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Biomedical subjects

W R Miller

Publications and source records attributed to W R Miller.

At least 163 records · Page 9Linked to original sources
PubMed1994

Growth inhibition of oestrogen receptor-positive human ovarian carcinoma by anti-oestrogens in vitro and in a xenograft model.

This paper presents results of the in vitro and in vivo effects of anti-oestrogens on the growth of human ovarian cancer cells. Tamoxifen and the "pure" anti-oestrogens, ICI 164,384 and ICI 182,780, inhibited the oestrogen-stimulated growth of the oestrogen receptor (ER)-positive PE04 and PE01 cell lines grown in culture, the latter two compounds being more potent than tamoxifen. In the absence of 17 beta-oestradiol (E2), tamoxifen, but not the pure anti-oestrogens, produced a small degree of growth stimulation in the PE01 and PE04 lines at concentrations between 10((7) and 10(-9) M. In contrast, growth of the ER-negative PE014 line was unaffected by E2 and all three anti-oestrogens. The effects of tamoxifen and ICI 182,780 on PE04 cells grown as xenografts in nude mice were also studied. Both anti-oestrogens produce significant growth inhibitory effects. These results indicate that ovarian carcinoma cells may be sensitive to anti-oestrogens in vitro and in vivo, and support the view that anti-oestrogens merit further clinical studies in patients with ER-positive tumours.

Adenocarcinoma↗
PubMed1994

The regulation of growth and protein expression by estrogen in vitro: a study of 8 human ovarian carcinoma cell lines.

The effects of 17 beta-estradiol (E2) on the growth and the levels of estrogen receptor (ER), progesterone receptor (PR) and pS2 protein were examined in a range of 8 ovarian carcinoma cell lines. E2 stimulated growth of the 3 cell lines with an ER content of 80-220 fmol/mg protein but not the 5 cell lines with ER concentrations less than 20 fmol/mg protein. After exposure to E2, ER concentration in 2 of the 3 responsive cell lines was decreased relative to untreated cells and in 2 lines, progesterone receptors were increased. No change in steroid receptor levels was observed in cell lines with low or negligible levels of receptors. The pS2 protein was not induced by E2 in the 5 ovarian carcinoma cell lines examined. These results indicate that E2 can stimulate the growth of some ER-positive ovarian carcinoma cells and that these effects may be associated with changes in the cellular levels of steroid hormone receptors.

Breast Neoplasms↗
PubMed1994

Protein kinase A (PK-A) regulatory subunit expression in colorectal cancer and related mucosa.

Photoaffinity labelling (PAL) with [32P]8-azido-cAMP and polyacrylamide gel electrophoresis (PAGE) has been used to identify three specific cAMP-binding proteins (cAMP-BPs) within cytosols derived from the centre and periphery of 32 human colorectal cancers and from related adjacent (less than 5 cm from the tumour) and distant (more than 5 cm from the tumour) microscopically benign mucosa. By immunoprecipitation with specific anti-RI and anti-RII antibodies these proteins have subsequently been characterised as a single form of RI (48 kDa) and two forms of RII (50 and 52 kDa). The relative expression of isoforms in each specimen has been quantified by laser densitometry. There was significantly more RI expressed in both tumour centre and periphery than in either adjacent or distant mucosa (P < 0.008 by Wilcoxon signed-rank test). There was no significant difference in relative RI expression between tumour centre and periphery, or between adjacent and distant mucosa. There was no association between relative RI expression and Dukes' stage. Poorly differentiated tumours expressed significantly more RI than those that were either moderately or well differentiated (P = 0.016 by Mann-Whitney U-test). This study is the first to have characterised cAMP-BPs within human colorectal tissues and has demonstrated that colorectal cancers, and in particular those of poor histological grade, relatively overexpress RI when compared with related benign mucosa.

Affinity Labels↗
PubMed1994

Expression of transforming growth factor beta mRNA isoforms in human breast cancer.

Using an RNAse protection assay, expression of messenger RNA for isoforms of TGF-beta was determined in a series of breast cancers. Of 50 tumours, 45 (90%) expressed TGF-beta 1 mRNA, 39 (78%) expressed TGF-beta 2, and 47 (94%) expressed TGF-beta 3. Patterns of expression varied between different tumours: 37 (74%) cancers expressed all three TGF-beta isoforms, ten (20%) expressed only two isoforms and two expressed TGF-beta 1 alone. One sample showed no evidence of TGF-beta mRNA expression. Although most breast cancers expressed mRNA for at least one isoform of TGF-beta, there were differences in patterns of mRNA expression between individual tumours. The relatively small number of tumours examined precluded detailed analysis between expression and other clinical parameters, but a significant association was identified between one aspect of isoform expression and lymph node status, in that the majority of tumours expressing all three isoforms were associated with lymph node involvement, whereas tumours without one or more isoform were usually lymph node negative (P = 0.025 by Fisher's exact test).

Adult↗
PubMed1994

Cyclic adenosine 3',5'-monophosphate-binding proteins in human ovarian cancers.

The aims of the present study were to characterise an assay for cAMP-binding proteins in ovarian cancer and then to measure levels in a series of tumours with a view to developing a potential prognostic indicator for this disease. Levels and types of binding proteins have been measured in cytosols from 50 ovarian tumours. Binding proteins were detected in all tumours but, as calculated from Scatchard analysis, binding levels ranged from 267 to 12,037 fmol per mg of cytosol protein (mean value of 4248 fmol mg-1). Dissociation constants of binding varied between 0.4 x 10(-8) and 5.9 x 10(-8) (mean value 2.3 x 10(-8)). Types of binding protein were detected by incubation with the photoaffinity ligand 8-N3-[32P]cAMP, followed by polyacrylamide gel electrophoresis and autoradiography. Labelled proteins with molecular weights of 52, 48, 43, 39 and 37 kDa were identified in the cytosols. The proportion and pattern of bands detected varied between different cytosols. The significance of these findings awaits clinical follow-up of the patients.

Adenine Nucleotides↗
PubMed1994

Models of alcoholism used in treatment: contrasting AA and other perspectives with which it is often confused.

Current popular and professional conceptions of alcoholism in the United States blend four models that differ in their emphases and implications and contain mutually contradictory beliefs. Elements of moral-volitional, personality and dispositional disease models have been confused with, and mistakenly attributed to, the essentially spiritual views of Alcoholics Anonymous (AA). An original AA model can be distinguished from prior and subsequent beliefs with which it has been added. Clarity regarding the essential elements of an AA understanding of alcoholism is important both for clinicians and for those who would undertake research on AA.

Alcoholics Anonymous↗
PubMed1994

Drinking and thinking: how does personal drinking affect judgments of prevalence and risk?

In two separate university samples, the effects of individual drinking habits on perceived riskiness and estimated prevalence of drinking practices were studied. In both populations, self-reported drinking behavior was inversely related to perceived riskiness of heavy drinking and drunk driving, but inconsistently related to prevalence estimates for these behaviors. Abstainers also overestimated the commonness of heavy drinking and drunk driving much more than did drinkers who similarly did not engage in these behaviors. These findings are interpreted as consistent with self-serving motivational biases in information processing. Relative to men, women in both populations provided higher estimates of prevalence and riskiness.

Adult↗
PubMed1994

Measurement of drinking behavior using the Form 90 family of instruments.

Although drinking behavior is clearly a central dependent variable in alcoholism treatment research, the field has reached no consensus on measurement methodology for alcohol consumption. At least four methods for quantifying consumption have been commonly used in outcome studies: quantity-frequency questions, average consumption grids, timeline follow-back and self-monitoring. The Form 90 family of structured interviews was developed by collaboration among the Project MATCH investigators, combining the strengths of prior assessment methodologies. The development, structure, supporting software and training approaches for the Form 90 instruments are described.

Alcohol Drinking↗
PubMed1994

Designing studies to investigate client-treatment matching.

The process of designing studies of client-treatment matching involves a number of methodological complexities. Besides the large number of potential client characteristics and a range of possible outcome variables, a variety of treatment attributes can be matched including modality, intensity, duration, format, setting, therapist and goal. Hindsight matching designs (which can include hypothesis testing) examine interactions between client characteristics and treatments to which they were not intentionally matched. Foresight matching designs involve a prospective experimental test of a matching hypothesis, comparing the outcomes of cases matched by specific decision rules with other cases not so matched. Under certain conditions, these hindsight and foresight matching designs are logically equivalent. Mathematical modeling of clinical judgment offers yet another promising avenue for future studies of matching schemas. Glaser's core-shell strategy provides a practical model for implementing clinical systems and research on matching within ongoing services.

Alcoholism↗
PubMed1994

Analysis of the aromatase cytochrome P450 gene in human breast cancers.

Aromatase activity may be detected in most, but not all, breast cancers, and in certain tumours there appears to be decreased sensitivity to the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA). The aims of the present study were to measure aromatase activity, and its sensitivity to 4-OHA, in breast tumours, and to examine the CYP19 gene encoding the aromatase cytochrome P450 (P450arom) for the presence of mutations. In vitro aromatase activity and sensitivity to 4-OHA were measured by determining the conversion of tritiated testosterone to tritiated oestradiol in breast tumour tissue in the absence and presence of 4-OHA (10 nM). Genomic DNA was extracted from five tumours: one showing no detectable aromatase activity and four displaying evidence of aromatase activity (two sensitive and two insensitive to 4-OHA). Subsequent PCR-single-strand conformation polymorphism analysis revealed a variation in the mobility of single-stranded DNA for exons III, VII and X, corresponding, as shown by direct sequencing of PCR products, to common polymorphism of the aromatase gene. This study does not provide evidence for mutation in the coding exons of the P450arom gene which would account for either the absence of aromatase activity or its changed sensitivity to 4-OHA in breast cancers.

Androstenedione↗
PubMed1993

Characterization of the aryl hydrocarbon receptor and aryl hydrocarbon responsiveness in human ovarian carcinoma cell lines.

The human ovarian carcinoma cell lines PE01, PE04, and PE06 express the estrogen receptor and studies with the PE04 cells have shown that tamoxifen inhibits 17 beta-estradiol-induced proliferation. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a broad spectrum antiestrogen which works through the aryl hydrocarbon receptor. Incubation of the three cell lines with [3H]TCDD followed by isolation of nuclear extracts showed that the PE01, PE04, and PE06 cells express the aryl hydrocarbon receptor (23 to 87 fmol/mg protein) which exhibits sedimentation properties (7.5 to 7.9 S) on sucrose gradients similar to that observed in other mammalian species. Aryl hydrocarbon responsiveness was determined by the induction of P4501A1 mRNA levels and ethoxyresorufin O-deethylase activity by TCDD. Induction of both parameters was observed only in the PE04 cells. Gel mobility shift assays with a consensus dioxin-responsive element (DRE, 26-mer) showed that after incubation of the nuclear extracts from the 3 cell lines with 32P-DRE a retarded band formed only with nuclear receptor complex from PE04 cells. 17 beta-Estradiol stimulated proliferation of the PE04 and PE06 but not the PE01 cells; 1 nM TCDD alone either did not affect or inhibited the growth of these cells and 1 nM TCDD significantly inhibited the 17 beta-estradiol-induced proliferation of the PE04 and PE06 cells. Treatment of the PE04 cells with 1 nM 17 beta-estradiol resulted in a time-dependent enhanced secretion of the M(r) 52,000 protein (procathepsin D) and, after 48 h, a 51% increase in the secretion of this protein was observed. Cotreatment of the PE04 cells with 0.1 or 1.0 nM TCDD completely inhibited the 17 beta-estradiol-induced secretion of the M(r) 52,000 protein. These data show that TCDD exhibits antiestrogenic activity in estrogen receptor-positive ovarian carcinoma cell lines; however, in the PE06 cells, there was no correlation between the effects of TCDD on the induction of CYP1A1 gene expression and the results of the gel shift assay (i.e., nonresponsiveness) versus the observed antiestrogenic activity.

Adenocarcinoma↗
PubMed1993

Tumour cyclic AMP binding proteins: an independent prognostic factor for disease recurrence and survival in breast cancer.

In two separate cohorts of breast cancer patients presenting without evidence of distant metastatic disease, high levels of tumour cyclic AMP binding proteins (> 8 pmol/mg cytosol protein) have been shown to be associated with poor prognosis in terms of both disease recurrence and overall survival. This association is independent of known established prognostic factors and allows the identification of a small subgroup of patients whose outlook warrants the implementation of aggressive systemic therapy.

Breast Neoplasms↗
PubMed1993

Factors influencing aromatase activity in the breast.

Particularly in postmenopausal women, peripheral aromatase appears to be the major source of oestrogens which may encourage the growth of hormone-dependent tumours. Studies have therefore been undertaken to determine factors which influence biosynthesis of oestrogens within breast tissues. Aromatase activity was measured in (i) breast cancers by incubating tumour homogenates with [7 alpha 3H]testosterone and characterizing the production of radioactively-labelled oestradiol and (ii) breast fat by incubation of sub-cellular fractions of fibroblast cell lines with [1 beta 3H]androstenedione and monitoring the formation of 3H2O. Evidence has been presented that (i) certain treatment regimes for cancer profoundly influence aromatase activity in breast tumours, (ii) aromatase activity is elevated in breast fat associated with malignancy and (iii) breast-derived fluids and extracts can markedly affect aromatase activity in cultured fibroblasts of breast fat.

Adipose Tissue↗
PubMed1993

Types of cyclic AMP binding proteins in human breast cancers.

Total level and type of cyclic AMP binding proteins have been measured in 117 breast cancers. Six major molecular species of binding proteins were detected. The pattern and relative proportion of binding proteins varied between individual tumours. However, there were highly significant correlations between the expression of different binding proteins, including positive relationships between 52 and 67 kD proteins, 43 kD and both 39 and 37 kD proteins and inverse correlations between 48 and 52 kD, 37 and 67 kD proteins. The expression of three binding proteins (48, 43 and 39 kD) was also positively related to total binding whereas that of the remaining three bindings proteins (67, 52 and 37 kD) was negatively correlated with total levels. It may be that differential expression of certain types of binding protein are the underlying rationale for our previously published finding that tumours with high levels of high binding protein are associated with poor prognosis.

Breast Neoplasms↗
PubMed1993

Enhancing motivation for change in problem drinking: a controlled comparison of two therapist styles.

To investigate the impact of counselor style, a 2-session motivational checkup was offered to 42 problem drinkers (18 women and 24 men) who were randomly assigned to 3 groups: (a) immediate checkup with directive-confrontational counseling, (b) immediate checkup with client-centered counseling, or (c) delayed checkup (waiting-list control). Overall, the intervention resulted in a 57% reduction in drinking within 6 weeks, which was maintained at 1 year. Clients receiving immediate checkup showed significant reduction in drinking relative to controls. The 2 counseling styles were discriminable on therapist behaviors coded from audiotapes. The directive-confrontational style yielded significantly more resistance from clients, which in turn predicted poorer outcomes at 1 year. Therapist styles did not differ in overall impact on drinking, but a single therapist behavior was predictive (r = .65) of 1-year outcome such that the more the therapist confronted, the more the client drank.

Adult↗
PubMed1993

Brief interventions for alcohol problems: a review.

Relatively brief interventions have consistently been found to be effective in reducing alcohol consumption or achieving treatment referral of problem drinkers. To date, the literature includes at least a dozen randomized trials of brief referral or retention procedures, and 32 controlled studies of brief interventions targeting drinking behavior, enrolling over 6000 problem drinkers in both health care and treatment settings across 14 nations. These studies indicate that brief interventions are more effective than no counseling, and often as effective as more extensive treatment. The outcome literature is reviewed, and common motivational elements of effective brief interventions are described. There is encouraging evidence that the course of harmful alcohol use can be effectively altered by well-designed intervention strategies which are feasible within relatively brief-contact contexts such as primary health care settings and employee assistance programs. Implications for future research and practice are considered.

Alcoholism↗