Breast cancer metastasis to the bone: mechanisms of bone loss

Breast cancer frequently metastasizes to the skeleton, interrupting the normal bone remodeling process and causing bone degradation. Osteolytic lesions are the end result of osteoclast activity; however, osteoclast differentiation and activation are mediated by osteoblast production of RANKL (receptor activator for NFκB ligand) and several osteoclastogenic cytokines. Osteoblasts themselves are negatively affected by cancer cells as evidenced by an increase in apoptosis and a decrease in proteins required for new bone formation. Thus, bone loss is due to both increased activation of osteoclasts and suppression of osteoblasts. This review summarizes the current understanding of the osteolytic mechanisms of bone metastases, including a discussion of current therapies

The importance of robust design methodology: case study of the infamous GM ignition switch recall

While a systematic quality strategy is of crucial importance for the success of manufacturing companies, the universal applicability and effectiveness of implemented quality management practices were called into question by a number of major product recalls in recent years. This article seeks to illustrate how already simple analyses and early stage design methods can help to better understand one of the potential reasons for these failures, namely the variation inherent in manufacturing, assembly, and use processes. Usually thoroughly controlled in production, it seems as if particularly the risk of unanticipated variation effects remain largely underestimated and thus unaccounted for in design practice, sometimes with disastrous consequences. To foster the awareness of this variation and to illustrate the benefits of its early consideration in product development, this paper reviews one of the most infamous recalls in automotive history, that of the GM ignition switch, from the perspective of Robust Design. It is investigated if available Robust Design methods such as sensitivity analysis, tolerance stack-ups, design clarity, etc. would have been suitable to account for the performance variation, which has led to a number of fatal product defects and the recall of 30 million vehicles. Furthermore, the disclosed legal case files were examined, offering a unique opportunity to examine how technical malfunctioning of the ignition switch could stay undetected long enough to result in fatalities