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Biomedical subjects

E D Williams

Publications and source records attributed to E D Williams.

At least 145 records · Page 8Linked to original sources
PubMed1989

Effect of raised serum prolactin on breast development.

The effect of serum prolactin elevation on the growth and development of the rat breast was investigated. Oral administration of the dopamine antagonist, perphenazine, led to a 5-10-fold elevation of serum prolactin after two days of treatment which was maintained for the 54 days of study. A significant (P less than 0.01) 3.4-fold increase in total breast volume was seen by Day 4 of serum prolactin elevation. Breast volume continued to rise up to Day 14 reaching an 8.9-fold peak (P less than 0.001) which was maintained for the duration of the experiment. Epithelial, myoepithelial, lumen and stromal volume changes in the ductular and alveolar compartments were quantified separately. Highly significant (P less than 0.01) volume increases were seen in all components within the first few days of prolactin elevation. Similar time courses of the growth response to elevated serum prolactin were seen in the ductal tissues reaching an approximate 3-fold peak by 7 days in duct epithelium, myoepithelium and duct stroma. Time coordinated growth responses were also seen in the alveolar tissues with larger (7-15-fold) increases in alveolar epithelium, alveolar myoepithelium and alveolar stroma, reaching a peak by 14 days.

Animals↗
PubMed1989

The clonal origin of thyroid nodules and adenomas.

The clonal origin of thyroid tumors in female mice heterozygous for a deficiency of the X-linked enzyme glucose-6-phosphate dehydrogenase (G6PD) was studied. Tumor phenotype was demonstrated by enzyme histochemistry. Because monophenotypia is not synonymous with monoclonality, a method to estimate the degree of mingling of the two cellular phenotypes in normal tissue was devised. Twenty-five point three percent of 624 randomly chosen pairs of adjacent follicular cells were of unlike phenotype, suggesting that if tumors were derived from 2 or more cells at least a quarter would express polyphenotypia. Four hundred fifty-three thyroid lesions induced in 20 GPDX (enzyme-deficient) mice, 20 C3H (normal) mice, and 48 heterozygous (C3HxGPDX) mice by radiation and long-term goitrogen treatment were studied. One hundred twenty-eight adenomas (sharply defined or encapsulated hypercellular lesions) were found in heterozygotes; 108 (84%) were monophenotypic, and 20 (16%) were largely monophenotypic with degenerate areas or included normal cells. None were clearly polyphenotypic. Seventy-five nodules (circumscribed but not encapsulated, largely normocellular lesion with prominent stroma) were found in heterozygotes; 25 (33%) only were monophenotypic. It is concluded that thyroid adenomas are monoclonal and nodules polyclonal. The variegated pattern of polyphenotypia in the nodules together with their prominent stromal component leads to the suggestion that there is a causative role for the stroma in their generation.

Adenoma↗
PubMed1988

Activated ras oncogenes in human thyroid cancers.

Human thyroid epithelial (follicular) cells give rise to two malignant tumors--"follicular" carcinomas, which metastasize almost exclusively via the bloodstream, and "papillary" carcinomas, which metastasize predominantly via lymphatics (Williams, E. D. In: W. Duncan (ed.), Recent Results in Cancer Research: Thyroid Cancer, pp. 47-55. Berlin: Springer-Verlag, 1980). We have investigated whether this contrast in biological behavior might be associated with different patterns of oncogene activation. DNA transfection analysis of five follicular and ten papillary cancers indeed showed a statistically significant difference in the pattern of genes responsible, activated ras oncogenes being found in 80% of follicular tumors but only 20% of papillary tumors. In addition, in follicular cancers we have found activation of all three ras oncogenes (H-ras, K-ras, and N-ras), the first time that this has been demonstrated in a primary human tumor type (as opposed to cell lines). We suggest therefore that ras activation may be an important determinant of metastatic capability in these epithelial cancers.

Animals↗
PubMed1988

N-myc expression in neoplasia of human thyroid C-cells.

In view of the frequent reports of the increased expression of myc oncogenes in several neuroendocrine tumor types, we have investigated c- and N-myc expression in human medullary carcinoma, a malignant tumor derived from the neuroendocrine "C"-cell subpopulation of the thyroid gland. In situ nucleic acid hybridization was used to permit analysis not only of tumors but also of normal C-cells which form a tiny, scattered, minority of the thyroid epithelial cell population. N-myc expression was readily demonstrable in 6 of 21 tumor samples and c-myc in one case, whereas neither N- nor c-myc mRNA was ever detected in normal C-cells. We conclude that N-myc expression is a specific feature of C-cell tumors and is not merely a differentiation marker of their cell of origin. The data therefore strengthen the hypothesis that myc oncogene activation plays a role in neuroendocrine neoplasia.

Gene Expression Regulation↗
PubMed1988

Demonstration of somatic mutation and colonic crypt clonality by X-linked enzyme histochemistry.

Cellular mosaicism resulting from X-chromosome inactivation in heterozygous females can be shown histochemically; using this approach we have demonstrated age-related gene reactivation and tumour clonality. We now show in female mice heterozygous for reduced expression of glucose-6-phosphate dehydrogenase (G6PD) activity that colonic epithelial cells express either normal or low enzyme activity, and form patches composed of multiple crypts of uniform phenotype. We also show that a low-enzyme colonic epithelial cell phenotype can be induced in normal mice by carcinogen treatment, these cells again occur in patches, but are restricted to scattered single crypts, the frequency of which is related to treatment. A small proportion of colonic tumours in carcinogen treated normal mice are also of low-enzyme phenotype. We conclude that we have visualized the effects of a sporadic carcinogen induced somatic mutation in the G6PD gene of crypt stem cells and that a single stem cell maintains each colonic crypt. This inducible defective activity of a ubiquitous 'housekeeping' enzyme provides a somatic clonal marker system of wide potential application.

Animals↗
PubMed1988

The demonstration of tissue clonality by X-linked enzyme histochemistry.

We report here the first demonstration in normal, as opposed to chimaeric mice, of the clonal architecture of the small intestine, oesophagus, breast, and thyroid, using polymorphism of the X-linked enzyme glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49) as a clonal marker. Reproducible results using X-linked histochemistry were found to depend upon the simultaneous study of tissue from normal mice, mice homozygous for abnormal enzyme levels, and heterozygous mice. In tissues from homozygous animals where levels of enzyme activity normally vary, the use of a physiological stimulus to reduce this metabolic heterogeneity allowed interpretation of clonality in the heterozygotes. The details of the histochemical technique used require modification for each of the different tissues studied. A dual population of cells was seen in the heterozygous animals in all tissues studied. Oesophageal epithelium showed sharply separated alternating patches of positive and negative cells. Small intestinal crypts were always monophenotypic, while villi were polyphenotypic, indicating that crypts are monoclonal and villi derive from more than one crypt, confirming work in allophenic animals. In contrast, thyroid follicles and breast acini showed a mixture of mono- and polyphenotypia, consistent with a polyclonal origin. These results, which have important implications for the study of the clonal origins of normal and neoplastic growth, require the direct in situ demonstration of the cellular phenotype.

Animals↗
PubMed1988

Endocrine cell hyperplasia and appendiceal carcinoids.

As endocrine tumours in a number of organs may arise in a background of hyperplasia, the density of endocrine cells in appendices from ten patients with carcinoid tumours was compared with that in appendices from ten age- and sex-matched control patients. Crypt and lamina propria endocrine cells were quantified separately. The density of argentaffin endocrine cells in the crypts was significantly higher in appendices with carcinoid tumours when compared with the controls. No difference was found in non-argentaffin endocrine cells, and no difference was found in either argentaffin or argyrophil endocrine cells in the lamina propria. While it is possible that carcinoid tumours induce an increase in the number of enterochromaffin (EC) cells in the background mucosa, it is considered more likely that EC cell hyperplasia predisposes to the development of carcinoid tumours of the appendix.

Adolescent↗
PubMed1988

Loss of dependence on IGF-1 for proliferation of human thyroid adenoma cells.

The proliferative responses to IGF-1 (Somatomedin C) and TSH, as assessed by 3H-thymidine (3H-TdR) incorporation and autoradiographic labelling index (LI), of suspension and monolayer cultures of human thyroid follicular epithelium derived from both normal and adenoma tissue have been compared. In cultures of normal follicles, whilst neither TSH nor IGF-1 alone produced any effect, a combination of TSH (0.1 mU ml-1) together with IGF-1 (10 ng ml-1) induced a highly significant proliferative response as shown by a peak of 3HTdR incorporation and LI, 4-5 days after growth factor addition. The TSH concentration-effect curve was bell-shaped, a higher concentration of TSH (10 mU ml-1) resulting in a reduced response. In cultures derived from adenoma tissue, however, TSH alone at 0.1 mU ml-1 was sufficient to permit a highly significant proliferative response (equivalent to, or greater than the normal) in 4 out of 5 adenomas examined; again a higher concentration of TSH (10 mU ml-1) resulted in a diminished response. Addition of IGF-1 (10 ng ml-1) produced no significant change in the response to TSH (0.1 mU ml-1) in 3 of these 4 adenomas, and significantly inhibited the response in the fourth adenoma. It is concluded that escape from the requirement for an exogenous source of IGF-1 may be a key step in the development of human thyroid epithelial (follicular cell) neoplasia.

Adenoma↗
PubMed1988

Ha-ras restriction fragment length polymorphisms in colorectal cancer.

The possibility of an association between restriction fragment length polymorphisms (RFLPs) at the Ha-ras gene locus and susceptibility to develop colorectal cancer has been investigated. Leucocyte DNA from 46 carcinoma patients and 49 controls was analysed by Southern blotting to determine the size distribution of restriction fragments containing the variable tandem repeat 3' to the Ha-ras gene. Four predominant allelic fragments were found in both groups (in AvaII digests having sizes of 1.55, 2.0, 2.65 and 3.15 kilobases [kb]), together with a variety of 'rare' alleles (with individual frequencies less than 5%). The overall prevalence of rare alleles was not significantly different between cancer and control groups. The distribution of the common alleles, however, differed significantly. The combined frequency of the two larger alleles (a3 and a4) was approximately twice as high in the cancer group (34%) as in controls (18%) (P less than 0.025), which was reflected in a highly significant increase in the proportion of individuals carrying an a3 or a4 allele.

Alleles↗
PubMed1988

Light microscopic immunocytochemical demonstration of thyroid-stimulating hormone (TSH) receptors on normal rat thyroid cells.

We present a method for immunohistochemical demonstration of surface-associated thyroid-stimulating hormone (TSH) receptors on direct imprints of rat thyroid follicular cells at the light microscopic level, by use of dinitrophenyl (DNP)-labeled bovine TSH as the primary probe in a DNP-hapten sandwich staining (DHSS) procedure. The light microscopically invisible diaminobenzidine (DAB) product of the enzyme reaction was amplified with a DAB enhancement technique (silver amplification), which yielded a reliable and distinct light microscopically visible cell surface staining. The consistently negative control results after inhibition with TSH receptor-specific reagents provide evidence in support of immunohistochemical localization of surface membrane-associated TSH receptors.

Animals↗
PubMed1988

Agent-specific ras oncogene activation in rat thyroid tumours.

Activated ras oncogenes have been detected in a number of rodent tumour model systems (Balmain et al., 1986; Barbacid 1987), in which chemical carcinogens have been the most widely used inducing agents. We have investigated the involvement of activated oncogenes in a single well-characterised tumour model, rat thyroid neoplasia, produced not only by chemical carcinogen (nitrosomethylurea, NMU) and by ionizing radiation but also by elevated trophic stimulation alone. We have indentified a striking specificity in patterns of ras oncogene activation, with exclusively Ha-ras activated in 87% of NMU-induced tumours and exclusively Ki-ras activated in 60% of radiation-induced tumours.

Amitrole↗
PubMed1987

Control of human thyroid follicular cell proliferation in suspension and monolayer culture.

We have used both suspension and monolayer cultures to investigate the in vitro control of normal human thyroid follicular cell proliferation as assessed by both [3H]TdR incorporation and autoradiography. In suspension cultures, whilst TSH alone produced no effect, inclusion of two permissive factors, namely a supraphysiological concentration of insulin (80 micrograms/ml) and a low concentration of FCS (1%) (which, in the absence of TSH, gave only a weak proliferative response) permitted a highly significant response to TSH at 0.1 mU/ml. A higher concentration of TSH (10 mU/ml) resulted in a reduced response. In monolayer cultures in contrast, insulin and FCS were themselves highly growth stimulatory, with no super-added effect on addition of TSH. Our data indicate that suspension culture provides a more valid in vitro model for the investigation of growth factor control of normal and neoplastic human thyroid epithelium.

Cell Division↗
PubMed1987

In vitro demonstration of a TSH-specific growth desensitising mechanism in rat thyroid epithelium.

Sustained elevation of serum thyrotropin (TSH) induces an initial proliferation of rat thyroid follicular cells, leading to goitre formation followed by a 'plateau phase' in which the growth response to TSH is lost. To investigate this growth desensitisation mechanism, we have compared the sensitivity to growth factors of normal and 'plateau phase' rat thyroid epithelium in primary follicle cultures. Insulin at supraphysiological concentrations stimulates growth (DNA synthesis) in both cell types. TSH at a concentration found in 'plateau phase' animals (0.1 mU/ml) is maximally growth stimulatory for normal, but not significantly stimulatory for 'plateau' epithelium. At much higher concentrations however (greater than or equal to mU/ml) an equal response is obtained from both. We conclude that the growth desensitising mechanism is intrinsic to the follicular cell, is at least partly specific to TSH, and is effective only over the range of TSH concentrations found in vivo.

Animals↗
PubMed1987

Proliferative response to cyclic AMP elevation of thyroid epithelium in suspension culture.

The role of cyclic AMP (cAMP) as an intracellular growth signal in thyroid epithelial (follicular) cells has been studied using primary suspension cultures of rat thyroid follicles closely resembling the in vivo state. TSH at 0.1 mU/ml in the presence of insulin (0.08 microgram/ml) induced a 9.6-fold increase in [3H]thymidine incorporation with a peak after 48-72 h. The response to the cAMP elevating agent cholera toxin (10 ng/ml) was identical both in timing, magnitude and dependence on insulin. A lower amplitude response occurred with forskolin. The data further support the conclusion that elevation of intracellular cAMP concentration is a major, if not the only, signal required for the proliferative response of the follicular cell to its physiological mitogen, TSH.

Animals↗
PubMed1987

The optimum technique for 201T1 tomography of myocardium: an investigation using phantoms.

Rotating gamma-camera tomography is the method of choice for 201Tl perfusion imaging to detect myocardial ischaemia or infarction, but the optimum technique has not previously been investigated. Variables which can affect the utility of the images include acquisition time, collimator sensitivity and resolution, spatial filtering, reconstruction matrix and display parameters. An 'Iowa' design myocardial phantom containing 201Tl, with a defect representing an unperfused area, was used to study the effect of these variables. Results were assessed by measuring image contrast and non-uniformity and by observer grading trials. Receiver operator characteristic (ROC) curves and contrast ratios indicated that filtering the acquisition data with a count-dependent (Metz) filter before reconstruction and using a narrow slice width gave best results. No single collimator was superior for all four defect locations investigated but low-energy general purpose and high-resolution collimators were preferred to those with greater sensitivity. Reducing acquisition time by a factor of four compared with that for routine patient imaging affected contrast ratio, uniformity and area under ROC curves insignificantly, provided the optimum reconstruction was used. Displaying tomographic sections in colour gave no improvement in ROC curves over monochrome images. Data acquisition time or administered 201Tl radioactivity might therefore be reduced below the 25 min and 80 MBq often used for patient studies.

Heart↗