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Biomedical subjects

B R Williams

Publications and source records attributed to B R Williams.

At least 181 records · Page 10Linked to original sources
PubMed1985

Growth inhibitory effect of gene-cloned interferons on human myeloblast colonies.

The effect on marrow myeloblast colony formation in blood from nine patients with acute myeloid leukemia was studied by using three recombinant-DNA-derived human leukocyte interferons (IFN alpha 2, IFN alpha-A, and IFN alpha-C). In preliminary experiments, a brief exposure of leukemic marrow cells to IFN alpha resulted in a sharp increase in the IFN-induced enzyme 2-5A synthetase, indicating the expression of IFN cell receptors as well as the ability of leukemia cells to respond metabolically. Dose-response studies showed a dose-dependent suppression of myeloblast colony formation in all experiments using concentrations of 10(2)-10(5) U/ml of the three IFN subtypes. In self-renewal assays derived from the primary cultures that initially contained IFN alpha 2, a "carryover" antiproliferative effect was observed with a dose-dependent decline in secondary growth. In comparison studies of IFN alpha-A and IFN alpha-C, the suppressive effect on primary myeloblast growth was much more pronounced with IFN alpha-C at concentrations of 10(3) U/ml and higher; in self-renewal assays, the antiproliferative effect of IFN alpha-C on secondary growth was no longer observed, whereas that of IFN alpha-A persisted. These three subtypes of gene-cloned IFN have antileukemic properties in vitro, with differences in degree of suppression of primary myeloblast growth and of self-renewal.

2',5'-Oligoadenylate Synthetase↗
PubMed1984

Characterization and regulation of alpha-interferon receptor expression in interferon-sensitive and -resistant human lymphoblastoid cells.

Interferon-sensitive (IFN-S) and IFN-resistant (IFN-R) Daudi lymphoblastoid cells were studied for IFN-alpha receptor expression and regulation by steady state and kinetic procedures, utilizing a homogeneous 125I-IFN-alpha 2 probe. Heterogeneity in the binding of this probe to IFN-S cells was determined to result from negatively cooperative interactions between an initially homogeneous class of IFN receptor. No such heterogeneity was noted in the IFN-R cells, indicating an apparent difference in the interaction of IFN-alpha 2 with these cells. The apparent dissociation constants (Kd) for IFN-S cell receptors were calculated to be 1 X 10(-10) M and 1 X 10(-8) M, for the high and low affinity sites, respectively. The Kd for sites on the IFN-R cells was estimated to be 4 X 10(-9) M. IFN-R and IFN-S cells expressed 2.4 X 10(4) and 3.5 X 10(4) binding sites per cell, respectively, representing an increase of at least 6-fold over previous reports of IFN-S Daudi IFN receptor density. Both IFN-S and IFN-R cells were capable of down-regulating expression of the IFN-alpha receptor in response to low concentrations of IFN-alpha 2. Furthermore, both cell lines were shown to be capable of internalizing specifically bound 125I-IFN-alpha 2 to an equivalent degree. Accordingly, we propose that the relative insensitivity of the Daudi IFN-R phenotype involves the loss of a high affinity interaction between cellular receptors and IFN-alpha 2, in addition to the reduced level of expressed low affinity binding sites.

Drug Resistance↗
PubMed1984

Modulation of human interferon-alpha receptor expression by human interferon-gamma.

The human neuroblastoma cell line T98G is sensitive to the antiproliferative activity of both alpha- and gamma-interferons (IFNs). Specific binding of a homogeneous 125I-IFN-alpha 2 probe to high-affinity membrane receptors (apparent Kd = 6.2 X 10(-10) M) can be decreased by pretreatment of these cells with human IFN-gamma (HuIFN-gamma, derived by recombinant DNA techniques). The regulation of HuIFN-alpha 2 binding by such pretreatment is reflected by subsequent inhibition of both the antiviral and antiproliferative activities of HuIFN-alpha 2 on T98G cells. Thus, binding of HuIFN-gamma to its distinct cell-surface receptor can modify expression of the separate IFN-alpha receptor, presumably through an indirect effect on the apparent Kd of the IFN-alpha 2 receptor-ligand interaction.

Burkitt Lymphoma↗
PubMed1984

Molecular cloning of cDNAs from androgen-independent mRNA species of DBA/2 mouse sub-maxillary glands.

cDNA libraries have been constructed from mRNAs isolated from mature male DBA/2 mouse submaxillary glands. Several recombinant plasmids have been assigned to particular mRNA species and their in vitro translation products by HART and hybrid selection. Clones containing copies of two abundant mRNA species that showed no sexual dimorphism were selected for detailed characterisation. Nucleotide sequences determined from one series of clones define an 850 nucleotide mRNA encoding a polypeptide of 16.5 kd having an N-terminal signal sequence, an acidic core and four glycosylation sites. A second family of clones correspond to an mRNA of 800 nucleotides, the sequence of which can be interpreted as coding for an intracellular protein of 14.7 kd. Computer searches of protein and nucleic acid sequences have not revealed the identity of either of these submaxillary gland products.

Amino Acid Sequence↗
PubMed1984

The effect of interferon on cells deficient in nucleoside transport or lacking thymidine kinase activity.

Mutants of mouse T-lymphoma S49 cells lacking thymidine kinase activity or deficient in nucleoside transport were selected by growth in the presence of 5'-fluorodeoxyuridine and their sensitivity to interferon tested. All five thymidine kinase and both transport deficient mutants were sensitive to the antiproliferative effects of interferon. The replication of encephalomyocarditis virus was also inhibited by interferon, and the intracellular levels of (2'-5')oligo-adenylate synthetase were elevated in all mutants tested. These results suggest that an intact nucleoside transport system or thymidine kinase activity are not essential for the expression of interferon sensitivity in these cells.

2',5'-Oligoadenylate Synthetase↗
PubMed1984

Interferon-induced 2-5A synthetase activity in human peripheral blood mononuclear cells after immunization with influenza virus and rubella virus vaccines.

The interferon-induced enzyme 2-5A synthetase can be a sensitive indicator of activation of the human interferon system during viral infection or interferon therapy. To determine the response of the human interferon system to viral antigens, the level of 2-5A synthetase activity was monitored in peripheral blood mononuclear cells of healthy adults before and after immunization with influenza or rubella virus vaccine. The influenza virus-vaccinated individuals demonstrated increases in enzyme activity on days 1 and 11 in vivo, whereas those vaccinated with rubella virus vaccine showed an increase only on day 11. The difference in the day 1 in vivo 2-5A synthetase response in the two vaccinated groups could be demonstrated by in vitro incubations of peripheral blood mononuclear cells isolated approximately 90 days postvaccination with the two vaccines. The day 11 increase of enzyme activity in the rubella virus group showed a positive correlation with an increase in serum antibody titer, suggesting activation of the interferon system during antibody production in vivo after human exposure to virus antigens. The demonstration of increased 2-5A synthetase activity at specific times postimmunization in this investigation indicates that the interferon system is involved in the human in vivo response to virus vaccination.

2',5'-Oligoadenylate Synthetase↗
PubMed1984

The host defense system in the human newborn: the role of interferon and the natural killer cell.

The human newborn is particularly susceptible to infections in the neonatal period, due in part to the immaturity and naive state of the immune system. The role of interferon and natural killer cells in host defense in this age group is poorly defined. We have studied natural killer cells and the activation of the interferon system in cord blood. Most newborns (75%) had low natural killer cell activity, and this was unrelated to levels of the intracellular interferon-associated enzyme, 2'-5' oligoadenylate synthetase (2-5A synthetase). Newborn cells responded to interferon in vitro with an increase in natural killer activity, suggesting that this low natural killer cell activity is the result of fewer numbers of effector cells rather than a functional immaturity. Circulating serum interferon was detected in greater than 50% of maternal samples tested; however, this did not correlate with 2-5A synthetase levels in maternal or the corresponding cord blood mononuclear cells. Natural killer cell activity was low in the newborn in spite of activation of the interferon system in 39% of these individuals. This may be an important factor in susceptibility to infections in this period.

2',5'-Oligoadenylate Synthetase↗
PubMed1984

In vitro hyporeactivity to alpha-interferon in children with severe combined immunodeficiency disease.

Interferon (IFN) treatment of peripheral blood mononuclear cells from seven children with severe combined immunodeficiency (SCID) failed, with one exception, to induce the IFN-dependent enzyme, 2-5A synthetase or enhance natural killer cell activity. In one patient this hyporeactivity was demonstrated in both T cell enriched and T cell depleted lymphocyte preparations. These results may reflect the absence of an IFN reactive lymphocyte subpopulation or of the IFN receptor. This defect in SCID patients may be partly responsible for their increased susceptibility to viral infections and may contribute to the regulatory imbalances in T lymphocyte subpopulations.

2',5'-Oligoadenylate Synthetase↗
PubMed1983

Differential binding of human interferon-alpha subtypes to receptors on lymphoblastoid cells.

Highly purified human interferon-alpha subtype A (HuIFN alpha A) was iodinated for use in direct ligand binding studies on human lymphoblastoid (Daudi) cells. Unlabelled preparations of HuIFN alpha subtypes A, C, D, and hybrid molecules AD (Bgl II), AD (Pvu II), and DA (Bgl II) showed different responses in competition experiments with labelled alpha A probe. Specifically, IFNs alpha D and alpha DA were unable to displace the probe, whereas IFNS alpha A, alpha C, and the hybrid alpha ADs showed similar competition curves. These results support a two-idiotope model of IFN recognition by its receptor. IFN effects on [3H]-thymidine incorporation and cell growth (long term effects) did not reflect the apparent affinities of HuIFN alpha subtypes for cell surface receptor.

Binding, Competitive↗
PubMed1982

Molecular cloning of partial cDNA copies of two distinct mouse IFN-beta mRNAs.

Two cDNA libraries were constructed, using respectively the 12S and the 16S sucrose gradient fractions of polysomal poly (A)+ RNA from mouse C243 cells induced with Newcastle disease virus. Screening of a part of both libraries by mRNA selection hybridization assays revealed the presence of two plasmids hybridizing to an mRNA, whose translation product was characterized as mouse IFN-beta. Blot analysis of RNA indicated that mRNA hybridizing to the DNA from both plasmids could be detected in induced but not in uninduced C243 cells. The two cDNA inserts did not cross hybridize and had distinct restriction maps. Sequencing revealed that both inserts represented the end of the coding region and the entire 3' non coding region of two district mRNAs. Although different, the putative 39 AA and 65 AA carboxy termini of both Mu IFN-beta s display some homology to human IFN-beta 1. Thus there are at least two different murine IFN-beta genes.

Amino Acid Sequence↗
PubMed1981

Photoelastic stress analysis of hemimandibulectomy bone reconstruction devices.

The results presented show the relative importance of muscle force and occlusal resistance locations and prosthesis/hemimandible interface length. For the prosthesis design used, the addition of muscle function on the prosthesis side has little effect upon bone stress. However, occlusal resistance on the prosthesis side produces much more stress in the bone than other resistance positions. Stress produced by the shorter prosthesis is higher at the areas of bolt/bone interface than for the long prosthesis. However, superimposed inherent stress patterns somewhat obscured the comparison with longer prostheses.

Dental Stress Analysis↗