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Biomedical subjects

T Thomas

Publications and source records attributed to T Thomas.

At least 289 records · Page 16Linked to original sources
PubMed1989

Regulation of ornithine decarboxylase gene expression in MCF-7 breast cancer cells by antiestrogens.

Ornithine decarboxylase (ODC) is an enzyme intimately related to cell growth regulation. The metabolic products of ODC, the polyamines, are known to play a vital role in the structure and function of biological macromolecules including nucleic acids and proteins. The activity of ODC is stimulated by estrogens in their target cells. In order to gain insight into the molecular mechanism of action of antiestrogens in human breast cancer, we studied the effect of tamoxifen and 4-hydroxytamoxifen on the concentration of ODC mRNA, ODC activity, and the polyamine levels in a hormone-responsive breast cancer cell line, MCF-7. ODC mRNA concentration was reduced to 40% of the controls after 6 h of treatment of the cells with 100 nM 4-hydroxytamoxifen, but tamoxifen had no significant effect on ODC mRNA after treating with even 1 microM concentration for 36 h. ODC activity was, however, reduced to 40 and 75% of the controls after 24 h of treatment with 4-hydroxytamoxifen and tamoxifen, respectively. There was a significant reduction in the concentration of putrescine to 63% of control in tamoxifen-treated cells, but spermidine and spermine levels were not affected. With 4-hydroxytamoxifen, putrescine, spermidine, and spermine levels were reduced to 41, 62, and 79% of the control, respectively. In addition, exogenous putrescine was able to reverse the growth inhibitory effects of 4-hydroxytamoxifen. Overall, these results indicate that ODC and polyamine levels in MCF-7 cells are controlled by antiestrogens, and that suppression of polyamine biosynthesis plays a critical role in the growth inhibitory effects of antiestrogens.

Blotting, Northern↗
PubMed1989

Up-regulation of estrogen receptors by nonsteroidal antiestrogens in human breast cancer.

Development of resistance to hormonal therapy in breast cancer is frequently associated with a decline or loss of cellular estrogen receptors. Agents which up-regulate the receptor may reduce the incidence of hormonal resistance. Antiestrogens at concentrations ranging from 0.1 to 1 microM produced a 2- to 4-fold increase of estrogen receptors in MCF-7 and T-47D breast cancer cells. This increase, which occurred as early as 3 h and was sustained throughout the 4 days of continuous exposure to tamoxifen, was primarily due to an enhancement in receptor synthesis.

Breast Neoplasms↗
PubMed1989

High affinity binding of estrogen receptor to recombinant plasmids containing (dA-dC)n.(dG-dT)n sequences.

Estrogen receptor is a gene regulatory protein that is present in a subset of breast tumors and in normal sex accessory tissues of vertebrates. The receptor protein forms a high affinity complex with estradiol and mediates its action. The mechanism of action of estrogen receptor (ER) involves its binding to specific DNA sequences in the genome and the stimulation of the expression of estrogen-responsive genes. In order to understand the molecular characteristics of ER-DNA interactions, we studied the relative binding affinity of rabbit uterine ER to recombinant plasmids: pDHf2 with 23-base pair (dA-dC)n.(dG-dT)n insert; pDHf14 with 60-base pair (dA-dC)n.(dG-dT)n insert; pDHg16 with 23-base pair (dG-dC)n.(dG-dC)n insert; and the parental plasmid pDPL6 without any insert. We conducted this study by using a DNA-cellulose elution assay in which the receptor was bound to DNA-cellulose and then eluted with different concentrations of plasmid DNAs in 10 mM Tris.HCl and 1 mM dithiothreitol, pH 7.4. The efficacy of a plasmid to bind to ER was determined from the concentration of the plasmid DNA required to elute 50% of the receptor from DNA-cellulose. The 50% elution concentrations were as follows: pDHf2, 3.2 micrograms/ml; pDHf14, 0.85 micrograms/ml; pDHg16, 200 micrograms/ml; and pDPL6, 340 micrograms/ml. Linearization of pDHf14 with HindIII reduced its binding efficacy only slightly, with a 50% elution concentration of the linear plasmid at 3.2 micrograms/ml. In contrast, the linear polynucleotide, poly(deoxyadenylate-deoxycytidylate).poly(deoxyguanylate-deoxythymidylat e [poly(dA-dC).poly(dG-dT)] and calf thymus DNA were 1650 and 880-fold less efficient, respectively, than pDHf14 in eluting ER from DNA-cellulose. These results show that the presence of short stretches of (dA-dC)n.(dG-dT)n sequences has a dramatic effect in increasing the binding affinity of ER to DNA. Since these sequences are reported to be conformationally ultrapolymorphic, a possible explanation for this increased binding might be the assumption of a conformational state of the inserted sequence to a form that has high affinity for ER.

Animals↗
PubMed1989

Direct evidence for the presence of left-handed conformation in a supramolecular assembly of polynucleotides.

Hexammine cobalt(III) chloride (Co(NH3)6(3+) provokes a B-DNA----Z-DNA----psi-DNA conformational transition in poly(dG-dC).poly(dG-dC) and poly(dG-m5dC).poly(dG-m5dC). The circular dichroism spectrum of psi-DNA is characterized by a manyfold increase of positive ellipticity in the range of 300-225 nm and the complete absence of a negative peak. In order to ascertain the helical handedness of psi-DNA, we used a recently developed enzyme immunoassay technique. This method consisted of treating the polynucleotides with Co(NH3)6(3+) to convert them to the Z- or psi-DNA forms and immobilizing these conformations on a microtiter plate. The plates were subsequently treated with a monoclonal anti-Z-DNA antibody Z22, alkaline phosphatase conjugated, affinity purified immunoglobulins, and the phosphatase substrate. The enzyme-substrate reaction was monitored by reading the absorbance at 405 nm with a microplate autoreader. The monoclonal anti-Z-DNA antibody had no reactivity to the B-DNA form, but bound strongly to both the Z- and psi-DNA forms, showing that Co(NH3)6(3+)-induced psi-DNA form of the polynucleotides exists in the left-handed Z-DNA conformation.

Antibodies↗
PubMed1989

The expression of alpha(1)-acid glycoprotein mRNA during rat development. High levels of expression in the decidua.

During the acute phase response to inflammation the plasma concentration of some proteins, such as alpha(1-acid glycoprotein (AGP), increases dramatically. Since breakdown and remodeling of tissue is common to both nidation and inflammation we studied the tissue distribution and regulation of AGP mRNA levels during the embryonic development of the rat. High levels of mRNA coding for AGP were detected in the placenta during early fetal development. Expression of this mRNA was confined to the decidua and was first observed approximately 1 day after implantation when proliferation of the decidua is already well advanced. Maximum levels were attained about 5 days after implantation, after which the levels decreased rapidly. In contrast to the high levels of AGP mRNA in the decidua only very low levels were detected in fetal liver and visceral yolk sac, and there was only a small increase in the levels in maternal liver. Corticosteroid hormone responsiveness of AGP mRNA synthesis by hepatocytes appeared 3 days before birth. It is likely that the synthesis of AGP by the cells of the decidua is important in establishing the precisely controlled interaction between mother and embryo during nidation.

Aging↗
PubMed1989

The expression of genes coding for positive acute-phase proteins in the reproductive tract of the female rat. High levels of ceruloplasmin mRNA in the uterus.

High levels of ceruloplasmin mRNA were measured in the uterus of both pregnant and non-pregnant rats. No mRNA for alpha 2-macroglobulin and alpha 1-acid glycoprotein could be detected in the uterus in contrast to the high levels of those two mRNAs found in the decidua in the mid-gestation period. Synthesis of plasma proteins with a protective function in the decidua or uterus may be important in maintaining homeostasis at different stages of reproduction. In addition, ceruloplasmin synthesis by the uterus may be part of a system transporting copper to the fetus.

Acute-Phase Proteins↗
PubMed1989

Lung cancer in motor exhaust-related occupations.

The association between employment in motor exhaust-related occupations and the risk for lung cancer was examined in 2,291 male cases of lung cancer and 2,570 controls in data pooled from three U.S. case control studies carried out by the National Cancer Institute between 1976 and 1983. Most analyses were limited to subjects providing direct, in-person interviews, including 1,444 cases and 1,893 controls. For those providing direct interviews and employed 10 years or more in motor exhaust-related (MER) occupations, the age, smoking, and study area adjusted odds ratio (OR) for lung cancer was 1.5 (95% CI = 1.2-1.9). Risk was elevated for truck drivers (OR = 1.5; 95% CI = 1.1-1.9) and for other MER occupations (OR = 1.4; 95% CI = 1.1-2.0). The odds ratios associated with MER employment of 10+ years were 1.6 (95% CI = 1.2-2.1) for whites and 1.4 (95% CI = 0.9-2.1) for nonwhites; 1.2 (95% CI = 0.7-2.0) [corrected] for those with possible exposure to other recognized or reported lung carcinogens; and 1.6 (95% CI 1.2-2.1) for those without such exposure. The 50% excess risk for lung cancer associated with employment in motor exhaust-related occupations could not be explained by greater use of cigarettes or by other occupational exposures among these workers.

Aged↗
PubMed1989

Developmental patterns of gene expression of secreted proteins in brain and choroid plexus.

The proteins secreted by the choroid plexus throughout rat brain development were analyzed by two-dimensional polyacrylamide gel electrophoresis following biosynthetic labeling of choroid plexus pieces with [14C]leucine in vitro. Approximately 20 major protein species were resolved which, with the exception of transferrin, transthyretin, and alpha 2-macroglobulin, appear to be unrelated to proteins found in high concentrations in plasma. Several patterns of developmental regulation were observed. At least two of the proteins were synthesized and secreted at high levels only by fetal choroid plexus, whereas the secretion of several other proteins including transferrin and proteins comigrating with cystatin C and alpha 2-macroglobulin increased only after birth. The levels of mRNA coding for transferrin, ceruloplasmin, cystatin C, alpha 2-macroglobulin, beta 2-microglobulin, and transthyretin were measured in the brain during development by dot hybridization and northern gel analysis. No mRNA was detected coding for the proteins alpha-fetoprotein, alpha 1-antitrypsin, haptoglobin, and thiostatin in the brain at any stage. For those proteins, which are produced in other parts of the brain as well as by the choroid plexus, the changes in their corresponding mRNA levels measured in whole brain paralleled the changes in their secretion by the choroid plexus. The results presented in this paper show that the choroid plexus is active in protein secretion at all stages studied. The changing pattern of protein secretion by the choroid plexus, combined with its early development compared with other tissues in the brain, suggests that it is active in providing the appropriate extracellular environment for the growth and differentiation of the brain.

Aging↗
PubMed1989

Corticosterone's dual metabolic actions.

Corticosterone possesses two distinctly opposite metabolic actions. The actions are strictly dose-dependent and are linked to type I and type II corticosteroid receptor binding. These conclusions are drawn from continuous infusion studies where corticosterone yields a bitonic dose-response curve for body weight gain and feeding efficiency. Anabolic at low serum levels, corticosterone concentrations above 2 micrograms/dl bring about an opponent catabolic process that intensifies and eventually masks the anabolic action. Relatively pure type I (aldosterone) and type II (RU28362 and dexamethasone) corticosterone receptor agonists produce opposite monotonic functions that respectively mimic the ascending and descending arms of the corticosterone dose-response curve. Stimulation of either receptor increases the proportion of carcass fat to lean body mass by either increasing carcass lipids (type I) or by reducing protein (type II).

Aldosterone↗
PubMed1989

The acute phase response in the rodent.

In the rodent, the general response to acute inflammation and tissue damage is characterized by a complex rearrangement in the pattern of concentrations of proteins in the plasma leading to an increase in the sedimentation rate of erythrocytes, an increase in leukocyte concentration in the bloodstream, and a decrease in the hematocrit. Body temperature changes only slightly or not at all. The reasons for the change in plasma concentrations of proteins are changes in their rates of synthesis in the liver. Degradation of plasma proteins is not affected. The details of the acute phase response evolved in the interaction of species with their environment. Therefore, it is not surprising to find differences in the details of the acute phase response among species. For example, alpha 2-macroglobulin is a strongly positive acute phase reactant in the rat, but not in the mouse; C-reactive protein is a strongly positive acute phase protein in the mouse, but is not found in the rat. An inducible acute phase cysteine proteinase inhibitor system, which has evolved from a primordial kininogen gene, has been observed so far only in the rat. The changes in the synthesis rates of acute phase proteins during inflammation are closely reflected by corresponding changes in intracellular mRNA levels. In the liver, the capacity to induce the acute phase pattern of synthesis and secretion of plasma proteins probably develops around birth. Changes in mRNA levels are brought about by changes in transcription rates or by changes in mRNA stability. Kinetics of mRNA changes during the acute phase response differ for individual proteins. The main signal compound for eliciting the acute phase response in liver seems to be interleukin-6/interferon-beta 2/hepatocyte stimulating factor, whereas interleukin-1 leads to typical acute phase changes in mRNA levels only for alpha 1-acid glycoprotein, albumin, and transthyretin. Plasma protein genes are expressed in various extrahepatic tissues, such as the choroid plexus, the yolk sac, the placenta, the seminal vesicles, and other sites. All these tissues are involved in maintaining protein homeostasis in associated extracellular compartments by synthesis and secretion of proteins. Synthesis and secretion of plasma proteins in paracompartmental organs other than the liver is not influenced by the acute phase stimuli.

Acute-Phase Proteins↗
PubMed1988

Proportion of lung cancers in males, due to occupation, in different areas of the USA.

Occupational data from 5 case-control studies in the United States involving 2,973 male cases and 3,210 controls were analyzed to estimate the percentage of lung cancer attributable to well-known and suspected lung carcinogens. The studies were conducted in areas heterogeneous in terms of industrial activities. The percentage of lung cancers attributable to occupations entailing potential exposure to well-recognized carcinogens ranged, by study area, from 3 to 17%. The further inclusion of occupational groups with suspect carcinogenic exposures changed these estimates very little. Exclusion of data derived from next-of-kin interviews influenced the estimates of attributable risks, but not in a systematic fashion. The estimates also varied according to ethnic group, smoking status and birth cohort, with higher values in non-whites, non-smokers and among members of more recent birth cohorts. Possible errors in exposure classification, which may make these estimates conservative, are discussed.

Humans↗
PubMed1988

Morbidity profile of the Mamre community.

Various morbidity parameters in Mamre, a village of 4,623 residents in the western Cape, are described. Acute morbidity (either injury or illness) occurring in the 2 weeks before the survey was reported by 4% of respondents. Investigation of several chronic conditions for which people said that they were receiving treatment yielded rates of 57/1,000 for hypertension, 29/1,000 for 'nerves', 13/1,000 for diabetes and 19/1,000 for tuberculosis; 9.9% of respondents reported disability. Reported morbidity increased with age, was commoner in women than in men, and agreed with perceptions of individuals' health. Tuberculosis, inadequate sewerage and water facilities, alcohol abuse and dusty roads were perceived to be the main health problems by the community. The morbidity profile and the relatively high rate of pscyhosocial problems found are consistent with a process of urbanisation in a predominantly working-class community.

Adolescent↗
PubMed1988

Mamre Community Health Project--demographic, social and environmental profile of Mamre at baseline.

Demographic, social and environmental information was collected from 4,623 residents in 870 Mamre households: 34.3% of the population were under 15 years and 4.4% over 65 years of age, while 2.7% of adults had had no education, 42.1% had only primary school education, 51.1% secondary school education and 4.1% had had some tertiary education. Education and age were inversely related. Of employable adults 64.7% were working. Community, social and personal services and manufacturing accounted for 76% of the male and 92% of the female jobs. Cape Town or Atlantis was the workplace for 78% of male and 87.2% of female workers. Of the labour supply 17.2% were unemployed; 75% of employed people were semi-skilled and unskilled workers. There was a mean of 5.3 persons per household, with a median of 3 rooms per household. Of the houses 18.4% were older than 80 years; 38% of households had inside taps and 98% had outside tap(s). Sewage disposal by the bucket system was used in 86% of households while 13% used flush toilets. The mean amount of money spent on fuel was R10.92 per person per month. The Mamre community is well past the initial phase of rural-urban transition in terms of its sociodemographic profile. At present, critical environmental infrastructural changes are being introduced.

Demography↗
PubMed1988

A twenty-two-fold increase in the relative affinity of estrogen receptor to poly (dA-dC).poly (dG-dT) in the presence of polyamines.

We studied the relative efficacy of polyamines to facilitate the binding of estrogen receptor to poly(dA-dC).poly(dG-dT). In the absence of polyamines, 1,400 micrograms/ml of this polynucleotide eluted 50% of bound estrogen receptor from DNA-cellulose. In contrast, 50% estrogen receptor was eluted by 65 micrograms/ml of poly(dA-dC).poly(dG-dT) complexed with 150 microM spermidine. Putrescine and spermine also enhanced the ability of poly(dA-dC).poly(dG-dT) to elute estrogen receptor, but the magnitude of the effect was not as high as that of spermidine. Control experiments with calf thymus DNA and poly(dA-dT).poly(dA-dT) showed 6- and 3-fold increase, respectively in their affinity for estrogen receptor in the presence of spermidine. The dramatic increase in the affinity of poly(dA-dC).poly(dG-dT) for estrogen receptor in the presence of polyamines might be a result of the conversion of the polynucleotide to the left-handed Z-DNA form. These results show that polyamines are capable of participating in estrogenic regulation of gene expression by altering the affinity of the receptor for specific DNA sequences.

Animals↗