta sub-unit in patients with productive tumors.

Human chorionic gonadotropin (hCG) and its beta sub-unit (hCG beta) are secreted by trophoblast cells during pregnancy, and by tumoral cells of trophoblastic and non-trophoblastic origin. In contrast to hCG, the free hCG beta sub-unit is consistently undetectable in healthy non-pregnant subjects. With this in mind, we sought to determine whether an immune response to hCG beta can be detected in patients with bladder or germ-cell testis cancers. Peripheral-blood mononuclear cells (PBMC) from 31% of patients with hCG beta-productive bladder cancers and 33% of testis-tumor-bearing patients displayed an hCG beta-specific proliferative response, whereas no patients with non-hCG beta-productive cancers had a proliferative response. PBMC from pregnant women and healthy controls did not elicit significant reactivity. By the use of overlapping synthetic peptides, the immunogenic regions of hCG beta were delineated within the central 20-65 portion. Moreover, in 2 bladder-cancer patients with the HLA DR7, DQ2 haplotype, the T-cell response to hCG beta was focused on the hCG beta (20-47) peptide. Taken together, these results indicate that hCG beta is a tumor-associated antigen capable of inducing a cell-mediated immune response in patients with productive tumors.

Aged↗
PubMed1995

Studies on the interdependence of gp39 and B7 expression and function during antigen-specific immune responses.

Interactions between T and B cells are dynamic and regulated by interacting receptor: co-receptors. Interactions between CD40 and its ligand, gp39, and the CD28/CTLA-4 and B7 family members play a decisive role in regulating the progression of cognate interactions. The interdependence of gp39-CD40 and CD28/CTLA-B7 expression and function was studied in vitro during an antigen-induced immune response using T cells from mice expressing a transgenic T cell receptor (TCR). gp39 was induced on pigeon cytochrome c (PCC)-transgenic T cells in the presence of antigen and antigen-presenting cells. The antigen-induced expression of gp39 on transgenic T cells was inhibited by antibodies to class II major histocompatibility complex, CD4 and LFA-1, but not by CTLA-4 Ig, anti-B7-1 or anti-B7-2. These data established that the antigen-induced expression of gp39 was not dependent on co-stimulation via CD28/CTLA-4. The addition of PCC also resulted in the modest expression of B7-1 and a more robust expression of B7-2 on the cognate B cells. The addition of anti-gp39 blocked the up-regulated expression of B7-1 and partially blocked the up-regulated expression of B7-2. The addition of anti-gp39 and anti-interleukin-4 inhibited antigen-induced expression of B7-2 on B cells to near background levels. Studies on the up-regulation of B7-1 and B7-2 on resting B cells showed that soluble gp39 up-regulated B7-1 and B7-2 expression on B cells. In addition, interleukin-4 and interferon-gamma up-regulated B7-2 expression on B cells. Taken together, these data demonstrate that the antigen-induced expression of gp39 is dependent on TCR-derived signals, yet independent of CD28/CTLA-4 co-stimulatory signals. Cognate interactions also resulted in the modest enhancement of B7-1 expression and a more profound expression of B7-2 which were completely or partially dependent on gp39-CD40 interactions.

Abatacept↗
PubMed1995

Primary proliferative T cell response to wild-type p53 protein in patients with breast cancer.

Mutations in the p53 tumor suppressor gene are the most frequent genetic alterations found in human tumors. There are mainly point mutations that lead to single amino acid substitutions. The mutated proteins have a longer half-life than wild-type p53 and accumulate in the nucleus of tumor cells. Anti-p53 antibodies have been found in sera of patients with several types of cancers including breast cancer. This report describes a T cell immune response in three patients with breast tumors who had mutated p53 gene and accumulated p53 protein. All showed a humoral response to p53 protein and the T cells of these patients recognized the wild-type p53 protein and proliferated in response to it. The data reported here are relevant to the immune processes leading to autoimmunity and have a bearing on anti-p53 vaccine development in tumor immunology.

Antibodies↗
PubMed1995

Evidence for a cholesterol-lowering gene in a French-Canadian kindred with familial hypercholesterolemia.

We describe a four-generation kindred with familial hypercholesterolemia (FH) in which two of the eight heterozygotes for a 5-kb deletion (exons 2 and 3) in the low density lipoprotein (LDL) receptor gene were found to have normal LDL-cholesterol levels. In our search for a gene responsible for the cholesterol-lowering effect in this family, we have studied variation in the genes encoding the LDL receptor, apolipoprotein (apo) B, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, apoAI-CIII-AIV, and lipoprotein lipase. The analysis showed that it was unlikely that variation in any of these genes was responsible for the cholesterol-lowering effect. Expression of the LDL receptor, as assessed in vitro with measurements of activity and mRNA levels, was similar in normo and hyperlipidemic subjects carrying the deletion. Analysis of the apo E isoforms revealed that most of the e2 allele carriers in this family, including the two normolipidemic 5-kb deletion carriers, were found to have LDL-cholesterol levels substantially lower than subjects with the other apo E isoforms. Thus, this kindred provides evidence for the existence of a gene or genes, including the apo e2 allele, with profound effects on LDL-cholesterol levels.

Cholesterol↗
PubMed1995

New methods for rapid detection of low-density lipoprotein receptor and apolipoprotein B gene mutations causing familial hypercholesterolemia.

Due to a genetic founder effect, five mutations in the low-density lipoprotein receptor gene account for approximately 83% of familial hypercholesterolemia (FH) diagnosed in French-Canadians. The most frequent mutation, present in 61% of heterozygotes, is a > 10 kb deletion of the 5' region of the gene that removes the promoter and the first exon, resulting in a null allele. Other less prevalent mutations include a gene deletion of approximately 5 kb, which removes exons 2 and 3 (2% of cases) and three missense mutations: Trp66-->Gly (exon 3) (12%), Glu207-->Lys (exon 4) (3%), and Cys646-->Tyr (exon 14) (6%). The apoB Arg3500-->Gln mutation was absent in 228 French Canadians with the FH phenotype. Taking advantage of the availability of fluorescent DNA detection, we have substantially improved the assays for these mutations.

Adult↗
PubMed1995

Impact of a common mutation of the LDL receptor gene, in French-Canadian patients with familial hypercholesterolemia, on means, variances and correlations among traits of lipid metabolism.

Structural and functional studies of the gene coding for the low density lipoprotein receptor in patients with familial hypercholesterolemia have uncovered over 180 mutant alleles of the gene. Although the classical familial hypercholesterolemia phenotype is well known, the range of phenotypic variability in lipid traits associated with particular mutations in familial hypercholesterolemia has not been extensively documented. We investigated the phenotypic distributions of plasma markers of lipid metabolism from a large sample of unrelated individuals who are heterozygous for a single mutation, a > 10 kb deletion in the low density lipoprotein receptor gene, and compared these distributions with those from a sample of healthy controls. Patients were pair-matched for sex and age with healthy individuals selected from a previously studied French-Canadian population from the same region. We examined the level and variation of seven lipid traits, the correlations between the traits, and the amount of overlap of the sample distributions for each trait. The low density lipoprotein receptor defect was found to affect the levels and variability of traits, and correlations between traits. There was some overlap of the distributions of lipid traits including that for low density lipoprotein cholesterol, which is a cardinal feature of familial hypercholesterolemia. The low density lipoprotein receptor gene has a sex-specific pleiotropic effect and should be considered as a variability gene as well as a level gene. The extensive dynamic changes observed in the relationships between lipid traits testify to the biological complexity of genome type-environment interactions.

Adult↗
PubMed1995

Supplementation with selenium restores age-related decline in immune cell function.

This study examined the effect of dietary (2.00 ppm for 8 weeks) supplementation with selenium (as sodium selenite) on the ability of lymphocytes from aged (24-month-old), male, C57BL/6JNIA mice to respond to: (i) stimulation with mitogen (phytohemagglutinin) or alloantigen; (ii) develop into cytotoxic effector cells; and (iii) destroy tumor cells. Supplementation with selenium resulted in a significant increase in the ability of spleen lymphocytes from aged animals to undergo blastogenesis, as indicated by significantly higher amounts of nuclear incorporation of 3H-thymidine after stimulation with mitogen. The dietary regimen restored the age-related deficiency of the cells to respond to stimulation by nuclear DNA synthesis and cell proliferation, at least, to the level of cells from unsupplemented young adult animals. Furthermore, populations of in vivo, alloantigen-activated lymphocytes from Se-supplemented aged animals contained significantly higher numbers of cytotoxic lymphocytes than those from Se-normal aged animals, which resulted in an enhanced capacity to destroy tumor cells. The significant increase in the number of cytotoxic effector cells within these activated T-lymphocyte populations was probably the result of an enhanced clonal proliferation of cytotoxic precursors cells, followed by the differentiation of greater numbers of cytotoxic effector cells. This effect occurred in the absence of changes in the ability of the cells to produce IL-2, which confirmed our earlier observation that dietary supplementation with selenium does not affect the production of IL-2. The data suggested that selenium restores the age-related defect in cell proliferation through an increase in the number of high-affinity IL-2 receptors.

Aging↗
PubMed1994

Hydromorphone patient-controlled analgesia (PCA) after coronary artery bypass surgery.

We conducted a study to compare the effectiveness of patient-controlled analgesia (PCA) technique to conventional analgesic therapy (CAT) after coronary artery bypass graft (CABG). The PCA group received hydromorphone 0.1 mg.hr-1 basal infusion and bolus doses of 0.2 mg Q 5 min (maximum 1.2 mg.hr-1) while the CAT group received morphine 2.5 mg iv Q 30 min prn until extubation followed by prn meperidine 1 mg.kg-1 im Q 4 hr or acetaminophen 325 mg with codeine 30 mg po (1 or 2 tablets) when oral intake was possible. The degree of pain was assessed using a Visual Analogue Scale (VAS) starting after extubation and every 6-8 hr for the next 60 hr. Holter monitoring was initiated one hour after patient arrival in the Intensive Care Unit (ICU) and continued for 72 hr. Other measured variables were pulmonary function, sedation, side effects and total opioid requirements. Results show that the day-to-day VAS pain score decreased in the PCA group (P < 0.001) while it remained unchanged in CAT patients. The PCA patients had lower VAS pain scores at extubation (P < 0.05). During the third postoperative day, the PCA group had a lower VAS pain score, a lower incidence of severe pain defined as a score > 5 on the VAS scale, and a reduced incidence of myocardial ischaemia (P < 0.01). However, there was no difference in the duration, severity, area under the curve (AUC), or heart rate during ischaemic events. Postoperative pulmonary function was abnormal in both groups (NS) with minimal recovery by the fourth day.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1993

Some serum enzymes in burns and their probable correlation with surgical shock--a prospective combined surgicobiochemical study.

Serum enzymes such as phosphohexoisomerase, aldolase and amylase were estimated in serum of 100 patients with thermal burn of different degrees. These enzymes were estimated at the time of admission, at 12th hour, 24th hour, 36th hour, 72nd hour, 7th day and 14th day. The patients with high serum levels of these enzymes till 72nd hour showed grave prognosis and serial measurements of these enzymes might help in predicting the outcome.

Adolescent↗
PubMed1992

C-type natriuretic peptide in bovine chromaffin cells. The regulation of its biosynthesis and secretion.

We report here the regulation of the biosynthesis and the secretion of C-type natriuretic peptide (CNP) in cultured bovine chromaffin cells. The combined treatment with protein kinase A and -C activators induced a 6-fold increase of intracellular levels of CNP-(1-103). The biosynthesized CNP-(1-103) was co-released with its mature forms, typically CNP-(51-103), upon stimulation by nicotine or depolarizing agents. This confirms the neuropeptidic character of this third member of the natriuretic peptide family, which might act as a neuromodulator or neurotransmitter.

Adrenal Medulla↗
PubMed1992

A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells.

CD40 is a B-cell surface molecule that has been shown to induce B-cell growth upon ligation with monoclonal antibodies. This report shows that triggering via CD40 is essential for the activation of resting B cells by helper T cells (Th). A soluble fusion protein of CD40 and human immunoglobulin, CD40-Ig, inhibited the induction of B-cell cycle entry, proliferation, and differentiation by activated Th1 and Th2. The ligand for CD40 was identified as a 39-kDa membrane protein that was selectively expressed on activated Th. A monoclonal antibody specific for the 39-kDa protein inhibited CD40-Ig binding and also inhibited the activation of B cells by Th. These data indicate that the 39-kDa membrane protein expressed on activated Th is a binding protein for CD40 and functions to transduce the signal for Th-dependent B-cell activation.

Animals↗
PubMed1992

Secondary structure and topology of interleukin-1 receptor antagonist protein determined by heteronuclear three-dimensional NMR spectroscopy.

Interleukin-1 (IL-1) proteins, such as IL-1 beta, play a key role in immune and inflammatory responses. Interaction of these cytokines with the IL-1 receptor induces a variety of biological changes in neurologic, metabolic, hematologic, and endocrinologic systems. Interleukin-1 receptor antagonist protein (IRAP) is a naturally occurring inhibitor of the interleukin-1 receptor. The 153-residue protein binds to the receptor with an affinity similar to that of IL-1 beta but does not elicit any physiological responses. As a first step toward understanding IRAP's mode of action, we have used multidimensional, heteronuclear NMR spectroscopy to determine the antagonist's solution secondary structure and global fold. Using a combination of 3D 1H-15N NOESY-HMQC and TOCSY-HMQC and 3D 1H-15N-13C HNCA and HN(CO)CA experiments on uniformly 15N- or doubly 13C/15N-enriched IRAP, we have made resonance assignments for more than 90% of the main-chain atoms. Analysis of short- and long-range NOE's indicates that IRAP is predominantly beta-sheet, with the same overall topology as IL-1 beta but with different regions of the primary sequence comprising the beta-strands. Two short helical segments also were identified. The 14% sequence identity between IL-1 beta and IRAP increases to 25% when differences in the locations of secondary structure elements in the primary sequences are taken into account. Still, numerous differences in side chains, which ultimately play a major role in receptor interaction, exist.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Studies of the association and conformational properties of metal-free insulin in alkaline sodium chloride solutions by one- and two-dimensional 1H NMR.

One- and two-dimensional 1H NMR spectroscopy have been employed to probe the association and subsequent conformational changes of metal-free insulin in sodium chloride solution at pH 9 and 9.4. These studies establish that the proton resonances of His(B5) and His(B10) are useful signatures of aggregation and conformation. Changes in chemical shifts and areas of resonances due to the C2 protons of His(B10) and His(B5) and transfer of magnetization experiments served to identify the association as the assembly of tetramer from dimers under our experimental conditions (pH 9.4, [insulin] greater than 1 mM, [NaCl] = 0.1 M). Sodium chloride also alters the equilibrium distribution of species in favor of a tetrameric species. The association equilibrium constant was estimated from area measurements to be approximately 5 x 10(3) M-1 at pH 9.4, 26 +/- 0.1 degrees C, and 0.1 M sodium chloride. Under conditions of 0.1 M sodium chloride concentration, nuclear Overhauser effect experiments in the one- and two-dimensional modes revealed an operative nuclear Overhauser effect between the His(B5) C2 protons and the 2,6 ring protons of a Tyr residue provisionally assigned as Tyr(B16). We conclude that this interaction is a diagnostic signature of a conformational transition whereupon an extended chain from residues B1 to B9 (T-state) is transformed into an alpha-helix (R-state) thus bringing the rings of His(B5) and Tyr(B16) from adjacent subunits across the monomer-monomer interface into van der Waals contact. This conformational flexibility is an added consideration to the discussion of the relevant structure of insulin for receptor binding.

Animals↗
PubMed1992

Dissection of a pollen-specific promoter from maize by transient transformation assays.

We have previously reported the isolation and characterization of a gene (Zm13) from Zea mays which shows a pollen-specific pattern of expression. Stably transformed tobacco plants containing a reporter gene linked to portions of the Zm13 5' flanking region show correct temporal and spatial expression of the gene. Here we present a more detailed analysis of the 5' regions responsible for expression in pollen by utilizing a transient expression system. Constructs containing the beta-glucuronidase (GUS) gene under the control of various sized fragments of the Zm 13 5' flanking region were introduced into Tradescantia and Zea mays pollen via high-velocity microprojectile bombardment, and monitored both visually and with a fluorescence assay. The results suggest that sequences necessary for expression in pollen are present in a region from -100 to -54, while other sequences which amplify that expression reside between -260 and -100. The replacement of the normal terminator with a portion of the Zm13 3' region containing the putative polyadenylation signal and site also increased GUS expression. While the -260 to -100 region contains sequences similar to other protein-binding domains reported for plants, the -100 to -54 region appears to contain no significant homology to other known promoter fragments which direct pollen-specific expression. The microprojectile bombardment of Tradescantia pollen appears to be a good test system for assaying maize and possibly other monocot promoter constructs for pollen expression.

Gene Expression↗
PubMed1992

Phenotypic heterogeneity associated with defective apolipoprotein B-100 and occurrence of the familial hypercholesterolemia phenotype in the absence of an LDL-receptor defect within a Canadian kindred.

Of 163 individuals with a diagnosis of heterozygous familial hypercholesterolemia (FH), only one subject was found to be positive for familial defective apo B-100 (FDB). The eight-member kindred ascertained through this subject who presented with both a clinical phenotype of FH and the FDB apo B-100 (Arg3500----Gln) mutation was studied. Plasma lipid and lipoprotein profiles, apo E phenotypes, apo B gene markers at the 3' hypervariable region and LDL-receptor haplotypes (ApaLI, PvuII, NcoI), were determined, together with LDL-receptor activity on freshly isolated blood lymphocytes. The FDB mutation, present in four relatives, was associated with three different phenotypes: FH and severe hypercholesterolemia, moderate hypercholesterolemia and normolipidemia. The FH phenotype occurred in the absence of any functional LDL-receptor defect. In homozygotes for the absence of the PvuII cutting site who had the apo B mutation, LDL-cholesterol levels were low in the presence of the apo E3/2 phenotype and high in the presence of the apo E4/4 phenotype. None of the major known environmental influences accounted for the wide range of variation in LDL-cholesterol among the affected members. Further observations in the spouse and offspring of the normolipidemic FDB subject confirmed the association of apo E4, the FDB mutation and the PvuII(-/-) genotype with high cholesterol levels. It is concluded that the phenotypic expression of the FDB mutation may vary widely as a function of the genetic environment within a family.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗