Search PubMed⌕ Search

Biomedical subjects

R Clarke

Publications and source records attributed to R Clarke.

At least 19 recordsLinked to original sources
PubMed1996

Animal models of breast cancer: their diversity and role in biomedical research.

Animal models of breast cancer have been widely used to study various aspects of breast cancer biology, and are remarkably diverse, encompassing chemically and virally induced tumors, human tumor xenografts, and transgenic mouse models. Several novel models have become available during the past few years, including tumors induced by polyomavirus and adenovirus, and a series of human cell line variants. The several following articles describe, in some detail, the characteristics of these models and their relevance to the human disease. Descriptions of each of the major models, e.g., 7,12-dimethylbenz(a)anthracene-induced, MMTV-associated, and human breast cancer cell line xenografts, also are included. The limitations and advantages of several of these models, and some issues relating to the choice of models, are briefly discussed in this overview.

Animal Welfare↗
PubMed1996

Human breast cancer cell line xenografts as models of breast cancer. The immunobiologies of recipient mice and the characteristics of several tumorigenic cell lines.

The ability to maintain and study human tissues in an in vivo environment has proved to be a valuable tool in breast cancer research for several decades. The most widely studied tissues have been xenografts of established human breast cancer cell lines into athymic nude mice. Human breast tumor xenografts provide the opportunity to study various important interactions between the tumor and host tissues, including endocrinologic, immunologic, and tumor-stroma interactions. The nude mouse is not the only immune-deficient recipient system in which to study xenografts. Additional single and combined mutant strains have been used successfully, including mice homozygous for the severe combined immune deficiency mutation (scid), both the beige (bg) and nude (nu) mutations in combination (bg/nu), and mice bearing the combined bg/nu/xid mutations. The differing immunobiologies are discussed, with particular reference to the immunobiology of breast cancer, as are the characteristics of several of the more frequently utilized breast cancer xenografts and cell lines. The ability of several endocrine treatments to modulate effectors of cell mediated immunity, e.g., estrogens and antiestrogens, and the effect of site of inoculation on tumor take and metastasis, also are described.

Animals↗
PubMed1996

Specific binding of estradiol to rat coronary artery smooth muscle cells.

We report the expression and characteristics of the estrogen receptor in rat coronary artery-derived smooth muscle cells. Polymerase chain reaction analyses of total and poly(A) + mRNA from rat coronary artery-derived smooth muscle cells indicate the presence of estrogen receptor mRNA. Binding analyses reveal the presence of high affinity binding sites for 17 beta-estradiol, with a Kd equivalent to that observed for authentic estrogen receptors in other estrogen responsive tissues. Scatchard and Hill plot analyses of the properties of receptor-ligand binding indicate the presence of a single site, and the absence of cooperative binding. Unlabeled E2 but not testosterone, dexamethasone or progesterone compete with [3H] 17 beta-estradiol for binding sites. The affinity, specificity and non-cooperative nature of the estrogen binding sites are identical to those observed in other estrogen-responsive tissues. These cells may provide a novel model in which to study the effects of estrogens on the proliferation, differentiation and function of vascular smooth muscle cells.

Animals↗
PubMed1996

MDA435/LCC6 and MDA435/LCC6MDR1: ascites models of human breast cancer.

We have established a novel ascites tumour model (MDA435/LCC6) from the oestrogen receptor-negative, invasive and metastatic MDA-MB-435 human breast cancer cell line. MDA435/LCC6 cells grow as both malignant ascites and solid tumours in vivo in nude mice and nude rats, with a tumour incidence of approximately 100%. Untreated mice develop ascites following i.p. inoculation of 1 x 10(6) cells and have a reproducible life span of approximately 30 days, with all animals dying within a 48 h period. The in vivo response of MDA435/LCC6 ascites to several cytotoxic drugs, including doxorubicin, etoposide (VP-16), BCNU and mitomycin C, closely reflects the activity of these single agents in previously untreated breast cancer patients. MDA435/LCC6 cells also retain the anchorage-dependent and anchorage-independent in vitro growth properties of the parental MDA-MB-435 cells, and can be used in standard in vitro drug screening assays. The drug resistance pattern of the MDA435/LCC6 cells suggests that they may have few active endogenous drug resistance mechanisms. To generate a model for the screening of MDR1-reversing agents, MDA435/LCC6 were transduced with a retroviral vector directing the constitutive expression of the MDR1 cDNA, producing a cell line with a classical MDR1 resistance pattern (MDA435/LCC6MDR1). THese ascites models may be a viable alternative to the murine leukaemia ascites (L1210, P388) and, in conjunction with other breast cancer cell lines, facilitate the in vitro and in vivo screening of new cytotoxic drugs and drug combinations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Cigarette smoking, tar yields, and non-fatal myocardial infarction: 14,000 cases and 32,000 controls in the United Kingdom. The International Studies of Infarct Survival (ISIS) Collaborators.

OBJECTIVES: To assess the effects of cigarette smoking on the incidence of non-fatal myocardial infarction, and to compare tar in different types of manufactured cigarettes. METHODS: In the early 1990s responses to a postal questionnaire were obtained from 13,926 survivors of myocardial infarction (cases) recently discharged from hospitals in the United Kingdom and 32,389 of their relatives (controls). Blood had been obtained from cases soon after admission for the index myocardial infarction and was also sought from the controls. 4923 cases and 6880 controls were current smokers of manufactured cigarettes with known tar yields. Almost all tar yields were 7-9 or 12-15 mg/cigarette (mean 7.5 mg for low tar (< 10 mg) and 13.3 for medium tar (> or = 10 mg). The cited risk ratios were standardised for age and sex and compared myocardial infarction rates in current cigarette smokers with those in non-smokers who had not smoked cigarettes regularly in the past 10 years. RESULTS: At ages 30-49 the rates of myocardial infarction in smokers were about five times those in non-smokers (as defined); at ages 50-59 they were three times those in non-smokers, and even at ages 60-79 they were twice as great as in non-smokers (risk ratio 6.3, 4.7, 3.1, 2.5, and 1.9 at 30-39, 40-49, 50-59, 60-69, 70-79 respectively; each 2P < 0.00001). After standardisation for age, sex, and amount smoked, the rate of non-fatal myocardial infarction was 10.4% (SD 5.4) higher in medium tar than in low tar cigarette smokers (2P = 0.06). This percentage was not significantly greater at ages 30-59 (16.6% (7.1)) than at 60-79 (1.0% (8.5)). In both age ranges the difference in risk between cigarette smokers and non-smokers was much larger than the difference between one type of cigarette and another (risk ratio 3.39 and 3.95 at ages 30-59 for smokers of similar numbers of low and of medium tar cigarettes, and risk ratio 2.35 and 2.37 at ages 60-79). Most possible confounding factors that could be tested for were similar in low and medium tar users, with no significant differences in blood lipid or albumin concentrations. CONCLUSION: The present study indicates that the imminent change of tar yields in the European Union to comply with an upper limit of 12 mg/cigarette will not increase (and may somewhat decrease) the incidence of myocardial infarction, unless they indirectly help perpetuate tobacco use. Even low tar cigarettes still greatly increase rates of myocardial infarction, however, especially among people in their 30s, 40s, and 50s, and far more risk is avoided by not smoking than by changing from one type of cigarette to another.

Adult↗
PubMed1995

Effect of estrogen withdrawal on energy-rich phosphates and prediction of estrogen dependence monitored by in vivo 31P magnetic resonance spectroscopy of four human breast cancer xenografts.

The effect of estrogen withdrawal on energy metabolism was studied in four human breast cancer xenografts: the estrogen-dependent MCF-7 and ZR75-1 and the estrogen-independent ZR75/LCC-3 and MDA-MB-231. The tumors were grown in ovariectomized nude mice with a s.c. implanted estrogen pellet. After Gompertzian growth was verified, the estrogen pellet was removed from half of the animals. In vivo 31P magnetic resonance spectroscopy of the tumors was performed 1 day before and on days 2, 6, and 14 after estrogen removal. Estrogen withdrawal induced a significant increase in the nucleoside triphosphate:Pi ratio in the two estrogen-dependent xenografts, whereas this ratio remained unchanged in the estrogen-independent tumors. In ZR75/LCC-3 tumors a slight decrease in nucleoside triphosphate:Pi was observed following onset of estrogen stimulation after initial growth without estrogen. Extracts of freeze-clamped tumors prepared 14 days after estrogen removal were analyzed for ATP and phosphocreatine content. Our findings suggest a correlation between estrogen withdrawal and the steady-state concentrations of ATP, phosphocreatine, and Pi in human breast cancer xenografts. Discrimination analysis of the pretherapeutic spectra enabled us to identify the tumor line and the estrogen dependence of the tumors in 80-90% of all cases.

Animals↗
PubMed1995

Hormone dependence of breast cancer cells and the effects of tamoxifen and estrogen: 31P NMR studies.

Many breast tumors appear to progress from estrogen-dependent growth to a more malignant phenotype characterized by estrogen-independent growth, antiestrogen resistance, and a high metastatic potential. Utilizing 31P NMR spectroscopy on human breast cancer cells growing in vitro, we have investigated the effects of 17 beta-estradiol and tamoxifen on the metabolic/bioenergetic spectra of a series of human breast cancer cells that vary in their estrogen and antiestrogen responsiveness. A comparison of baseline spectra associates higher levels of phosphodiesters and UDP-glucosides (e.g. UDP-glucose, UDP-N-acetylglucosamine), and lower phosphocholine/glycerylphosphocholine and phosphocholine/phosphoethanolamine ratios, with the acquisition of estrogen-independent growth in estrogen receptor expressing cells. No metabolic changes are clearly associated with the metastatic phenotype. Whilst estrogen treatment produces no consistently significant spectral changes in any of the cell lines, the estrogen-independent and estrogen-responsive MCF7/MIII cell line responds to tamoxifen treatment by significantly increasing all spectral resonances 30%-40% above baseline values. This may reflect a tamoxifen-induced change to a more differentiated or apoptotic phenotype, or an attempt by the cells to reverse the inhibitory effects of the drug. The ability to detect metabolic changes in response to tamoxifen by NMR spectroscopy may provide a novel means to identify those tumors that are responsive to antiestrogen therapy.

Adenocarcinoma↗
PubMed1995

Reversible hepatic dysfunction in association with cyclophosphamide therapy.

A 5.5-year-old child with nephrotic syndrome was treated with cyclophosphamide. After 9 weeks of therapy she developed jaundice and abnormal liver function tests. No infective aetiology was found and the abnormal liver function tests resolved within 5 weeks of discontinuing cyclophosphamide. Cyclophosphamide has rarely been reported to cause liver dysfunction, but not in children treated for nephrotic syndrome, and paediatricians should therefore be aware of its potential for inducing reversible hepatic dysfunction.

Child, Preschool↗
PubMed1995

Use of a monoclonal antibody to ovine IgE for fly strike studies in sheep.

A new monoclonal raised against sheep IgE was used to examine sera and wound exudates from sheep which had been struck by Lucilia cuprina in the field. The antibody was also used to detect the presence of IgE in sera and skin sections from sheep which had been artificially infected with fly larvae 3 times. Neither total, nor L. cuprina specific circulating IgE could be detected in serum or wound exudates from struck sheep. Cell bound IgE was, however, identified by the monoclonal in skin sections from struck sheep and from a control sheep which had not been struck. No difference in the number of IgE positive cells was observed between the control and 2 of the 3 artificially infected sheep, and none of the latter showed an increase in IgE positive cells even after 3 infections. One sheep showed twice as many IgE positive cells as the other treated sheep and the third larval infection was difficult to establish and limited in size and severity. This suggests a relationship between innate resistance to strike and the number of IgE positive cells present in skin.

Animals↗
PubMed1995

FMS mutations in patients following cytotoxic therapy for lymphoma.

Point mutations at codons 301 and 969 of the FMS proto-oncogene have been reported in both myelodysplasia (MDS) and acute myeloid leukaemia (AML). We report here the incidence of such mutations in patients at risk of developing secondary MDS and AML. Peripheral blood DNA from 70 patients in remission from lymphoma was screened for mutations by oligonucleotide (ONH) using mutant specific probes. Codon 969 mutations were detected in 11 of the 70 (15.7%) cases. No codon 301 mutations were detected. Five of these mutations were confirmed using an independent technique (single nucleotide primer extension analysis, SNPE) and a further mutation was detected in a single patient using single-stranded conformational polymorphism analysis (SSCP). No codon 969 mutations were detected in 62 lymphoma biopsy specimens from these patients or from three patients with detectable FMS mutations where pre-therapy marrow was investigated by ONH. No mutations at either codons 301 or 969 were detected by ONH in 61 normal controls. Somatic mutations at codon 969 of the FMS gene occur commonly following cytotoxic therapy for lymphoma and their detection indicates the presence of a clonally expanded population of abnormal cells.

Adult↗
PubMed1995

Non-neoplastic glandular structures in bone marrow: a technical artefact.

A case of non-neoplastic glandular structures embedded in the centre of a bone marrow trephine biopsy is described. This is a hitherto unreported phenomenon. These glandular structures originated from the dermal sweat gland and represented an artefactual lesion produced by the biopsy procedure. The importance of considering the possibility of non-neoplastic glandular structures in bone marrow is stressed, in order to avoid a misdiagnosis of metastatic adenocarcinoma.

Adenocarcinoma↗