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Biomedical subjects

W R Miller

Publications and source records attributed to W R Miller.

At least 73 records · Page 4Linked to original sources
PubMed2000

A simple scale of Gorski's warning signs for relapse.

OBJECTIVE: Though it has enjoyed widespread popularity, Gorski's post-acute withdrawal syndrome (PAWS) model of relapse has been subjected to little scientific scrutiny. A scale to operationalize Gorski's 37 warning signs was developed and tested in a larger prospective study of predictors of relapse. Of central interest were: (1) whether the warning signs hypothesized by Gorski are interrelated in a meaningful single factor and (2) whether the hypothesized syndrome would accurately predict subsequent relapses. METHOD: A sample of 122 individuals (84 men) entering treatment for alcohol problems was followed at 2-month intervals for 1 year. The Assessment of Warning-signs of Relapse (AWARE) scale was administered at each assessment point, and the occurrence of both slips (any drinking) and relapses (heavy drinking) was monitored during each subsequent 2-month interval. Principal factor analysis was used to study the factor structure of the warning signs. RESULTS: Of the 37 warning signs, 28 clustered as a robust single factor with excellent internal consistency (Cronbach's alpha: 0.92-0.93). A conservative evaluation of test-retest stability across 2-month intervals estimated reliability at r = 0.80. After covarying for prior drinking status, clients' AWARE scores significantly predicted subsequent slips and relapses. Relapse rates for clients with highest AWARE scores, as projected by regression equations, were 33 to 46 percentage points higher than those for clients with lowest AWARE scores, after taking into account prior drinking status. CONCLUSIONS: This scale of Gorski's warning signs appears to be a reliable and valid predictor of alcohol relapses.

Adult↗
PubMed2000

Antiaromatase agents: preclinical data and neoadjuvant therapy.

Novel drugs such as exemestane are highly potent and specific inactivators of aromatase activity in test systems such as placental microsomes, breast cancer homogenates, and cultures of mammary fibroblasts, with IC50 values in the nmol range. When given in daily milligram amounts to postmenopausal women, exemestane almost totally blocks peripheral aromatase and reduces circulating estrogens to levels that are at the limit of detection of current assays. Additionally, exemestane profoundly inhibits in situ aromatase activity both in breast cancers and surrounding nonmalignant breast. In postmenopausal women with large estrogen receptor-rich cancers, these endocrine influences translate into antitumor effects, and, for example, following exemestane treatment in the neoadjuvant setting, tumor resolution may be observed on mammography. In conclusion, the ability to block estrogen biosynthesis peripherally and locally within the breast provides new options for the treatment of hormone-sensitive breast cancers in postmenopausal women

Aromatase Inhibitors↗
PubMed2000

Rediscovering fire: small interventions, large effects.

Unexpected findings are often the spark for new discoveries and theories. A puzzle emerged from a series of unanticipated findings over 3 decades, indicating that for problem drinkers (a) relatively brief interventions can trigger significant change, (b) increasing the intensity of treatment does not consistently improve outcome, (c) therapist empathy can be a potent predictor of client change, and (d) a single empathic counseling session can substantially enhance the outcome of subsequent treatment. These phenomena are considered in light of other findings in the addictions-treatment-outcome literature. There is, at present, no cogent explanation for the efficacy of brief interventions. An ancient construct is explored as one possible factor in how some brief encounters may exert large effects in human change.

Alcoholism↗
PubMed2000

The effects of neoadjuvant anastrozole (Arimidex) on tumor volume in postmenopausal women with breast cancer: a randomized, double-blind, single-center study.

Anastrozole, an orally active, nonsteroidal aromatase inhibitor, was evaluated in a randomized, double-blind, single-center study to determine its efficacy as neoadjuvant therapy in postmenopausal women with newly diagnosed, estrogen receptor-rich, locally advanced or large (>3 cm), operable breast cancers. Twenty-four eligible patients were recruited into the study and received either 1 mg (n = 12) or 10 mg (n = 12) of anastrozole daily over a 3-month period. Tumor volumes were estimated clinically, by using caliper measurements and ultrasound (at baseline and after 1, 2, and 3 months' treatment) and by mammography (at baseline and after 3 months). Tumor volume was also measured in surgical specimens. Twenty-one patients were classified as T2, two patients as T3, and one patient as T4B at baseline. Three patients had clinical evidence of lymph node involvement. When considering the difference between the volume as measured by each assessment and the actual pathological volume, the interquartile range and the difference between the maximum and minimum values were smaller for ultrasound when compared with those measured with calipers and mammography. Therefore, of the three clinical assessments of tumor volume used in this study, the data suggest that ultrasound may be the most accurate. The median reductions in tumor volumes as measured by ultrasound for those patients with a measurable 12-week assessment were 80.5 and 69.6% for anastrozole (1 and 10 mg, respectively) after 12 weeks of treatment and 75.5% when both doses were grouped together. Moreover, of these patients, 11 of 12 given 1 mg and 7 of 11 given 10 mg of anastrozole were found on ultrasound to have a >50% reduction in tumor volume after 12 weeks of treatment. Of the 17 patients who would have required a mastectomy at initiation of treatment, 15 were suitable for breast conservation after anastrozole treatment. These results suggest that anastrozole is highly effective as neoadjuvant therapy in postmenopausal women with estrogen receptor-rich, large, operable breast cancer. Future studies comparing anastrozole with tamoxifen as a neoadjuvant treatment should be considered.

Aged↗
PubMed1999

Risk of breast cancer in women with palpable breast cysts: a prospective study. Edinburgh Breast Group.

BACKGROUND: 7% of women in the western world develop palpable breast cysts. Studies of the relation between cysts and breast cancer have conflicting results. There are two clearly defined types of cyst. We investigated whether one cyst type is associated with a higher rate of breast-cancer development than the other. METHODS: We studied 1374 women with palpable breast cysts presenting between 1981 and 1987, who had cysts aspirated between 1981 and 1989. Cysts were classified as type I if the sodium/potassium (Na+/K+) ratio in the cyst fluid was less than 3, or type II if the Na+/K+ ratio was 3 or more. Data on incidence of breast cancer were available until January, 1995, and we compared them with the expected numbers of cancers calculated from age-specific breast-cancer incidence in Scotland in 1988. FINDINGS: 65 cancers developed during follow-up. The overall standardised incidence rate of breast cancer in patients with palpable cysts was 2.81 (95% CI 2.17-3.59). The relative incidence rate was increased for all cyst types. The standardised incidence rate of developing breast cancer among women younger than 45 years was highest at 5.94 (2.97-10.63), with a significant trend for decreasing relative incidence rate with age (p<0.05). Women older than 54 years had a standardised incidence rate of 1.73 (0.86-3.10). The standardised incidence rate of breast cancer was highest in the first year after aspiration (7.02 [3.73-12.00]) but the risk was still raised after 5 years (2.68 [1.84-3.76]). INTERPRETATION: Women with breast cysts are at an increased risk of breast cancer, especially at younger ages. The type of cyst did not alter the associated relative incidence rate of breast-cancer development.

Adult↗
PubMed1999

Expression of enzymes of covalent protein modification during regulated and dysregulated proliferation of mammary epithelial cells: PKA, PKC and NMT.

Three proteins are functionally interlinked in the targeting of protein phosphorylation catalyzed by the C-subunit of PKA: PKA itself, AKAPs and NMT. Furthermore, in a variety of biological contexts, mechanisms exist whereby PKA and PKC are able to modulate the activity of one another. We have investigated the expression and subcellular distribution of these proteins in two models of mammary cell proliferation and differentiation--the normal rat mammary gland during pregnancy and lactation and human breast tissue before and after malignant transformation. Modulation of PKA does not acutely affect activity or sub-cellular distribution of PKC in mammary acini, nor does modulation of PKC acutely affect PKA activity or subcellular distribution. Therefore, the co-ordinate expression of these two protein kinases in normal and cancerous mammary epithelial cells and the greater basal activation level of them both accompanying increased mitogenic activity, which we have reported, does not result from short-term cross-talk between them. Although basal and total levels of PKA diminish in rodent mammary epithelial cells during the transition from proliferative to secretory functional mode, the level of expression of AKAPs increases. The expression of two apparently mammary-specific and mostly membrane-associated AKAPs is tightly linked to the onset and maintenance of differentiated function in rat mammary tissue. Paradoxically, the probable analogues of these two AKAPs in human mammary tissue are hyperexpressed when normal epithelial cells transform to a cancer phenotype--conventionally regarded as a process involving a degree of dedifferentiation. Mammary AKAP hyperexpression in breast cancers is accompanied by increases in the levels of total and basal PKA. One mechanism whereby NMT is targeted to membranes, via interaction with ribosomal proteins, has recently been elucidated. Our data support the contention that the localization of NMT is an important variable in the regulation of cellular proliferation, but they do not characterize the mechanisms whereby the differential targeting of NMT is achieved. As yet we lack a full tool-kit with which to examine NMT either to draw firm conclusions regarding the identity of particular isoforms found in particular sub-cellular locations or to define the relationships between these different molecular variants. However, it is technically possible to transfect cells with inducible NMT expression constructs engineered in such a way that the recombinant, catalytically competent, NMT that they encode is targeted either to membranes or to cytosol: an exploration of the effects of such transfections on cellular proliferation would afford a critical test of the mechanistic involvement of NMT in the control of mitogenesis.

Acyltransferases↗
PubMed1999

Paracrine regulation of ovarian cancer by endothelin.

Previous studies have demonstrated that endothelin (ET) isoforms (ET-1, ET-2 and ET-3) can act in an autocrine manner in ovarian cancer while in breast cancer their role has been proposed to be that of a paracrine mitogen. To explore the possibility that endothelin isoforms might function not only as autocrine regulators but also as paracrine mitogens in ovarian cancers, we investigated their effects on the growth of ovarian fibroblasts derived from ovarian carcinomas, the interaction between ovarian carcinoma and fibroblast cells and the location of the isoform expression in primary ovarian tumours. ET-1, ET-2 and ET-3 stimulated the growth of three ovarian fibroblast cell lines at concentrations ranging from 10(-12) M to 10(-7) M. Inhibition of 125I-ET binding by the ETA receptor antagonist BQ123 and the ETB receptor antagonist BQ788 suggested the presence of both types of ET receptors in fibroblast cells. In the absence of ET-1, neither BQ 123 nor BQ 788 inhibited growth. However, both antagonists inhibited ET-1 stimulated growth suggesting the involvement of both receptor types in ET-1 growth regulation. In contrast to carcinoma cells which secrete measurable levels of ET-1, fibroblast cell lines did not secrete detectable protein. Co-culture experiments (using porous membrane insert wells) of fibroblasts with carcinoma cells demonstrated that growth of both populations of cells was increased compared with either grown in isolation. In this system, growth of the fibroblast cell line was partially inhibited by both BQ123 and BQ788, whilst growth of the PE014 carcinoma cell line was inhibited by only BQ123. RT-PCR measurements detected the presence of the ETA receptor subtype in 10/10 primary ovarian cancers but the presence of ETB receptor in only 6/10 cancers. Using specific antibodies, ET-1 was found in 11/15, ET-2 in 5 of 7 and ET-3 in 5/7 primary ovarian cancers predominantly in the epithelial cells but with some stromal expression. These data indicate that the ET isoforms may stimulate growth of the fibroblast population within an ovarian cancer in addition to stimulating the epithelial cells and since the ETs are expressed in the majority of ovarian cancers, this paracrine effect may contribute to the overall growth of the tumour.

Cell Division↗
PubMed1999

Engaging the unmotivated in treatment for alcohol problems: a comparison of three strategies for intervention through family members.

In a randomized clinical trial, 130 concerned significant others (CSOs) were offered 1 of 3 different counseling approaches: (a) an Al-Anon facilitation therapy designed to encourage involvement in the 12-step program, (b) a Johnson Institute intervention to prepare for a confrontational family meeting, or (c) a community reinforcement and family training (CRAFT) approach teaching behavior change skills to use at home. All were manual-guided, with 12 hr of contact. Follow-up interviews continued for 12 months, with 94% completed. The CRAFT approach was more effective in engaging initially unmotivated problem drinkers in treatment (64%) as compared with the more commonly practiced Al-Anon (13%) and Johnson interventions (30%). Two previously reported aspects of the Johnson intervention were replicated: that most CSOs decide not to go through with the family confrontation (70% in this study) and that among those who do, most (75%) succeed in getting the drinker into treatment. All 3 approaches were associated with similar improvement in CSO functioning and relationship quality. Overall treatment engagement rates were higher for CSOs who were parents than for spouses. On average, treatment engagement occurred after 4 to 6 sessions.

Adult↗
PubMed1999

Inhibition of transforming growth factor alpha (TGF-alpha)-mediated growth effects in ovarian cancer cell lines by a tyrosine kinase inhibitor ZM 252868.

The modulating effects of the epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor ZM 252868 on cell growth and signalling have been evaluated in four ovarian carcinoma cell lines PE01, PE04, SKOV-3 and PE01CDDP. Transforming growth factor alpha (TGF-alpha)-stimulated growth was completely inhibited by concentrations > or =0.3 microM in the PE01 and PE04 cell lines and by > or =0.1 microM in SKOV-3 cells. TGF-alpha inhibition of PE01CDDP growth was reversed by concentrations > or =0.1 microM ZM 252868. TGF-alpha-stimulated tyrosine phosphorylation of both the EGF receptor and c-erbB2 receptor in all four cell lines. The inhibitor ZM 252868, at concentrations > or =0.3 microM, completely inhibited TGF-alpha-stimulated tyrosine phosphorylation of the EGF receptor and reduced phosphorylation of the c-erbB2 protein. EGF-activated EGF receptor tyrosine kinase activity was completely inhibited by 3 microM ZM 252868 in PE01, SKOV-3 and PE01CDDP cells. These data indicate that the EGF receptor-targeted TK inhibitor ZM 252868 can inhibit growth of ovarian carcinoma cells in vitro consistent with inhibition of tyrosine phosphorylation at the EGF receptor.

Cell Division↗
PubMed1999

Regulation and function of the extracellular matrix protein tenascin-C in ovarian cancer cell lines.

The extracellular matrix glycoprotein tenascin-C (TN) is overexpressed in the stroma of malignant ovarian tumours particularly at the interface between epithelia and stroma leading to suggestions that it may be involved in the process of invasion (Wilson et al (1996) Br J Cancer 74: 999-1004). To define regulation of TN further and investigate its function in ovarian cancer, a range of cell line models were studied. Concentrations of secreted TN in media from cultures of ovarian fibroblast cell lines were at least 100-fold greater than from carcinoma cell lines. Evidence for paracrine regulation of TN secretion was obtained by co-culture of carcinoma cells with fibroblast cells wherein secretion into the media was greater than from fibroblasts alone. Transforming growth factor (TGF)-beta1, insulin-like growth factor (IGF)-II and progesterone all stimulated TN secretion while human choriogonadotropin (hCG), follicle-stimulating hormone (FSH) and gamma-interferon inhibited secretion. TGF-beta1 produced the greatest stimulation of TN in cultured fibroblasts and its co-expression with TN was examined in primary ovarian tumours. There was a significant association between the presence of moderate-strong expression of TN and TGF-beta1. Evidence for TN having a functional role in ovarian carcinoma was obtained from adhesion and migration assays. The PE01, PE04, SKOV-3 and 59M cell lines all demonstrated marked adhesion to plastic coated with TN relative to the control protein bovine serum albumin (BSA) and expressed alpha2beta1 and alpha3beta1 integrins. The SKOV-3 cell line migrated more rapidly through TN than through BSA indicating that TN can facilitate migration of ovarian carcinoma cells.

Animals↗
PubMed1999

Reproducibility of microvessel counts in breast cancer specimens.

Assessment of tumour vascularity in core biopsy specimens may be a useful predictor of response to primary therapy. This study addresses practical methodological issues regarding accuracy of tumour vascularity assessments in different breast cancer specimens. Issues addressed in the study are variation caused by (i) inherent observer variation in the method, (ii) tumour heterogeneity and (iii) previous surgical manipulation of tumours. Microvessel counts were performed by two observers on separate occasions and by two different observers. Counts were performed on core biopsies and tumour sections taken simultaneously (n = 16) and with an intervening time interval (n = 21). In addition core biopsies were obtained from the same tumour on two separate occasions (n = 10). A highly significant correlation was found in counts performed by the same observers at different times and between two different observers. No significant correlation was found in counts of core biopsies and tumour sections taken either simultaneously or subsequently. No correlation was found between counts of sequential core biopsies. Study findings suggest that, although microvessel counts may be assessed reproducibly by the same and different observers, counts performed in core biopsies do not accurately reflect those of overall tumour, limiting their potential as predictive or prognostic markers.

Adult↗
PubMed1999

Nipple aspirate fluid in relation to breast cancer.

Samples of breast ductal fluid can be obtained by nipple aspiration. Such samples may contain a variety of exfoliated or shed cells and display a distinctive biochemical profile reflecting the microenvironment of the ductal-alveolar system of the breast. Study of nipple aspirates may, therefore, shed light on the biology of breast cancer. This review summarizes the more important aspects of published data and explores potential avenues for future study with particular regard to molecular-biological approaches.

Journal Article↗
PubMed1999

Findings of a pilot study of motivational interviewing with pregnant drinkers.

OBJECTIVE: Cost-effective interventions are needed for counseling pregnant drinkers, in order to reduce risk of fetal alcohol effects. METHOD: 42 pregnant women who reported alcohol consumption participated in this pilot study of motivational interviewing. Following a comprehensive alcohol use assessment, the participants were randomly assigned to receive either written information about the risks related to drinking during pregnancy or a one-hour motivational interview. The motivational interview was an empathic, client-centered, but directive session focusing on the health of the participants' unborn babies. RESULTS: At the end of a 2-month follow-up period, the 34 women (81%) who remained in the study showed a significant reduction in alcohol consumption and peak intoxication levels. Women who had reported the highest blood alcohol concentration (BAC) levels during early pregnancy showed a significantly greater reduction in their estimated BACs at follow-up (during later pregnancy) if assigned to the treatment rather than the control condition. CONCLUSIONS: Motivational interviewing shows promise as a specific intervention for initiating a reduction in drinking among pregnant women who are at greatest risk. Simpler assessment and advice may suffice for women with lower initial consumption levels.

Adult↗
PubMed1999

Biology of aromatase inhibitors: pharmacology/endocrinology within the breast.

Both mammary adipose tissue and breast cancers have the ability to aromatize androgens into oestrogens. Such potential may maintain the growth of hormone-dependent tumours. It has therefore been important to determine the effects of new aromatase inhibitors such as formestane, exemestane, anastrozole and letrozole on oestrogen biosynthesis and concentrations of endogenous hormones within the breast. Studies based on in vitro incubations of breast cancer and cultures of mammary adipose tissue fibroblasts demonstrate that these drugs are highly effective inhibitors, with IC50 values ranging between 1 and 50 nM (although the relative efficacy varies between tissues and test systems). Despite this potential, in vitro incubations of breast tissues from patients treated with type II inhibitors such as aminoglutethimide and letrozole can display paradoxically high aromatase activity; this appears to be caused by the reversible nature of the inhibition, coupled with induction/stabilization of the aromatase enzyme. To assess in situ effects within the breast, postmenopausal women with large primary breast cancers have been treated neoadjuvantly with aromatase inhibitors using a protocol that included (i) breast biopsy before treatment, (ii) definitive surgery after 3 months of treatment and (iii) infusion of [3H]androstenedione and [14C]oestrone in the 18 h immediately before biopsy and surgery. With this study design, it has been shown that drugs such as letrozole profoundly inhibit in situ aromatase activity and reduce endogenous oestrogens within the breast.

Antineoplastic Agents↗
PubMed1999

Effects of aromatase inhibitors on the pathobiology of the human breast, endometrial and ovarian carcinoma.

It is very important to examine the influence of inhibition of in situ estrogen production on the pathobiology of human sex steroid-dependent tumors in order to understand the clinical effects of aromatase inhibitors. We have examined the biological changes before and after aromatase inhibitor treatment in vitro (endometrial and ovarian cancer) and in vivo (breast cancer). First, we analyzed these changes using histoculture of 15 human endometrial cancers and 9 ovarian cancers. Five of the fifteen endometrial cancers and four of the nine ovarian cancers demonstrated decreased [3H]thymidine uptake or Ki67 labeling index after 14alpha-hydroxy-4-androstene-3,6,17-trione (NKS01) treatment. In ovarian cancer cases, the responsive cases tended to be associated with higher aromatase and estrogen receptor alpha (ER) expression compared with the other cases but this was not seen in the endometrial cancer cases. There were no changes in ER and aromatase expression before and after NKS01 treatment in either ovarian or endometrial cancer cases. We then studied the same primary human breast tumors before and after aminoglutethimide (AMG, n=3) and 4-hydroxyandrostenedione (4-OHA, n=3) treatment. Tumor aromatase activity increased in 3 cases and decreased or was unchanged in 3 cases but aromatase immunoreactivity in stroma and adipocytes was unaltered in 5 cases. There were no changes in the ER labeling index before or after treatment. Five of the six cases including the responsive cases tended to be associated with decreased cell proliferation or Ki67 expression and increased apoptosis when examined by the TUNEL method. These results indicate that aromatase inhibitors may exert their effects on human breast and other cancers through decreasing proliferation and increasing apoptosis, possibly without altering ER status.

Antineoplastic Agents↗
PubMed1999

Lessons from the use of aromatase inhibitors in the neoadjuvant setting.

Postmenopausal patients with oestrogen receptor-positive locally advanced T4b, N0-1, M0 and large operable breast cancers T2>3 cm, T3, T4, N0-1 and M0 have been treated with 2.5 mg letrozole (12 patients), 10 mg letrozole (12 patients), 1 or 10 mg anastrozole (24 patients) and 20 mg tamoxifen (65 patients). There was no apparent difference in response rate between 2.5 and 10 mg letrozole. Only 17 patients with anastrozole have so far completed the 3-month treatment period. Median clinical, mammographic and ultrasound reductions in tumour volumes for patients treated with letrozole were 81% (95% confidence interval (CI) 66-88), 77% (95% CI 64-82) and 81% (95% CI 69-86) respectively and for anastrozole, values were 87% (95% CI 59-97), 73% (95% CI 58-82) and 64% (95% CI 52-76) respectively. This compares with a median reduction in tumour volume for tamoxifen-treated patients as assessed by ultrasound of 48% (95% CI 27-48). There were seven complete clinical responses (CR), sixteen patients who achieved 50% or greater reduction in tumour volume (PR) and one no change (NC) for letrozole and four CRs, twelve PRs and one progressive disease for anastrozole. Best radiological responses were one CR, twenty PRs and three NCs for letrozole and one CR, fifteen PRs and one NC for anastrozole. This study has shown that the new aromatase inhibitors, letrozole and anastrozole, are highly effective agents in the neoadjuvant setting and they should now be compared with tamoxifen as first-line treatment in a randomised study.

Aged↗