Biomedical subjects
Publications and source records attributed to K Adams.
The survival of clonogenic cells in the B16 melanoma has been studied simultaneously by 3 methods: an in vitro assay in soft agar, a lung-colony assay, and the end-point dilution technique. Details of the first 2 methods have previously been reported, but those of the third are described here. The 3 methods have agreed well in investigations of the response of the B16 melanoma to cyclophosphamide.
The formation of lung colonies by i.v. injected Lewis lung-tumour cells in syngeneic recipients was greatly enhanced by prior treatment of the mice with cyclophosphamide. The lung-cloning efficiency was linearly related to cyclophosphamide dose and the optimum time of treatment was 2-4 days before the injection of tumour cells. The resulting lung colonies had a similar size distribution to colonies in untreated recipients. Bleomycin, local thoraric irradiation and whole-body irradiation were much less effective in enhancing the lung-cloning efficiency. Cyclophosphamide also enhanced the take probability of i.m. implanted tumour cells.
The survival of Lewis lung tumor cells has been studied after a single ip dose of BCNU. In dissectible subcutaneous and intramuscular tumors and artificial lung metastases survival was measured by colony formation in soft agar and in vivo in the lung. The long-term control of small lung nodules by single doses of BCNU was studied and cell-survival estimates were inferred. The results demonstrate that the cytotoxic action of BCNU shows a strong dependence upon tumor size.
Quasi-static pressure-volume (P-V) curves in normal seated human subjects were determined with pressure at the airway opening (Pa0) set below (negative pressure), above (positive pressure), or equal to ambient pressure. Dynamic compliance (Cdyn) during controlled continuous negative pressure breathing (CNPB) was also studied. Quasi-static P-V curves at negative pressure were decreased in slope, reflected a decrease in total lung capacity, and intersected the P-V curve obtained at ambient Pa0. At positive pressure the P-V curves showed an increase in slope and an increase in total lung capacity. During CNPB a fall in Cdyn was found. The fall in Cdyn was rapid and persisted for the duration of CNPB. Cdyn promptly returned to control levels when Pa0 was adjusted to ambient pressure.
Erythrocyte filterability, an index of deformability, and lysosomal enzyme activity were studied in 34 patients requiring cardiopulmonary bypass. In addition fresh human erythrocytes were analyzed after incubation for filterability changes after exogenous lysosomal enzymes were added to the suspension medium. The results showed statistically significant elevations of the filterability index (decrease in filterability of the red cells) after 10 minutes on cardiopulmonary bypass as well as postoperatively. Likewise cathepsin D concentration after 10 minutes of cardiopulmonary bypass of 8.4 plus or minus 0.8 U. was significantly elevated over the preoperative level of 5.3 plus or minus 0.7 U. Furthermore, the pump prime was found to have the highest filterability index as well as concentration of cathepsin D. Supporting our hypothesis that lysosomal enzymes may be a factor affecting erythrocyte integrity was the elevation of the filtration index to 10.5 plus or minus 0.3 U. during incubation with exogenous lysosomal enzymes compared with the control index of 9.0 plus or minus 0.2 U. This stduy implies that the pump prime should be an area of further investigation if alterations of erythrocyte filterability (deformability) and lysosomal enzymes during extracorporeal circulation are shown to have clinical importance.
The stem-cell response of the Lewis lung carcinoma to single doses of cyclophosphamide has been studied by three assay techniques: in vitro colony formation, lung colony formation, and the end-point dilution assay. These three techniques have given comparable results, and the end-point dilution results showed that 50 percent takes could be achieved with as few as 1 to 3 cells. Studies have been made of the growth of small i.m. implants and of the time following implantation at which they could be eradicated by cyclophosphamide. The results were compared with the curability that would be expected on the basis of cell survival studies. It was found that older (and therefore larger) implants were cured than might have been expected. It seems unlikely that this discrepancy was due to additional cell kill caused by an immune response. An alternative explanation, that the surviving fraction following a dose of cyclophosphamide was lower in small implants than in larger i.m. tumors, was supported by studies of cell survival in dissectable lung colonies.
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Studies have been made on the growth and cell population kinetics of a spontaneous rat mammary fibroadenoma and of 10 successive transplantation passages. The volume doubling time decreased from about 30 days in the primary tumour and first two transplants to 1·7 days in the tenth transplant. This acceleration was accompanied by a considerable shortening of the mitotic cycle and of its S and G(1) phases but without change in the proportion of time spent in S. There was also a reduction in the apparent extent of cell loss and a considerable increase in the growth fraction. Histological changes were noted and studies by feulgen densitometry indicated a considerable shift in ploidy from hyperdiploid to hypertetraploid. The results constitute a detailed example of the effect on tumour growth kinetics of serial transplantation.
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The ability of 1,6-dinitropyrene to induce chromosome damage in peripheral human lymphocyte cultures has been demonstrated. Low levels of clastogenic activity were detected following 3-h treatments with 1,6-dinitropyrene in the presence of a rat-liver cytosol fraction. The clastogenic activity reached a peak at a concentration of 1.25 micrograms/ml of 1,6-dinitropyrene after which the frequency of aberrations decreased. This unusual genotoxic dose response is similar to that found previously in yeast and rat-liver cells. The fact that a positive result was obtained using human lymphocytes shows that, in the presence of the appropriate activation system, dinitropyrene is genotoxic in human cells.
Considerable excitement has been generated as of late over reports that fragments of the amyloid precursor protein can be neurotoxic both in vivo and in vitro. In this brief report we study the neurotoxicity of the fragment corresponding to amino acids 25-35 of the beta-amyloid protein in the hippocampus in vivo. Under the conditions studied, we do not observe any evidence of consistent, dose-related damage above that seen with vehicle alone.
Male weanling rats of the Charles River Sprague-Dawley strain were exposed to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the water for 3 months at the concentration of 75 ml/litre. Other real or potential risk factors were administered, alone or in combination with MNNG. When MNNG was administered in combination with NaCl, bile acids, aspirin or BHA, forestomach tumours were enhanced. MNNG-induced tumours were inhibited by selenium or by difluoromethylornithine, an ornithine decarboxylase inhibitor. BHA alone caused forestomach tumours. When BHA was administered by dietary means or by gavage, alone or in combination with MNNG, the gavage method resulted in greater tumorigenesis than dietary exposure. This increase was associated with increased [3H]thymidine labelling of forestomach epithelium and increased hyperplasia. Oesophageal carcinogenesis induced by methylbenzylnitrosamine (MBN) was enhanced by zinc deficiency, alcohol and 13-cis-retinoic acid. Zinc deficiency also resulted in oesophageal tumours in rats exposed to the hepatocarcinogen dimethylnitrosamine. Riboflavin deficiency injured oral and oesophageal epithelium and increased sensitivity to MBN-induced oesophageal tumours.
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A new conventional simple and direct 125I-radioimmunoassay (RIA) for serum progesterone is described. In comparison with the classical tritiated assays which are preceded by extraction, the assay is more simple, less time-consuming, less subject to error and hence less expensive. In normal cycling females the serum progesterone range during the follicular phase was 0.9 to 5.5 ng/ml (mean 2.5 ng/ml). Levels above 12 ng/ml occurring during the luteal phase are indicative of adequate luteal function. The actual progesterone levels assayed with this method are significantly greater than those found using the classical tritiated technique, and the reasons for this discrepancy are discussed. The assay is also capable of being used to assess the response to treatment for infertility, thus indicating that, in spite of the higher values obtained, there is no impairment in diagnostic sensitivity.