The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux.

Because the activities of HER family members are elevated and/or aberrant in a variety of human neoplasms, these cell surface receptors are receiving increasing attention as potential therapeutic targets. In the present study, we examined the effect of combining the HER family tyrosine kinase inhibitor CI1033 (PD 183805) with the topoisomerase (topo) I poison 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, in a number of different cell lines. Colony-forming assays revealed that the antiproliferative effects of simultaneous treatment with CI1033 and SN-38 were synergistic in T98G glioblastoma cells and HCT8 colorectal carcinoma cells, whereas sequential treatments were additive at best. In additional studies examining the mechanistic basis for these findings in T98G cells, immunoblotting revealed that the inhibitory effects of CI1033 on epidermal growth factor receptor autophosphorylation were unaffected by SN-38. Likewise, CI1033 had no effect on topo I polypeptide levels, localization, or activity. Nonetheless, CI1033 markedly enhanced the number of covalent topo I-DNA complexes stabilized by SN-38 or the related agent topotecan (TPT). Analysis of intracellular SN-38 levels by high-performance liquid chromatography and intracellular TPT levels by flow microfluorometry revealed that CI1033 increased the steady-state accumulation of SN-38 and TPT by 9.4 +/- 1.9- and 1.8 +/- 0.2-fold, respectively. Further evaluation revealed that the initial rate of TPT uptake was unaffected by CI1033, whereas the rate of efflux was markedly diminished. Additional studies demonstrated that T98G and HCT8 cells express the breast cancer resistance protein (BCRP), a recently cloned ATP binding cassette transporter. Moreover, CI1033 enhanced the uptake and cytotoxicity of SN-38 and TPT in cells transfected with BCRP but not empty vector. Conversely, CI1033 accumulation was diminished in cells expressing BCRP, suggesting that CI1033 is a substrate for this efflux pump. These results indicate that CI1033 can modulate the accumulation and subsequent cytotoxicity of two widely used topo I poisons in cells that have no history of previous exposure to these agents.

Cost-effectiveness analysis with defined budget: how to distribute resources for the prevention of cardiovascular disease?

The aim of the study was to undertake cost-effectiveness calculations subject to a defined budget. The setting chosen was the prevention of cardiovascular disease (CVD) by means of three intervention programmes in a Swedish county council. The population in the county was divided into subgroups according to risk level. For each subgroup the cost per years of life saved was calculated, as well as the annual budget claims. The budget available was defined as present direct cost in the programmes. The calculations resulted in a programming solution showing the optimal distribution of resources between the programmes. Also a league table was constructed and the cut-off value for a 'acceptable' cost-effectiveness was shown. The conclusion that can be drawn is that a combination of internationally published intervention results and local data regarding epidemiology and resource improves the accuracy and usefulness of cost-effectiveness ratios. However, the model presented is a first attempt containing only three interventions: the planned next phase is to integrate more interventions in the model.

Data warehousing as a basis for web-based documentation of data mining and analysis.

In this paper we present a case study for data warehousing intended to support data mining and analysis. We also describe a prototype for data retrieval. Further we discuss some technical issues related to a particular choice of a patient record environment.

[Cost-effectiveness analysis of cardiovascular disease prevention: a graded list as aid to the rational distribution of resources]. / Analys av kostnadseffektiviteten vid prevention av hjärt-kärlsjukdom: rankinglista ett hjälpmedel för att rätt fördela resurserna.

In a study designed to compare the cost-effectiveness of three cardiovascular disease prevention programmes, subject to a defined budget, a population was subgrouped according to risk levels. Cost per year of life saved and annual budget expenditure were calculated for each subgroup. Budget expenditure was defined in terms of current direct costs. A ranked list was constructed, and the cut-off level of 'acceptable' cost-effectiveness elicited.

Reduction of selection bias in primary prevention of cardiovascular disease through involvement of primary health care.

OBJECTIVE: To examine selection bias in social and health factors in a community intervention programme for the prevention of cardiovascular disease by comparing programme data with both census data and a random sample of the same population. DESIGN: Cross sectional studies. SETTING: All 35 primary health care centres in Västerbotten County, Sweden. SUBJECTS: 24,870 individuals who during 1992 and 1993 became 30, 40, 50 or 60 years of age. MAIN OUTCOME MEASURES: Total income, socio-economic group, employment, education, body mass index (BMI), total cholesterol, systolic and diastolic blood pressure, and daily smoking. RESULTS: The differences in social characteristics between participants and non-participants were marginal, indicating that the social selection bias was small. However, unemployment, low income, and younger age tended to be associated with somewhat lower preference to participate. The overall pattern of health status, as measured by risk factors, was similar rather than dissimilar. While the participants in the intervention health survey had lower mean total cholesterol, their blood pressure was generally higher compared with the reference random sample. CONCLUSIONS: The primary health care system in Sweden might serve as a useful base for educational health counselling, at least within a community intervention programme, for all levels of society.

Markers of high fish intake are associated with decreased risk of a first myocardial infarction.

High intake of fish has been associated with reduced risk of CHD. The high content of n-3 polyunsaturated fatty acids (PUFA) in fish has been suggested to be a protective factor. In addition, fish is the entirely dominating source of methylmercury for the general population, and the concentration of Hg in erythrocytes (Ery-Hg) is often used as an index of fish consumption. Our aim was to study the relationships between a first-ever myocardial infarction, Ery-Hg, activity of gluthathione peroxidase in erythrocytes (Ery-GSH-Px) and plasma concentration of the n-3 PUFA eicosapentaenoic and docosahexaenoic acids (P-PUFA). In a population-based prospective nested case-control study within Northern Sweden seventy-eight cases of a first-ever myocardial infarction were compared with 156 controls with respect to Ery-Hg, P-PUFA and Ery-GSH-Px. Both Ery-Hg and P-PUFA, but not Ery-GSH-Px, were significantly higher in subjects reporting high fish intake (at least one meal per week) than in those with lower intake. This finding suggests that Ery-Hg and P-PUFA reflect previous long-term fish intake. Low risk of myocardial infarction was associated with high Ery-Hg or high P-PUFA. In a multivariate model the risk of myocardial infarction was further reduced in subjects with both high Ery-Hg and high P-PUFA (odds ratio 0.16, 95 % CI 0.04, 0.65). In conclusion, there is a strong inverse association between the risk of a first myocardial infarction and the biomarkers of fish intake, Ery-Hg and P-PUFA, and this association is independent of traditional risk factors.