Conservation surgery for breast cancer as the preferred choice: a prospective analysis.

PURPOSE: To describe the proportion of women who anticipate having breast-conserving surgery (BCS) versus modified radical mastectomy (MRM), the factors they considered when making treatment choices, the degree to which they perceived they had participated in and had control of the treatment decision, and to explore factors associated with type of planned surgery. PATIENTS AND METHODS: Prospective cohort study conducted among patients attending a tertiary care hospital in Alberta, Canada from 1992 to 1995. Participants had a first diagnosis of localized unilateral breast cancer, and were, in the opinions of their surgeons, candidates for either BCS or MRM. RESULTS: Of 157 participants, 71.3% anticipated having BCS and 28.7% anticipated MRM. Referents perceived to play an important role in decision making included self, doctor, and significant other. The two top-ranked items perceived to have influenced treatment choice were doctor's advice and possibility of complete cure. Most women (60%) participated in treatment choice to the degree that they preferred, but only 13.6% received their preferred amount of information. The type of planned surgery was predicted by surgeon, contribution of doctor to choice of treatment, importance of breasts to sexuality, self-efficacy, and concerns about cancer recurrence from a multivariable logistic regression model. CONCLUSION: Both patient and surgeon factors are important predictors of type of planned surgery. There is a gap between women's preferences and actual experiences with regard to information provided and patient participation in treatment choices, with women's desire for more information about their treatment being most prevalent.

Pneumococci induced TLR- and Rac1-dependent NF-kappaB-recruitment to the IL-8 promoter in lung epithelial cells.

Streptococcus pneumoniae is the major pathogen of community-acquired pneumonia. The respiratory epithelium constitutes the first line of defense against invading lung pathogens, including pneumococci. We analyzed the involvement of Toll-like receptors (TLR) and Rho-GTPase signaling in the activation of human lung epithelial cells by pneumococci. S. pneumoniae induced release of interleukin-8 (IL-8) by human bronchial epithelial cell line BEAS-2B. Specific inhibition of Rac1 by Nsc23766 or a dominant-negative mutant of Rac1 strongly reduced cytokine release. In addition, pneumococci-related cell activation (IL-8 release, NF-kappaB-activation) depended on MyD88, phosphatidylinositol 3-kinase, and Cdc42 but not on RhoA. Pneumococci enhanced TLR1 and TLR2 mRNA expression in BEAS-2B cells, whereas TLR4 and TLR6 expression was constitutively high. TLR1 and 2 synergistically recognized pneumococci in cotransfection experiments. TLR4, TLR6, LPS-binding protein, and CD14 seem not to be involved in pneumococci-dependent cell activation. At the IL-8 gene promoter, recruitment of phosphorylated NF-kappaB subunit p65 was blocked by inhibition of Rac1, whereas binding of the phosphorylated activator protein-1 subunit c-Jun to the promoter was not diminished. In summary, these results suggest that S. pneumoniae activate human epithelial cells by TLR1/2 and a phosphatidylinositol 3-kinase- and Rac1-dependent NF-kappaB-recruitment to the IL-8 promoter.

Streptococcus pneumoniae-induced p38 MAPK-dependent phosphorylation of RelA at the interleukin-8 promotor.

Streptococcus pneumoniae is the major cause of community-acquired pneumonia and one of the most common causes of death by infectious disease in industrialized countries. Little is known concerning the mechanisms of target cell activation in this disease. The present study shows that NF-kappaB and p38 MAPK signaling pathways contribute to chemokine synthesis by lung epithelial cells in response to pneumococci. In infected lungs of mice pneumococci stimulate expression of the interleukin (IL)-8 homolog keratinocyte-derived chemokine and granulocyte-macrophage colony-stimulating factor, as well as activate p38 MAPK. Human bronchial epithelium was chosen as a cellular model, because it establishes the first barrier against pathogens, and little is known about its function in innate immunity. Pneumococci infection induces expression of IL-8 and granulocyte-macrophage colony-stimulating factor as well as activation of p38 MAPK in human bronchial epithelial cells (BEAS-2B). Inhibition of p38 MAPK activity by SB202190 and SB203580 blocks pneumococci-induced cytokine release. In mouse lungs in vivo as well as in cultured cells, pneumococci activate NF-kappaBinanIkappaB kinase-dependent manner. Inhibition of p38 MAPK by chemical inhibitors or by RNA interference targeting p38alpha reduces pneumococci-induced NF-kappaB-dependent gene transcription. Blockade of p38 activity did not affect inducible nuclear translocation and recruitment of NF-kappaB/RelA to the IL-8 promotor but did reduce the level of phosphorylated RelA (serine 536) at IL-8 promotor and inhibited pneumococci-mediated recruitment of RNA polymerase II to IL-8 promotor. Thus, p38 MAPK contributes to pneumococci-induced chemokine transcription by modulating p65 NF-kappaB-mediated transactivation.