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Immunotherapy utilizing checkpoint inhibitors has shown remarkable success in the treatment of cancers. In addition to immune checkpoint inhibitors, immune co-stimulation has the potential to enhance immune activation and destabilize the immunosuppressive tumor microenvironment. CD137, also known as 4-1BB, is one of the potent immune costimulatory receptors that could be targeted for effective immune co-stimulation. The interaction of the 4-1BB receptor with its natural ligand (4-1BBL) generates a strong costimulatory signal for T cell proliferation and survival. 4-1BBL lacks costimulatory activity in soluble form. To obtain co-stimulatory activity in soluble form, a recombinant 4-1BBL protein was generated by fusing the extracellular domains of murine 4-1BBL to a modified version of streptavidin (SA-4-1BBL). Treatment with SA-4-1BBL inhibited the development of lung tumors in A/J mice induced by weekly injections of the tobacco carcinogen NNK for eight weeks. The inhibition was dependent on the presence of T cells and NK cells; depletion of these cells diminished the SA-4-1BBL antitumor protective effect. The number of lung tumor nodules was significantly reduced by the administration of SA-4-1BBL to mice during ongoing exposure to NNK. The data presented in this paper suggest that utilizing an immune checkpoint stimulator as a single agent generate a protective immune response against lung cancer in the presence of a carcinogen. More broadly, this study suggests that immune checkpoint stimulation can be extended to a number of other cancer types, including breast and prostate cancers, for which improved diagnostics can detect disease at the preneoplastic stage. [ABSTRACT FROM AUTHOR]

An automaton is k-visit-bounded if during any computation its work tape head visits each tape cell at most k times. In this paper we consider stack automata which are k-visit-bounded for some integer k. This restriction resets the visits when popping (unlike similarly defined Turing machine restrictions) which we show allows the model to accept a proper superset of context-free languages and also a proper superset of languages of visit-bounded Turing machines. We study two variants of visit-bounded stack automata: one where only instructions that move the stack head downwards increase the number of visits of the destination cell, and another where any transition increases the number of visits. We prove that the two types of automata recognize the same languages. We then show that all languages recognized by visit-bounded stack automata are effectively semilinear, and hence are letter-equivalent to regular languages, which can be used to show other properties. [ABSTRACT FROM AUTHOR]

This paper addresses the controversy of Granzyme B (GzmB) expression by murine Myeloid Derived Suppressor Cells (MDSCs). MDSCs are a heterogenous immature myeloid population that are generated in chronic inflammatory pathologies for the purpose to suppress inflammatory responses. MDSCs express a multitude of factors to induce suppressive function such as PD-L1, reactive oxygen species (ROS), nitric oxide synthase (iNOS), and Arginase-1. Recently, Dufait et al. sought to demonstrate GzmB as an additional mechanism for suppression by MDSCs. They reported that murine MDSCs not only significantly express GzmB as well as Perforin (Prf1), but this expression is functionally important for tumor growth in vivo as well as tumor migration in vitro. We conducted experiments to address the same question but made confounding observations: MDSCs under stringent developmental process do not express GzmB. Our results show that not only GzmB protein is not produced at functional level, but the mRNA transcript is not detectable either. In fact, the GzmB protein found in the media of MDSC culture was due to T cells or natural killer cells contained in bone marrow and cultured alongside MDSCs. We strengthen this finding by genetically deleting GzmB from the myeloid lineage and measuring tumor burden compared to WT counterpart. Our results show no significant difference in tumor burden, suggesting that even if there is minor expression of GzmB, it is not produced at a functional amount to affect tumor growth. Therefore, this paper proposes alternative theories that align with the known understanding of GzmB expression and secretion. [ABSTRACT FROM AUTHOR]

The Major Histocompatibility Complex (MHC) binds to the derived peptides from pathogens to present them to killer T cells on the cell surface. Developing computational methods for accurate, fast, and explainable peptide-MHC binding prediction can facilitate immunotherapies and vaccine development. Various deep learning-based methods rely on separate feature extraction from the peptide and MHC sequences and ignore their pairwise binding information. This paper develops a capsule neural network-based method to efficiently capture the peptide-MHC complex features to predict the peptide-MHC class I binding. Various evaluations confirmed our method outperformance over the alternative methods, while it can provide accurate prediction over less available data. Moreover, for providing precise insights into the results, we explored the essential features that contributed to the prediction. Since the simulation results demonstrated consistency with the experimental studies, we concluded that our method can be utilized for the accurate, rapid, and interpretable peptide-MHC binding prediction to assist biological therapies. A capsule neural network-based method captures pairwise information to accurately predict MHC-I and peptide binding. The comprehensive test of the model indicated both its superiority in performance and interpretability. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are one of the innate immune cells that play an important role in preventing and controlling tumors and viral diseases, but their role in hematopoietic stem cell transplantation (HCT) is not yet fully understood. However, according to some research, these cells can prevent infections and tumor relapse without causing graft versus host disease (GVHD). In addition to NK cells, several studies are about the anti-leukemia effects of NK cell-derived exosomes that can highlight their roles in graft-versus-leukemia (GVL). In this paper, we intend to investigate the results of various articles on the role of NK cells in allogeneic hematopoietic cell transplantation and also their exosomes in GVL. Also, we have discussed the antiviral effects of these cells in post-HCT cytomegalovirus infection. [ABSTRACT FROM AUTHOR]

In this paper, operational principles of a cryogenic memory cell that utilizes high-temperature superconductors (high-Tc) are presented. Such a cell consists of three inductively coupled Josephson junctions coupled via inductors. Design and operational logic of this type of cell were recently introduced and demonstrated for low temperature 4 K environment. The basic memory cell operations (read, write, reset) can be implemented on the same simple circuit and both destructive and non-destructive memory cell operations can be realized. Here, we present the design principles and computational validation of basic memory cell operations (write, read, and reset) for the high-Tc memory cell. Our results for the high-Tc memory cell operations show very good resemblance with the previously presented low-temperature 4 K memory cell operations. [ABSTRACT FROM AUTHOR]