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In recent years, advanced smart contract languages (ASCLs) have been proposed to solve the problem of difficult reading, comprehension, and collaboration when writing smart legal contracts among people in different fields. However, this kind of languages are still hard to put into practice due to the lack of an effective conversion method from the ASCLs to executable smart contract programs. Aiming at this problem, we take SPESC as example to explore how to design conversion rules from the contract in it to the target programming language in Solidity, and to propose a three-layer smart contract framework, including advanced smart-contract layer, general smart-contract layer, and executable machine-code layer. These rules provide an approach to convert the definition of SPESC contracting parties into party-contracts on target language, as well as to produce SPESC contract terms into main-contract on target language. Moreover, the proposed framework specifies not only program architecture and storage structure on general smart-contract layer, but also important mechanisms, including personnel management, timing control, exception handling, etc., which can assist programmers to write smart contract programs. Furthermore, taking four SPESC contracts as testing objects, we provide the whole process of converting from SPESC contracts to Solidity programs by the SPESC-Translator, and verify the efficiency and security of the conversion process, including coding, deploying, running, and testing through Ethereum. The instance results show that the conversion rules and the three-layer framework can simplify the writing of smart contracts, standardize the program structure, and help programmers to verify the correctness of the contract programs. [ABSTRACT FROM AUTHOR]

Introduction: Monitoring of laboratory indicators is important for predicting changes in disease severity and clinical outcomes. We aimed to identify the critical predictors that can effectively assess the disease conditions of patients with COVID‐19 by analyzing the clinical characteristics and laboratory findings of patients with SARS‐CoV‐2 infection. Methods: All consecutive patients (n = 294) with confirmed SARS‐CoV‐2 infection admitted to the General Hospital of Central Theater Command of the PLA from February 6 to February 21, 2020, were enrolled. These patients were divided into the severe group and the nonsevere group according to disease severity during hospitalization. Results: The median neutrophil‐to‐lymphocyte ratio (NLR) value of the severe patients was dramatically higher than that of the nonsevere patients (10.4 vs 2.6; P <.001). The NLR value equal to 5 was a boundary value worthy of reference, because more than 80% severe patients had an NLR value greater than 5 and over 80% nonsevere patients had an NLR value less than 5. The NLR value of these COVID‐19 patients was positively and respectively correlated with the values of C‐reactive protein (R =.5921, P <.001), lactate dehydrogenase (R =.4509, P <.001), procalcitonin (R =.5504, P <.001), fibrinogen (R =.4710, P <.001), and D‐dimers (R =.4425, P <.001). However, the NLR value was merely and positively correlated with the interleukin‐6 value (R =.3594, P <.05), but had no correlations with the values of interleukin‐10, interleukin‐4, interleukin‐17, interferon‐γ, and tumor necrosis factor‐α (P >.05). Discussion: Neutrophil‐to‐lymphocyte ratio is a critical predictor for assessment of disease severity in patients with COVID‐19, and it has a close relation with the laboratory indicators related to disease conditions. [ABSTRACT FROM AUTHOR]

With the development of high-throughput genomic analysis, sequencing a mouse primary cancer model provides a new opportunity to understand fundamental mechanisms of tumorigenesis and progression. Here, we characterized the genomic variations in a hepatitis-related primary hepatocellular carcinoma (HCC) mouse model. A total of 12 tumor sections and four adjacent non-tumor tissues from four mice were used for whole exome and/or whole genome sequencing and validation of genotyping. The functions of the mutated genes in tumorigenesis were studied by analyzing their mutation frequency and expression in clinical HCC samples. A total of 46 single nucleotide variations (SNVs) were detected within coding regions. All SNVs were only validated in the sequencing samples, except the Hras mutation, which was shared by three tumors in the M1 mouse. However, the mutated allele frequency varied from high (0.4) to low (0.1), and low frequency (0.1–0.2) mutations existed in almost every tumor. Together with a diploid karyotype and an equal distribution pattern of these SNVs within the tumor, these results suggest the existence of subclones within tumors. A total of 26 mutated genes were mapped to 17 terms describing different molecular and cellular functions. All 41 human homologs of the mutated genes were mutated in the clinical samples, and some mutations were associated with clinical outcomes, suggesting a high probability of cancer driver genes in the spontaneous tumors of the mouse model. Genomic sequencing shows that a few mutations can drive the independent origin of primary liver tumors and reveals high heterogeneity among tumors in the early stage of hepatitis-related primary hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Co-signaling molecules in the B7-CD28 family have been intensively studied over the past decade and have brought much excitement to the field of immune regulation. The discovery of new functions for the classical pathways CD80/CD86/CD28/CTLA-4 and the identification of novel pathways of the family, including B7-H1/B7-DC/PD-1, B7-H2/ICOS, B7-H3, B7-H4 and BTLA, are greatly broadening our understanding of the control of T cell-mediated immune responses and tolerance. [Copyright &y& Elsevier]

Background: Autologous tumor-infiltrating lymphocytes (Tils) immunotherapy is a promising treatment in patients with advanced hepatocellular cancer. Although Tils treatment has shown great promise, their persistence and the efficacy after adoptive-transfer are insufficient and remain a challenge. Studies have demonstrated that IL-15 and Akt inhibitor can regulate T cell differentiation and memory. Here, we constructed S-15 (Super human IL-15), a fusion protein consisting of human IL-15, the sushi domain of the IL-15 receptor α chain and human IgG-Fc. Herein we compared the effects of S-15 with IL-2 or in combination with Akti on the expansion and activation of Tils. Methods: Hepatocellular cancer tissues were obtained from 6 patients, Tils were expanded using IL-2, IL-2/S-15, IL-2/Akti or in combination IL-2/S-15/Akti. At day 10, anti-CD3 antibody was added to the culture media and expanded to day 25. The composition, exhaustion and T-cell differentiation markers (CD45RA/CCR7) were analyzed by flow cytometry. Results: We found that IL-2/S-15/Akti expanded Tils and showed the highest percentage of central memory CD45RA−CCR7+ phenotype prior to anti-CD3 antibody activation and after anti-CD3 antibody activation. T cells cultured with IL-2/S-15/Akti exhibited a mixture of CD4+, CD8+, and CD3+CD4−CD8− T cells; S-15 in combination with Akt inhibitor downregulated the expression of PD-1+Tim-3+ on Tils and decreased the Tregs in Tils. Additionally, the Tils expanded in the presence of the Akt inhibitor and S-15 showed enhanced antitumor activity as indicated by the increase in IFN-γ producing tumor infiltrating CD8+ T cells and without comprising the Tils expansion. Conclusion: Our study elucidates that IL-2/S-15/Akti expanded Tils and represent a viable source for the cellular therapy for patients with hepatocellular cancer. [ABSTRACT FROM AUTHOR]

Immunization with high-dose heat shock protein gp96, an endoplasmic reticulum counterpart of the Hsp90 family, significantly enhances regulatory T cell (Treg) frequency and suppressive function. Here, we examined the potential role and mechanism of gp96 in regulating immune-mediated hepatic injury in mice. High-dose gp96 immunization elicited rapid and long-lasting protection of mice against concanavalin A (Con A)-and anti-CD137-induced liver injury, as evidenced by decreased alanine aminotransaminase (ALT) levels, hepatic necrosis, serum pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6), and number of IFN-γ + CD4+ and IFN-γ + CD8+ T cells in the spleen and liver. In contrast, CD4+CD25+Foxp3+ Treg frequency and suppressive function were both increased, and the protective effect of gp96 could be generated by adoptive transfer of Treg cells from gp96-immunized mice. In vitro co-culture experiments demonstrated that gp96 stimulation enhanced Treg proliferation and suppressive function, and up-regulation of Foxp3, IL-10, and TGF-β1 induced by gp96 was dependent on TLR2- and TLR4-mediated NF-κB activation. Our work shows that activation of Tregs by high-dose gp96 immunization protects against Con A- and anti-CD137-induced T cell-hepatitis and provides therapeutic potential for the development of a gp96-based anti-immune hyperactivation vaccine against immune-mediated liver destruction. [ABSTRACT FROM AUTHOR]

The Eulerian–Eulerian two-fluid model coupled with the EMMS/Matrix drag model was employed to investigate the gas–solid flow hydrodynamics in the riser of high-density circulating fluidized bed using Geldart B particles under the dense suspension upflow (DSU) regime. Based on the 2D simulations of two test cases, the predicted axial and radial profiles of solid volume fraction agreed well with the experimental observations, and it could capture the key characteristics of the DSU regime. The transient solid flux and the power spectral density of pressure fluctuation were discussed. The 2D simulation results using the EMMS/Matrix and the Gidaspow drag models were compared in details, and the EMMS/Matrix drag model gave better radial distributions against experimental data, but the predicted radial profiles were improved by solving partial differential equation of granular temperature with the Gidaspow drag model. The 3D simulation with the EMMS/Matrix drag model was also performed, and the differences in the predicted axial and radial profiles of solid volume fraction between 2D and 3D simulations were not significant. The two-dimensional two-fluid model with the EMMS/Matrix drag model is applicable to the simulation of gas–solid flow in the riser under the DSU regime. [ABSTRACT FROM AUTHOR]

Background & Aims Liver cancer has a very dismal prognosis due to lack of effective therapy. Here, we studied the therapeutic effects of hyper-interleukin15 (hyper-IL-15), which is composed of IL-15 and the sushi domain of the IL-15 receptor α chain, on metastatic and autochthonous liver cancers. Methods Liver metastatic tumour models were established by intraportally injecting syngeneic mice with murine CT26 colon carcinoma cells or B16-OVA melanoma cells. Primary hepatocellular carcinoma (HCC) was induced by diethylnitrosamine (DEN). A hydrodynamics-based gene delivery method was used to achieve sustained hyper-IL-15 expression in the liver. Results Liver gene delivery of hyper-IL-15 robustly expanded CD8 + T and NK cells, leading to a long-term (more than 40 days) accumulation of CD8 + T cells in vivo , especially in the liver. Hyper-IL-15 treatment exerted remarkable therapeutic effects on well-established liver metastatic tumours and even on DEN-induced autochthonous HCC, and these effects were abolished by depletion of CD8 + T cells but not NK cells. Hyper-IL-15 triggered IL-12 and interferon-γ production and reduced the expression of co-inhibitory molecules on dendritic cells in the liver. Adoptive transfer of T cell receptor (TCR) transgenic OT-1 cells showed that hyper-IL-15 preferentially expanded tumour-specific CD8 + T cells and promoted their interferon-γ synthesis and cytotoxicity. Conclusions Liver delivery of hyper-IL-15 provides an effective therapy against well-established metastatic and autochthonous liver cancers in mouse models by preferentially expanding tumour-specific CD8 + T cells and promoting their anti-tumour effects. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we demonstrate that an effective immune response against prostate tumors in mouse tumor model can be elicited using a strategy that combines CTLA-4 blockade and pSLC-3P-Fc-modified tumor cell vaccine (named B16F10-SLC-3P-Fc). Treatment of B16F10-3P-bearing mice resulted in a significant reduction in tumor incidence as assessed 2 months after treatment. In vivo Ab depletion confirmed that the antitumor effect was primarily CD8+ T cells and CD4+ T lymphocytes were required for the induction of CD8+ CTL response in B16F10-SLC-3P-Fc+anti-CTLA-4 mAb-immunized mice. Moreover, mice that were cured of an established tumor were protected against a rechallenge with the same tumor for at least 4 months, suggesting the generation of memory responses. Adoptive transfer experiments further indicate that antitumor reactivity can be transferred to naïve mice by splenocytes. These findings demonstrate that this combinatorial treatment can elicit a potent anti-tumor immune response and suggest potential of this approach for treatment of prostate cancer. [Copyright &y& Elsevier]

Microglia/macrophages make up the largest population of tumor-infiltrating cells. Numerous studies have demonstrated that glioma-associated microglia/macrophages (GAMs) could promote the malignant progression of gliomas in various pathways. However, the primary function of GAMs in glioma remains inconclusive. First, by the CIBERSORT algorithm, we evaluated the content of microglia/macrophages in glioma tissues by bioinformatic analysis of omic data from thousands of glioma samples. Subsequently, we analyzed and confirmed the significant relationship between GAMs and the malignant phenotype of glioma, including survival time, IDH mutation status, and time of symptom onset. Afterward, Epithelial-Mesenchymal Transition (EMT) was identified by Gene Set Enrichment Analysis (GSEA) from numerous biological processes as the most relevant mechanism of malignant progression to GAMs. Moreover, a series of clinical samples were detected, including normal brain and various-grade glioma tissues. The results not only showed that GAMs were significantly associated with gliomas and their malignancy but also that GAMs were highly correlated with the degree of EMT in gliomas. In addition, we isolated GAMs from glioma samples and constructed co-culture models ( in vitro ) to demonstrate the promotion of the EMT process in glioma cells by GAMs. In conclusion, our study clarified that GAMs exert oncogenic effects with EMT in gliomas, suggesting the possibility of GAMs as immunotherapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 He, Guo, Yu, Zhang and Wang.)

High-mobility group protein B1 (HMGB1) is a danger signaling molecule that has been found to trigger an effective antitumor immune response. However, the mechanisms underlying its antitumor effects are not fully understood. Here, we found that HMGB1 release induced by chemotherapy in patients with non-small cell lung cancer was negatively correlated with PD-1 expression on CD8+ T cells. In vitro analysis indicated that treatment with HMGB1 led to a significant decrease in the level of expression of PD-1 on CD8+ T cells. Further analysis demonstrated that HMGB1 reduced PD-1 expression by inducing dynamin-mediated internalization of the protein, leading to early endocytosis in the cytoplasm, and subsequently degradation in the lysosomes. In a xenograft model, HER2-targeted chimeric antigen receptor (CAR) T cells had enhanced function in the presence of HMGB1. These data identify a role for HMGB1 as a negative regulator of PD-1 signaling in lung cancer and the observed antitumor effect of HMGB1 on CAR T cells may provide a theoretical foundation for a new immunotherapy combination., (©2022 American Association for Cancer Research.)