Understanding acquired resistance to Lapatinib in breast cancer cells

Signaling through epidermal growth factor receptor (EGFR/ErbB) family members plays a very important role in regulating proliferation, development, and malignant transformation of mammary epithelial cells. ErbB family members are often over-expressed in human breast carcinomas. Lapatinib is an ErbB1 and ErbB2 tyrosine kinase inhibitor that has been shown to have anti-proliferative effects in breast and lung cancer cells. Cells treated with Lapatinib undergo G1 phase arrest, followed by apoptosis. Lapatinib has been approved for clinical use, though patients have developed resistance to the drug, as seen previously with other EGFR inhibitors. Moreover, the therapeutic efficacy varies significantly within the patient population, and the mechanism of drug sensitivity is not fully understood. Expression levels of ErbB2 are used as a prognostic marker for Lapatinib response; however, even among breast tumor cell lines that express similar levels of ErbB2 there is marked difference in their proliferative responses to Lapatinib. To understand the mechanisms of acquired resistance, we established a cell line SkBr3-R that is resistant to Lapatinib, from a Lapatinib-sensitive breast tumor cell line, SkBr3. We have characterized the cell lines and demonstrated that Lapatinib resistance in our system is not facilitated by receptor-level activity or by previously known mutations in the ErbB receptors. Significant changes were observed in cell proliferation, cell migration, cell cycle and cell death between the Lapatinib resistant SkBr3-R and sensitive SkBr3 cell lines. Recent studies have suggested STAT3 is upregulated in Lapatinib resistant tumors in association with ErbB signaling. We investigated the role that STAT3 may play in Lapatinib resistance and discovered higher STAT3 activity in these resistant cells. In addition, transcriptional profiling indicated higher expression of STAT3 target genes, as well as of other genes that promote survival. The gene array data also revealed cell cycle regulators and cell adhesion/junction component genes as possible mediator of Lapatinib resistance. Altogether, this study has identified several possible mechanisms of Lapatinib resistance.

A Model for Family Preservation Case Assessment

The outcomes of family preservation practice have been researched and debated. The effectiveness of family preservation is still inconclusive and many of the findings may only be inferred to specific situations. Few studies have addressed the assessment techniques or outcome factors from a qualitative perspective. This article synthesizes current literature, research and practice, and proposes a practice framework with questioning techniques to assist practitioners in assessing the strengths and characteristics of a family, and making decisions on whether or not familybased services are appropriate for the family. Two actual cases are presented to illustrate how the worker can benefit from having the assessment data derived from this model.

Alternative Strategies for Identifying High-Performing Charter Schools in Texas

The Obama administration's recurring policy emphasis on high-performing charter schools begs the obvious question: how do you identify a high-performing charter school? That is a crucially important policy question because any evaluation strategy that incorrectly identifies charter school performance could have negative effects on the economically and/or academically disadvantaged students who frequently attend charter schools. If low-performing schools are mislabeled and allowed to persist or encouraged to expand, then students may be harmed directly. If high-performing schools are driven from the market by misinformation, then students will lose access to programs and services that can make a difference in their lives. Most of the scholarly analysis to date has focused on comparing the performance of students in charter schools to that of similar students in traditional public schools (TPS). By design, that research measures charter school performance only in relative terms. Charter schools that outperform similarly situated, but low performing, TPSs have positive effects, even if the charter schools are mediocre in an absolute sense. This analysis describes strategies for identifying high-performing charter schools by comparing charter schools with one another. We begin by describing salient characteristics of Texas charter schools. We follow that discussion with a look at how other researchers across the country have compared charter school effectiveness with TPS effectiveness. We then present several metrics that can be used to identify high-performing charter schools. Those metrics are not mutually exclusive—one could easily justify using multiple measures to evaluate school effectiveness—but they are also not equally informative. If the goal is to measure the contributions that schools are making to student knowledge and skills, then a value-added approach like the ones highlighted in this report is clearly superior to a levels-based approach like that taken under the current accountability system.