Prolonged tamoxifen exposure selects a breast cancer cell clone that is stable in vitro and in vivo

The effects of long-term tamoxifen exposure on cell growth and cell cycle kinetics were compared between oestrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. In the MCF-7 cell line, prolonged tamoxifen exposure (0.5 mumol/l for > 100 days) blocked cells in G0-G1 of the cell cycle, and slowed the doubling time of cells from 30 to 59 h. These effects corresponded to an increase in the cellular accumulation of tamoxifen over time [mean area under concentration curve (AUC) = 77.92 mumoles/10(6)/cells/day]. In contrast, in the MDA-MB-231 cell line, long-term tamoxifen exposure had no obvious effect on the doubling time, and reduced cellular tamoxifen accumulation (mean AUC = 50.50 mumoles/10(6)/cells/day) compared to the MCF-7 cells. Flow cytometric analysis of MDA-MB-231 cells demonstrated that a new tetraploid clone emerged following 56 days of tamoxifen exposure. Inoculation of the MDA-MB-231 tetraploid clone and MDA-MB-231 wildtype cells into the opposite flanks of athymic nude mice resulted in the rapid growth of tetraploid tumours. The tetraploid tumours maintained their ploidy following tamoxifen treatment for nine consecutive serial transplantations. Histological examination of the fifth transplant generation xenografts revealed that the tetraploid tumour had a 25-30 times greater mass, area of haemorrhage and necrosis, a slightly higher mitotic index and was more anaplastic than the control neoplasm. The control wildtype MDA-MB-231 tumours maintained a stable ploidy following tamoxifen treatment until the eighth and ninth transplantation, when a tetraploid population appeared, suggesting that tamoxifen treatment may select for this clone in vivo. These studies suggest that prolonged tamoxifen exposure may select for new, stable, fast growing cell clones in vitro as well as in vivo.     

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Revising deductive knowledge and stereotypical knowledge in a student model

A user/student model must be revised when new information about the user/student is obtained. But a sophisticated user/student model is a complex structure that contains different types of knowledge. Different techniques may be needed for revising different types of knowledge. This paper presents a student model maintenance system (SMMS) which deals with revision of two important types of knowledge in student models: deductive knowledge and stereotypical knowledge. In the SMMS, deductive knowledge is represented by justified beliefs. Its revision is accomplished by a combination of techniques involving reason maintenance and formal diagnosis. Stereotypical knowledge is represented in the Default Package Network (DPN). The DPN is a knowledge partitioning hierarchy in which each node contains concepts in a sub-domain. Revision of stereotypical knowledge is realized by propagating new information through the DPN to change default packages (stereotypes) of the nodes in the DPN. A revision of deductive knowledge may trigger a revision of stereotypical knowledge, which results in a desirable student model in which the two types of knowledge exist harmoniously.     

新一代NV SRAM技术

第一代NV SRAM模块问世近20年来，NVSRAM技术不断更新，以保持与各种应用同步发展，同时满足新的封装技术不断增长的需求。