A microparticle platform for STING-targeted immunotherapy enhances natural killer cell- and CD8 + T cell-mediated anti-tumor immunity

Immunotherapies have significantly improved cancer patient survival, but response rates are still limited. Thus, novel formulations are needed to expand the breadth of immunotherapies. Pathogen associated molecular patterns (PAMPs) can be used to stimulate an immune response, but several pathogen recognition receptors are located within the cell, making delivery challenging. We have employed the biodegradable polymer acetalated dextran (Ace-DEX) to formulate PAMP microparticles (MPs) in order to enhance intracellular delivery. While treatment with four different PAMP MPs resulted in tumor growth inhibition, cyclic GMP-AMP (cGAMP) MPs were most effective. cGAMP MPs showed anti-tumor efficacy at doses 100-1000 fold lower than published doses of soluble cGAMP in two murine tumor models. Treatment with cGAMP MPs resulted in increased natural killer cell numbers in the tumor environment. Immune cell depletion studies confirmed that NK cells were responsible for the anti-tumor efficacy in an aggressive mouse melanoma model. NK cells and CD8 + T cells were both required for early anti-tumor function in a triple negative breast cancer model. In summary, cGAMP MP treatment results in NK and T cell-dependent anti-tumor immune response

Materializing digital collecting: an extended view of digital materiality

If digital objects are abundant and ubiquitous, why should consumers pay for, much less collect them? The qualities of digital code present numerous challenges for collecting, yet digital collecting can and does occur. We explore the role of companies in constructing digital consumption objects that encourage and support collecting behaviours, identifying material configuration techniques that materialise these objects as elusive and authentic. Such techniques, we argue, may facilitate those pleasures of collecting otherwise absent in the digital realm. We extend theories of collecting by highlighting the role of objects and the companies that construct them in materialising digital collecting. More broadly, we extend theories of digital materiality by highlighting processes of digital material configuration that occur in the pre-objectification phase of materialisation, acknowledging the role of marketing and design in shaping the qualities exhibited by digital consumption objects and consequently related consumption behaviours and experiences

A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination

Most FDA-approved adjuvants for infectious agents boost humoral but not cellular immunity, and have poorly-understood mechanisms. Stimulator of interferon genes (STING, also known as MITA, MPYS, or ERIS) is an exciting adjuvant target due to its role in cyclic dinucleotide (CDN)-driven anti-viral immunity; however, a major hindrance is STING's cytosolic localization which requires intracellular delivery of its agonists. As a result, STING agonists administered in a soluble form have elicited suboptimal immune responses. Delivery of STING agonists via particle platforms has proven a more successful strategy, but the opportunity for improved formulations and bioactivity remains. In this study we evaluated the adjuvant activity of the potent STING agonist, CDN 3′3′-cGAMP (cGAMP), encapsulated in acid-sensitive acetalated dextran (Ace-DEX) polymeric microparticles (MPs) which passively target antigen-presenting cells for intracellular release. This formulation was superior to all particle delivery systems evaluated and maintained its bioactivity following a sterilizing dose of gamma irradiation. Compared to soluble cGAMP, the Ace-DEX cGAMP MPs enhanced type-I interferon responses nearly 1000-fold in vitro and 50-fold in vivo, caused up to a 104-fold boost in antibody titers, increased Th1-associated responses, and expanded germinal center B cells and memory T cells. Furthermore, the encapsulated cGAMP elicited no observable toxicity in animals and achieved protective immunity against a lethal influenza challenge seven months post-immunization when using CDN adjuvant doses up to 100-fold lower than previous reports. For these reasons, Ace-DEX MP-encapsulated cGAMP represents a potent vaccine adjuvant of humoral and cellular immunity

Measurement of the partial widths of the Z into up- and down-type quarks

Using the entire OPAL LEP1 on-peak Z hadronic decay sample, Z -> qbarq gamma decays were selected by tagging hadronic final states with isolated photon candidates in the electromagnetic calorimeter. Combining the measured rates of Z -> qbarq gamma decays with the total rate of hadronic Z decays permits the simultaneous determination of the widths of the Z into up- and down-type quarks. The values obtained, with total errors, were Gamma u = 300 ^{+19}_{-18} MeV and Gamma d = 381 ^{+12}_{-12} MeV. The results are in good agreement with the Standard Model expectation.Comment: 22 pages, 5 figures, Submitted to Phys. Letts.

Search for R-Parity Violating Decays of Scalar Fermions at LEP

A search for pair-produced scalar fermions under the assumption that R-parity is not conserved has been performed using data collected with the OPAL detector at LEP. The data samples analysed correspond to an integrated luminosity of about 610 pb-1 collected at centre-of-mass energies of sqrt(s) 189-209 GeV. An important consequence of R-parity violation is that the lightest supersymmetric particle is expected to be unstable. Searches of R-parity violating decays of charged sleptons, sneutrinos and squarks have been performed under the assumptions that the lightest supersymmetric particle decays promptly and that only one of the R-parity violating couplings is dominant for each of the decay modes considered. Such processes would yield final states consisting of leptons, jets, or both with or without missing energy. No significant single-like excess of events has been observed with respect to the Standard Model expectations. Limits on the production cross- section of scalar fermions in R-parity violating scenarios are obtained. Constraints on the supersymmetric particle masses are also presented in an R-parity violating framework analogous to the Constrained Minimal Supersymmetric Standard Model.Comment: 51 pages, 24 figures, Submitted to Eur. Phys. J.

A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1-insensitive models of triple-negative breast cancer

Triple-negative breast cancer (TNBC) has few therapeutic options, and alternative approaches are urgently needed. Stimulator of IFN genes (STING) is becoming an exciting target for therapeutic adjuvants. However, STING resides inside the cell, and the intracellular delivery of CDNs, such as cGAMP, is required for the optimal activation of STING. We show that liposomal nanoparticle-delivered cGAMP (cGAMP-NP) activates STING more effectively than soluble cGAMP. These particles induce innate and adaptive host immune responses to preexisting tumors in both orthotopic and genetically engineered models of basal-like TNBC. cGAMP-NPs also reduce melanoma tumor load, with limited responsivity to anti-PD-L1. Within the tumor microenvironment, cGAMP-NPs direct both mouse and human macrophages (M), reprograming from protumorigenic M2-like phenotype toward M1-like phenotype; enhance MHC and costimulatory molecule expression; reduce M2 biomarkers; increase IFN-γ-producing T cells; augment tumor apoptosis; and increase CD4+ and CD8+ T cell infiltration. Activated T cells are required for tumor suppression, as their depletion reduces antitumor activity. Importantly, cGAMP-NPs prevent the formation of secondary tumors, and a single dose is sufficient to inhibit TNBC. These data suggest that a minimal system comprised of cGAMP-NP alone is sufficient to modulate the tumor microenvironment to effectively control PD-L1-insensitive TNBC

Measurement of the Strong Coupling alpha s from Four-Jet Observables in e+e- Annihilation

Data from e+e- annihilation into hadrons at centre-of-mass energies between 91 GeV and 209 GeV collected with the OPAL detector at LEP, are used to study the four-jet rate as a function of the Durham algorithm resolution parameter ycut. The four-jet rate is compared to next-to-leading order calculations that include the resummation of large logarithms. The strong coupling measured from the four-jet rate is alphas(Mz0)= 0.1182+-0.0003(stat.)+-0.0015(exp.)+-0.0011(had.)+-0.0012(scale)+-0.0013(mass) in agreement with the world average. Next-to-leading order fits to the D-parameter and thrust minor event-shape observables are also performed for the first time. We find consistent results, but with significantly larger theoretical uncertainties.Comment: 25 pages, 15 figures, Submitted to Euro. Phys. J.

Measurement of the Hadronic Photon Structure Function F_2^gamma at LEP2

The hadronic structure function of the photon F_2^gamma is measured as a function of Bjorken x and of the factorisation scale Q^2 using data taken by the OPAL detector at LEP. Previous OPAL measurements of the x dependence of F_2^gamma are extended to an average Q^2 of 767 GeV^2. The Q^2 evolution of F_2^gamma is studied for average Q^2 between 11.9 and 1051 GeV^2. As predicted by QCD, the data show positive scaling violations in F_2^gamma. Several parameterisations of F_2^gamma are in agreement with the measurements whereas the quark-parton model prediction fails to describe the data.Comment: 4 pages, 2 figures, to appear in the proceedings of Photon 2001, Ascona, Switzerlan

A measurement of the tau mass and the first CPT test with tau leptons

We measure the mass of the tau lepton to be 1775.1+-1.6(stat)+-1.0(syst.) MeV using tau pairs from Z0 decays. To test CPT invariance we compare the masses of the positively and negatively charged tau leptons. The relative mass difference is found to be smaller than 3.0 10^-3 at the 90% confidence level.Comment: 10 pages, 4 figures, Submitted to Phys. Letts.

Measurement of Rb in e+e- Collisions at 182 - 209 GeV

Measurements of Rb, the ratio of the bbbar cross-section to the qqbar cross- section in e+e- collisions, are presented. The data were collected by the OPAL experiment at LEP at centre-of-mass energies between 182 GeV and 209 GeV. Lepton, lifetime and event shape information is used to tag events containing b quarks with high efficiency. The data are compatible with the Standard Model expectation. The mean ratio of the eight measurements reported here to the Standard Model prediction is 1.055+-0.031+-0.037, where the first error is statistical and the second systematic.Comment: 21 pages, 5 figures, Submitted to Phys. Letts