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E D Williams

Publications and source records attributed to E D Williams.

At least 109 records · Page 6Linked to original sources
PubMed1992

Oestrogen receptor protein and mRNA in adenocarcinoma of the uterine cervix.

We have investigated the oestrogen receptor (ER) status of 20 cervical adenocarcinomas by immunocytochemistry for ER protein and non-isotopic in situ hybridisation for ER mRNA. Both methods, which are applicable to paraffin sections, were developed and validated in breast carcinomas with known ER content. Six cervical adenocarcinomas contained immunocytochemically demonstrable ER protein; all contained ER mRNA, but staining was less intense in poorly differentiated areas of four tumours. This disparity between protein and mRNA detection needs further investigation as does the possibility that oestrogens may play a role in the pathogenesis of cervical adenocarcinoma.

Adenocarcinoma↗
PubMed1992

Production of thyroid tumours in mice by demethylating agents.

Previous studies on thyroid tumorigenesis in rodents have explored the role of oncogene mutation in tumour development. However, many mutagens are also known to decrease DNA methylation, another factor known to be important in the regulation of gene expression. We report the results of a small study to examine whether the demethylating agents 5-azacytidine and 5-aza-2-deoxycytidine could promote radiation- or goitrogen-induced tumorigenesis in the mouse, and whether they could potentiate the effect of a combined radiation and goitrogen regime. Three single doses of either 5-azacytidine or 5-aza-2-deoxycytidine increased the frequency of lesions in the goitrogen-treated animals; one of these lesions was a metastasising carcinoma. Thyroid carcinomas are very rare in mice in the absence of mutagen treatment, and metastasis is particularly unusual. There was no significant difference, at the dosages used, between the number of tumours induced by demethylating agents and those induced by a mutagen (radiation) in goitrogen-treated animals. Unlike goitrogens, demethylating agents did not promote radiation-induced tumorigenesis, and they did not produce any significant potentiation of the conventional regime of radiation and goitrogen at the dosages used. This study suggests that the role of non-genotoxic factors, such as agents affecting patterns of DNA methylation, warrants consideration in thyroid tumorigenesis.

Animals↗
PubMed1992

Information for patients and staff concerning nuclear medicine.

Providing information to patients and staff is an important part of the practice of nuclear medicine. To assist in improving the standard of communications, guidance has been prepared covering the content, style and presentation of letters and leaflets for patients and for medical and nursing staff. Examples are provided which describe nuclear medicine procedures and related radiation safety precautions. They also attempt to answer questions frequently put by the various groups to whom they are addressed.

Humans↗
PubMed1992

The clonal organization of the squamous epithelium of the tongue.

Knowledge of the kinetics and stem cell localization of the mouse lingual epithelium is largely based on studies using DNA labelling techniques. We have adopted a different approach, using histochemistry for the X-linked enzyme glucose-6-phosphate dehydrogenase (G6PD). We have deduced clone size and morphology from studies of patch size and distribution in mice heterozygous for G6PD deficiency and from the identification of clonal enzyme loss induced in normal mice by application of a mutagen. Lingual epithelium of female mice (CBA X GPDX) heterozygous for G6PD deficiency showed multiple clearly defined patches of strong or weak enzyme activity, corresponding in intensity to the strong staining uniformly present in the normal parental strain (CBA) or to the weak staining uniformly present in the G6PD deficient parental strain (GPDX). This pattern results from the random suppression of either the paternal or the maternal X chromosome in each cell early in embryonic development, and the subsequent inheritance of X inactivation in daughter cells, giving rise to phenotypic patches each composed of one or more clones. The patch borders intersected the base of the lingual epithelium at small indentations or at the apices of connective tissue papillae; the surface intersection in some cases bisected filiform papillae. Patch width measured in tissue sections at the mid rete ridge level, showed a clear mode close to 40 microns, corresponding very closely to the mode for rete ridge width (i.e. distance between connective tissue papillae). Further evidence for clonal organization was obtained by inducing mutations in the lingual epithelium of CBA mice by topical mutagen application. A few clearly defined patches of enzyme loss were found with a mean diameter of 36 microns. Their morphology was very similar to that of patches in the heterozygous animals. We interpret these patches as clones derived from stem cells with induced somatic G6PD mutations. We conclude that the mouse lingual epithelium is a stem cell epithelium composed of clonal units of about 40 microns diameter, based on the rete ridge structure and that both connective tissue papillae and filiform papillae occur at the junction of two or more epithelial clones.

Animals↗
PubMed1992

Oestrogen enhancement of the myometrial response to exogenous parathyroid hormone-related protein (PTHrP), and tissue localization of endogenous PTHrP and its mRNA in the virgin rat uterus.

Classical pharmacological studies have shown that oestrogen dominance in humans and other animals can increase the responsiveness of the uterus to many locally acting peptides. Parathyroid hormone-related protein (PTHrP) has been shown to be expressed in the pregnant and non-pregnant rat uterus and exogenous PTHrP is known to relax uterine contraction in vitro. We investigated whether oestrogen dominance can influence the responsiveness of the uterine horn to PTHrP, and further studied the localization of PTHrP mRNA and protein in the rat uterine horn using in-situ hybridization and immunohistochemistry. Exogenous PTHrP(1-34) inhibited spontaneous and electrically induced contractions in uteri isolated from non-cycling rats. Pretreatment of non-cycling rats with oestradiol-17 beta increased uterine sensitivity to PTHrP: EC50 values for inhibition of spontaneous contractions by PTHrP were 0.33 nmol/l, 1.1 nmol/l, 2.6 nmol/l and 7800 nmol/l in uteri from animals treated for 2 days with oestradiol-17 beta alone, 2 days with oestradiol-17 beta + 1 day progesterone, 1 day with oestradiol-17 beta alone and in untreated rats respectively. Similar EC50 values were obtained for electrically stimulated uteri. In agreement with these findings, uterine horns from cycling rats in pro-oestrous and oestrous phases of the cycle showed a higher responsiveness to PTHrP(1-34) when compared with uterine horns taken from rats in metoestrus and dioestrus. PTHrP mRNA and protein were detected in the endometrial epithelium lining of the lumen and the endometrial glands, as well as in the myometrium of rats which were either pretreated for 2 days with oestradiol-17 beta or untreated. This study suggests that PTHrP may act in an autocrine and/or paracrine manner to modulate uterine motility and function.

Animals↗
PubMed1992

A stem cell niche theory of intestinal crypt maintenance based on a study of somatic mutation in colonic mucosa.

In both large and small intestine, mutagen administration leads to the occurrence of isolated crypts that are completely populated by a mutated phenotype; therefore, it has been proposed that crypts are maintained by a single stem cell. We show in mice that a single dose of mutagen leads to an early transient increase in frequency of colonic crypts that show a partial mutated phenotype and a later increase in frequency of crypts that show a complete mutated phenotype. This increase reaches a plateau at about the same time as the disappearance of partially mutated crypts. The same is true in the small intestine, but the time course is much slower. We propose an explanation based on multiple crypt stem cells that occupy a "stem cell niche," with random cell loss after stem cell division. A small difference in the number of crypt stem cells that occupy the niche provides a simple explanation for the surprisingly large difference in the time course of phenotypic changes in the large and small intestines after administration of a single dose of mutagen.

Animals↗
PubMed1991

Evidence for and possible mechanisms of non-genotoxic carcinogenesis in the rodent thyroid.

Thyroid tumours are a common finding in toxicity tests in rodents. It is known that prolonged administration of antithyroid drugs leads to the development of multiple thyroid tumours, and the role of genotoxic and non-genotoxic mechanisms in this needs definition. The role of drugs with an antithyroid action in thyroid carcinogenesis requires a knowledge of thyroid physiology. This review briefly discusses the anatomy and physiology of the thyroid before concentrating on the cellular pathology of the changes that take place in the transition from a normal to a neoplastic thyroid cell. The malignant cell is characterised by excess growth and invasiveness. The normal thyroid cell does not possess an unlimited growth potential because of a growth-desensitising mechanism (GDM) of the antioncogene type. Spontaneous thyroid carcinogenesis requires three key steps which are presumed to arise by mutation and clonal selection: the loss of the GDM, the acquisition of TSH-independent growth, and the acquisition of invasiveness. The sequence of the cell biological changes involved is not fully understood, but it has been shown that IGF-1 is a necessary co-factor for the growth-stimulating effect of TSH in the normal cell, and that autocrine production of IGF-1 is a feature of spontaneous thyroid adenomas. Another early change that has been shown in both experimental and human thyroid tumours is mutation of one of the ras oncogenes. In carcinogenesis due to the prolonged administration of an agent known to interfere with thyroid hormone metabolism and to induce a high TSH, two rather than three key steps will be required for carcinogenesis, as the development of TSH independent growth will not confer any selective advantage. We have shown that monoclonal lesions induced in this way regress when the goitrogen is withdrawn and therefore retain TSH dependence. The development of the other two key changes--the loss of the GDM and the acquisition of invasiveness--may be due to genotoxic or non-genotoxic mechanisms. They can occur in man in the absence of any known mutagenic agent. In patients with dyshormonogenesis a congenital defect in one of the steps of thyroid hormone synthesis is associated with multiple tumour production. It is reassuring that in these patients, exposed to decades of high TSH levels, benign lesions are common, but malignant thyroid tumours are very rare. The occurrence of thyroid tumours following the use of substances known to interfere with thyroid hormone metabolism does not itself exclude a genotoxic component to the carcinogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Reversibility of the malignant phenotype in monoclonal tumours in the mouse.

Longterm goitrogen administration to rodents is well known to result in multiple proliferative lesions of the thyroid. The regression of these lesions on withdrawal of goitrogen has led to their neoplastic nature being questioned, and they have been regarded as 'nodules' rather than as true tumours. We have induced multiple thyroid lesions by the combined use of high dose radiation as a mutagen, together with goitrogen administration to induce prolonged TSH growth stimulation. G6PD histochemistry was used in heterozygous G6PD deficient female mice to show that all the thyroid lesions induced by this regime were monophenotypic, and therefore monoclonal in origin. The great majority of induced tumours were adenomas, a minority were carcinomas. The number of carcinomas observed was significantly lower in a group of animals from which goitrogen was withdrawn for 4 weeks prior to killing, when compared to animals killed while on goitrogen treatment. Both adenomas and carcinomas, including areas of intravascular tumour, showed morphological features of regression on withdrawal of the goitrogen. There are three key cellular changes which must occur in spontaneous thyroid carcinogenesis--escape from a growth limiting mechanism, acquisition of TSH independent growth and acquisition of invasiveness. In the natural selection of mutations or epimutations during carcinogenesis, prolonged high levels of TSH are likely to remove any selective advantage from mutations that lead to TSH independent growth. Tumours induced by a regime including prolonged goitrogen treatment may therefore develop following two rather than three key stages. They will occur with an increased frequency relative to lesions observed in spontaneous carcinogenesis, but will retain TSH dependency. We speculate that several mechanisms may lead to loss of the growth limiting mechanism, including translocation of an oncogene to the region of a TSH induced promoter. Other carcinogenic regimes may also increase the yield of tumours by creating conditions which reduce the number of essential steps required for carcinogenesis, and may involve translocation to a carcinogen inducible promoter.

Animals↗
PubMed1991

Mutation of the p53 gene in a differentiated human thyroid carcinoma cell line, but not in primary thyroid tumours.

The p53 gene has been implicated as a tumour suppressor, with mutations occurring in many carcinomas, such as colon, breast and lung. We have sequenced exons 5, 7 and 8 containing conserved gene regions in the only available differentiated thyroid follicular carcinoma cell line and found a mutation at position 273, Arg----His, with no normal allele present. The same mutation was also present in DNA from the tumour of origin. However immunohistochemical analysis of 129 human thyroid tumours using a panel of p53 antibodies was unequivocally negative. Southern blotting in 20 cases failed to demonstrate any deletion or rearrangement, and direct genomic sequencing of 20 carcinomas showed normal DNA sequence for exons 5, 7 and 8. Thus p53 abnormalities may not be important in human thyroid carcinogenesis, in contrast to colon, breast and lung. However, the FTC 133 cell line was only established after 132 unsuccessful attempts with other differentiated thyroid follicular tumours. Since this line and the corresponding tumour of origin have a p53 mutation, we propose that p53 mutation may confer on thyroid follicular tumour cells the ability to grow in culture. This has potential applications for the future development of thyroid carcinoma cell lines.

Antibodies, Monoclonal↗
PubMed1991

Radiation-associated and 'spontaneous' human thyroid carcinomas show a different pattern of ras oncogene mutation.

Activated ras oncogenes in experimentally induced rodent tumours have been demonstrated to show specific patterns of oncogene activation which depend on the inducing agent, with H-ras activation in nitrosomethylurea (NMU) induced tumours, and K-ras activation in tumours induced by ionising radiation. We report a study of 12 radiation-associated human thyroid tumours, using polymerase chain reaction (PCR) amplification of paraffin-embedded material and allele-specific hybridisation with mutant-specific probes for the 3 ras oncogenes. Compared to 68 'spontaneous' human thyroid tumours, the radiation-associated cases show the same overall prevalence of ras mutation. However there is a significantly higher rate of K-ras mutation in radiation-associated follicular carcinomas than in 'spontaneous' follicular carcinomas (60% compared to 6%, P less than 0.05), suggesting that radiation may preferentially activate K-ras in human as well as rodent tumours.

Adenocarcinoma↗
PubMed1990

The use of a Diasonics DRF400 duplex ultrasound scanner to measure volume flow in arterio-venous fistulae in patients undergoing haemodialysis: an analysis of measurement uncertainties.

A pilot study to measure volume flow in arterio-venous fistulae in patients undergoing haemodialysis was undertaken to determine the accuracy and precision of values obtained using a modern duplex ultrasound scanner. A Diasonics DRF400 duplex ultrasound scanner was used with a small parts 10 MHz mechanical sector probe incorporating a 4.5 MHz Doppler transducer. Volume flow was measured in the brachial artery of 13 patients with surgically created arterio-venous fistulae in the distal circulation. Volume flow was also measured using a flow phantom in which the true volume flow was known. An analysis of the measurements made by the duplex scanner was performed to determine the sources of random and systematic uncertainty. Repeatability was improved with the probe clamped in position over the brachial artery giving a coefficient of variation in repeated measurements of volume flow in a patient of +/- 12%. Measured flows ranged from 884-3088 mL min-1. Comparison with measurements on the flow phantom showed these values from patients to be overestimated by 200-600 mL min-1. The values from the phantom should therefore be used to calibrate patient measurements. Analysis of uncertainties showed that precision was limited by random uncertainties in the measurement of vessel diameter and Doppler angle.

Aged↗
PubMed1990

Combined use of Doppler and conventional ultrasound for the diagnosis of vascular and other lesions in the head and neck.

Twenty-three patients with swellings of the head and neck were prospectively investigated by Doppler ultrasound and ultrasound imaging to determine the type and vascularity of the lesions and thereby aid pre-operative diagnosis. Four vascular lesions were correctly identified while vascularity was not found in patients with lipoma, cysts, abscess, or muscular hypertrophy. Increased vascularity was found in or near some tumours and lymphangiomas, but by careful comparison of findings these lesions were not confused with true vascular lesions. The value of the investigations was demonstrated by a change in the treatment in 6 of the cases in this series.

Abscess↗
PubMed1990

Consistency in nuclear medicine reporting--a pilot study using bone scans.

In a pilot study of consistency in nuclear medicine reporting, a panel of three observers evaluated 60 bone scans carried out for detection of metastases. The bone scans had originated from 10 departments. Difficulties arose in evaluation of the quality of the images by the panel members because of the differing criteria each chose to adopt. This highlights the need to define strictly, in advance, the parameters to be included in quality assessment. All three panel members agreed on the lesions present in 54 out of 60 studies. The observers' consensus report showed material differences from the original departmental report in the number of lesions present in 10 out of 60 studies. Material differences in the interpretation of the study occurred between panel members in two cases and between the panel and the original report in four cases. The pilot study has shown an acceptable level of consistency in bone scan reporting in the departments contributing images. A national study assessing consistency of reporting would be difficult to organize but alternative, more local, schemes are suggested.

Bone Neoplasms↗
PubMed1990

Effect of sustained serum prolactin elevation on breast epithelial and myoepithelial cell proliferation.

Oral administration of the dopamine antagonist perphenazine (0.01% in drinking water) to adult female Sprague-Dawley rats led to a three- to fourfold increase in serum prolactin by the first time point sampled (day 2) and a sustained fourfold elevation from day 4 of treatment to the end of the experiment (day 54). In response, five- to sixfold (day 7) and three- to fourfold (day 4) peak elevations in the epithelial cell metaphase indices were seen in the breast lobular and ductular compartments respectively. Both indices fell to basal levels on day 14 but returned to a second, but diminished, peak on day 27. By day 54, the mitotic activity of the epithelium had fallen to just above basal levels in both compartments. A similar mitotic response occurred in the myoepithelial cells, clearly indicating that these must be considered an important cell kinetic component during breast stimulation. Breast epithelial cell number increased 13-14 fold in the lobular but only two- to threefold in the ductular compartments in response to perphenazine administration. Again, similar responses were seen in the myoepithelial cell population. The major proliferative response therefore occurred within the lobular as opposed to the ductular compartment. A considerable discrepancy was shown between the cell number at each time point and that predicted on the assumption of constant cell death rate. We conclude that a growth desensitizing mechanism exists in the rat breast which limits breast growth in the presence of a sustained trophic hormone stimulation. Furthermore, we suggest that this limitation in breast growth is brought about by a mechanism which involves increased cell death in addition to decreased mitotic activity.

Animals↗
PubMed1990

In-situ analysis of calcitonin and CGRP expression in medullary thyroid carcinoma.

A combination of immunocytochemistry (ICC) and in-situ hybridization (ISH) applied to formalin-fixed tissue sections was used to analyse the differential expression of calcitonin and CGRP genes, at both peptide and mRNA levels, in normal and neoplastic human thyroid C cells. Calcitonin peptide was readily detectable in normal C cells but its abundance in the neoplastic C cells of medullary thyroid carcinoma (MTC) was reduced in correlation with the degree of tumour differentiation. Conversely, the content of calcitonin mRNA was higher in MTC than in normal C cells and was not significantly related to tumour differentiation. Both the peptide and mRNA of CGRP were present at much lower levels than those of calcitonin in normal C cells but were increased in neoplastic C cells. We conclude that neoplasia of thyroid C cells is associated with (i) an increase in the content of CGRP mRNA and peptide relative to that of calcitonin, consistent with a defect in control of transcript processing, and (ii) a decrease in the ratio of calcitonin peptide to mRNA abundance relative to the normal, suggesting a defect in synthesis or storage of the peptide. ISH analysis of calcitonin mRNA may therefore be a very valuable addition to ICC analysis of the peptide as a diagnostic and prognostic marker for MTC.

Adult↗
PubMed1990

Conditional immortalization of human thyroid epithelial cells: a tool for analysis of oncogene action.

To overcome the difficulty of assessing oncogene action in human epithelial cell types, such as thyroid, which have limited proliferative potential in culture, we have explored the use of temperature-sensitive (ts) mutants of simian virus 40 (SV40) early region to create conditionally immortalized epithelial cell lines. Normal primary cultures of human thyroid follicular cells were transfected with a plasmid containing the SV40 early region from mutant tsA58. Expanding epithelial colonies were observed after 2 to 3 months, all of which grew to greater than 200 population doublings without crisis. All showed tight temperature dependence for growth. After switch-up to the restrictive temperature (40.5 degrees C), no further increase in cell number was seen after 1 to 2 days. However, DNA synthesis declined much more slowly; the dissociation from cell division led to marked polyploidy. Viability was maintained for up to 2 weeks. Introduction of an inducible mutant ras gene into ts thyroid cells led, as expected, to morphological transformation at the permissive temperature when ras was induced. Interestingly, this was associated with a marked reduction in net growth rate. At the restrictive temperature, induction of mutant ras caused rapid cell death. These results demonstrate the utility of a ts SV40 mutant to permit the study of oncogene action in an otherwise nonproliferative target cell and reveal important differences in the interaction between ras and SV40 T in these epithelial cells compared with previously studied cell types.

Animals↗