Cell-directed aptamer therapeutic targeting for cancers including those within the central nervous system.

Osteopontin (OPN) is produced by tumor cells as well as by myeloid cells and is enriched in the tumor microenvironment (TME) of many cancers. Given the roles of OPN in tumor progression and immune suppression, we hypothesized that targeting OPN with aptamers that have high affinity and specificity could be a promising therapeutic strategy. Bi-specific aptamers targeting ligands for cellular internalization were conjugated to siRNAs to suppress OPN were created, and therapeutic leads were selected based on target engagement and in vivo activity. Aptamers as carriers for siRNA approaches were created including a cancer targeting nucleolin aptamer Ncl-OPN siRNA and a myeloid targeting CpG oligodeoxynucleotide (ODN)-OPN siRNA conjugate. These aptamers were selected as therapeutic leads based on 70-90% OPN inhibition in cancer (GL261, 344SQ, 4T1B2b) and myeloid (DC2.4) cells relative to scramble controls. In established immune competent 344SQ lung cancer and 4T1B2b breast cancer models, these aptamers, including in combination, demonstrate therapeutic activity by inhibiting tumor growth. The Ncl-OPN siRNA aptamer demonstrated efficacy in an immune competent orthotopic glioma model administered systemically secondary to the ability of the aptamer to access the glioma TME. Therapeutic activity was demonstrated using both aptamers in a breast cancer brain metastasis model. Targeted inhibition of OPN in tumor cells and myeloid cells using bifunctional aptamers that are internalized by specific cell types and suppress OPN expression once internalized may have clinical potential in cancer treatment.

WITHDRAWN: One-Year Freedom from Amputation, Survival, and Cost of Care following Tibial and Pedal Endovascular Interventions for Critical Limb Ischemia: The Role of Atherectomy and Drug-Eluting Stents

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Comparison of transcriptomes from two chemosensory organs in four decapod crustaceans reveals hundreds of candidate chemoreceptor proteins.

Crustaceans express genes for at least three classes of putative chemosensory proteins. These are: Ionotropic Receptors (IRs), derived from the heterotetrameric ionotropic glutamate receptors (iGluRs); Transient Receptor Potential (TRP) channels, a diverse set of sensor-channels that include several families of chemoreceptor channels; and Gustatory Receptor Like receptors (GRLs), ionotropic receptors that are homologues of Gustatory Receptors (GRs) of insects and are expressed sparingly in most crustaceans so far studied. IRs are typically numerically the most dominant of these receptor proteins in crustaceans and include two classes: co-receptor IRs, which are necessary for making a functional receptor-channel; and tuning IRs, whose specific combination in the IR subunits in the heterotetramer confers chemical specificity. Previous work showed that the transcriptomes from two major chemosensory organs-the lateral flagellum of the antennule (LF) and the tips of the legs (dactyls)-of the Caribbean spiny lobster Panulirus argus express four co-receptor IRs and over 100 tuning IRs. In this paper, we examined and compared the transcriptomes from the LF and dactyls of P. argus and three other decapod crustaceans-the clawed lobster Homarus americanus, red swamp crayfish Procambarus clarkii, and the blue crab Callinectes sapidus. Each species has at least ca. 100 to 250 IRs, 1 to 4 GRLs, and ca. 15 TRP channels including those shown to be involved in chemoreception in other species. The IRs show different degrees of phylogenetic conservation: some are arthropod-conserved, others are pancrustacean-conserved, others appear to be crustacean-conserved, and some appear to be species-specific. Many IRs appear to be more highly expressed in the LF than dactyl. Our results show that decapod crustaceans express an abundance of genes for chemoreceptor proteins of different types, phylogenetic conservation, and expression patterns. An understanding of their functional roles awaits determining their expression patterns in individual chemosensory neurons and the central projections of those neurons.