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Sailing True North: Ten Admirals and the Voyage of Character By James Stavridis Penguin Press, 2019 336 pp. $28.00 ISBN 978-0525559931 Character is being widely discussed on the national stage [...]

Background BRCA1-mutant breast tumors are typically estrogen receptor alpha (ER([alpha]) negative, whereas most sporadic tumors express wild-type BRCA1 and are ER[alpha] positive. We examined a possible mechanism for the observed ER[alpha]-negative phenotype of BRCAI-mutant tumors. Methods We used a breast cancer disease-specific microarray to identify transcripts that were differentially expressed between paraffin-embedded samples of 17 BRCA1-mutant and 14 sporadic breast tumors. We measured the mRNA levels of estrogen receptor 1 (ESR1) (the gene encoding ER [alpha]), which was differentially expressed in the tumor samples, by quantitative polymerase chain reaction. Regulation of ESR1 mRNA and ER[alpha] protein expression was assessed in human breast cancer HCC1937 cells that were stably reconstituted with wild-type BRCA1 expression construct and in human breast cancer T47D and MCF-7 cells transiently transfected with BRCA1-specific short-interfering RNA (siRNA). Chromatin immunoprecipitation assays were performed to determine if BRCA1 binds the ESR1 promoter and to identify other interacting proteins. Sensitivity to the antiestrogen drug fulvestrant was examined in T47D and MCF-7 cells transfected with BRCAl-specific siRNA. All statistical tests were two-sided. Results Mean ESR1 gene expression was 5.4-fold lower in BRCA1-mutant tumors than in sporadic tumors (95% confidence interval [CI] = 2.6-fold to 40.1-fold, P = .0019). The transcription factor Oct-1 recruited BRCA1 to the ESR1 promoter, and both BRCA1 and Oct-1 were required for ER[alpha] expression. BRCAl-depleted breast cancer cells expressing exogenous ER[alpha] were more sensitive to fulvestrant than BRCA1-depleted cells transfected with empty vector (T47D cells, the mean concentration of fulvestrant that inhibited the growth of 40% of the cells [[IC.sub.40]] for empty vector versus ER[alpha]: >[10.sup.-5] versus 8.0 x [10.sup.-9] M [95% CI = 3.1 x [10.sup.-10] to 3.2 x [10.sup.-6 M]; MCF-7 cells, mean [IC.sub.40] for empty vector versus ER[alpha]: >[10.sup.-5] versus 4.9 x [10.sup.-8] M [95% CI = 2.0 x [10.sup.-9] to 3.9 x [10.sup.-6] G M]). Conclusions BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly modulating ERa expression. J Natl Cancer Inst 2007;99:1683-94

We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. Methods: Specimens of tumor tissue (5-[micro]m-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. Results: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P [is less than] .0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P [is less than] .0001), and a lower mitotic count (P = .003) than control cancers. Conclusions: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients. [J Natl Cancer Inst 1998;90:1138-45]

This paper provides a historical snapshot of personal ICT usage in 2005/2006, specifically shedding light on how Australian and German couples (N= 48) had integrated the internet into their homes with a focus on spatial and social transformations. Using a home ethnographic approach, this qualitative study implemented in-depth interviews across two countries. From a spatial perspective, Australian couples had their laptops or PCs highly integrated into the family life usually in multifunctional rooms or open areas, whereas German couples’ laptops and PCs were most often found in separate study rooms. From a social perspective, internet use can be related to elements that bring couples together, but also to elements of disintegration. A shift in how couples spent their time together was observed from watching TV together in the same room, to going online in the same room at two PCs or one person being online while the other conducted other activities.

Plan now for the presidential transition to guard against false starts in the new term. On the evening of Nov. 4, as the nation awaits the presidential election results, the [...]

Byline: Peter H. Daly and Michael Watkins Forget about business - leading in the public eye brings a whole new set of hurdles and measures. Business and government leadership are [...]

Byline: Peter H. Daly Seven ways to prepare for executive leadership. Oscar Wilde once wrote that experience is the name everyone gives to their mistakes. Mistakes have consequences beyond teaching [...]