Deacetylated Sialic Acid Sensitizes Lung and Colon Cancers to Novel Cucurbitacin-Inspired Estrone Epidermal Growth Factor Receptor (EGFR) Inhibitor Analogs.

Cancers utilize sugar residues such as sialic acids (Sia) to improve their ability to survive. Sia presents a variety of functional group alterations, including O-acetylation on the C6 hydroxylated tail. Previously, sialylation has been reported to suppress EGFR activation and increase cancer cell sensitivity to Tyrosine Kinase Inhibitors (TKIs). In this study, we report on the effect of deacetylated Sia on the activity of three novel EGFR-targeting Cucurbitacin-inspired estrone analogs (CIEAs), MMA 294, MMA 321, and MMA 320, in lung and colon cancer cells. Acetylation was modulated by the removal of Sialate O-Acetyltransferase, also known as CAS1 Domain-containing protein (CASD1) gene via CRISPR-Cas9 gene editing. Using a variety of cell-based approaches including MTT cell viability assay, flow cytometry, immunofluorescence assay and in-cell ELISA we observed that deacetylated Sia-expressing knockout cells (1.24-6.49 µM) were highly sensitive to all CIEAs compared with the control cells (8.82-20.97 µM). Apoptosis and varied stage cell cycle arrest (G0/G1 and G2/M) were elucidated as mechanistic modes of action of the CIEAs. Further studies implicated overexpression of CIEAs' cognate protein target, phosphorylated EGFR, in the chemosensitivity of the deacetylated Sia-expressing knockout cells. This observation correlated with significantly decreased levels of key downstream proteins (phosphorylated ERK and mTOR) of the EGFR pathway in knockout cells compared with controls when treated with CIEAs. Collectively, our findings indicate that Sia deacetylation renders lung and colon cancer cells susceptible to EGFR therapeutics and provide insights for future therapeutic interventions.

Using GIS in a first national mapping of functional disability among older American Indians and Alaska Natives from the 2000 census.

BACKGROUND: Geographical information systems (GIS) have been used mainly in understanding infectious diseases and environmental threats in health research. Here, GIS was used to examine patterns of functional disability as one impact of chronic disease in American Indians and Alaska Natives. The study purpose was to create the first national mapping of functional disability for AIANs using the 2000 U.S. Census. RESULTS: American Indians and Alaska Natives over age 65 reported disability at a rate of 57.6% versus 41.9% for all people over 65 (P < or = 0.0001). Regional differences in levels and type of disability were evident. CONCLUSION: Maps help visualize those who might otherwise be 'lost' from the data. The significance of this study is that gerontologic programs and policies are data-driven, yet there is a lack of reliable national level data from US health systems on functional disability among American Indians and Alaska Natives. One study limitation was that Census questions regarding disability differed from traditional measures of activities of daily living and instrumental activities of daily living. An immediate policy recommendation would be to incorporate standard activities of daily living and instrumental activities of daily living language into future Census for a comprehensive, linked database for the future.

GIS(c): a scientific framework and methodological tool for nursing research.

The purpose of this article was to bring to nursing science a theoretical framework and technology that can transport with it new ways of knowing by exploiting microperspectives and macroperspectives, both from "within the map" and globally. Nursing continues to find its voice, but it also must lend its voice to the forming of Geographic Information Systems and Science in a pan-disciplinary partnership with geography, cartography, sociology, public health, and information technology. It is proposed that nursing take advantage of the latest databases that hold "person" information and layer these over geographical maps holding "environment" and "health" information as a new way of seeing and applying the metaparadigms of nursing. By using Geographic Information Systems for understanding spatial, numeric, health, and population relationships as they relate to nursing practice, research, and teaching, nursing science will continue to evolve at a speed needed to be effective in the new millennia.