Aromatase expression in atypical ductal hyperplasia in women.

PURPOSE: To determine the levels of aromatase in atypical ductal hyperplasia (ADH) lesions, tissue surrounding the ADH, and in dense and non-dense normal breast tissue. We postulated that excess aromatase in breast tissue might, through production of increased estrogen, drive the carcinogenic process. Estrogens and their metabolites are thought to contribute to the development of breast cancer through estrogen receptor-mediated mechanisms and genotoxic effects of estrogen metabolites. ADH is a benign lesion of the breast which is associated with substantially increased risk for subsequent development of breast cancer. After 25 years, approximately 30% of women with ADH develop breast cancer. In women with three or more separate ADH lesions at the same time, 47% will develop breast cancer over that time period. Another important risk factor for breast cancer is the presence of mammographically dense breast tissue. METHODS: We utilized quantitative immunochemical analysis of aromatase in biopsy tissue to test this possibility. Previously published results comparing dense with non-dense breast tissue in normal women (Vachon et al. Breast Cancer Res Treat 125:243-252, 2011) were used for comparisons with ADH. A well-characterized histochemical H-score was employed for quantitative assessment of aromatase in the various tissue studied. RESULTS: The H-score of aromatase staining was statistically significantly higher (p = 0.003) in the ADH epithelium than surrounding epithelial tissue. In order of H-score from highest to lowest were ADH, issue surrounding ADH, dense normal and non-dense normal breast tissues. The levels of aromatase in a subset of women with ADH who went on to develop breast cancer were not higher than in women who did not. CONCLUSIONS: We suggest from these studies that overexpression of aromatase in breast tissue and its resultant increase in estradiol levels may contribute to the later development of breast cancer in women with ADH.

Androgen receptor in triple negative breast cancer.

The clinical management of triple negative breast cancer (TNBC) is challenging due to the relatively aggressive biological behaviour and paucity of specific targeted therapy. A subset of TNBC patients has been reported to express androgen receptor (AR) in carcinoma cells and the manipulation of androgen signalling or AR targeted therapies have been proposed. However, the biological significance of AR in TNBC has remained relatively unknown. Therefore, this review aims to summarise the reported studies assessing the rates of AR positivity in TNBC patients and androgenic effects in TNBC cell lines. The rates of AR positivity among TNBC cases varied depending on the study population (0-53% of all TNBC patients). This difference among the reported studies may be largely due to the methodological differences of analysing AR. While the majority of cell line studies suggest that androgen increase proliferation and preliminary clinical studies suggest that AR antagonists improve the prognosis of AR positive TNBC patients, cell line transfection experiments and survival analyses of histological samples suggest that the presence of AR in tumour is either benign or predicts better survival. Therefore further translational investigations regarding the mechanisms of androgen action in TNBC are required to explain this discrepancy between clinical and basic studies.

Measurement of sex steroids in murine blood and reproductive tissues by liquid chromatography-tandem mass spectrometry.

Accurate measurement of sex steroids is essential to evaluate mouse models for human reproductive development and disorders. The recent advent of liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays that match the sensitivity of steroid immunoassay could overcome problems arising from the limited specificity of steroid immunoassay. In this current study we validate a LC-MS/MS assay for the measurement of key sex steroids from murine serum and reproductive tissues. The assay gave excellent dilutional linearity (r(2)> or =0.98) and reproducibility (CV< or =10% of replicate samples) in serum and reproductive tissues with sensitive quantitation limits; testosterone (T; 2pg), dihydrotestosterone (DHT; 10pg), 5alpha-androstane-3alpha,17beta-diol (3alphaDiol; 40pg), 5alpha-androstane-3beta,17beta-diol (3betaDiol; 40pg), estradiol (E2; 0.5pg) and estrone (E1; 0.3pg). Using 0.1mL sample, T was the only consistently detectable steroid (detection limit 20pg/ml) in both male and female mouse serum. In the testis, T and DHT were quantifiable as were both diols at relatively high levels. Prostatic T levels were low and DHT was determined to be the most abundant androgen in this tissue. Uterine and ovarian levels of E2, E1 and T were measurable, with levels varying according to estrous cycle stage. Hence, we demonstrate that this LC-MS/MS method has the sensitivity, specificity and multi-analyte capability to offer accurate steroid profiling in mouse serum and reproductive tissues.

Periodontitis and cytokine expression in CD14 deficient patients.

Patients with paroxysmal nocturnal haemoglobinuria (PNH) are deficient in monocytic CD14. The aim of this research was to determine the interrelationships among periodontal disease status, local levels, and monocytic secretion of inflammatory mediators in patients with PNH and matched controls. This study utilised a cross sectional, non-randomised design. PNH patients and matched controls (age, race, gender) were assessed for periodontal status, levels of PGE2 and IL-1beta within the gingival crevicular fluid (GCF), and levels released from lipopolysaccharide (LPS) stimulated peripheral blood monocytes in culture. Results indicate no statistical differences in extent and severity of periodontal disease or GCF mediator levels between the two groups. Monocyte responses to LPS demonstrated significant differences in PGE2 (P = 0.0009) and IL-1beta (P = 0.003) secretion with PNH monocytes secreting significantly less than controls. A significant positive association was found between the monocytic and GCF levels of PGE2 for all subjects (P = 0.003), PNH (P = 0.015), and control (P = 0.049) groups. This study demonstrated that GPI anchor deficient monocytes have reduced expression of inflammatory mediators in vitro.

Intervention-based assessment: rates of evaluation and eligibility for specific learning disability classification.

Intervention-based assessment, a systematic form of prereferral intervention, represents a viable alternative to "test and place" models for identifying and teaching children with a variety of learning-related problems in schools. Data obtained from 13 schools participating for a third year in a pilot study of statewide implementation of intervention-based assessment suggested that, in comparison to a prior prereferral intervention model, fewer children are evaluated and found eligible for special education. Of those children receiving intervention-based assessment, a slight decrease occurs in the percentage classified as specifically learning disabled.