CD44-hyaluronan mediating endocytosis of iron-platinum alloy nanoparticles induces ferroptotic cell death in mesenchymal-state lung cancer cells with tyrosine kinase inhibitor resistance.

While tyrosine kinase inhibitor resistance in cancer is a critical issue in the medical field, it is important for clinical testing as well, since it affects the ultimate outcome of cancer therapy. Yet, no effective solutions have been implemented till date. Clinical observations after tyrosine kinase inhibitor treatment reveal that acquired resistance inevitably limits the curative effects of non-small cell lung cancer treatment because of mutations in the epidermal growth factor receptor gene, which are accompanied by epithelial-mesenchymal transition. Here, for the first time, we report that the transmembrane glycoprotein CD44, which is associated with epithelial-mesenchymal transition, chemoresistance, and cancer progression, mediates enhanced endocytosis of iron-platinum alloy nanoparticles (FePt NPs) in the mesenchymal-state gefitinib-resistant (GR+ and M6) cells, via the binding of the CD44 ligand, hyaluronan, to the surface-absorbed hyaluronan-binding protein 2. Upon treatment with FePt NPs, there was higher cellular uptake in mesenchymal-state GR+ and M6 cells, resulting from cell death through ferroptosis and mitochondrial dysfunction, as compared to that observed in the epithelial-state cells. Mechanistically, inactivation of dihydroorotate dehydrogenase elevated the production of mitochondrial lipid peroxidation, and enhanced the cell death in the epithelial-state HCC827 cells, thereby indicating its role in defense against FePt NPs-induced ferroptosis. Furthermore, induction of ferroptosis has been shown to specifically promote the cell death of drug-tolerant "persister" cells and reverse their resistance as well. Therefore, we concluded that FePt NPs preferentially target mesenchymal drug-tolerant "persister" cells and promote ferroptosis, to overcome their resistance. STATEMENT OF SIGNIFICANCE: In the present study, we identified FePt NPs as an innovative agent for cancer treatment, particularly in mesenchymal-state cells that exhibit TKI resistance. Mesenchymal-state cancer cells showed enhanced uptake of FePt NPs via CD44-HA-mediated endocytosis, accompanied by severe cell death and mitochondrial morphology alterations, in comparison to epithelial-state cells. We further elucidated the mechanism underlying FePt NPs-induced ferroptotic cell death as via a burst of mitochondrial LPO and DHODH protein inactivation. In addition, we found that FePt NPs inhibit tumor growth in TKI-resistant mesenchymal GR+ cell-bearing mice with better efficacy than the ferroptotic inducer RSL3. Our current findings on using FePt NPs to overcome TKI resistance through ferroptosis activation may offer a alternative strategy for improved cancer treatment.

New concepts of science and medicine in science and technology studies and their relevance to science education.

Science education often adopts a narrow view of science that assumes the lay public is ignorant, which seemingly justifies a science education limited to a promotional narrative of progress in the form of scientific knowledge void of meaningful social context. We propose that to prepare students as future concerned citizens of a technoscientific society, science education should be informed by science, technology, and society (STS) perspectives. An STS-informed science education, in our view, will include the following curricular elements: science controversy education, gender issues, historical perspective, and a move away from a Eurocentric view by looking into the distinctive patterns of other regional (in this case of Taiwan, East Asian) approaches to science, technology, and medicine. This article outlines the significance of some major STS studies as a means of illustrating the ways in which STS perspectives can, if incorporated into science education, enhance our understanding of science and technology and their relationships with society.

Inhibition of the mammalian target of rapamycin promotes cyclic AMP-induced differentiation of NG108-15 cells.

To clarify the involvement of autophagy in neuronal differentiation, the effect of rapamycin, an mTOR complex inhibitor, on the dibutyryl cAMP (dbcAMP)-induced differentiation of NG108-15 cells was examined. Treatment of NG108-15 cells with 1 mM dbcAMP resulted in induction of differentiation, including neurite outgrowth and varicosity formation, enhanced voltage-sensitive Ca2+ channel activity and expression of microtubule-associated protein 2, and these effects involved phosphorylation of cAMP-response element binding protein (CREB) and extracellular signal regulated kinase (ERK). Simultaneous application of dbcAMP and rapamycin synergistically increased and accelerated differentiation. mTOR or raptor silencing with siRNA had a similar effect to rapamycin. Rapamycin and silencing of mTOR or raptor evoked autophagy, while blockade of autophagy by addition of 3-methyladenine or beclin 1 or Atg5 silencing prevented the potentiation of differentiation. Silencing of rictor also evokes autophagy, at a level 55% of that induced by raptor silencing and enhancement of differentiation is proportional. Rapamycin also caused increased ATP generation and cell cycle arrest in G0/G1 phase, but had no effect on CREB and ERK phosphorylation. dbcAMP also induced ATP generation, but not autophagy or cell cycle arrest. These results suggest that the increased autophagy, ATP generation and cell cycle arrest caused by mTOR inhibition promotes the dbcAMP-induced differentiation of NG108-15 cells.

Women scientists in Taiwan: an update.

This paper reflects upon issues of gender and science in Taiwan. Its starting point is the first academic paper on the subject published in Taiwan in 1996 by Fu and Wang, and then it draws upon the biographical accounts of 20 women scientists. We emphasize the importance of focusing on the specific contexts of the history of science and women in Taiwan. Partly as a result of Taiwan's colonial past and women's limited access to education, women scientists did not emerge in Taiwan until the second half of the 20(th) century when higher education became available to women. The gender issues with which women scientists in Taiwan have had to cope include the ways in which women have been excluded or included, their marital and career status, the local and global politics of scientific knowledge, and negotiating social networks. These issues have remained largely the same since the Fu and Wang study, but they have certainly gained wider attention and understanding, and greater articulation, both within academia and society.