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Invention and characterization of a systemically administered, attenuated and killed bacteria-based multiple immune receptor agonist for anti-tumor immunotherapy
Activation of immune receptors, such as Toll-like (TLR), NOD-like (NLR) and Stimulator of Interferon Genes (STING) is critical for efficient innate and adaptive immunity. Gram-negative bacteria (G-NB) contain multiple TLR, NOD and STING agonists. Potential utility of G-NB for cancer immunotherapy is supported by observations of tumor regression in the setting of infection and Coley’s Toxins. Coley reported that intravenous (i.v.) administration was likely most effective but produced uncontrollable toxicity. The discovery of TLRs and their agonists, particularly the potent TLR4 agonist lipopolysaccharide (LPS)-endotoxin, comprising ~75% of the outer membrane of G-NB, suggests that LPS may be both a critical active ingredient and responsible for dose-limiting i.v. toxicity of G-NB. This communication reports the production of killed, stabilized, intact bacteria products from non-pathogenic G-NB with ~96% reduction of LPS-endotoxin activity. One resulting product candidate, Decoy10, was resistant to standard methods of cell disruption and contained TLR2,4,8,9, NOD2 and STING agonist activity. Decoy10 also exhibited reduced i.v. toxicity in mice and rabbits, and a largely uncompromised ability to induce cytokine and chemokine secretion by human immune cells
in vitro
, all relative to unprocessed, parental bacterial cells. Decoy10 and a closely related product, Decoy20, produced single agent anti-tumor activity or combination-mediated durable regression of established subcutaneous, metastatic or orthotopic colorectal, hepatocellular (HCC), pancreatic, and non-Hodgkin’s lymphoma (NHL) tumors in mice, with induction of both innate and adaptive immunological memory (syngeneic and human tumor xenograft models). Decoy bacteria combination-mediated regressions were observed with a low-dose, oral non-steroidal anti-inflammatory drug (NSAID), anti-PD-1 checkpoint therapy, low-dose cyclophosphamide (LDC), and/or a targeted antibody (rituximab). Efficient tumor eradication was associated with plasma expression of 15-23 cytokines and chemokines, broad induction of cytokine, chemokine, innate and adaptive immune pathway genes in tumors, cold to hot tumor inflammation signature transition, and required NK, CD4+ and CD8+ T cells, collectively demonstrating a role for both innate and adaptive immune activation in the anti-tumor immune response.
Journal Article
Emergency department visits for electric scooter-related injuries after introduction of an urban rental program
Providers in Salt Lake City emergency departments (EDs) anecdotally noted a significant number of electronic scooter (e-scooter)-related injuries since the launch of e-scooter rentals in the downtown area in June 2018. The aim of this study was to quantify and characterize these injuries.
We reviewed the electronic medical records of the University of Utah ED and the Salt Lake Regional Medical Center ED. Using a broad keyword search for “scooter,” we examined all notes for ED visits between June 15–November 15, 2017, and June 15–November 15, 2018, and identified e-scooter related injuries. The 2017 data pre-dated the launch of the e-scooter share programs in Salt Lake City and served as a control period.
We noted 8 scooter-related injuries in 2017 and 50 in 2018. Injury types from the 2018 period included: major head injury (8%); major musculoskeletal injury (36%); minor head injury (12%); minor musculoskeletal injury (34%); and superficial soft tissue injury (40%). 24% of patients presented via ambulance and 6% presented as a trauma activation. 16% of patients required hospital admission and 14% had an injury requiring operative repair. 16% reported alcohol intoxication and none of the patients reported wearing a helmet at the time of the injury.
Since the launch of e-scooter share programs in Salt Lake City, we have seen a substantial increase in e-scooter related trauma in our EDs. Of particular note is the number of patients with major head injuries and major musculoskeletal injuries.
Journal Article
Socialism : a very short introduction
What is socialism? Does it have a future, or has it become an outdated ideology in the 21st century? This Very Short Introduction considers the major theories in socialism, and explores its historical evolution from the French Revolution to the present day. Michael Newman argues that socialism has always been a diverse doctrine, while nevertheless containing a central core of interconnected values and goals: a critique of capitalism; an optimistic view of human beings; and the belief that it is possible to establish societies based on egalitarianism, social solidarity, and co-operation.
Book
Yoked surface codes
One of the biggest obstacles to building a large scale quantum computer is the high qubit cost of protecting quantum information. For two-dimensional architectures, the surface code has long been the leading candidate quantum memory, but can require upwards of a thousand physical qubits per logical qubit to reach algorithmically-relevant logical error rates. In this work, we introduce a hierarchical memory formed from surface codes concatenated into high-density parity check codes. These yoked surface codes are arrayed in a rectangular grid, with parity checks (yokes) measured along each row, and optionally along each column, using lattice surgery. Our construction assumes no additional connectivity beyond a nearest-neighbor square qubit grid operating at a physical error rate of 10
−3
. At algorithmically-relevant logical error rates, yoked surface codes use as few as one-third the number of physical qubits per logical qubit as standard surface codes, enabling moderate-overhead fault-tolerant quantum memories in two dimensions.
For architectures with local connectivity, the surface code has been the leading approach to constructing fault-tolerant logical qubits, but typically requires over 1000 physical qubits per logical qubit. Here, the authors introduce a hierarchical code that maintains the same connectivity requirements as the surface code while reducing the physical qubit overhead by up to a factor of three.
Journal Article
Legitimating Television
Legitimating Television: Media Convergence and Cultural Status explores how and why television is gaining a new level of cultural respectability in the 21st century. Once looked down upon as a \"plug-in drug\" offering little redeeming social or artistic value, television is now said to be in a creative renaissance, with critics hailing the rise of Quality series such as Mad Men and 30 Rock. Likewise, DVDs and DVRs, web video, HDTV, and mobile devices have shifted the longstanding conception of television as a household appliance toward a new understanding of TV as a sophisticated, high-tech gadget. Newman and Levine argue that television’s growing prestige emerges alongside the convergence of media at technological, industrial, and experiential levels. Television is permitted to rise in respectability once it is connected to more highly valued media and audiences. Legitimation works by denigrating \"ordinary\" television associated with the past, distancing the television of the present from the feminized and mass audiences assumed to be inherent to the \"old\" TV. It is no coincidence that the most validated programming and technologies of the convergence era are associated with a more privileged viewership. The legitimation of television articulates the medium with the masculine over the feminine, the elite over the mass, reinforcing cultural hierarchies that have long perpetuated inequalities of gender and class. Legitimating Television urges readers to move beyond the question of taste—whether TV is \"good\" or \"bad\"—and to focus instead on the cultural, political, and economic issues at stake in television’s transformation in the digital age.
eBook
