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Biomedical subjects

J G Wilson

Publications and source records attributed to J G Wilson.

At least 37 records · Page 2Linked to original sources
PubMed1996

Xenogeneic ICAM-1 gene transfer suppresses tumorigenicity and generates protective antitumor immunity.

Tumorigenicity in Fischer rats was not significantly reduced when the rat ICAM-1 gene was overexpressed in the rat tumor cell lines, JM-1 and SST-2. When these rat tumor cell lines were genetically modified with a gene encoding human ICAM-1, tumorigenicity was dramatically reduced. Expression of xenogeneic ICAM-1 did not alter the growth rate, expression of the major histocompatibility complex, nor morphological appearance of the cells. However, it did facilitate a tumor-specific immunological recognition and rejection of the genetically modified tumor cells. This effect resulted in a tumor-specific, long-term protective immunity directed against genetically unmodified tumor cells. Most importantly, administration of tumor cells genetically modified with genes encoding xenogeneic ICAM-1 can facilitate an immunological response to genetically unaltered pre-existing tumors. Transferring splenocytes from animals 'vaccinated' with the xenogeneic ICAM-1 gene altered tumor cells was able to transfer the antitumor response into recipient animals. Furthermore, transfer of CD8+ T lymphocytes produced the same result. These results suggested that tumors specific CD8+ T lymphocytes were activated by the xenogeneic altered tumor cells. THis activation generated the long-term, tumor-specific immunity.

Animals↗
PubMed1995

2-Amino-6-methoxypurine arabinoside: an agent for T-cell malignancies.

Earlier studies have shown guanine arabinoside (ara-G) is an effective agent against growth of T-cell lines and freshly isolated human T-leukemic cells. However, poor water solubility of ara-G limits clinical use. 2-Amino-6-methoxypurine arabinoside (506U) is a water-soluble prodrug converted to ara-G by adenosine deaminase. 506U is not a substrate for deoxycytidine kinase, adenosine kinase, or purine nucleoside phosphorylase and is phosphorylated by mitochondrial deoxyguanosine kinase at a rate 4% that of ara-G phosphorylation. Mitochondrial DNA polymerase was the least sensitive to ara-GTP inhibition of the five human DNA polymerases tested. [3H]506U was anabolized to ara-G 5'-phosphates in CEM cells but not to phosphorylated metabolites of 506U. 506U was selective for transformed T over B cells and also inhibited growth in two of three monocytic lines tested. 506U given i.v. to cynomolgus monkeys was rapidly converted to ara-G; the ara-G had a half-life of approximately 2 h. 506U had in vivo dose-dependent efficacy against human T-cell tumors in immunodeficient mice. A Phase 1 trial of 506U against refractory hematological malignancies is now in progress at two study sites.

Animals↗
PubMed1995

Targets of nitric oxide in a mouse model of liver inflammation by Corynebacterium parvum.

Treatment of mice with Corynebacterium parvum induces chronic inflammation. This treatment followed by an injection of lipopolysaccharide (LPS) produces hepatic necrosis and death. We examined liver tissue by using electron paramagnetic resonance (EPR) spectroscopy and found that, in addition to the previously reported nonheme nitrosyl complexes, heme nitrosyl complexes were also formed. Hemoglobin nitrosyl complexes measured in the whole blood of mice treated with C. parvum were not increased after additional LPS treatment. However, this treatment significantly increased the heme nitrosyl complexes in the liver, whereas the nonheme nitrosyl complex concentration was unaffected. EPR signals from whole blood and liver tissues from mice treated with C. parvum and C. parvum + LPS were inhibited by prolonged treatment with NG-monomethyl-L-arginine (L-NMA). Nitric oxide (.NO) is known to bind to cytochrome P450 heme, and we consistently found a suppression of EPR signals attributable to ferric low-spin cytochrome P450/P420 peaks in the livers of mice treated with C. parvum and C. parvum + LPS. By performing analyses of EPR spectra obtained from hepatocytes exposed to .NO, we were able to unambiguously identify EPR signals attributable to cytochrome P420 and nonheme nitrosyl complexes in the livers of both treatments. Deconvolution of the composite in vivo EPR spectra indicated that hemoglobin nitrosyl complexes contributed weakly in the C. parvum livers, but threefold more in the C. parvum + LPS livers, suggesting that hemorrhage may have occurred. Experiments with L-NMA treatment revealed that this additional .NO production did not correlate with hepatic necrosis and onset of death. Immunoprecipitation of liver cytosols from C. parvum- and (C. parvum + LPS)-treated mice using an antibody against mouse inducible nitric oxide synthase showed that this enzyme was indeed present in the cytosolic fractions and was absent in those from control livers. Our novel detection of cytochrome P420 nitrosyl complex in vivo may be linked to any role of hepatic P450's functions during liver inflammation.

Animals↗
PubMed1994

Microenvironmental factors involved in the establishment of erythropoiesis in bone marrow.

Human erythropoiesis is focused near the venous sinuses of the bone marrow in EBI that are comprised of erythroblasts in intimate contact with supportive CM. The surface molecules and secreted products of fibroblastic reticular cells support the adhesion of erythroblasts and CM, and sequester growth factors near their surfaces. Cohesiveness within the EBI decreases as its associated erythroid cells mature, and the erythroblasts cease to express certain cytoadhesive molecules. Finally, the erythroblasts enucleate and separate from the EBI. Transiently motile reticulocytes enter the circulation through intracellular pores of venous sinus endothelial cells, and their nuclear remnants are ingested by CM or perisinal macrophages.

Animals↗
PubMed1993

A novel 37-Kd adhesive membrane protein from cloned murine bone marrow stromal cells and cloned murine hematopoietic progenitor cells.

The adhesion of hematopoietic progenitor cells to bone marrow stromal cells is critical to hematopoiesis and involves multiple effector molecules. Stromal cell molecules that participate in this interaction were sought by analyzing the detergent-soluble membrane proteins of GBI/6 stromal cells that could be adsorbed by intact FDCP-1 progenitor cells. A single-chain protein from GBI/6 cells having an apparent molecular weight of 37 Kd was selectively adsorbed by FDCP-1 cells. This protein, designated p37, could be surface-radiolabeled and thus appeared to be exposed on the cell membrane. An apparently identical 37-Kd protein was expressed by three stromal cell lines, by Swiss 3T3 fibroblastic cells, and by FDCP-1 and FDCP-2 progenitor cells. p37 was selectively adsorbed from membrane lysates by a variety of murine hematopoietic cells, including erythrocytes, but not by human erythrocytes. Binding of p37 to cells was calcium-dependent, and was not affected by inhibitors of the hematopoietic homing receptor or the cell-binding or heparin-binding functions of fibronectin. It is proposed that p37 may be a novel adhesive molecule expressed on the surface of a variety of hematopoietic cells that could participate in both homotypic and heterotypic interactions of stromal and progenitor cells.

Adsorption↗
PubMed1992

Physiological modeling of disposition of potential tumor-imaging radiopharmaceuticals in tumor-bearing mice.

Radiopharmaceuticals have great potential in the early detection of human tumors. Three potential 99mTc-labeled platinum compounds based on cisplatin have been synthesized and tested in tumored mice. This report presents the analysis of the disposition data obtained after a single intravenous injection with an empirical, physiologically based pharmacokinetic model. The radioactivity of each radiopharmaceutical after administration was measured in blood, urine, and 15 tissues, including tumor. Parameters included in the model were tissue volumes (experimentally determined), tissue blood flows (determined from literature values), tissue:blood extraction ratios (determined by nonlinear least-squares regression with MULTI-FORTE), and clearance terms (also determined by nonlinear least-squares regression). Data were weighted by the reciprocal of the square of the observed values. Good fits to the experimental data were obtained. As expected, the compound producing the best tumor:blood profile (3) also had the highest tumor extraction ratio (6.2 versus 2.0 and 1.3 for 1 and 2, respectively). Total body clearance values for the radioactivity associated with the three compounds 1-3 were calculated to be 0.09, 0.04, and 0.016 mL/min, respectively. Analysis of data with such an empirical, physiologically based model may assist future development of suitable tumor-imaging agents.

Animals↗
PubMed1992

Potentiation by thiopurines and sulfhydryl-reactive agents of the inhibition by 3-deazaadenosine of mononuclear phagocytes.

Combination effects of 3-deazaadenosine (c3Ado) on antibody-dependent phagocytosis in mouse resident peritoneal cells and human peripheral blood monocytes precultured with cytotoxic thiols, azathioprine (AZA) or 6-mercaptopurine (6-MP), and thiol-reactive agents, 2-cyclohexene-1-one (2-CH) or ethacrynic acid (ETA), are described. In the mouse cell preparations, a non-inhibitory concentration of 10 microM AZA or 6-MP potentiated the inhibition by 5 and 10 microM c3Ado of phagocytosis. Higher concentrations of AZA or 6-MP (50, 100 microM) and c3Ado (40, 50 microM) were needed to achieve similar effects in human monocytes. Both 2-CH (50 microM) and ETA (25 microM) inhibited mouse cell phagocytosis and acted synergistically with c3Ado. Precultivation of mouse cells with an inhibitor of glutathione synthesis, buthionine sulfoximine (BSO, 50 microM) caused no inhibition of phagocytosis and no potentiation of the inhibition by c3Ado, although BSO potentiated the inhibition by 2-CH (50 microM). In human monocytes, non-inhibitory concentrations (10 and 25 microM) of gold sodium thiomalate (GST), AZA, and c3Ado, but not 6-MP, potentiated the inhibition by 2-CH (25-37.5 microM) of phagocytosis. Results are discussed in connection with the possible modulation by endogenous sulfhydryl-reactive metabolites of phospholipid turnover of the effects of c3Ado.

Animals↗
PubMed1990

Genotoxicity and cell cycle effects of platinum-based imaging agents in cisplatin-resistant human tumour cells.

A series of cis-dichloroplatinum(II) 2,3-diaminopropionamide complexes synthesised as potential imaging agents was tested for activity against a human ovarian tumour cell line (CI-80-13S) with high natural resistance to cisplatin and carboplatin as compared with other human cells. The most potent compound, the dimethyl ester of dichloro-[4-(methyleneiminodiacetic acid)phenyl (2',3'-diamino-propionamide)]platinum(II) (complex III), exhibited toxicity towards CI-80-13S cells similar to that observed in other cell lines, an effect that was not shown by the ligand alone or by cis-dichloroplatinum(II) 2,3-diaminopropionamide. However, complex III ester reproduced the genotoxic effects of cisplatin as judged by differential inactivation of two strains of adenovirus and by inhibition of cellular DNA and RNA synthesis; no major differences in these properties were observed between CI-80-13S and cisplatin-sensitive cells. Substantial inhibition of DNA and RNA synthesis was found within 2 h of treatment, much earlier than the effect of cisplatin. Complex III ester, which was 30- to 100-fold less potent than cisplatin, inhibited cell cycle progression in a similar way to equitoxic cisplatin, with cells accumulating in G2 at a dose of low toxicity and being arrested in all stages at higher levels. The latter in combination with colcemid caused extensive fragmentation of CI-80-13S cells. These results suggest that the mechanism of toxicity of such complexes involves factors, in addition to DNA damage, which rapidly inhibit nucleic acid synthesis and overcome natural resistance to cisplatin in the CI-80-13S cell line.

Adenoviridae↗
PubMed1990

Biological evaluation of 99mTc labelled cis-platinum containing benzyliminodiacetic acids as potential tumour imaging agents.

The synthesis of three new potential tumour-imaging radiopharmaceuticals in which a cis-platin derivative is attached to benzyl iminodiacetic acid, a ligand capable of forming a stable complex with 99mTc, has previously been reported by us [Awaluddin et al. Appl. Radiat. Isot. 38, 671-674 (1987)]. We have now carried out extensive biodistribution studies on these compounds as well as on two fragments of their structures which do not contain platinum. The results suggest that the presence of platinum is not essential for the tumour-localizing properties of the radiopharmaceuticals.

Animals↗
PubMed1989

Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele.

Structural and quantitative polymorphisms have been described in human CR1. In the former, the S allotype is larger than the F allotype by 40-50 kD, the size of a long homologous repeat (LHR). In the latter, homozygotes for a 7.4-kb Hind III fragment express fourfold more CR1 per erythrocyte than do homozygotes for the allelic 6.9-kb restriction fragment. The basis for these genomic polymorphisms has been determined by restriction mapping the entire S allele and part of the F allele. The S allele is 158 kb and contains 5 LHRs of 20-30 kb, designated -A, -B/A, -B, -C, and -D, respectively, 5' to 3'. Extensive homology was found among the LHRs in their restriction maps, exon organization, and the coding and noncoding sequences. The presence of LHR-B/A in the S allele but not in the F allele accounts for the longer transcripts and polypeptide associated with the former allotype. At least 42 exons are present in the S allele, with distinct exons for the leader sequence, the transmembrane and cytoplasmic regions and most of the SCRs comprising the extracellular portion of CR1. Consistent with the mapping of the ligand binding site to the first two SCRs in each LHR, the second SCRs in LHR-A, -B/A, -B, and -C are encoded by two exons, reflecting a specialized function for this unit. The allelic 7.4/6.9-kb Hind III fragments extend from the 3' region of LHR-C to LHR-D. The 6.9-kb restriction fragment is the result of a new Hind III site generated by a single base change in the intron between the exons encoding the second SCR of LHR-D. A second cluster of genomic clones has been identified by hybridization to CR1 probes. Although they contain regions of hybridization to the cDNA and genomic probes derived from CR1, these cannot be overlapped with the structural gene owing to their distinct restriction maps. Three genomic polymorphisms previously identified by CR1 cDNA probes map to this region. These additional clones may represent part of a duplicated allele located nearby within the CR1 locus.

Alleles↗
PubMed1988

Structure-distribution studies on some 99mTc-o-hydroxybenzyliminodiacetic acid complexes.

Biodistributions of a series of thirteen 99mTc-o-hydroxy-benzyliminodiacetic acid complexes were carried out in rats and their hepatobiliary and urinary outputs correlated with lipophilicity, molecular weight, influence of substituent and plasma protein binding. Hepatobiliary output was moderate for those ligands with large alkyl substituents [t-butyl (36%), and iso-octyl (42%)] but compared to HIDA compounds was relatively low, indicating that they would not be suitable for clinical use. Halogen substituents had only a small effect on increasing hepatobiliary output but a large effect on reducing the urinary clearance.

Animals↗
PubMed1987

Deficiency of the C3b/C4b receptor (CR1) of erythrocytes in systemic lupus erythematosus: analysis of the stability of the defect and of a restriction fragment length polymorphism of the CR1 gene.

The role of genetic factors in controlling CR1 quantitative expression on erythrocytes (E) of patients with systemic lupus erythematosus (SLE) was reexamined by determining the temporal stability of CR1 numbers and the frequency of a CR1 genomic restriction fragment length polymorphism (RFLP). The mean number of binding sites/(E) for Yz-1 monoclonal anti-CR1 correlated with the number of sites for polyclonal anti-CR1 that had been determined 2 to 4 yr previously in 18 normal persons (p less than 0.001), 18 patients (p less than 0.001), and 28 relatives (p less than 0.001), indicating that CR1 sites/E was a stable characteristic in all three groups. The mean number of Yz-1 sites/E was 281 +/- 34 (+/- SEM) in 28 probands with SLE and 457 +/- 21 in 93 relatives, both determinations being less than that for 100 normal persons, 553 +/- 21 (p less than 0.002). Thirty-six patients and 51 normal individuals were also assessed for the presence of the 7.4 kb and 6.9 kb HindIII CR1 allelic restriction fragments that correlate with high and low expression, respectively, of CR1 on E. The distribution of patients differed from normal (p less than 0.05), with a smaller proportion being homozygous for the 7.4 kb allele. In addition, the mean numbers of Yz-1 sites/E for patients and relatives who were homozygous (p less than 0.02) and heterozygous (p less than 0.05) for the 7.4 kb allele were significantly lower than those for normal persons matched for the HindIII RFLP, suggesting the existence of additional heritable factors that decrease CR1 expression. The stability over time of the CR1 deficiency among patients, the finding of decreased CR1 number among an expanded group of relatives, the altered frequency among patients of CR1 alleles defined by the HindIII RFLP, and the decreased expression of CR1 on E among patients and relatives compared with normal individuals having the same HindIII RFLP indicate a role for genetic factors in CR1 deficiency in SLE.

Alleles↗
PubMed1987

Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristics of C3/C4 binding proteins.

10 overlapping CR1 cDNA clones that span 5.5 kb were isolated from a tonsillar library and sequenced in whole or in part. A single long open reading frame beginning at the 5' end of the clones and extending 4.7 kb downstream to a stop codon was identified. This sequence represents approximately 80% of the estimated 6 kb of coding sequence for the F allotype of CR1. Three tandem, direct, long homologous repeats (LHRs) of 450 amino acids were identified. Analysis of the sequences of tryptic peptides provided evidence for a fourth LHR in the F allotype of CR1. Amino acid identity between the LHRs ranged from 70% between the first and third repeats to 99% between the NH2-terminal 250 amino acids of the first and second repeats. Each LHR comprises seven short consensus repeats (SCRs) of 60-70 amino acids that resemble the SCRs of other C3/C4 binding proteins, such as complement receptor type 2, factors B and H, C4 binding protein, and C2. Two additional SCRs join the LHRs to a single membrane-spanning domain of 25 amino acids; thus, the F allotype of CR1 probably contains at least 30 SCRs, 23 of which have been sequenced. Each SCR is predicted to form a triple loop structure in which the four conserved half-cystines form disulfide linkages. The linear alignment of 30 SCRs as a semi-rigid structure would extend 1,140A from the plasma membrane and might facilitate the interaction of CR1 with C3b and C4b located within the interstices of immune complexes and microbial cell walls. The COOH-terminal cytoplasmic domain of 43 residues contains a six-amino-acid sequence that is homologous to the sequence in the epidermal growth factor receptor that is phosphorylated by protein kinase C.

Amino Acid Sequence↗
PubMed1987

Human diseases associated with C3 receptor deficiencies.

Genetic deficiencies of complement receptors have recently been described. CR1 expression is reduced on erythrocytes, leucocytes and podocytes of many patients with systemic lupus erythematosus because of both genetic and acquired mechanisms. CR1 deficiency is also found in AIDS and AIDS-related syndromes and correlates with clinical subpopulations of HIV-infected patients. The pathogenic significance of CR1 deficiency relates to the functions of CR1 in clearance of immune complexes, phagocytosis and immune regulation. CR3 deficiency occurs as an autosomal recessive inherited disease characterized by the lack of or severe reduction in expression of the leucocyte antigens CR3, LFA1, p150,95 and their common chain. The disease is associated with severe defects in neutrophil and lymphocyte functions and recurrent bacterial infections. The in vivo effects of C3 receptor deficiencies emphasize the critical role of these membrane molecules in immunity.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Peptic erosion of gastric mucus in the rat.

1. The effect of pepsin on the loss of mucus glycoprotein from the gastric epithelial mucus layer was studied in the rat. 2. Pepsin was instilled into the gastric lumen, and luminal contents were subsequently assayed. 3. Glycoprotein loss increased with luminal pepsin, up to a concentration of 1 mg pepsin/ml. 4. Luminal glycoprotein had a molecular size distribution intermediate between subunit, and native mucus glycoprotein of the epithelial mucus layer. 5. Incubation of gastric epithelial scrapings with pepsin demonstrated that insoluble, native mucus glycoprotein was rapidly degraded to soluble glycoprotein of similar molecular size distribution to that found in vivo in the lumen.

Animals↗