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Biomedical subjects

J R Williams

Publications and source records attributed to J R Williams.

At least 163 records · Page 9Linked to original sources
PubMed1989

Yttrium-90 and iodine-131 radioimmunoglobulin therapy of an experimental human hepatoma.

Therapeutic trials were performed on the HepG2 human hepatoblastoma implanted s.c. in the athymic nude mouse. Animals were treated with polyclonal and monoclonal antiferritin and control antibodies labeled with either iodine-131 (131I) or yttrium-90 (90Y). Administration of 400 muCi of 131I-labeled polyclonal antiferritin or 300 muCi of 90Y-labeled polyclonal antiferritin significantly increased survival (P less than 0.001). There were no tumor cures with radiolabeled polyclonal antibody therapy. Animals treated with 200 or 300 muCi of 131I-labeled monoclonal antiferritin (QCI054) did not show increased survival compared to controls. Although 400 muCi of 131I-labeled QCI significantly prolonged survival, treatment resulted in no long-term survivors. Monoclonal antiferritin labeled with 90Y significantly prolonged survival of animals (P less than 0.001) at doses of 100, 200, or 300 muCi compared with untreated controls. Fifty % of the animals treated with 200 muCi and 75% of the animals treated with 300 muCi showed no evidence of disease at 140 days following treatment. Four hundred muCi of 90Y-labeled QCI proved toxic to the animals. Increased survival was accompanied by a decrease in tumor mitotic rate and increase in cellular polymorphism as determined by pathological examination. The radiation dose absorbed in the tumor correlated directly with tumor response following treatment. The absorbed dose in tumors for complete decay of the isotope ranged from 165 and 330 cGy at the periphery and center of small tumors for an administered activity of 200 muCi of 131I-labeled polyclonal antiferritin, to 7,573 and 12,400 cGy for 300 muCi of 90Y-labeled monoclonal antiferritin QCI.

Animals↗
PubMed1989

DNA topoisomerases and models of sister-chromatid exchange.

Pommier et al. (1985) suggested that sister-chromatid exchange (SCE) results from exchange of topoisomerase II subunits. "Homologous displacement", an alternative mechanism, is proposed in which strand switching occurs during removal of parental helical turns by topoisomerases. The steps in the SCE model proposed by Ishii and Bender (1980) for SCE occurring at a blocked replication fork could occur by this mechanism and would require the action of both topoisomerases I and II. Homologous displacement involving topoisomerase II alone provides a mechanism for the strand switching required in the models of Kato (1977) and Cleaver (1981) in which SCE occur between replicated double strands. These mechanisms and models are discussed in relation to current knowledge of the locations and functions of topoisomerases during DNA replication.

DNA Replication↗
PubMed1989

Increased chromosomal radiosensitivity in patients undergoing radioimmunoglobulin therapy.

Lymphocytes from individual patients undergoing radiolabeled immunoglobulin therapy have been examined both for chromosome aberrations expressed immediately upon explant, or for chromosome aberrations induced by a subsequent challenge of gamma-rays after PHA-stimulated proliferation. Despite interpatient variation, there is strong correlation between levels of chromosome aberrations observed in the initial mitosis after mitogenic stimulation and levels induced by a challenge dose of radiation in replicate cultures after several cell cycles of growth. These data indicated that even after proliferation, human lymphocytes retain a memory of in vivo exposure to ionizing radiation that can be observed by challenge with a clastogenic agent. This persistent hypersensitivity occurs at high frequency, suggesting that it may be related to initial steps in multistage carcinogenesis.

Carcinoma, Hepatocellular↗
PubMed1989

Commissions and biomedical ethics: the Canadian experience.

Canadians frequently have recourse to public commissions as a means of dealing with contentious public policy issues. This essay examines the role of philosophers and philosophy in nine such commissions, all of which have dealt with issues in biomedical ethics. The principal findings of this essay are that philosophers have not been used extensively by these commissions, and that the philosophical aspects of the issues under investigation have been dealth with quite inadequately. The essay concludes with suggestions for an expanded role for philosophers in such commissions.

Advisory Committees↗
PubMed1989

Heritable hypersensitivity to induced mutagenesis in the progeny of cell populations exposed to UVC (254 nm).

The ability of mutagens to transform benign papillomas to malignancy in the mouse skin model of multistage carcinogenesis [Hennings et al. Nature 303, 67-68 (1983)] suggests that multiple events may underlie carcinogenic progression, and that mutagenic exposures separated by time can act synergistically. Such synergism may result from initial mutagenic exposure which induces heritable sensitivity to subsequent mutagenic exposures. For example, progeny of X-irradiated V79 cells are hypersensitive to subsequent mutation induced by psoralen plus long-wave ultraviolet light, PUVA [Frank and Williams, Science 216, 307-308 (1982)]. In the present studies 100 to 200 surviving clones of short-wave ultraviolet light (UVC) irradiated V79 cells were assayed for mutation at two loci. Cultures derived from these cells were found to be hypermutable at the hypoxanthine guanine phosphoribosyl transferase (HGPRT) locus following exposure to PUVA, but showed mutant frequencies similar to control cells following UVC challenge at the HGPRT and ATPase loci.

Adenosine Triphosphatases↗
PubMed1989

Update on beta blockers.

Beta adrenergic blockers have been one of the most prescribed category of drugs during the past 15 years. Recently, many new beta blockers have been introduced because they have unique pharmacokinetic and pharmacodynamic properties that benefit patients. The purpose of this article is to review the pharmacological properties and clinical uses of beta blockers. The latter part of this review will discuss the anesthesia implications of this group of drugs.

Adrenergic beta-Antagonists↗
PubMed1988

Use of an established human hepatoma cell line with endogenous bioactivation for gene mutation studies.

Genetic toxicology assays that rely on S9 microsomal mixes are subject to artifacts related to the generation of mutagenic metabolites by acidic pHs, variation in individual isolations of microsomes and the failure of subcellular fractions to faithfully produce metabolites generated in intact cells. We have developed a gene mutation assay utilizing the human hepatoma cell line HepG2, which has been shown to metabolize a broad spectrum of promutagens. Optimal conditions for assaying the induction of 6-thioguanine-resistant mutants in this cell line include: 1) growth of colonies for three weeks on lethally irradiated feeder layers of 10(6) thioguanine-resistant HepG2 cells (average plating efficiency = 60-80%); 2) a thioguanine concentration in selection dishes of 10(-4) M with a maximum seeding density of 2.5 x 10(5) cells per 100 mm culture dish; and 3) a minimum expression time of 6 days. In addition to ultraviolet light C (254 nm), a cytochrome P450 (cyclophosphamide)-dependent and a cytochrome P448 (aflatoxin B1)-dependent promutagen were shown to induce cytotoxicity and mutations in this test system. The present studies, therefore, suggest that the HepG2 cell line may be useful for a variety of assays in genetic toxicology.

Aflatoxins↗
PubMed1988

Physical properties of addition silicones as a function of composition.

The effects of molecular weight of the base silicone, filler and copolymer concentrations on compression set, strain, creep and dynamic elastic modulus were determined. The molecular weight of the base silicone had the least effect on these properties although low molecular weights showed better properties. Chain extenders were detrimental to physical properties of creep, compression set and dynamic elastic modulus. Increased copolymer concentrations decreased compression set, strain and creep and increased the dynamic elastic modulus. The useful copolymer/base functional group ratio was from 1:1 to 3:1. Filler affected properties to a lesser extent than copolymer ratio. Compression set, strain, and creep decreased and the dynamic elastic modulus increased with increasing filler with the properties being directly proportional to the weight fraction. All properties were interrelated with ln strain linearly related to ln compression set, creep proportional to set, and the dynamic elastic modulus was inversely correlated with strain and creep.

Chemical Phenomena↗
PubMed1988

Effects of methylxanthines on cell-cycle redistribution and sensitization to killing by low-dose-rate radiation.

The effects of two methylxanthines, caffeine and isobutylmethylxanthine (IBMX), on the response to radiation given at two low dose rates were studied in a human hepatoma cell line, HepG2. These dose rates are in the range to which tumor cells are exposed in radiolabeled immunoglobulin therapy of primary hepatoma. At the higher dose rate (0.3 Gy/hr for 24 hr), the radiation completely inhibited growth, and cells accumulated in the G2 phase of the cell cycle. Caffeine (1 mM), given either continuously or during the last 4 hours of the radiation exposure, counteracted the growth inhibition and G2 accumulation and enhanced cell killing. The 0.5-mM dose of IBMX had little effect on cells. For a lower dose rate and longer exposure period (0.06 Gy/hr for 3 days), the radiation partially inhibited growth and the accumulation of cells in G2 was small. Continuous, but not short, exposure to caffeine enhanced killing at this dose rate and counteracted the G2 accumulation. At the lower dose rate, IBMX enhanced the growth inhibition, G2 accumulation, and killing above that with radiation alone.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Cell cycle dependence of sister chromatid exchange induction by DNA topoisomerase II inhibitors in Chinese hamster V79 cells.

The cell cycle dependence of sister chromatid exchange (SCE) induced by topoisomerase II inhibitors was studied in Chinese hamster V79 cells. 4'-(9-Acridinylamino)methansulfon-m-anisidide, which increases the concentration of covalently linked DNA-topoisomerase II complexes (cleavable complexes), induces SCE strongly in only a short period of the cell cycle. The sensitive period was identified an occurring in early to mid-S phase through the use of labeled thymidine incorporation and flow cytometry. Novobiocin, an inhibitor which prevents formation of the cleavable complex, did not induce SCEs in any part of the cell cycle. However, novobiocin did decrease the level of 4'-(9-acridinylamino)methansulfon-m-anisidide-induced SCEs. These results indicate that the cleavable complex may be important in 4'-(9-acridinylamino)methansulfon-m-anisidide-induced SCE.

Amsacrine↗
PubMed1987

Effect of chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on sister chromatid exchange levels in peripheral lymphocytes of the rhesus monkey.

Frequencies of sister chromatid exchanges and chromosomal aberrations were examined in peripheral lymphocytes of Rhesus monkeys which had been fed a diet containing 25 parts per trillion 2,3,7,8-tetrachlorodibenzo-p-dioxin for a period of 4 years. When compared to non-exposed control animals, no significant differences were noted for either of these cytogenetic endpoints. In addition, there was not a significant difference in sister chromatid exchange response to a challenge dose of mitomycin C in cells from 2,3,7,8-tetrachlorodibenzo-p-dioxin exposed animals compared to controls. Our results confirm the lack of genotoxic effects associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure.

Animals↗
PubMed1987

Fast neutron therapy for squamous cell carcinoma in the head and neck region: results of a randomized trial.

A randomized trial of fast neuron therapy compared with 4MV photons for patients with head and neck cancer is reported. One hundred and sixty-eight patients were recruited between 1977 and 1984. The minimum follow-up is 2 years. Three patients were withdrawn before treatment began. Eighty-five were allocated to neutron therapy and 80 to receive photon therapy. All patients had squamous cell cancers in one of four primary sites: oral cavity, oropharynx, larynx, and hypopharynx. Local tumor control was similar in both groups: 44.7% after neutrons and 45.0% after photons. Salvage surgery was performed on 18 patients in each treatment group for residual or recurrent cancer. Acute radiation reactions of the mucous membranes were significantly more severe after photons. The number of patients with serious late reactions was greater after neutron therapy but the difference was not statistically significant. There were six deaths related to late morbidity after neutron therapy but none after photon therapy. Survival was better after photon therapy but the difference compared with the neutron group failed to reach statistical significance. When intercurrent deaths are excluded, the difference is less marked. Photon therapy was clearly better in terms of disease-free survival giving a 2-year local disease-free rate of 41.3% (s.e. 5.5%) compared with 29.4% (s.e. 4.9%) after neutrons.

Carcinoma, Squamous Cell↗
PubMed1987

Transient abrogation of immunosuppression in a patient with chronic mucocutaneous candidiasis following vaccination with Candida albicans.

A patient with long-standing chronic mucocutaneous candidiasis had reversed T helper/suppressor (TH/TS) cell ratios, hypergammaglobulinaemia E and serum inhibitors of lymphocyte transformation to mitogens and candida antigens. Following vaccination with whole heat-killed yeasts of Candida albicans, temporary clinical improvement coincided with the return of the TH/TS cell ratio to normal, reduction in concentration of IgE and reduced serum inhibitory activity to Concanavalin A and candida antigens. These changes were not permanent and 6 months after vaccination all indices had reverted to their pretreatment values. The production of antibody to a 47 kDa antigen of C. albicans has been shown to coincide with recovery from systemic disease. High concentrations of this antibody were demonstrated initially in the patient's serum and were unaffected by vaccination. If the 47 kDa antibody is protective, the results of this study suggest that separate immune responses may protect against mucocutaneous and systemic candidiasis and that defective immune responses against mucocutaneous disease need not imply lack of protection against systemic spread.

Antibodies, Fungal↗