Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an ...unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2+ breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.
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•Macrophages are immunosuppressive because of upregulated PD-L1 and IDO after ADCP•AIM2 is recruited to phagosomes and activated by tumor DNA in ADCP macrophages•AIM2 cleaves cGAS and upregulates PD-L1 and IDO by caspase-1/IL-1β•Synergistic effects between therapeutic antibodies and ICIs are macrophage dependent
Therapeutic antibody-based cancer treatment leads to ADCP-induced, AIM2-mediated immunosuppression by macrophages that can be overcome with concomitant immune checkpoint blockade.
Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two ...cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.
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•CD10 and GPR77 define a new CAF subset•CD10+GPR77+ CAFs sustain cancer stemness and promote tumor chemoresistance•Complement signaling maintains NF-κB activation•Targeting CD10+GPR77+ CAFs restores chemosensitivity
CD10 and GPR77 identify a cancer stemness-sustaining cancer-associated fibroblast subset.
Lung cancer has become the most common cancer type and caused the most cancer deaths. Lung adenocarcinoma (LUAD) is one of the major type of lung cancer. This study aimed to establish a signature ...based on immune related genes that can predict patients' OS for LUAD.
The expression data of 976 LUAD patients from The Cancer Genome Atlas database (training set) and the Gene Expression Omnibus database (four testing sets) and 1534 immune related genes from the ImmPort database were used for generation and validation of the signature. The glmnet Cox proportional hazards model was used to find the best gene model and construct the signature. To assess the independently prognostic ability of the signature, the Kaplan-Meier survival analysis and Cox's proportional hazards model were performed.
A gene model consisting of 30 immune related genes with the highest frequency after 1000 iterations was used as our signature. The signature demonstrated robust prognostic ability in both training set and testing set and could serve as an independent predictor for LUAD patients in all datasets except GSE31210. Besides, the signature could predict the overall survival (OS) of LUAD patients in different subgroups. And this signature was strongly associated with important clinicopathological factors like recurrence and TNM stage. More importantly, patients with high risk score presented high tumor mutation burden.
This signature could predict prognosis and reflect the tumor immune microenvironment of LUAD patients, which can promote individualized treatment and provide potential novel targets for immunotherapy.
The actinomycetes have proven to be a rich source of bioactive secondary metabolites and play a critical role in the development of pharmaceutical researches. With interactions of host organisms and ...having special ecological status, the actinomycetes associated with marine animals, marine plants, macroalgae, cyanobacteria, and lichens have more potential to produce active metabolites acting as chemical defenses to protect the host from predators as well as microbial infection. This review focuses on 536 secondary metabolites (SMs) from actinomycetes associated with these marine organisms covering the literature to mid-2021, which will highlight the taxonomic diversity of actinomycetes and the structural classes, biological activities of SMs. Among all the actinomycetes listed, members of
(68%),
(6%), and
(3%) are dominant producers of secondary metabolites. Additionally, alkaloids (37%), polyketides (33%), and peptides (15%) comprise the largest proportion of natural products with mostly antimicrobial activity and cytotoxicity. Furthermore, the data analysis and clinical information of SMs have been summarized in this article, suggesting that some of these actinomycetes with multiple host organisms deserve more attention to their special ecological status and genetic factors.
With the deep combination of both modern information technology and traditional agriculture, the era of agriculture 4.0, which takes the form of smart agriculture, has come. Smart agriculture ...provides solutions for agricultural intelligence and automation. However, information security issues cannot be ignored with the development of agriculture brought by modern information technology. In this paper, three typical development modes of smart agriculture (precision agriculture, facility agriculture, and order agriculture) are presented. Then, 7 key technologies and 11 key applications are derived from the above modes. Based on the above technologies and applications, 6 security and privacy countermeasures (authentication and access control, privacy-preserving, blockchain-based solutions for data integrity, cryptography and key management, physical countermeasures, and intrusion detection systems) are summarized and discussed. Moreover, the security challenges of smart agriculture are analyzed and organized into two aspects: 1) agricultural production, and 2) information technology. Most current research projects have not taken agricultural equipment as potential security threats. Therefore, we did some additional experiments based on solar insecticidal lamps Internet of Things, and the results indicate that agricultural equipment has an impact on agricultural security. Finally, more technologies (5 G communication, fog computing, Internet of Everything, renewable energy management system, software defined network, virtual reality, augmented reality, and cyber security datasets for smart agriculture) are described as the future research directions of smart agriculture.
Tip-enhanced Raman spectroscopy (TERS) with sub-nanometer spatial resolution has been recently demonstrated experimentally. However, the physical mechanism underlying is still under discussion. Here ...we theoretically investigate the electric field gradient of a coupled tip-substrate system. Our calculations suggest that the ultra-high spatial resolution of TERS can be partially attributed to the electric field gradient effect owning to its tighter spatial confinement and sensitivity to the infrared (IR)-active of molecules. Particularly, in the case of TERS of flat-lying H₂TBPP molecules,we find the electric field gradient enhancement is the dominating factor for the high spatial resolution, which qualitatively coincides with previous experimental report. Our theoretical study offers a new paradigm for understanding the mechanisms of the ultra-high spatial resolution demonstrated in tip-enhanced spectroscopy which is of importance but neglected.
Hypoxia-inducible factor-1 (HIF-1) is a master driver of glucose metabolism in cancer cells. Here, we demonstrate that a HIF-1α anti-sense lncRNA, HIFAL, is essential for maintaining and enhancing ...HIF-1α-mediated transactivation and glycolysis. Mechanistically, HIFAL recruits prolyl hydroxylase 3 (PHD3) to pyruvate kinase 2 (PKM2) to induce its prolyl hydroxylation and introduces the PKM2/PHD3 complex into the nucleus via binding with heterogeneous nuclear ribonucleoprotein F (hnRNPF) to enhance HIF-1α transactivation. Reciprocally, HIF-1α induces HIFAL transcription, which forms a positive feed-forward loop to maintain the transactivation activity of HIF-1α. Clinically, high HIFAL expression is associated with aggressive breast cancer phenotype and poor patient outcome. Furthermore, HIFAL overexpression promotes tumor growth in vivo, while targeting both HIFAL and HIF-1α significantly reduces their effect on cancer growth. Overall, our results indicate a critical regulatory role of HIFAL in HIF-1α-driven transactivation and glycolysis, identifying HIFAL as a therapeutic target for cancer treatment.
In industrial automation, numerous devices are interconnected in smart factories for further monitor and control. Various infrastructure devices in industrial automation are usually used for control ...instruction distribution, data collection, and collaboration of the industrial applications. Recent security threats on industrial automation are more frequent and the industrial control systems lack trust mechanism. Blockchain has been introduced due to its decentralization and security promise, but the election results in the original designs could be biased without collaboration trust, which leads the blockchain-based industry applications invalid. In addition, in existing solutions, neither supernodes nor normal nodes in blockchain can transfer their control authorities for disaster backup. To address the aforementioned challenges, this article proposes a collaborative trust based unbiased control transfer mechanism (CTM), which realizes a dynamic assignment of industrial control. First, a collaborative trust based delegated proof of stake consensus is proposed for determining the authorities of control dynamically and unbiasedly, by designing a lightweight trust propagation protocol. Second, a CTM for checking, alarming, and restarting CTM is devised for the disaster backup. The simulation results demonstrate the CTM, which is feasible and effective for industrial automation security.
This paper proposes a strategy for transporting a large object to a goal using a large number of mobile robots that are significantly smaller than the object. The robots only push the object at ...positions where the direct line of sight to the goal is occluded by the object. This strategy is fully decentralized and requires neither explicit communication nor specific manipulation mechanisms. We prove that it can transport any convex object in a planar environment. We implement this strategy on the e-puck robotic platform and present systematic experiments with a group of 20 e-pucks transporting three objects of different shapes. The objects were successfully transported to the goal in 43 out of 45 trials. When using a mobile goal, teleoperated by a human, the object could be navigated through an environment with obstacles. We also tested the strategy in a 3-D environment using physics-based computer simulation. Due to its simplicity, the transport strategy is particularly suited for implementation on microscale robotic systems.
Swine enteric coronaviruses are a group of most significant pathogens causing diarrhea in piglets with similar clinical symptoms and pathological changes. To develop a simple, rapid, accurate, and ...high-throughput detection method for diagnosis and differential diagnosis on swine enteric coronaviruses, specific primers and probes were designed based on the highly conserved regions of transmissible gastroenteritis virus (TGEV) N, porcine epidemic diarrhea virus (PEDV) M, porcine deltacoronavirus (PDCoV) M, and porcine enteric alphacoronavirus (PEAV) N genes respectively. A TaqMan-probe-based multiplex real-time RT-qPCR assay was developed and optimized to simultaneously detect these swine enteric coronaviruses. The results showed that the limit of detection can reach as low as 10 copies in singular real-time RT-qPCR assays and 100 copies in multiplex real-time RT-qPCR assay, with all correlation coefficients (
R
2
) at above 0.99, and the amplification efficiency at between 90 and 120%. This multiplex real-time RT-qPCR assay demonstrated high sensitivity, extreme specificity, and excellent repeatability. The multiplex real-time RT-qPCR assay was then employed to detect the swine enteric coronavirus from 354 field diarrheal samples. The results manifested that TGEV and PDCoV were the main pathogens in these samples, accompanied by co-infections. This well-established multiplex real-time RT-qPCR assay provided a rapid, efficient, specific, and sensitive tool for detection of swine enteric coronaviruses.
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