InGen of creative production in the health sciences: A workbook companion to innovation generation

InGen of Creative Production in the Health Sciences is a compendium of innovative thinking exercises for individuals and groups, derived from an eclectic array of practical guides for professionals in a variety of fields. Segmented into five subcategories across twenty two chapters, the effort seeks to make techniques for increasing innovative problem solving more accessible to a diverse audience of problem solvers. The chapters of Roberta Ness. Innovation Generation (2012, Oxford University Press) provide the themes for each of the chapters in the workbook. It is intended that those who read Ness. Innovation Generation will benefit from practicing the constructs of innovative thinking exemplified in each exercise.^ The methods used to gather data, in this case mostly innovative thinking exercises, included literature reviews of existing innovative thinking tools, classroom materials, and theory-driven exploration of exercises to fill in gaps in extant materials. Specifically, Google.com and Amazon.com searches were conducted using the terms “innovation,” “innovative,” “innovator,” “creative,” “novelty,” “thinking,” together with some variance of “book,” “workbook,” and “exercise.” The results were sorted thematically to show correspondence with the themes in Ness (2012) and compared to suggested best practices of 50 years of scientific research on innovative thinking. Where themes were suggested by Ness (2012) and peer-reviewed research on innovation but unavailable in published innovation thinking workbooks, new exercises were developed. The five type subcategories into which these results were organized are: individual direct, individual indirect, group direct, group indirect and probing question. It is anticipated that the five type subcategories and spectrum of themes will equip problem solvers in a variety of capacities.^

Design, synthesis and cellular and molecular pharmacology of 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401): A novel non-cross-resistant anthracycline antibiotic with the intrinsic ability to circumvent P -glycoprotein-mediated drug resistance

We designed and synthesized a novel daunorubicin (DNR) analogue that effectively circumvents P-glycoprotein (P-gp)-mediated drug resistance. The fully protected carbohydrate intermediate 1,2-dibromoacosamine was prepared from acosamine and effectively coupled to daunomycinone in high yield. Deprotection under alkaline conditions yielded 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401). The in vitro cytotoxicity and cellular and molecular pharmacology of WP401 were compared with those of DNR in a panel of wild-type cell lines (KB-3-1, P388S, and HL60S) and their multidrug-resistant (MDR) counterparts (KB-V1, P388/DOX, and HL60/DOX). Fluorescent spectrophotometry, flow cytometry, and confocal laser scanning microscopy were used to measure intracellular accumulation, retention, and subcellular distribution of these agents. All MDR cell lines exhibited reduced DNR uptake that was restored, upon incubation with either verapamil (VER) or cyclosporin A (CSA), to the level found in sensitive cell lines. In contrast, the uptake of WP401 was essentially the same in the absence or presence of VER or CSA in all tested cell lines. The in vitro cytotoxicity of WP401 was similar to that of DNR in the sensitive cell lines but significantly higher in resistant cell lines (resistance index (RI) of 2-6 for WP401 vs 75-85 for DNR). To ascertain whether drug-mediated cytotoxicity and retention were accompanied by DNA strand breaks, DNA single- and double-strand breaks were assessed by alkaline elution. High levels of such breaks were obtained using 0.1-2 $\mu$g/mL of WP401 in both sensitive and resistant cells. In contrast, DNR caused strand breaks only in sensitive cells and not much in resistant cells. We also compared drug-induced DNA fragmentation similar to that induced by DNR. However, in P-gp-positive cells, WP401 induced 2- to 5-fold more DNA fragmentation than DNR. This increased DNA strand breakage by WP401 was correlated with its increased uptake and cytotoxicity in these cell lines. Overall these results indicate that WP401 is more cytotoxic than DNR in MDR cells and that this phenomenon might be related to the reduced basicity of the amino group and increased lipophilicity of WP401. ^