The role of inflammation in atrial fibrillation following open heart surgery.

This study investigated the role of systemic inflammation in the development of atrial fibrillation (AF) after coronary artery bypass grafting (CABG). CABG was performed using cardiopulmonary bypass in 77 patients. Pre-operative AF was present in six patients (7.8%) and postoperative AF developed in 13 (18.3%) of the 71 patients with pre-operative sinus rhythm. Post-operative mediastinal drainage was significantly increased in patients with post-operative AF compared with those with sinus rhythm. Plasma E-selectin, P-selectin and vascular cell adhesion molecule levels were not significantly different between patients with pre- and post-operative sinus rhythm, those with pre-operative sinus rhythm and post-operative AF, and those with pre- and post-operative AF. There were significant differences between pre- and post-operative C-reactive protein, interleukin (IL)-6 and IL-10 levels within all three groups, but no differences in these parameters between the groups. Thus, in all groups there were significant alterations in mediators indicative of systemic inflammation following CABG, but comparisons between the groups revealed no differences predictive of AF.

Relationship between basic fibroblast growth factor and transforming growth factor-beta 2 in breast cyst fluid.

Women with "apocrine" breast cysts (usually having intracystic Na/K < 3) may have a higher risk of developing breast cancer than women with breast cysts lined by flattened epithelium (usually having intracystic Na/K > 3). In this study the concentrations of basic fibroblast growth factor (bFGF), a potent mitogen, and transforming growth factor-beta 2 (TGF-beta 2), which exerts a growth inhibitory effect on epithelial cell types, were measured in breast cyst fluid and their relationship studied. Both growth factors were measured by "sandwich" enzyme immunometric assays. The concentrations of both bFGF and TGF-beta 2 were significantly higher (P < 0.001) in the Na/K > 3 group (median 444 fmol/L, range: < 56 fmol/L-7,890 fmol/L, n = 23 and median 1,776 pmol/L, range: 20.4 pmol/L-5,000 pmol/L, n = 19 respectively) than in the Na/K < 3 group (median < 56 fmol/L, range: < 56 fmol/L-2,722 fmol/L, n = 21 and median 176 pmol/L, range: 12 pmol/L-1,940 pmol/L, n = 23 respectively). Significantly positive correlations were found between bFGF and TGF-beta 2 (rS = 0.496, n = 37, P = 0.002), bFGF and Na/K (rS = 0.599, n = 44, P < 0.001) and TGF-beta 2 and Na/K (rS = 0.521, n = 42, P < 0.001). The significantly higher concentrations of the growth inhibitory TGF-beta 2 in the Na/K > 3 cyst group may provide an explanation for the lower risk of breast cancer which has been observed in this group of women. The role of bFGF in mammary carcinogenesis is unclear as lower levels of this growth factor are present in breast cancer tissue and breast cancer cell lines than in normal breast tissue and cell lines. The positive correlation between bFGF and TGF-beta 2 may indicate regulation by a common factor or that one of these growth factors may regulate the production of the other. This is the subject of further study.

Insulin-like growth factor binding protein-3 in breast cyst fluid: relationships with insulin-like growth factors I and II and transforming growth factor-beta 1 and 2.

Women who have palpable breast cysts with intracystic Na/K > 3 may have a lower risk of developing breast cancer than those with intracystic Na/K < 3. In this study significantly higher concentrations of insulin-like growth factor-binding protein-3 (IGFBP-3), insulin-like growth factors I and II (IGF-I, IGF-II) and transforming growth factor-beta 2 (TGF-beta2) were found in the Na/K > 3 sub-group. No difference was found in transforming-growth factor-beta 1 (TGF-beta1) levels between the two sub-groups of breast cysts. A positive correlation was obtained for IGFBP-3 and TGF-beta1 in the Na/ K > 3 sub-group consistent with reports that TGF-beta1 may regulate the production of IGFBP-3. Equimolar amounts of total IGFs and IGFBP-3 in breast cyst fluid imply that most, if not all, of these IGFs are protein-bound. The significantly higher concentrations of TGF-beta2 in the Na/K > 3 sub-group may partly explain the lower risk of breast cancer in this group of women.

Effect of transforming growth factor beta 2 on oestrogen metabolism in the MCF-7 breast cancer cell line.

Transforming growth factor beta (TGF-beta) is a multifunctional regulator of cellular growth and differentiation in many cell types and has a growth inhibitory effect on mammary epithelial cells. The TGF-beta 2 isoform has been shown to be present in high concentrations in breast cyst fluid and might have a protective role in breast cancer. In addition, oestrogens play an important role in breast cancer development, and oestrone sulphate (E1S) might be the main source of active oestrogens in the breast. The aim of this study was to assess the effect of TGF-beta 2 on oestrogen synthesis in an attempt to understand the mechanism by which TGF-beta 2 may exert a protective effect in breast cancer. In this study, higher concentrations of TGF-beta 2 significantly inhibited the conversion of E1S to oestrone (E1) and the conversion of E1 to the potent oestrogen, oestradiol (E2). TGF-beta 2 did not have any effect on MCF-7 cell growth or on E2 to E1 conversion. In conclusion, TGF-beta 2 might exert a protective role in breast cancer by reducing the amount of active oestrogens present in the breast.

Latent forms of transforming growth factor-beta 2 (TGF-beta 2) in breast cyst fluid.

Transforming growth factor-beta (TGF-beta) is secreted by cells in high molecular weight, latent forms and the in vivo mechanisms for the activation remain largely an enigma. Women who have palpable breast cyst with intracystic Na/K < 3 may have a higher risk of developing breast cancer than those with intracystic Na/K > 3. Finding of significantly higher concentrations of TGF-beta 2 in the Na/K > 3 group than Na/K < 3 group may explain the lower risk of breast cancer in the Na/K > 3 group. The aim of the present study was to characterise the latent forms of TGF-beta 2 in breast cyst fluid using HPLC, affinity chromatography, SDS-PAGE and immunostaining techniques. We found that TGF-beta 2 is present in high molecular weight, latent forms in breast cyst fluid: as a complex, probably with alpha 2-macroglobulin and a 56 kD protein which is likely to be a precursor form of TGF-beta 2.

Effect of breast cyst fluid on oestrone sulphatase activity in MCF-7 breast cancer cells.

Breast cyst fluid is a rich source of growth factors and sex hormones but the pathophysiology of cystic breast disease is largely unknown. In this study the net effects of breast cyst fluid on growth of, and oestrone sulphatase activity (oestrone sulphate --> oestrone) in the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cell lines were assessed. Using a final breast cyst fluid dilution of 16.7% (v/v) MCF-7 cell growth was significantly inhibited by 7 of 21 samples (16% - 54%) while MDA-MB-231 cell growth was significantly inhibited by 17 of 20 samples (15% - 45%). Oestrone sulphatase activity was significantly inhibited in the MCF-7 cell line by 19 of 21 samples (22% - 81%) while significant stimulation of oestrone sulphatase activity was observed in MDA-MB-231 cells in 11 of 20 samples (17% - 149%). The presence of endogenous substances in breast cyst fluid which inhibit oestrone sulphatase activity in the MCF-7 cell line is exciting because of the therapeutic potential of oestrone sulphatase inhibition in hormone-dependent breast cancers.

Transforming growth factor alpha, beta 1 and beta 2 in breast cyst fluid.

Women who have palpable breast cysts lined by apocrine metaplastic epithelium (intracystic Na/K < 3) may have a higher risk of breast cancer than those who have breast cysts lined by flattened epithelium (intracystic Na/K > 3). Transforming growth factor-alpha (TGF-alpha) exerts a proliferative effect on many cell types and may play a role in mammary carcinogenesis. Transforming growth factor-beta (TGF-beta) stimulates the proliferation of mesenchymal cells but inhibits mammary epithelial cell proliferation and may exert a protective effect against breast cancer development. The aim of this study was to measure the distribution of TGF-alpha, TGF-beta 1 and TGF beta 2 in the two sub-groups of breast cysts. TGF-alpha was undetectable in all but 2 of the 46 samples of breast cyst fluid tested. TGF-beta 1 ranged from undetectable up to 25.4 ng/ml (n = 46) while the intracystic concentrations of TGF-beta 2 were generally higher, ranging from 0.30 ng/ml to 125 ng/ml (n = 42). There was no significant difference between the distribution of TGF-beta 1 levels in the 2 cyst groups, but TGF-beta 2 levels were significantly higher (P < 0.001) in the high electrolyte ratio group (Na/K > 3). A negative correlation was found between TGF-beta 1 and TGF-beta 2 levels in the high electrolyte ratio group (rs = 0.605, p = 0.006, n = 19). TGF-alpha is unlikely to play an important role in breast cancer development in women with palpable breast cysts. The significantly higher concentrations of TGF-beta 2 in the high electrolyte ratio group may explain, in part, the lower risk of breast cancer in this group of women.

Prostate-specific antigen in breast cyst fluid: possible role of prostate-specific antigen in hormone-dependent breast cancer.

Prostate-specific antigen (PSA) is a 33 kDa serine protease which is produced by many different tissues in the body and has been shown to be present in low concentrations in breast milk and in about 30% of breast cancers. The presence of PSA in breast cancers is associated with the presence of steroid-hormone receptors and may be a favourable prognostic indicator. In this study, PSA immunoreactivity was measured in breast cyst fluid obtained from women with palpable breast cysts which is the most common benign breast disease. PSA was found to be present in very low concentrations in breast cyst fluid. In an attempt to understand the possible role of PSA in the breast, the effect of PSA on growth of the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 human breast cancer cell lines was studied. In addition, the effect of PSA on oestrone sulphatase activity and oestrogen 17-oxidoreductase activity in these cell lines was investigated. PSA, in low concentrations, was found to inhibit MCF-7 cell growth and to stimulate the conversion of oestradiol to the less potent oestrogen oestrone in this cell line. PSA had no effect on the MDA-MB-231 cell line. Our findings suggest that PSA may act as a negative growth regulator in hormone-dependent breast cancers.