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Biomedical subjects

K J Cullen

Publications and source records attributed to K J Cullen.

At least 55 records · Page 3Linked to original sources
PubMed1989

Purification and characterization of an insulin-like growth factor II variant from human plasma.

An insulin-like growth factor II variant (IGF-II variant) was purified from Cohn fraction IV1 of human plasma by ion exchange, gel filtration, and reversed-phase high pressure liquid chromatography. The amino-terminal sequence of the first 35 amino acid residues showed a replacement of Ser-29 of IGF-II with the tetrapeptide Arg-Leu-Pro-Gly of IGF-II variant. Peptides isolated and sequenced after digestion with endoproteinase Asp-N and endoproteinase Glu-C disclosed no differences with the sequence predicted from an IGF-II variant cDNA clone isolated by Jansen, M., van Shaik, F. M. A., van Tol, H., Van den Brande, J. L., and Sussenbach, J. S. (1985) FEBS Lett., 179, 243-246. The molecular ion of intact IGF-II variant was 7809.4 mass units, as measured by plasma desorption mass spectrometry. This is in close agreement with the molecular ion of 7812.8 mass units calculated from the determined sequence and indicates the entire amino acid sequence had been accounted for. Binding of IGF-II variant to purified insulin-like growth factor I (IGF-I) receptors demonstrated a 2-3-fold lower affinity for this receptor compared with IGF-I or IGF-II. The dissociation constants for IGF-I, IGF-II, and IGF-II variant are 0.23, 0.38, and 0.80 nM, respectively. In a growth assay, the concentration of IGF-II and IGF-II variant required to stimulate the half-maximal growth of MCF-7 cells was 4 and 13 nM, respectively. Finally, the amount of IGF-II variant that can be purified by this method constitutes approximately 25% of the total IGF-II isolated from Cohn fraction IV1 of human plasma.

Amino Acid Sequence↗
PubMed1989

The insulin-like growth factor binding protein BP-25 is expressed by human breast cancer cells.

Specific binding proteins are thought to modulate the effects of IGF-I. Previous work has demonstrated that media conditioned by human breast cancer cells contains IGF-I binding activity. Radiolabelled IGF-I incubated with serum-free conditioned media from the breast cancer cell line MDA-MB 231 eluted with an apparent M.W. of 35-40 kDa when analyzed by gel filtration chromatography at pH 7.4. The M.W. of this binding activity corresponded to that of BP-25, a binding protein cloned from the hepatocellular carcinoma cell line HepG2. Two breast cancer cell lines, MDA-MB 231 and Hs578T, were found to express BP-25 RNA. Specific BP-25 radioimmunoassay detected BP-25 production in the conditioned media of these two cell lines. Immunoprecipitation confirmed that metabolically labelled MDA-MB 231 released 30 kDa BP-25 into its medium. This study demonstrates that some breast cancer cells express the IGF-I binding protein, BP-25.

Breast Neoplasms↗
PubMed1989

Atrial fibrillation and mortality in an elderly population.

Prospective data from Busselton, Western Australia, collected during triennial surveys from 1966-81 with follow-up of subjects to 1983, showed that atrial fibrillation (AF) was frequent in elderly people and associated with increased mortality. Of 1770 people aged over 60 years, 40 were in atrial fibrillation when first seen and a further 47 developed it during follow-up. Atrial fibrillation was positively associated with angina, history of a myocardial infarction and left bundle branch block. Relative mortality in those with atrial fibrillation compared with those without it, was 1.92 for all causes, 1.82 for death from cardiovascular causes (excluding stroke) and 3.78 for deaths from stroke, after adjustment by proportional hazards regression for confounding effects of age, sex, history of a myocardial infarction, an abnormal electrocardiogram, angina, cholesterol level systolic blood pressure and Quetelet's Index (weight/height2). The excess relative mortality declined with increasing age for both women and men. This raised relative mortality remained constant with time from the first detection of AF for all causes and cardiovascular causes but appeared to increase with time from detection for stroke death. The risk of death from stroke was greatest in the younger women. The observed risk of death from stroke in patients with AF suggests that anticoagulant use should be considered in selected patients.

Aged↗
PubMed1989

Analysis of insulin-like growth factor I gene expression in malignancy: evidence for a paracrine role in human breast cancer.

Insulin-like growth factor I (IGF-I) activity has been reported to be produced by several human cancers. Identification of RNAs transcribed from the IGF-I gene has been complicated by the detection of multiple hybridizing bands on Northern analysis. To determine if any of these RNAs are transcribed from the IGF-I gene, we have used a sensitive and specific ribonuclease (RNAse) protection assay for IGF-I. We have also studied the breast cancer tissue expression of IGF-I using in situ hybridization histochemistry. We have found no IGF-I mRNA in breast (zero of 11) or colon cancer (zero of 9) cell lines; both of these tumors have been previously reported to express IGF-I mRNA. However, three of three neuroepithelioma and one of two Ewing's sarcoma cell lines express IGF-I mRNA; therefore, in these tumors IGF-I may be an autocrine growth factor. In contrast to breast cancer cell lines, RNA extracted from breast tissues has easily detectable IGF-I mRNA. In situ hybridizations show that IGF-I mRNA is expressed in the stromal cells, and not by normal or malignant epithelial cells. These findings suggest that although IGF-I is not produced by breast epithelial cells it may function as either a paracrine stimulator of epithelial cells or an autocrine stimulator of stromal cells.

Blotting, Northern↗
PubMed1989

Regulation of human breast cancer by secreted growth factors.

Laboratory evidence is presented that estrogens are able to induce the production of numerous growth factors which can act in an autocrine or paracrine fashion in estrogen dependent breast cancer. Estrogen independent tumors can produce these same growth factors constitutively and so escape the need for estrogen stimulation. Growth inhibitory factors such as TGF-beta can also be controlled by estrogens and antiestrogens. It is unclear at present, however, how much of the cytostatic effect of antiestrogens in vivo is explained by the production of growth inhibitors. The overall control of breast cancer growth is mediated by the combined effects of these growth stimulatory and inhibitory factors in both breast stroma and epithelium. Interruption of the action of growth factors and the use of growth inhibitors may provide opportunities for new approaches to the treatment of breast cancer.

Breast Neoplasms↗
PubMed1989

Endocrine therapy of human breast cancer cells: the role of secreted polypeptide growth factors.

Endocrine therapy is an important modality in the treatment of breast cancer. However, the precise molecular mechanisms underlying the growth inhibitory effect of endocrine therapy are unknown. Recently, it has been shown that breast cancer cells express and secrete polypeptide growth factors that can regulate the growth of the cells through autocrine and/or paracrine pathways. These growth factors are thought to be involved in the response to endocrine therapy. Three different mechanisms have been suggested: (1) stimulation of growth inhibitory peptides; (2) repression of mitogenic peptides; and (3) stimulation of mitogenic growth factors in cells overexpressing the corresponding receptor. This article reviews the scientific evidence on which these hypotheses are based.

Breast Neoplasms↗
PubMed1988

Insulin-like growth factor II mRNA expression in human breast cancer.

Insulin-like growth factor II is a growth factor important in fetal development. Several cancer tissues and cell lines have been reported to express IGF-II and rat IGF-II is mitogenic for breast cancer cell lines. Using Northern analysis and ribonuclease protection assays, IGF-II mRNA was detected in normal fibroblasts and in the established breast cancer cell line, T47D. In this cell line, steady state levels of IGF-II message were increased by treatment with estradiol. 10 nM IGF-II, purified from human serum, was mitogenic for breast cancer cell lines. In vitro, IGF-II may act as an autocrine growth factor for some cell lines. RNA derived from breast cancer, pathologically normal breast tissue, and benign breast disease also contained IGF-II mRNA. When paired samples of normal and cancer tissue were obtained from the breast of the same patient, the level of IGF-II mRNA expression in the normal tissue was at least that found in the cancer. This is consistent with previous observations that show IGF-II is expressed in mesenchyme. These findings suggest that in breast cancer IGF-II is produced by stromal tissue elements and potentially by the malignant epithelial cells. Therefore, IGF-II may function as an autocrine or a paracrine growth factor in different breast tumors.

Blotting, Northern↗
PubMed1980

Alcohol consumption and cigarette smoking in Busselton, 1966-1978.

In Busselton, mass health examination (MHE) questionnaires about alcohol consumption indicate that more people are drinking wine and fewer people are drinking beer. The evidence suggests an increase in the number of women consuming alcohol. The proportion of drinkers was higher among patients attending doctors with interests in wineries and/or vineyards compared with those patients attending doctors without such interests. More patients of doctors who smoked were smokers compared with those patient of doctors who were non-smokers. Smoking in Busselton appears to be declining at the rate of 0.5% to 1% of the population per annum; this decline is more marked in people who had attended one or more MHEs than in newcomers to MHEs. These trends have encouraged a more active approach to the prevention of smoking in school children.

Adult↗
PubMed1979

Changing mortality due to strokes in men following treatment of Busselton hypertensives 1967-77.

Regular biennial health screenings of the Busselton population between 1966-75 resulted in the recognition of individuals with hypertension and a progressive increase in the adequacy of control of blood pressure in those on treatment. Between 1973-77 observed mortality from strokes (CVA) in males 50 yrs and over declined significantly as might be expected from the smaller numbers at risk from raised blood pressure. No favourable trends occurred in the incidence of CVA in women despite better control of hypertension. In the population as a whole, CVA mortality in untreated or inadequately controlled hypertensives was significantly greater than in normo-tensives or adequately controlled hypertensives.

Age Factors↗
PubMed1978

Sporting activities and exercise habits of the 1975 Busselton population.

Studies of the sporting activities and exercise habits of the 1975 Busselton population indicated that two out of three subjects exercised either not at all, or less than once a week, and only 7% stated they tried to get out of breath during their exertions. Those in sedentary occupations undertook more leisure exercise than those in non-sedentary occupations, with men exercising more frequently than women. Comparisons of body weights, blood pressures, serum levels of cholesterol and triglycerides, glucose levels, uric acid levels, lung function tests and electrocardiogram tracings between those who exercised four or more times per week and those who exercised less than four times per week revealed significant differences only in relation to lung function tests, which favoured the higher exercise group. This evidence suggested that the levels of activity involved in the Busselton population's sport and exercise habits were failing to provide additional protection against future coronary heart disease.

Adolescent↗
PubMed1976

A six-year controlled trial of prevention of children's behavior disorders.

Preschool interviews between a clinician and mothers were studied to determine their influence upon the behavioral patterns and learning abilities of the mother's children. After six years, 124 children of this experimental group were compared with 122 control children; the results indicated that a significant number of experimental children had fewer fears, sleep disorders, eating problems, loud modes of speech, and aggression toward others and fewer of the girls distorted events to their advantage or demanded their parents to share in joint play. A larger proportion of the experimental children had positive feelings, and to a lesser degree negative feelings, toward their mothers, but a greater number were late for school, with more of the boys being excitable and hard to control. The greater benefits, which were more apparent in the girls than in the boys, were consistent with an effectiveness of more firmly expressed views about the girls, whereas the confidence of the boys' mothers may well have been affected by too cautious an approach to discipline problems. The interviews probably had no influence on the children's learning capacities.

Adult↗
PubMed1976

Carcinoembryonic antigen (CEA), smoking, and cancer in a longitudinal population study.

In 1969, the prevalence of raised levels (5 ng/ml of serum) of carcinoembryonic antigen (CEA) was estimated in 2372 persons aged 40 years and over in Busselton, Western Australia. There were raised levels of CEA in 73 subjects (3%). The prevalence increased progressively with age in both non-smokers and smokers with a higher rate of prevalence at all ages in smokers, and a peak of 11% in smokers aged 65--74 years. Among non-smokers, the prevalence was similar in both men and women (1%), in smokers there was a stepwise rise in prevalence with increasing tobacco consumption. Subsequently, levels of CEA of 5 ng/ml or over tended to disappear from the sera in a greater proportion of the non/exsmokers than of smokers. In the following five years, "CEA-associated" cancer occurred in nine of 73 subjects (13%) with raised levels of CEA compared with 25 in 2299 (1%) in those with normal CEA levels. This association was independent of the confounding effects of age, sex, and smoking habit. The five year data on 2372 subjects have confirmed that CEA screening of healthy Busselton subjects has identified a group at future risk of developing "CEA-associated" cancers, in addition to drawing attention to the presence of existing cancers.

Adult↗
PubMed1976

Community control of hypertension.

The adequacy of treatment of hypertension in a community was monitored at triennial mass health examinations. Hypertensives were not adequately retained on treatment until a disease register was developed and a practice nurse given responsibility for maintaining contact with patients on the register. The advent of newer therapeutic agents and intensification of the interest of both doctor and patient in the results of treatment were associated with progressive improvement in the adequacy of control of blood pressure.

Antihypertensive Agents↗
PubMed1975

Carcinoembryonic antigen in an unselected elderly population: a four year follow up.

Sera obtained in 1969 from 956 unselected elderly persons in Busselton, Western Australia were tested for carcinoembryonic antigen (CEA) by a "double antibody" microradioimmunoassay. Forty-four (4-5%) were positive for CEA (5 ng/ml or greater). Review of health records for the 4-year period subsequent to accession of sera showed that 6 (14%) of the 44 persons positive for CEA died of CEA associated cancers, 15 were heavy smokers, 2 had colonic diverticula and 1 a peptic ulcer. On the other hand, 18 (2%) of the 912 persons negative for CEA developed CEA associated cancers. Thus, a significantly greater proportion of cancers (P = 0-01) was found in the persons positive for CEA. Furthermore, when 21 persons who were positive for CEA in 1969, but clinically well 4 years later, were examined 2 had occult cancer of lung and colon respectively. However, the relatively low yield of diagnosis of cancer from our present population survey led to the conclusion that, if screening for cancer were to be solely dependent on testing for CEA, increased specificity and sensitivity of test systems should be awaited.

Adenocarcinoma↗