Integration of genomic technology into healthcare settings establishes new capabilities to predict disease susceptibility and optimize treatment regimes. Yet, Indigenous peoples remain starkly underrepresented in genetic and clinical health research and are unlikely to benefit from such efforts. To foster collaboration with Indigenous communities, we propose six principles for ethical engagement in genomic research: understand existing regulations, foster collaboration, build cultural competency, improve research transparency, support capacity building, and disseminate research findings. Inclusion of underrepresented communities in genomic research has the potential to expand our understanding of genomic influences on health and improve clinical approaches for all populations.
In a recent study, the well documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells, but not the “normal” breast cell line MCF-10A. Further, the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, was found not to target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study was the issue of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting, as well as the possible cellular uptake of the disaccharide. In the present study, we have conjugated BLM, deglycoBLM and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells, and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreas cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells, and comparable to BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.
Meta-analyses of association results for blood pressure using exome-centric single-variants and gene-based tests identified 31 novel loci in discovery among 146,562 individuals with follow-up and meta-analysis in 180,726 additional individuals (Ntotal=327,288). These blood pressure loci are enriched for known cardiometabolic trait variants. Associations were also observed for the aggregation of rare/low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure loci suggests new therapeutic strategies for hypertension emphasizing a link with cardiometabolic risk.
Biotinylated bleomycin A(5) was attached to streptavidin-derivatized microbubbles, and a solution containing the conjugate was passed over a monolayer of cultured MCF-7 cells. The bleomycin-derivatized microbubbles adhered to the MCF-7 cells, and the association could be monitored by the use of a microscope. Three other cancer cell lines gave similar results. The bleomycin-microbubble conjugate did not bind to a normal breast cell line (MCF-10A) or to the matched noncancer cell lines corresponding to the other cancer cell lines targeted by bleomycin. No binding to any tested cell line was observed when the microbubbles lacked conjugated bleomycin A(5) or when the microbubble contained a bleomycin A(5) analogue lacking the carbohydrate moiety.
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