Rethinking immune checkpoint blockade: Beyond the T cell

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies

A Survey of Source Code Search: A 3-Dimensional Perspective

(Source) code search is widely concerned by software engineering researchers because it can improve the productivity and quality of software development. Given a functionality requirement usually described in a natural language sentence, a code search system can retrieve code snippets that satisfy the requirement from a large-scale code corpus, e.g., GitHub. To realize effective and efficient code search, many techniques have been proposed successively. These techniques improve code search performance mainly by optimizing three core components, including query understanding component, code understanding component, and query-code matching component. In this paper, we provide a 3-dimensional perspective survey for code search. Specifically, we categorize existing code search studies into query-end optimization techniques, code-end optimization techniques, and match-end optimization techniques according to the specific components they optimize. Considering that each end can be optimized independently and contributes to the code search performance, we treat each end as a dimension. Therefore, this survey is 3-dimensional in nature, and it provides a comprehensive summary of each dimension in detail. To understand the research trends of the three dimensions in existing code search studies, we systematically review 68 relevant literatures. Different from existing code search surveys that only focus on the query end or code end or introduce various aspects shallowly (including codebase, evaluation metrics, modeling technique, etc.), our survey provides a more nuanced analysis and review of the evolution and development of the underlying techniques used in the three ends. Based on a systematic review and summary of existing work, we outline several open challenges and opportunities at the three ends that remain to be addressed in future work.Comment: submitted to ACM Transactions on Software Engineering and Methodolog

Analysis of the Brayton cycle coupled with a small fluoride salt-cooled high-temperature reactor

Considering the environmental conditions and transportation conditions of remote areas, an inherently safe integrated energy conversion system featuring miniaturization, modularization, and high environmental adaptability is needed. The small fluoride salt-cooled high-temperature reactor (FHR) coupled with the Brayton cycle is a promising design. In this paper, the efficiency, exergy efficiency, and exergy loss of four different configurations of the supercritical carbon dioxide (S-CO2) Brayton cycle coupled with a new small fluoride salt-cooled high-temperature reactor are compared. The S-CO2 recompressor Brayton cycle has the best overall performance. Meanwhile, the effects of the cooling conditions on the thermal efficiency and exergy efficiency of different cycle configurations are discussed. When the core outlet temperature is 700°C, the efficiency of the designed S-CO2 recompressor Brayton cycle is approximately 42–44% when the cycle minimum temperature is 20–40°C. In conclusion, the designed small FHR coupled with the Brayton cycle system offers interesting performances in power generation, mineral mining, industrial steam supply, molten salt energy storage, and high-temperature hydrogen production in remote areas

Stromal and therapy-induced macrophage proliferation promotes PDAC progression and susceptibility to innate immunotherapy

Tumor-associated macrophages (TAMs) are abundant in pancreatic ductal adenocarcinomas (PDACs). While TAMs are known to proliferate in cancer tissues, the impact of this on macrophage phenotype and disease progression is poorly understood. We showed that in PDAC, proliferation of TAMs could be driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression also drove response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy

Epigenetic regulation during cancer transitions across 11 tumour types

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasi

Case Report: Chronic hepatitis E virus Infection in an individual without evidence for immune deficiency

Chronic hepatitis E virus (HEV) infection occurs mainly in immunosuppressed populations. We describe an investigation of chronic HEV infection of genotype 3a in an individual without evidence for immune deficiency who presented hepatitis with significant HEV viremia and viral shedding. We monitored HEV RNA in plasma and stools, and assessed anti-HEV specific immune responses. The patient was without apparent immunodeficiency based on quantified results of white blood cell, lymphocyte, neutrophilic granulocyte, CD3+ T cell, CD4+ T cell, and CD8+ T cell counts and CD4/CD8 ratio, as well as total serum IgG, IgM, and IgA, which were in the normal range. Despite HEV specific cellular response and strong humoral immunity being observed, viral shedding persisted up to 109 IU/mL. After treatment with ribavirin combined with interferon, the indicators of liver function in the patient returned to normal, accompanied by complete suppression and clearance of HEV. These results indicate that HEV chronicity can also occur in individuals without evidence of immunodeficiency

Passive Vibration Reduction Analysis of the Mistuned Blisk Deposited Hard Coating Using Modified Reduced-Order Model

To improve the reliability and safety of the mistuned blisk (integrally bladed disk), a novel strategy for passive vibration reduction by the hard coating was developed, and the vibration and damping characteristics of the HCM (hard-coating mistuned) blisk were investigated in this work. Firstly, by the proposed criterion called FDSD (frequency difference and its standard deviation), a classical reduced-order model established by the component mode synthesis method was modified to carry out modal analysis for high computational efficiency. Then, forced vibration responses of the HCM blisk were achieved by the Rayleigh damping model. Next, a specific benchmark of a mistuned blisk deposited NiCoCrAlY + YSZ hard coating was chosen to conduct numerical calculations, and the results were compared with those obtained from the FOM (full-order model) and experimental test, respectively. Finally, the influence of the hard coating and coating thickness on the mistuned blisk were investigated, in particular

Research Article Mechanical Analysis of Submarine Oil Pipelines Considering Overhanging of Transition Section

Abstract: The purpose of the study is to protect the safety of the submarine pipelines by establishing and analyzing mechanical model of the overhanging pipeline. The calculation equations of the force and deformation of the overhanging pipeline are presented in this study. In especial, the transition section is introduced to analyze the overhanging oil pipeline. The calculation equations of the moment, stress and deformation of the overhanging pipeline by considering the premise of sediment reaction are created. The software FORTRAN is used to carry out numerical simulation and the changing laws of bending moment, stress and deformation of overhanging pipeline are obtained. On the basis, the calculation equations of maximum bending moment, maximum stress and maximum deformation can be also obtained. Therefore, theoretical support for calculating submarine pipelines is provided, which has great significance for the analysis and treatment of the overhanging of submarine pipelines

Molten salt synthesis of gadolinium boride nanocrystals suitable for methyl blue removal

Efficient removal of cationic dyes such as methyl blue (MB) is of great importance from the environmental perspective. Although adsorption methods have been employed for this purpose, it is not easy to find inorganic materials featuring both high adsorption capacity and ratio. Herein, a comprehensive study on the MB removal performance by GdB6 nanoparticles was provided. GdB6 was conveniently synthesized via the reaction of GdF3 and NaBH4 at 900 °C in molten LiCl-KCl, and the resulting nanoparticles exhibit cubic-shaped structures with an average size of 100 nm and BET surface area of 51.5 m2/g. During the evaluation of MB removal performance, reduction of MB to colorless leucomethylene (LMB) on the surface of GdB6 was observed for the first time, which makes it more reliable to determine the capability of GdB6 in the treatment of MB. In addition to reduction, MB decolorization mainly results from adsorption on the surface of GdB6 based on the adsorption-desorption tests. The adsorption behavior follows the pseudo-second-order kinetics and Freundlich isotherm model. An adsorption capacity of 3108.8 mg/g with an adsorption ratio of 77.7% was obtained, and the performance remained unchanged after six adsorption-desorption cycles, which demonstrate the excellent MB removal performance of GdB6 in comparison to other inorganic materials

Does Air Pollution Impact Fiscal Sustainability? Evidence from Chinese Cities

Fiscal sustainability is an issue of great concern for governments globally and air pollution control has become an important factor affecting fiscal sustainability. This study aims to examine the impact of air pollution on fiscal sustainability in the short and long run. We conducted an empirical analysis based on air pollution and local government debt data on China’s prefecture-level cities in 2014–2019, using regression discontinuity design (RDD) and a panel data model. The results show that air pollution reduces the debt burden of governments in the short run. However, in the long run, addressing the negative impacts of air pollution adds to the debt burden of local governments, hindering fiscal sustainability. Fiscal freedom and the level of public services significantly moderate the negative impact of air pollution on fiscal sustainability. A higher level of fiscal freedom generally indicates a greater incentive for local governments to raise pollutant emission standards, strengthen the construction of green infrastructure, and subsidize green enterprises. Furthermore, a higher level of public services reflects better infrastructure and higher levels of investment in environmental protection, which help to reduce the negative impact of air pollution. The governments are suggested to take measures to effectively control air pollution, so as to enhance fiscal stability in the long run