Search

This article is one in a series in which contributing authors discuss how the United Nations (UN) Sustainable Development Goals (SDGs) are linked to everyday clinical issues; national public health emergencies; and other nursing issues, such as leadership, shared governance, and advocacy. The 2030 Agenda for Sustainable Development, a 15-year plan of action to achieve the goals, was unanimously adopted by all UN member states in September 2015 and took effect on January 1, 2016. The Agenda consists of 17 SDGs addressing social, economic, and environmental determinants of health and 169 associated targets focused on five themes: people, planet, peace, prosperity, and partnership. The SDGs build on the work of the UN Millennium Development Goals, which were in effect from 2000 to 2015. The current article highlights SDGs 5 (gender equality), 8 (decent work and economic growth), and 17 (partnerships for the goals), along with the advocacy of these goals by Sigma Theta Tau International Honor Society of Nursing in the UN system.

A new type of metamaterial has been developed for the use in pulsed power systems. These materials have the applications in high-power microwave systems, dielectric-loaded components, and nonlinear transmission lines. We present a double-positive metamaterial created by incorporating several types of nickel–zinc ferrite powders into a silane binder. Measurements show these materials to possess positive relative permeability and permittivity values in the range of 3–6 for frequencies between 20 MHz and 2 GHz. The dielectric strengths of five different types of ferrite-based composites were measured to evaluate the potential of these materials for high-power applications. A pulse with a magnitude up to 100 kV and rise time on the order of tens of nanoseconds was used to determine the dielectric strength of disks with a diameter of 2.54 cm and a thickness of 0.2 cm. A maximum electric field of 163.79 kV/cm was sustained before breakdown. This paper presents a statistical analysis of the dielectric strength data and projects the power handling capabilities of the composites.

Permittivity and permeability parameters of dielectric composites made of ferrite particles coated in a barium titanate (BaTiO3) layer were analyzed and compared against composites of ferrite powders without a dielectric layer. A hydrothermal synthesis process combined barium hydroxide (Ba(OH)2) and titanium dioxide (TiO2) to form the coating of barium titanate around a ferrite core. These barium titanate ferrite composites particles are then combined with a unique binder to form a metamaterial. Discs of the metamaterial are characterized with an Agilent coaxial airline and dielectric measurement software to determine the permittivity and permeability responses within a frequency range of 200 MHz to 4 GHz. By comparing these results to previous work on ferrite composites, the merit of insulating the magnetic particles with a dielectric layer is examined.

Commercially available reagents for the detection of cytokines in pre-clinical species often rely on cross-reactivity from other species. Species-specific cytokine control materials are ideal for use in determining the suitability of the cross-reactive reagents within the intended pre-clinical species. To generate species specific cytokine positive control materials in a non-invasive manner, a systematic catalog of ex vivo whole blood mitogen stimulation and collection conditions was developed. Since naïve matrix (plasma or serum) is unlikely to have cytokines detectable above the lower limit of quantitation (LLOQ), ex vivo stimulation of whole blood using a variety of mitogens was performed in order to produce measureable cytokine release. Plasma harvested at specific time points from these stimulations was then spiked into naïve (species matched) plasma or serum to achieve analyte concentrations within the analytical measurement range of the assay. This ‘spike-in’ sample serves as a model of the intended test system, and allows for evaluation of the ability to detect species-specific cytokines within both plasma and serum matrices. A range of detection was determined for a number of analytes using a range of concentrations of spike-in using commercially available multiplex assays. By producing this catalog of stimulation conditions including multiple mitogens and durations of challenge for optimized collection per analyte, we are able to quickly generate positive control materials for a wide range of analytes across multiple species and thereby have simplified and streamlined the approach to generating these much-needed materials in the preclinical testing laboratory.

Non-adherent, three-dimensional sphere formation is used as an in vitro surrogate to evaluate cellular potential for tumor initiation and self-renewal. To determine if a shared molecular program underlies the capacity for sphere formation by cells originating from diverse tumor types, we characterized molecular and functional properties of ten independent cell lines derived from three ontogenetically distinct dog cancers: hemangiosarcoma, osteosarcoma, and glial brain tumors. Genome-wide gene expression profiling identified tumor-of-origin-dependent patterns of adjustment to sphere formation in a uniform culture condition. However, expression of the stem/progenitor markers CD34 and CD117, resistance to cytotoxic drugs, and dye efflux (side population assays) showed no association with these gene expression profiles. Instead, primary sphere-forming capacity was inversely correlated with the ability to reform secondary spheres, regardless of tumor ontogeny. Primary sphere formation seemed to be proportional to the number of pre-existing cells with sphere-forming capacity in the cell lines. Cell lines where secondary sphere formation was more proficient than primary sphere formation showed enrichment of genes involved in fatty acid synthesis and immunosuppressive cytokines. In contrast, cell lines where secondary sphere formation was approximately equivalent to or less proficient than primary sphere formation showed upregulation of CD40 and enrichment of genes involved in fatty acid oxidation. Our data suggest that in vitro sphere formation is associated with upregulation of gene clusters involved in metabolic and immunosuppressive functions, which might be necessary for self-renewal and for tumor initiation and/or tumor propagation in vivo.

Canine hemangiosarcoma is a rapidly progressive disease that is poorly responsive to conventional chemotherapy. Despite numerous attempts to advance treatment options and improve outcomes, drug resistance remains a hurdle to successful therapy. To address this problem, we used recently characterized progenitor cell populations derived from canine hemangiosarcoma cell lines and grown as non-adherent spheres to identify potential drug resistance mechanisms as well as drug-resistant cell populations. Cells from sphere-forming cultures displayed enhanced resistance to chemotherapy drugs, expansion of dye-excluding side populations and altered ATP-binding cassette (ABC) transporter expression. Invasion studies demonstrated variability between cell lines as well as between sphere and monolayer cell populations. Collectively, our results suggest that sphere cell populations contain distinct subpopulations of drug-resistant cells that utilize multiple mechanisms to evade cytotoxic drugs. Our approach represents a new tool for the study of drug resistance in hemangiosarcoma, which could alter approaches for treating this disease.

Targeted toxins have the potential to overcome intrinsic or acquired resistance of cancer cells to conventional cytotoxic agents. Here, we hypothesized that EGFuPA-toxin, a bispecific ligand-targeted toxin (BLT) consisting of a deimmunized Pseudomonas exotoxin (PE) conjugated to epidermal growth factor and urokinase, would efficiently target and kill cells derived from canine hemangiosarcoma (HSA), a highly chemotherapy resistant tumor, as well as cultured hemangiospheres, used as a surrogate for cancer stem cells (CSC). EGFuPA-toxin showed cytotoxicity in four HSA cell lines (Emma, Frog, DD-1 and SB) at a concentration of ≤100 nM, and the cytotoxicity was dependent on specific ligand-receptor interactions. Monospecific targeted toxins also killed these chemoresistant cells; in this case, a "threshold" level of EGFR expression appeared to be required to make cells sensitive to the monospecific EGF-toxin, but not to the monospecific uPA-toxin. The IC₅₀ of CSCs was higher by approximately two orders of magnitude as compared to non-CSCs, but these cells were still sensitive to EGFuPA-toxin at nanomolar (i.e., pharmacologically relevant) concentrations, and when targeted by EGFuPA-toxin, resulted in death of the entire cell population. Taken together, our results support the use of these toxins to treat chemoresistant tumors such as sarcomas, including those that conform to the CSC model. Our results also support the use of companion animals with cancer for further translational development of these cytotoxic molecules.

A new type of metamaterial has been developed at the University of Missouri for use in pulsed power and high power microwave systems. These materials also have direct applications in dielectric-loaded components and nonlinear transmission lines. We present a double-positive metamaterial that incorporates high permeability, high resistivity nickel-zinc ferrite powers into a dielectric matrix. The ferrite powers were diagnosed using XRD and SEM analysis. A bimodal particle distribution was investigated with particles 5μm and 30nm in diameter. The 3D models of composites were constructed using a custom Monte-Carlo algorithm to investigate the effect of particle distribution and density on material electromagnetic properties. Simulations are compared with experimental results in order to validate the models. Power handling and dielectric strength were also examined with a 100kV, 60ns pulse derived from a PA-80. A maximum electric field of 309.50 kV/cm was measured before breakdown using 0.2cm thick disks, 2.54cm in diameter. Tests performed on the electromagnetic frequency response showed materials with near equal values of positive relative permeability and permittivity that were between 3.0–6.0 for frequencies between 200MHz and 1GHz. This work presents a statistical analysis of the dielectric strength, power handling, and electromagnetic response of the composites with varying particle distributions.

We performed genomewide gene expression analysis of 35 samples representing 6 common histologic subtypes of canine lymphoma and bioinformatics analyses to define their molecular characteristics. Three major groups were defined on the basis of gene expression profiles: (1) low-grade T-cell lymphoma, composed entirely by T-zone lymphoma; (2) high-grade T-cell lymphoma, consisting of lymphoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified; and (3) B-cell lymphoma, consisting of marginal B-cell lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma. Interspecies comparative analyses of gene expression profiles also showed that marginal B-cell lymphoma and diffuse large B-cell lymphoma in dogs and humans might represent a continuum of disease with similar drivers. The classification of these diverse tumors into 3 subgroups was prognostically significant, as the groups were directly correlated with event-free survival. Finally, we developed a benchtop diagnostic test based on expression of 4 genes that can robustly classify canine lymphomas into one of these 3 subgroups, enabling a direct clinical application for our results.

Established cell lines are utilized extensively to study tumor biology and preclinical therapeutic development. However, they may not accurately recapitulate the heterogeneity of their corresponding primary disease. B-cell tumor cells are especially difficult to maintain under conventional culture conditions, limiting access to samples that faithfully represent this disease for preclinical studies. Here, we used primary canine diffuse large B-cell lymphoma to establish a culture system that reliably supports the growth of these cells. CD40 ligand, either expressed by feeder cells or provided as a soluble two-trimeric form, was sufficient to support primary lymphoma cells in vitro. The tumor cells retained their original phenotype, clonality and known karyotypic abnormalities after extended expansion in culture. Finally, we illustrate the utility of the feeder cell-free culture system for comparable assessment of cytotoxicity using dog and human B-cell malignancies. We conclude that this system has broad applications for in vitro preclinical development for B-cell malignancies.

Metamaterial composites with both ferroelectric and ferromagnetic phases have promising applications in the field of applied electromagnetics and directed energy. This metamaterial, which integrates the dielectric-ferromagnetic properties into a single composite, was synthesized using a hydrothermal process combining barium hydroxide (Ba(OH) 2 ), titanium dioxide (TiO 2 ), and nickel-zinc ferrites. The product of this reaction forms a shell of barium titanate around the ferrite particles. The dielectric strength of the resulting metamaterial has been tested and will be reported. The material was pressed with a binder to form discs for breakdown testing. The dielectric and magnetic losses have been measured with an airline waveguide, and the high voltage breakdown of the material was determined using DC measurements as well as nanosecond pulses from a PA-80, 100 KV pulser. The breakdown field of the core-shell material is compared to other known insulator materials.

Metamaterials are currently under development to reduce the size of high power antennas. These materials may also have applications in other high power, dielectric-loaded components, including nonlinear transmission lines. A new procedure has been developed at the University of Missouri-Columbia that produces a double-positive metamaterial by combining nickel-zinc ferrite powders with a dielectric binder. The resulting composite is a machinable bulk material produced at significantly lower temperatures than sintered components. Previous measurements have shown this material to possess positive relative permeability and permittivity values in the range of 4 to 6 for frequencies between 200 MHz and 2 GHz. The dielectric strengths of five different types of ferrite-based composites were measured to evaluate the potential of these materials for high power applications. A pulser with a magnitude up to 100 kV and rise time on the order of tens of nanoseconds was used to determine the dielectric strength of disks with a diameter of 2.54 cm and a thickness of 2 mm. This work presents a statistical analysis of the dielectric strength data and projects the power handling capabilities of the composites.

Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute ~20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6×10-7 and 2.7×10-6, respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps thevesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangiosarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers., Golden Retriever Foundation, Morris Animal Foundation (Grant D10CA-501), National Institutes of Health (U.S.) (P30CA077598 (MCC Core)), Land of PureGold Foundation, Inc., Uppsala University, American Kennel Club Canine Health Foundation, Inc. (Grant 422), American Kennel Club Canine Health Foundation, Inc. (Grant 615), American Kennel Club Canine Health Foundation, Inc. (Grant 2254), American Kennel Club Canine Health Foundation, Inc. (Grant 1131), American Kennel Club Canine Health Foundation, Inc. (Grant 593), American Kennel Club Canine Health Foundation, Inc. (Grant 1168), American Kennel Club Canine Health Foundation, Inc. (Grant 1169), National Institutes of Health (U.S.) (RO1CA112211), American Kennel Club Canine Health Foundation, Inc. (Grant 1147), American Kennel Club Canine Health Foundation, Inc. (Starlight Fund), National Institutes of Health (U.S.) (NIH Short-term Training Grant (T32 RR18267)), Swedish Medical Research Council, University of Minnesota, United States. Army Medical Research and Materiel Command (Training Grant (W81XWH-06-1-064)), European Research Council (ERC Young Investigator Award), European Science Foundation (European Young Investigator Award Program)

A new research effort at the University of Missouri-Columbia aims to develop metamaterials for high power antennas and other microwave devices. In the past, size reduction of high power antennas has focused on the development of materials with a high relative permittivity. However, the authors propose that by controlling both the permittivity and permeability, it will be possible to significantly reduce the component size while also optimizing the impedance for improved efficiency and bandwidth over previous designs that used only a high relative permittivity. This could lead to improved performance for various loaded antennas, as well as benefits to other microwave devices incorporating insulating material with an optimized impedance. Using techniques developed at the University of Missouri-Columbia for the production of high dielectric constant composite materials, initial metamaterial samples have been produced by insulating ferrites and binding them into a composite matrix. The initial stage of this project investigated taking a variety of ferrites and measuring their properties once incorporated into a composite. These ferrites ranged from having a relative permeability of 1200 at 200 MHz to 50 at 800 MHz. Permittivity and permeability measurements of initial samples indicate wavelength and impedance optimization via metamaterials is feasible.

A novel costimulatory molecule expressed on activated T cells, inducible costimulator (ICOS), and its ligand, B7-related protein-1 (B7RP-1), were recently identified. ICOS costimulation leads to the induction of Th2 cytokines without augmentation of IL-2 production, suggesting a role for ICOS in Th2 cell differentiation and expansion. In the present study, a soluble form of murine ICOS, ICOS-Ig, was used to block ICOS/B7RP-1 interactions in a Th2 model of allergic airway disease. In this model, mice are sensitized with inactivated Schistosoma mansoni eggs and are subsequently challenged with soluble S. mansoni egg Ag directly in the airways. Treatment of C57BL/6 mice with ICOS-Ig during sensitization and challenge attenuated airway inflammation, as demonstrated by a decrease in cellular infiltration into the lung tissue and airways, as well as by a decrease in local IL-5 production. These inhibitory effects were not due to a lack of T cell priming nor to a defect in Th2 differentiation. In addition, blockade of ICOS/B7RP-1 interactions during ex vivo restimulation of lung Th2 effector cells prevented cytokine production. Thus, blockade of ICOS signaling can significantly reduce airway inflammation without affecting Th2 differentiation in this model of allergic airway disease.

Although beta1 integrin-dependent T cell migration is required for immune function, little is known of the signaling pathways regulating this migration. We now show that the cytoplasmic tyrosine kinase, focal adhesion kinase (FAK) plays an essential role in the beta1 integrin-stimulated migration of T cells through regulation of the unique Crk-associated substrate (Cas) family docking protein, human enhancer of filamentation 1 (HEF1) and effects on "outside-in" beta1 integrin signaling. Overexpression of wild-type FAK promoted beta1 integrin-dependent Jurkat T cell migration, whereas FAK mutated in either its autophosphorylation site or proline rich region 1 (PR1)/HEF1 SH3 domain-binding site had a dominant negative effect on migration. In contrast, neither wild-type nor mutant FAK affected Jurkat cell adhesion to fibronectin, a beta1 integrin ligand. The migration of FAK-overexpressing cells directly correlated with the beta1 integrin-inducible tyrosine phosphorylation of endogenous plus wild-type exogenous FAK, and not with phosphorylation of the FAK-related kinase, Pyk2. FAK was also found to regulate both HEF1-promoted migration, and HEF1 tyrosine phosphorylation in beta1 integrin-stimulated cells, in a manner dependent upon the FAK autophosphorylation and PR1 sites, and HEF1 SH3 domain. Together, our results indicate that beta1 integrin-stimulated T cell migration requires a linear beta1 integrin-FAK-HEF1 effector pathway.

Interleukin-8 (IL-8) gene expression is highly up-regulated in canine hemangiosarcoma (HSA); however, its role in the pathogenesis of this disease is unknown. We investigated the expression of IL-8 in canine HSA tissues and cell lines, as well and the effects of IL-8 on canine HSA in vitro, and in vivo using a mouse xenograft model for the latter. Constitutive expression of IL-8 mRNA, IL-8 protein, and IL-8 receptor were variable among different tumor samples and cell lines, but they showed stable steady states in each cell line. Upon the addition of IL-8, HSA cells showed transient intracellular calcium fluxes, suggesting that their IL-8 receptors are functional and that IL-8 binding activates relevant signaling pathways. Yet, neither addition of exogenous IL-8 nor blockade of endogenous IL-8 by neutralizing anti-IL-8 antibody (α-IL-8 Ab) affected HSA cell proliferation or survival in vitro. To assess potential effects of IL-8 in other tumor constituents, we stratified HSA cell lines and whole tumor samples into "IL-8 high" and "IL-8 low" groups. Genome-wide gene expression profiling showed that samples in the "IL-8 high" tumor group were enriched for genes associated with a "reactive microenvironment," including activation of coagulation, inflammation, and fibrosis networks. Based on these findings, we hypothesized that the effects of IL-8 on these tumors were mostly indirect, regulating interactions with the microenvironment. This hypothesis was supported by in vivo xenograft experiments where survival and engraftment of tumor cells was inhibited by administration of neutralizing α-IL-8 Ab. Together, our results suggest that IL-8 contributes to establishing a permissive microenvironment during the early stages of tumorigenesis in HSA.

Canine hemangiosarcomas have been ascribed to an endothelial origin based on histologic appearance; however, recent findings suggest that these tumors may arise instead from hematopoietic progenitor cells. To clarify this ontogenetic dilemma, we used genome-wide expression profiling of primary hemangiosarcomas and identified three distinct tumor subtypes associated with angiogenesis (group 1), inflammation (group 2), and adipogenesis (group 3). Based on these findings, we hypothesized that a common progenitor may differentiate into the three tumor subtypes observed in our gene profiling experiment. To investigate this possibility, we cultured hemangiosarcoma cell lines under normal and sphere-forming culture conditions to enrich for tumor cell progenitors. Cells from sphere-forming cultures displayed a robust self-renewal capacity and exhibited genotypic, phenotypic, and functional properties consistent with each of the three molecular subtypes seen in primary tumors, including expression of endothelial progenitor cell (CD133 and CD34) and endothelial cell (CD105, CD146, and αvβ3 integrin) markers, expression of early hematopoietic (CD133, CD117, and CD34) and myeloid (CD115 and CD14) differentiation markers in parallel with increased phagocytic capacity, and acquisition of adipogenic potential. Collectively, these results suggest that canine hemangiosarcomas arise from multipotent progenitors that differentiate into distinct subtypes. Improved understanding of the mechanisms that determine the molecular and phenotypic differentiation of tumor cells in vivo could change paradigms regarding the origin and progression of endothelial sarcomas.

Targeted toxins have the potential to overcome intrinsic or acquired resistance of cancer cells to conventional cytotoxic agents. Here, we hypothesized that EGFuPA-toxin, a bispecific ligand-targeted toxin (BLT) consisting of a deimmunized Pseudomonas exotoxin (PE) conjugated to epidermal growth factor and urokinase, would efficiently target and kill cells derived from canine hemangiosarcoma (HSA), a highly chemotherapy resistant tumor, as well as cultured hemangiospheres, used as a surrogate for cancer stem cells (CSC). EGFuPA-toxin showed cytotoxicity in four HSA cell lines (Emma, Frog, DD-1 and SB) at a concentration of ≤100 nM, and the cytotoxicity was dependent on specific ligand-receptor interactions. Monospecific targeted toxins also killed these chemoresistant cells; in this case, a "threshold" level of EGFR expression appeared to be required to make cells sensitive to the monospecific EGF-toxin, but not to the monospecific uPA-toxin. The IC₅₀ of CSCs was higher by approximately two orders of magnitude as compared to non-CSCs, but these cells were still sensitive to EGFuPA-toxin at nanomolar (i.e., pharmacologically relevant) concentrations, and when targeted by EGFuPA-toxin, resulted in death of the entire cell population. Taken together, our results support the use of these toxins to treat chemoresistant tumors such as sarcomas, including those that conform to the CSC model. Our results also support the use of companion animals with cancer for further translational development of these cytotoxic molecules.