The development of tamoxifen resistance and consequent disease progression are common occurrences in breast cancers, often despite the continuing expression of estrogen receptors (ER). Tamoxifen is a mixed antagonist, having both agonist and antagonist properties. We have suggested that the development of tamoxifen resistance is associated with an increase in its agonist-like properties, resulting in loss of antagonist effects or even inappropriate tumor stimulation. Nuclear receptor function is influenced by a family of transcriptional coregulators, that either enhance or suppress transcriptional activity. Using a mixed antagonist-biased two-hybrid screening strategy, we identified two such proteins: the human homolog of the nuclear receptor corepressor, N-CoR, and a novel coactivator, L7/SPA (Switch Protein for Antagonists). In transcriptional studies, N-CoR suppressed the agonist properties of tamoxifen and RU486, and L7/SPA increased agonist effects. We speculated that the relative levels of these coactivators and corepressors may determine the balance of agonist and antagonist properties of mixed antagonists, such as tamoxifen. Using quantitative RT-PCR, we, therefore, measured the levels of transcripts encoding these coregulators, as well as the corepressor SMRT, and the coactivator SRC-1, in a small cohort of tamoxifen-resistant and sensitive breast tumors. The results suggest that tumor sensitivity to mixed antagonists may be governed by a complex set of transcription factors, which we are only now beginning to understand.

Breast Neoplasms↗

PubMedDate not supplied

Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial.

BACKGROUND: Adjuvant radiotherapy is effective treatment for stage I seminoma, but is associated with a risk of late non-germ-cell cancer and cardiovascular events. After good results in initial studies with one injection of carboplatin, we undertook a large randomised trial to compare the approaches of radiotherapy with chemotherapy in seminoma treatment. METHODS: Between 1996 and 2001, 1477 patients from 70 hospitals in 14 countries were randomly assigned to receive radiotherapy (para-aortic strip or dog-leg field; n=904) or one injection of carboplatin (n=573; dose based on the formula 7x[glomerular filtration rate+25] mg), at two trial centres in the UK and Belgium. The primary outcome measure was the relapse-free rate, with the trial powered to exclude absolute differences in 2-year rates of more than 3%. Analysis was by intention to treat and per protocol. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN27163214. FINDINGS: 885 and 560 patients received radiotherapy and carboplatin, respectively. With a median follow-up of 4 years (IQR 3.0-4.9), relapse-free survival rates for radiotherapy and carboplatin were similar (96.7% [95% CI 95.3-97.7] vs 97.7% [96.0-98.6] at 2 years; 95.9% [94.4-97.1] vs 94.8% [92.5-96.4] at 3 years, respectively; hazard ratio 1.28 [90% CI 0.85-1.93], p=0.32). At 2 years' follow-up, the absolute differences in relapse-free rates (radiotherapy-chemotherapy) were -1.0% (90% CI -2.5 to 0.5) by direct comparison of proportions, and 0.9% (-0.5 to 3.0) by a hazard-ratio-based approach. Patients given carboplatin were less lethargic and less likely to take time off work than those given radiotherapy. New, second primary testicular germ-cell tumours were reported in ten patients allocated irradiation (all after para-aortic strip field) and two allocated carboplatin (5-year event rate 1.96% [95% CI 1.0-3.8] vs 0.54% [0.1-2.1], p=0.04). One seminoma-related death occurred after radiotherapy and none after carboplatin. INTERPRETATION: This trial has shown the non-inferiority of carboplatin to radiotherapy in the treatment of stage I seminoma. Although the absence of disease-related deaths and preliminary data indicating fewer second primary testicular germ-cell tumours favour carboplatin use, these findings need to be confirmed beyond 4 years' follow-up.

Adult↗

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Tamoxifen resistant breast cancer: coregulators determine the direction of transcription by antagonist-occupied steroid receptors.

Pharmacological antagonists of steroid receptor action had been thought to exert their effects by a passive mechanism driven principally by the ability of the antagonist to compete with agonist for the ligand binding site. However, recent analyses of antagonist-occupied receptor function suggest a more complex picture. Antagonists can be subdivided into two groups, type I, or pure antagonists, and type II, or mixed antagonists that can have variable transcriptional activity based upon differential dimerization and DNA binding properties. This led us to propose that receptor antagonism may not simply be a passive competition for the ligand binding site, but may, in some cases, involve active recruitment of corepressor or coactivator proteins to produce a mixed transcriptional phenotype. We used a yeast two-hybrid screen to identify proteins that interact specifically with antagonist-occupied receptors. Two proteins have been characterized: L7/SPA, a ribosome-associated protein that is localized in both the cytoplasm and nucleus, but with no known extranucleolar nuclear function; and hN-CoR, the human homolog of the mouse thyroid receptor corepressor mN-CoR. In in vivo transcription assays we show that L7/SPA enhances the partial agonist activity of type II mixed antagonists, and that N-CoR and the related corepressor, SMRT, suppresses it. The coregulators do not affect agonists or pure antagonists. Moreover, the net agonist activity seen with mixed antagonists is a function of the ratio of coactivator to corepressor. Based upon these results, we proposed that in breast tumors the inappropriate agonist activity seen with therapeutic antagonists such as tamoxifen is responsible for the hormone-resistant state. To confirm this, we are quantitating coactivator/corepressor ratios in breast tumor cells lines and clinical breast cancers. Results should provide new insights into the mechanisms underlying the progression of breast cancer to hormone resistance, and may suggest strategies for delaying or reversing this process.

Animals↗

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Modeling for health care and other policy decisions: uses, roles, and validity.

The role of models to support recommendations on the cost-effective use of medical technologies and pharmaceuticals is controversial. At the heart of the controversy is the degree to which experimental or other empirical evidence should be required prior to model use. The controversy stems in part from a misconception that the role of models is to establish truth rather than to guide clinical and policy decisions. In other domains of public policy that involve human life and health, such as environmental protection and defense strategy, models are generally accepted as decision aids, and many models have been formally incorporated into regulatory processes and governmental decision making. We formulate an analytical framework for evaluating the role of models as aids to decision making. Implications for the implementation of Section 114 of the Food and Drug Administration Modernization Act (FDAMA) are derived from this framework.

Chlorofluorocarbons↗

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AIDS and biomedical research funding: comparative analysis.

One of the critical policy questions raised by the AIDS epidemic is the proper size of the United States federal government's commitment to AIDS-related research. The extent of the federal government's investment in AIDS-related research in relation to research investments in cancer, coronary heart disease, and unintentional injuries is examined. Appropriation levels for fiscal year 1986 are divided by indexes of projected disease burden for 1991 to create a research investment ratio for each health impairment. Indexes of disease burden include numbers of total deaths, early deaths, expected life years lost, and discounted life years lost and direct economic costs. Despite the uncertainty about the future of the AIDS epidemic, there is no indication that AIDS is being overfunded relative to cancer and heart disease. Injuries appear to receive relatively low funding priority. Confident conclusions about research priority depend upon resolution of qualitative considerations and better understanding of the dynamics of the AIDS epidemic.

Acquired Immunodeficiency Syndrome↗

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Oregon's Medicaid ranking and cost-effectiveness: is there any relationship?

The authors examine whether Oregon's 1990, 1991, 1992, and 1993 prioritized lists were ranked in a manner consistent with cost-effectiveness. Two sets of cost-effectiveness data are used: data from economic analyses and Oregon's own cost-effectiveness data. Comparing the ranks of Oregon's lists with the ranks of cost-effectiveness estimates from the literature reveals Spearman correlations of -0.08 for the 1990 list, +0.39 for the 1991 list, +0.25 for the 1992 list, and +0.24 for the 1993 list. Comparing Oregon's lists with Oregon's own cost-effectiveness data reveals rank correlations of +0.99 for the 1990 list, +0.06 for the 1991 list, -0.05 for the 1992 list, and -0.03 for the 1993 list. Thus, there appear to be essentially no relationship between the 1990 list and cost-effectiveness estimates from the economic literature and modest positive relationships between the 1991-93 lists and the literature. In addition, there is virtually no relationship between the 1991-93 lists and Oregon's own cost-effectiveness data. Further, the correlations are very different from +1.0, suggesting that other factors are at play. For example, the 1993 list that is currently being implemented was ranked primarily by improvement in five-year survival and human judgment, not cost-effectiveness.

Cost-Benefit Analysis↗

PubMedDate not supplied

The effect of surface treatments on the bond strength of a nonprecious alloy-ceramic interface.

PURPOSE: The purpose of this study was to compare the effect of seven different alloy surface treatments on the bond strength of the porcelain-metal interface. MATERIALS AND METHODS: Three layers of opaque porcelain and a measured thickness of dentin porcelain were applied to nickel-chromium alloy. A tensile bond strength test was used. RESULTS: The alloy surface treatment that exhibited the highest bond strength was sandblast + surface grinding + sandblast + de-gas, whereas the alloy surface treatment that exhibited the lowest bond strength was sandblast + surface grinding + sandblast + steam cleaning + de-gas. There was a significant difference between the two methods (P < 0.05). CONCLUSION: It was concluded that de-gassing the alloy prior to porcelain application increased the bond strength and excess surface grinding of the alloy reduced bond strength; steam cleaning the alloy surface prior to de-gassing and porcelain application also significantly reduced the bond strength.

Analysis of Variance↗

PubMedDate not supplied

The nature and properties of drugs which give rise to dependence.

Explore the source record for details and available documents.

Antidepressive Agents↗

PubMedDate not supplied

Late revision of fibular malunion in ankle fractures.

Eleven patients with fibular malunion after ankle fracture healed with stiff, painful joints and radiographic evidence of fibular malunion, diastasis of the ankle mortice, and talar tilt. Reconstruction was performed by mobilizing the fibula (by osteotomy or through the old fracture site), lengthening the fibula, and restoring the ankle mortice anatomically. The operation was done three months to three years after the initial fracture in patients ranging in age from 26 to 52 years. The average follow-up period was 3.3 years. Radiographically, seven patients had the ankle joint restored anatomically. Four patients had residual talar tilt. On clinical assessment, eight patients were rated as good, two fair and improving, and one poor resulting in fusion. Good functional results were maintained at long-term follow-up examination. The factors that determined the success of the revision were the duration of the malunion, the quality of the reduction achieved, and the condition of the articular cartilage at the time of revision. Late correction of the malunited fibula with diastasis of the ankle mortice is an effective means of salvaging function in a joint otherwise destined to be stiff and painful.

Adult↗

PubMedDate not supplied

Retention of the compression screw in sliding screw plate devices.

Distraction forces at the site of an unstable intertrochanteric fracture can cause disengagement of the sliding hip screw from the barrel of the side plate. If such a device is used for unstable comminuted intertrochanteric fractures, the compression screw should be retained.

Aged↗

PubMedDate not supplied

The cost effectiveness of three programs to increase use of bicycle helmets among children.

Each year in the United States, 280 children die from bicycle crashes and 144,000 are treated for head injuries from bicycling. Although bicycle helmets reduce the risk of head injury by 85 percent, few children wear them. To help guide the choice of strategy to promote helmet use among children ages 5 to 16 years, the cost effectiveness of legislative, communitywide, and school-based approaches was assessed. A societal perspective was used, only direct costs were included, and a 4-year period after program startup was examined. National age-specific injury rates and an attributable risk model were used to estimate the expected number of bicycle-related head injuries and deaths in localities with and without a program. The percentage of children who wore helmets increased from 4 to 47 in the legislative program, from 5 to 33 in the community program, and from 2 to 8 in the school program. Two programs had similar cost effectiveness ratios per head injury avoided. The legislative program had a $36,643 cost and the community-based one, $37,732, while the school-based program had a cost of $144,498 per head injury avoided. The community program obtained its 33 percent usage gradually over the 4 years, while the legislative program resulted in an immediate increase in usage, thus, considering program characteristics and overall results, the legislative program appears to be the most cost-effective. The cost of helmets was the most influential factor on the cost-effectiveness ratio. The year 2000 health objectives call for use of helmets by 50 percent of bicyclists. Since helmet use in all these programs is less than 50 percent, new or combinations of approaches may be required to achieve the objective.

Adolescent↗