BACKGROUND For the first time,we investigated the oncological role of plexin domain-containing 1(PLXDC1),also known as tumor endothelial marker 7(TEM7),in hepatocellular carcinoma(HCC).AIM To investigate the oncologic...BACKGROUND For the first time,we investigated the oncological role of plexin domain-containing 1(PLXDC1),also known as tumor endothelial marker 7(TEM7),in hepatocellular carcinoma(HCC).AIM To investigate the oncological profile of PLXDC1 in HCC.METHODS Based on The Cancer Genome Atlas database,we analyzed the expression of PLXDC1 in HCC.Using immunohistochemistry,quantitative real-time polymerase chain reaction(qRT-PCR),and Western blotting,we validated our results.The prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features,such as patient survival,methylation level,tumor immune microenvironment features,and immune cell surface checkpoint expression.Finally,to assess the immune evasion potential of PLXDC1 in HCC,we used the tumor immune dysfunction and exclusion(TIDE)website and immunohistochemical staining assays.RESULTS Based on immunohistochemistry,qRT-PCR,and Western blot assays,overexpression of PLXDC1 in HCC was associated with poor prognosis.Univariate and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic factor.In HCC patients with high methylation levels,the prognosis was worse than in patients with low methylation levels.Pathway enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling,and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 subgroup.The high-risk group had a significantly lower immune evasion rate as well as a poor prognosis,and PLXDC1-related risk scores were also associated with a poor prognosis.CONCLUSION As a result of this study analyzing PLXDC1 from multiple biological perspectives,it was revealed that it is a biomarker of poor prognosis for HCC patients,and that it plays a role in determining immune evasion status.展开更多
Background: Omicron JN.1 has become the dominant SARS-CoV-2 variant in recent months. JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation...Background: Omicron JN.1 has become the dominant SARS-CoV-2 variant in recent months. JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation. The immune evasion capability of JN.1 is a subject of scientific investigation. The US CDC used SGTF of TaqPath COVID-19 Combo Kit RT-qPCR as proxy indicator of JN.1 infections for evaluation of the effectiveness of updated monovalent XBB.1.5 COVID-19 vaccines against JN.1 and recommended that all persons aged ≥ 6 months should receive an updated COVID-19 vaccine dose. Objective: Recommend Sanger sequencing instead of proxy indicator to diagnose JN.1 infections to generate the data based on which guidelines are made to direct vaccination policies. Methods: The RNA in nasopharyngeal swab specimens from patients with clinical respiratory infection was subjected to nested RT-PCR, targeting a 398-base segment of the N-gene and a 445-base segment of the RBD of SARS-CoV-2 for amplification. The nested PCR amplicons were sequenced. The DNA sequences were analyzed for amino acid mutations. Results: The N-gene sequence showed R203K, G204R and Q229K, the 3 mutations associated with Omicron BA.2.86 (+JN.1). The RBD sequence showed 24 of the 26 known amino acid mutations, including the hallmark L455S mutation for JN.1 and the V483del for BA.2.86 lineage. Conclusions: Sanger sequencing of a 445-base segment of the SARS-CoV-2 RBD is useful for accurate determination of emerging variants. The CDC may consider using Sanger sequencing of the RBD to diagnose JN.1 infections for statistical analysis in making vaccination policies.展开更多
Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy...Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.展开更多
Spacecraft orbit evasion is an effective method to ensure space safety. In the spacecraft’s orbital plane, the space non-cooperate target with autonomous approaching to the spacecraft may have a dangerous rendezvous....Spacecraft orbit evasion is an effective method to ensure space safety. In the spacecraft’s orbital plane, the space non-cooperate target with autonomous approaching to the spacecraft may have a dangerous rendezvous. To deal with this problem, an optimal maneuvering strategy based on the relative navigation observability degree is proposed with angles-only measurements. A maneuver evasion relative navigation model in the spacecraft’s orbital plane is constructed and the observability measurement criteria with process noise and measurement noise are defined based on the posterior Cramer-Rao lower bound. Further, the optimal maneuver evasion strategy in spacecraft’s orbital plane based on the observability is proposed. The strategy provides a new idea for spacecraft to evade safety threats autonomously. Compared with the spacecraft evasion problem based on the absolute navigation, more accurate evasion results can be obtained. The simulation indicates that this optimal strategy can weaken the system’s observability and reduce the state estimation accuracy of the non-cooperative target, making it impossible for the non-cooperative target to accurately approach the spacecraft.展开更多
Ovarian cancer is one of the three major malignant tumors in gynecology, with increasing incidence and mortality rates. Currently, the main treatment methods remain surgical intervention in combination with chemothera...Ovarian cancer is one of the three major malignant tumors in gynecology, with increasing incidence and mortality rates. Currently, the main treatment methods remain surgical intervention in combination with chemotherapy. However, due to its high recurrence rate and the risk of drug resistance, the overall prognosis is poor. Ovarian cancer has been identified as an immunegenic tumor, and in recent years, with the continued advancement of research into immune evasion mechanisms, immunotherapy has emerged as a groundbreaking treatment modality. This article will focus on the immune escape mechanisms and their application in ovarian cancer, providing a comprehensive overview of its current status and the challenges it faces.展开更多
Antivirus vendors and the research community employ Machine Learning(ML)or Deep Learning(DL)-based static analysis techniques for efficient identification of new threats,given the continual emergence of novel malware ...Antivirus vendors and the research community employ Machine Learning(ML)or Deep Learning(DL)-based static analysis techniques for efficient identification of new threats,given the continual emergence of novel malware variants.On the other hand,numerous researchers have reported that Adversarial Examples(AEs),generated by manipulating previously detected malware,can successfully evade ML/DL-based classifiers.Commercial antivirus systems,in particular,have been identified as vulnerable to such AEs.This paper firstly focuses on conducting black-box attacks to circumvent ML/DL-based malware classifiers.Our attack method utilizes seven different perturbations,including Overlay Append,Section Append,and Break Checksum,capitalizing on the ambiguities present in the PE format,as previously employed in evasion attack research.By directly applying the perturbation techniques to PE binaries,our attack method eliminates the need to grapple with the problem-feature space dilemma,a persistent challenge in many evasion attack studies.Being a black-box attack,our method can generate AEs that successfully evade both DL-based and ML-based classifiers.Also,AEs generated by the attack method retain their executability and malicious behavior,eliminating the need for functionality verification.Through thorogh evaluations,we confirmed that the attack method achieves an evasion rate of 65.6%against well-known ML-based malware detectors and can reach a remarkable 99%evasion rate against well-known DL-based malware detectors.Furthermore,our AEs demonstrated the capability to bypass detection by 17%of vendors out of the 64 on VirusTotal(VT).In addition,we propose a defensive approach that utilizes Trend Locality Sensitive Hashing(TLSH)to construct a similarity-based defense model.Through several experiments on the approach,we verified that our defense model can effectively counter AEs generated by the perturbation techniques.In conclusion,our defense model alleviates the limitation of the most promising defense method,adversarial training,which is only effective against the AEs that are included in the training classifiers.展开更多
Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been id...Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy.However,the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood.This comprehensive review aims to provide an overview of CD47’s multifaced role in TME regulation and immune evasion,elucidating its impact on various types of immunotherapy outcomes,including checkpoint inhibitors and CAR T-cell therapy.Notably,CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes,especially when combined with other immunotherapeutic approaches.The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47.Despite the demonstrated effectiveness of CD47-targeted therapies,there are potential problems,including unintended effects on healthy cells,hematological toxicities,and the development if resistance.Consequently,further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches,ultimately improving cancer treatment outcomes.Overall,this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.展开更多
The host immune system functions as a guardian against tumor development. It has been demonstrated that cytotoxic T lymphocyte (CTL)-mediated cytotoxic pathways function to inhibit or delay human colorectal cancer dev...The host immune system functions as a guardian against tumor development. It has been demonstrated that cytotoxic T lymphocyte (CTL)-mediated cytotoxic pathways function to inhibit or delay human colorectal cancer development. However, the host anti-tumor immune responses also 'edit' the tumor and select for more aggressive variants, resulting in immune evasion and tumor escape. Fas is a death receptor that mediates one of the major cytotoxic effector mechanisms of the CTLs. Fas is highly expressed in normal human colon epithelial cells but is frequently silenced in colorectal carcinoma, especially in metastatic colorectal carcinoma, suggesting that loss of Fas expression and function may be an immune evasion and tumor escape mechanism. In addition, recent studies indicated that Fas also mediates cellular proliferation signaling pathways to promote tumor development. Therefore, the death receptor Fas may not only transduce death signals to suppress tumor development but also activate cellular proliferation and the migration process to promote tumor growth and progression. Thus, understanding the mechanisms by which the Fas receptor and its associated protein complex transduces the death and survival signals may identify molecular targets for the development of therapeutic strategy to enhance the Fas-mediated death signals to increase the efficacy of cancer immunotherapy.展开更多
Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows t...Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion.In this review,we systematically summarize the intricate crosstalk between GC cells and immune cells,including tumor-associated macrophages,neutrophils,myeloid-derived suppressor cells,natural killer cells,effector T cells,regulatory T cells,and B cells.We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack.We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies,both alone and in combination with conventional therapies.Anti-cytotoxic Tlymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment.However,the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients.This review provides a comprehensive understanding of the immune evasion mechanisms of GC,and highlights promising immunotherapeutic strategies.展开更多
Objective: It has been proposed that Fas ligand (FasL) may play an important role in immune escape of tumors and FLIP is an important mediator of Fas/FasL pathway. In this study, the expression of FLIP was determin...Objective: It has been proposed that Fas ligand (FasL) may play an important role in immune escape of tumors and FLIP is an important mediator of Fas/FasL pathway. In this study, the expression of FLIP was determined in human colon carcinoma cell lines and tissue to investigate the new mechanism of immune evasion of human colon carcinomas. Methods: RT-PCR and immunohistochemistry (IHC) were performed to investigate the expression of FLIP in human colon carcinoma cell lines SW480, LS174 and twenty human primary colon carcinoma specimens. Results: It was shown that SW480 cells, LS174 cells and primary colon carcinoma specimen constitutively expressed FLIP at the mRNA and protein level. The expression of FLIP was not found in the epithelial cells of normal colon mucosa. Conclusion: FLIP was expressed in human primary colon carcinoma specimens but not in the normal counterpart. It suggested that the expression of FLIP may occur during the malignant transformation from normal colon epithelial cells to colon carcinoma cells. Tumor cells might obtain the ability to resist the Fas-mediated apoptosis by expressing FLIP. The expression of FLIP might contribute to the formation of colon carcinomas.展开更多
The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypas...The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.展开更多
Immune evasion is a strategy used by pathogenic microbes to evade the host immune system in order to ensure successful propagation. Immune evasion is particularly important for the blood stages of Plasmodium falciparu...Immune evasion is a strategy used by pathogenic microbes to evade the host immune system in order to ensure successful propagation. Immune evasion is particularly important for the blood stages of Plasmodium falciparum, the causative agent of the deadly disease malaria tropica. Because Plasmodium blood stage parasites require human erythrocytes for replication, their ability to evade attack by the human immune system is essential for parasite survival. In order to escape immunity-induced killing, the intraerythrocytic parasites have evolved a variety of evasion mechanisms, including expansion of plasmodial surface proteins, organ-specific sequestration of the infected red blood cells and acquisition of immune-regulatory proteins by the parasite. This review aims to highlight recent advances in the molecular understanding of the immune evasion strategies by P. falciparum, including antigenic variation, surface protein polymorphisms and invasion ligand diversification. The review will further discuss new findings on the regulatory mechanisms applied by P. falciparum to avoid lysis by the human complement as well as killing by immune factors of the mosquito vector.展开更多
Explicitness evasion in communication is like lube that avoids hurting the other party's feeling. It lubricates human relationship in communication and helps to save face of communicators. Too much conversational ...Explicitness evasion in communication is like lube that avoids hurting the other party's feeling. It lubricates human relationship in communication and helps to save face of communicators. Too much conversational explicitness is easy to give rise to misunderstandings even if it is for good intentions. And when the divergence among two parties become exacerbated, the conflict or even fighting will arise as a result. So to create a light-hearted conversational atmosphere, explicitness evasion, an aesthetic speech art, is deeply thought-provoking. Therefore, this study attempts to touch on the validity of applying humor under Cooperative Principle to the explicitness evasion. Hopefully, readers can better understand how to avoid hurting others inadvertently when speaking and how to achieve successful conversations. Moreover, it can help practitioners to find some sound methods to combine speech and humanity together to make them harmonious in the long run.展开更多
Cryptojacking is a type of resource embezzlement attack,wherein an attacker secretly executes the cryptocurrency mining program in the target host to gain profits.It has been common since 2017,and in fact,it once beca...Cryptojacking is a type of resource embezzlement attack,wherein an attacker secretly executes the cryptocurrency mining program in the target host to gain profits.It has been common since 2017,and in fact,it once became the greatest threat to network security.To better prove the attack ability the harm caused by cryptojacking,this paper proposes a new covert browser-based mining attack model named Delay-CJ,this model was deployed in a simulation environment for evaluation.Based on the general framework of cryptojacking,Delay-CJ adds hybrid evasion detection techniques and applies the delayed execution strategy specifically for video websites in the prototype implementation.The results show that the existing detection methods used for testing may become invalid as result of this model.In view of this situation,to achieve a more general and robust detection scheme,we built a cryptojacking detection system named CJDetector,which is based on cryptojacking process features.Specifically,it identifies malicious mining by monitoring CPU usage and analyzing the function call information.This system not only effectively detects the attack in our example but also has universal applicability.The recognition accuracy of CJDetector reaches 99.33%.Finally,we tested the web pages in Alexa 50K websites to investigate cryptojacking activity in the real network.We found that although cryptojacking is indeed on the decline,it remains a part of network security threats that cannot be ignored.展开更多
Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites.In our effort to understand how ...Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites.In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer cells.We found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells.The coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX complex.Additionally,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells.Through our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells.Moreover,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.展开更多
Toxoplasma gondii is a protozoan of worldwide distribution and the agent of toxoplasmosis.It is estimated that 30%–50%of the world population could be infected with this parasite.Although the infection in immunocompe...Toxoplasma gondii is a protozoan of worldwide distribution and the agent of toxoplasmosis.It is estimated that 30%–50%of the world population could be infected with this parasite.Although the infection in immunocompetent individuals is mostly asymptomatic,the disease in immunosuppressed and pregnant is a risk condition.As a member of the phylum Apicomplexa,T.gondii has an obligatory intracellular lifestyle;therefore,invading a host cell and establishing it inside a parasitophorous vacuole(PV)are mandatories for the survival of this parasite.The construction of a perfect intracellular niche for T.gondii requires the secretion of an arsenal of proteins from unique secretory organelles.These proteins will remodel the vacuolar environment and the host cell organization and functions,allowing the parasite to access essential nutrients and stay“invisible”inside a host cell.In the present review,we will discuss the main steps involved in the PV formation and its differentiation to tissue cyst,focusing mainly on the strategies employed in the acquisition of nutrients and proteins involved in host cell modification.展开更多
Circulating tumor cells(CTCs)are neoplastic cells that are detached from primary tumors and enter circulation.Enumeration and characterization of CTCs are of significance in cancer diagnosis,prognosis,and treatment mo...Circulating tumor cells(CTCs)are neoplastic cells that are detached from primary tumors and enter circulation.Enumeration and characterization of CTCs are of significance in cancer diagnosis,prognosis,and treatment monitoring.CTC survival in the bloodstream is a limiting step for the development of metastases in distant organs.Recent technological advances,especially in single-cell molecular analyses have uncovered heterogeneous CTC survival mechanisms.Undergoing epithelial-to-mesenchymal transition(EMT),increasing stem cell-like properties,and forming cell clusters enable CTCs to adapt to the harsh microenvironment of the circulation.Expressing and releasing several immunosuppressive molecules help CTCs escape from anti-cancer immune mechanisms.This review article summarizes the biological characteristics of CTCs and focuses on the recent understanding of the mechanisms by which CTCs survive in circulation.Additionally,the clinical and therapeutic implications of CTCs are discussed.展开更多
This paper presents a novel evasion guidance law for hypersonic morphing vehicles,focusing on determining the optimized wing's unfolded angle to promote maneuverability based on an intelligent algorithm.First,the ...This paper presents a novel evasion guidance law for hypersonic morphing vehicles,focusing on determining the optimized wing's unfolded angle to promote maneuverability based on an intelligent algorithm.First,the pursuit-evasion problem is modeled as a Markov decision process.And the agent's action consists of maneuver overload and the unfolded angle of wings,which is different from the conventional evasion guidance designed for fixed-shape vehicles.The reward function is formulated to ensure that the miss distances satisfy the prescribed bounds while minimizing energy consumption.Then,to maximize the expected cumulative reward,a residual learning method is proposed based on proximal policy optimization,which integrates the optimal evasion for linear cases as the baseline and trains to optimize the performance for nonlinear engagement with multiple pursuers.Therefore,offline training guarantees improvement of the constructed evasion guidance law over conventional ones.Ultimately,the guidance law for online implementation includes only analytical calculations.It maps from the confrontation state to the expected angle of attack and the unfolded angle while retaining high computational efficiency.Simulations show that the proposed evasion guidance law can utilize the change of unfolded angle to extend the maximum overload capability.And it surpasses conventional maneuver strategies by ensuring better evasion efficacy and higher energy efficiency.展开更多
基金Supported by the Anhui Provincial Health Scientific Research Project Provincial Financial Support Key Project,No.AHWJ2023A10110College Teaching Quality Engineering Project of Anhui Educational Committee,No.2021jyxm0954College Student Innovation Training Program of Bengbu Medical College,No.Byycxz22110.
文摘BACKGROUND For the first time,we investigated the oncological role of plexin domain-containing 1(PLXDC1),also known as tumor endothelial marker 7(TEM7),in hepatocellular carcinoma(HCC).AIM To investigate the oncological profile of PLXDC1 in HCC.METHODS Based on The Cancer Genome Atlas database,we analyzed the expression of PLXDC1 in HCC.Using immunohistochemistry,quantitative real-time polymerase chain reaction(qRT-PCR),and Western blotting,we validated our results.The prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features,such as patient survival,methylation level,tumor immune microenvironment features,and immune cell surface checkpoint expression.Finally,to assess the immune evasion potential of PLXDC1 in HCC,we used the tumor immune dysfunction and exclusion(TIDE)website and immunohistochemical staining assays.RESULTS Based on immunohistochemistry,qRT-PCR,and Western blot assays,overexpression of PLXDC1 in HCC was associated with poor prognosis.Univariate and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic factor.In HCC patients with high methylation levels,the prognosis was worse than in patients with low methylation levels.Pathway enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling,and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 subgroup.The high-risk group had a significantly lower immune evasion rate as well as a poor prognosis,and PLXDC1-related risk scores were also associated with a poor prognosis.CONCLUSION As a result of this study analyzing PLXDC1 from multiple biological perspectives,it was revealed that it is a biomarker of poor prognosis for HCC patients,and that it plays a role in determining immune evasion status.
文摘Background: Omicron JN.1 has become the dominant SARS-CoV-2 variant in recent months. JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation. The immune evasion capability of JN.1 is a subject of scientific investigation. The US CDC used SGTF of TaqPath COVID-19 Combo Kit RT-qPCR as proxy indicator of JN.1 infections for evaluation of the effectiveness of updated monovalent XBB.1.5 COVID-19 vaccines against JN.1 and recommended that all persons aged ≥ 6 months should receive an updated COVID-19 vaccine dose. Objective: Recommend Sanger sequencing instead of proxy indicator to diagnose JN.1 infections to generate the data based on which guidelines are made to direct vaccination policies. Methods: The RNA in nasopharyngeal swab specimens from patients with clinical respiratory infection was subjected to nested RT-PCR, targeting a 398-base segment of the N-gene and a 445-base segment of the RBD of SARS-CoV-2 for amplification. The nested PCR amplicons were sequenced. The DNA sequences were analyzed for amino acid mutations. Results: The N-gene sequence showed R203K, G204R and Q229K, the 3 mutations associated with Omicron BA.2.86 (+JN.1). The RBD sequence showed 24 of the 26 known amino acid mutations, including the hallmark L455S mutation for JN.1 and the V483del for BA.2.86 lineage. Conclusions: Sanger sequencing of a 445-base segment of the SARS-CoV-2 RBD is useful for accurate determination of emerging variants. The CDC may consider using Sanger sequencing of the RBD to diagnose JN.1 infections for statistical analysis in making vaccination policies.
文摘Natural killer(NK)cells can elicit an immune response against malignantly transformed cells without recognizing antigens,and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy.Although several studies have shown the promising antitumor effects of NK cells in immunotherapy,their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death.Thus,for efficient tumor immunotherapy,the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood.Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered.In this review,we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression[NKG2A,programmed cell death1(PD-1),and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif(TIGIT)]on the NK cell surface,and thus inhibit NK cell activity.We also reviewed the current status of treatments based on these surface molecules.By comparing the therapeutic effects related to the treatment status and bypass mechanisms,we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.
基金supported by the National Key R&D Program of China (2020YFA0713502)the Special Fund Project for Guiding Local Scientific and Technological Development (2020ZYT003)+1 种基金the National Natural Science Foundation of China (U20B2055,61773021,61903086)the Natural Science Foundation of Hunan Province (2019JJ20018,2020JJ4280)。
文摘Spacecraft orbit evasion is an effective method to ensure space safety. In the spacecraft’s orbital plane, the space non-cooperate target with autonomous approaching to the spacecraft may have a dangerous rendezvous. To deal with this problem, an optimal maneuvering strategy based on the relative navigation observability degree is proposed with angles-only measurements. A maneuver evasion relative navigation model in the spacecraft’s orbital plane is constructed and the observability measurement criteria with process noise and measurement noise are defined based on the posterior Cramer-Rao lower bound. Further, the optimal maneuver evasion strategy in spacecraft’s orbital plane based on the observability is proposed. The strategy provides a new idea for spacecraft to evade safety threats autonomously. Compared with the spacecraft evasion problem based on the absolute navigation, more accurate evasion results can be obtained. The simulation indicates that this optimal strategy can weaken the system’s observability and reduce the state estimation accuracy of the non-cooperative target, making it impossible for the non-cooperative target to accurately approach the spacecraft.
文摘Ovarian cancer is one of the three major malignant tumors in gynecology, with increasing incidence and mortality rates. Currently, the main treatment methods remain surgical intervention in combination with chemotherapy. However, due to its high recurrence rate and the risk of drug resistance, the overall prognosis is poor. Ovarian cancer has been identified as an immunegenic tumor, and in recent years, with the continued advancement of research into immune evasion mechanisms, immunotherapy has emerged as a groundbreaking treatment modality. This article will focus on the immune escape mechanisms and their application in ovarian cancer, providing a comprehensive overview of its current status and the challenges it faces.
基金supported by Institute of Information&Communications Technology Planning&Evaluation(IITP)Grant funded by the Korea government,Ministry of Science and ICT(MSIT)(No.2017-0-00168,Automatic Deep Malware Analysis Technology for Cyber Threat Intelligence).
文摘Antivirus vendors and the research community employ Machine Learning(ML)or Deep Learning(DL)-based static analysis techniques for efficient identification of new threats,given the continual emergence of novel malware variants.On the other hand,numerous researchers have reported that Adversarial Examples(AEs),generated by manipulating previously detected malware,can successfully evade ML/DL-based classifiers.Commercial antivirus systems,in particular,have been identified as vulnerable to such AEs.This paper firstly focuses on conducting black-box attacks to circumvent ML/DL-based malware classifiers.Our attack method utilizes seven different perturbations,including Overlay Append,Section Append,and Break Checksum,capitalizing on the ambiguities present in the PE format,as previously employed in evasion attack research.By directly applying the perturbation techniques to PE binaries,our attack method eliminates the need to grapple with the problem-feature space dilemma,a persistent challenge in many evasion attack studies.Being a black-box attack,our method can generate AEs that successfully evade both DL-based and ML-based classifiers.Also,AEs generated by the attack method retain their executability and malicious behavior,eliminating the need for functionality verification.Through thorogh evaluations,we confirmed that the attack method achieves an evasion rate of 65.6%against well-known ML-based malware detectors and can reach a remarkable 99%evasion rate against well-known DL-based malware detectors.Furthermore,our AEs demonstrated the capability to bypass detection by 17%of vendors out of the 64 on VirusTotal(VT).In addition,we propose a defensive approach that utilizes Trend Locality Sensitive Hashing(TLSH)to construct a similarity-based defense model.Through several experiments on the approach,we verified that our defense model can effectively counter AEs generated by the perturbation techniques.In conclusion,our defense model alleviates the limitation of the most promising defense method,adversarial training,which is only effective against the AEs that are included in the training classifiers.
基金the Huzhou Science and Technology Bureau,Zhejiang Province,China(2020GZ41).
文摘Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer,with the tumor microenvironment(TME)playing a pivotal role in modulating the immune response.CD47,a cell surface protein,has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy.However,the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood.This comprehensive review aims to provide an overview of CD47’s multifaced role in TME regulation and immune evasion,elucidating its impact on various types of immunotherapy outcomes,including checkpoint inhibitors and CAR T-cell therapy.Notably,CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes,especially when combined with other immunotherapeutic approaches.The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47.Despite the demonstrated effectiveness of CD47-targeted therapies,there are potential problems,including unintended effects on healthy cells,hematological toxicities,and the development if resistance.Consequently,further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches,ultimately improving cancer treatment outcomes.Overall,this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.
文摘The host immune system functions as a guardian against tumor development. It has been demonstrated that cytotoxic T lymphocyte (CTL)-mediated cytotoxic pathways function to inhibit or delay human colorectal cancer development. However, the host anti-tumor immune responses also 'edit' the tumor and select for more aggressive variants, resulting in immune evasion and tumor escape. Fas is a death receptor that mediates one of the major cytotoxic effector mechanisms of the CTLs. Fas is highly expressed in normal human colon epithelial cells but is frequently silenced in colorectal carcinoma, especially in metastatic colorectal carcinoma, suggesting that loss of Fas expression and function may be an immune evasion and tumor escape mechanism. In addition, recent studies indicated that Fas also mediates cellular proliferation signaling pathways to promote tumor development. Therefore, the death receptor Fas may not only transduce death signals to suppress tumor development but also activate cellular proliferation and the migration process to promote tumor growth and progression. Thus, understanding the mechanisms by which the Fas receptor and its associated protein complex transduces the death and survival signals may identify molecular targets for the development of therapeutic strategy to enhance the Fas-mediated death signals to increase the efficacy of cancer immunotherapy.
基金The Natural Science Foundation of China,No.81672378,No.81201521,No.81873874 and No.81773089the Clinical Research Plan of SHDC,No.SHDC2020CR2021B。
文摘Gastric cancer(GC)is a malignancy with a high incidence and mortality.The tumor immune microenvironment plays an important role in promoting cancer development and supports GC progression.Accumulating evidence shows that GC cells can exert versatile mechanisms to remodel the tumor immune microenvironment and induce immune evasion.In this review,we systematically summarize the intricate crosstalk between GC cells and immune cells,including tumor-associated macrophages,neutrophils,myeloid-derived suppressor cells,natural killer cells,effector T cells,regulatory T cells,and B cells.We focus on how GC cells alter these immune cells to create an immunosuppressive microenvironment that protects GC cells from immune attack.We conclude by compiling the latest progression of immune checkpoint inhibitor-based immunotherapies,both alone and in combination with conventional therapies.Anti-cytotoxic Tlymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 therapy alone does not provide substantial clinical benefit for GC treatment.However,the combination of immune checkpoint inhibitors with chemotherapy or targeted therapy has promising survival advantages in refractory and advanced GC patients.This review provides a comprehensive understanding of the immune evasion mechanisms of GC,and highlights promising immunotherapeutic strategies.
文摘Objective: It has been proposed that Fas ligand (FasL) may play an important role in immune escape of tumors and FLIP is an important mediator of Fas/FasL pathway. In this study, the expression of FLIP was determined in human colon carcinoma cell lines and tissue to investigate the new mechanism of immune evasion of human colon carcinomas. Methods: RT-PCR and immunohistochemistry (IHC) were performed to investigate the expression of FLIP in human colon carcinoma cell lines SW480, LS174 and twenty human primary colon carcinoma specimens. Results: It was shown that SW480 cells, LS174 cells and primary colon carcinoma specimen constitutively expressed FLIP at the mRNA and protein level. The expression of FLIP was not found in the epithelial cells of normal colon mucosa. Conclusion: FLIP was expressed in human primary colon carcinoma specimens but not in the normal counterpart. It suggested that the expression of FLIP may occur during the malignant transformation from normal colon epithelial cells to colon carcinoma cells. Tumor cells might obtain the ability to resist the Fas-mediated apoptosis by expressing FLIP. The expression of FLIP might contribute to the formation of colon carcinomas.
基金Supported by International Medical University to Sim W,Lim WM,and Leong CO,No.BMS I/2020(10)Shanghai Municipal Science and Technology Commission to Mai CW,No.20WZ250460.
文摘The immune system plays a vital role in maintaining the delicate balance between immune recognition and tumor development.Regardless,it is not uncommon that cancerous cells can intelligently acquire abilities to bypass the antitumor immune responses,thus allowing continuous tumor growth and development.Immune evasion has emerged as a significant factor contributing to the progression and immune resistance of pancreatic cancer.Compared with other cancers,pancreatic cancer has a tumor microenvironment that can resist most treatment modalities,including emerging immunotherapy.Sadly,the use of immunotherapy has yet to bring significant clinical breakthrough among pancreatic cancer patients,suggesting that pancreatic cancer has successfully evaded immunomodulation.In this review,we summarize the impact of genetic alteration and epigenetic modification(especially histone deacetylases,HDAC)on immune evasion in pancreatic cancer.HDAC overexpression significantly suppresses tumor suppressor genes,contributing to tumor growth and progression.We review the evidence on HDAC inhibitors in tumor eradication,improving T cells activation,restoring tumor immunogenicity,and modulating programmed death 1 interaction.We provide our perspective in targeting HDAC as a strategy to reverse immune evasion in pancreatic cancer.
文摘Immune evasion is a strategy used by pathogenic microbes to evade the host immune system in order to ensure successful propagation. Immune evasion is particularly important for the blood stages of Plasmodium falciparum, the causative agent of the deadly disease malaria tropica. Because Plasmodium blood stage parasites require human erythrocytes for replication, their ability to evade attack by the human immune system is essential for parasite survival. In order to escape immunity-induced killing, the intraerythrocytic parasites have evolved a variety of evasion mechanisms, including expansion of plasmodial surface proteins, organ-specific sequestration of the infected red blood cells and acquisition of immune-regulatory proteins by the parasite. This review aims to highlight recent advances in the molecular understanding of the immune evasion strategies by P. falciparum, including antigenic variation, surface protein polymorphisms and invasion ligand diversification. The review will further discuss new findings on the regulatory mechanisms applied by P. falciparum to avoid lysis by the human complement as well as killing by immune factors of the mosquito vector.
文摘Explicitness evasion in communication is like lube that avoids hurting the other party's feeling. It lubricates human relationship in communication and helps to save face of communicators. Too much conversational explicitness is easy to give rise to misunderstandings even if it is for good intentions. And when the divergence among two parties become exacerbated, the conflict or even fighting will arise as a result. So to create a light-hearted conversational atmosphere, explicitness evasion, an aesthetic speech art, is deeply thought-provoking. Therefore, this study attempts to touch on the validity of applying humor under Cooperative Principle to the explicitness evasion. Hopefully, readers can better understand how to avoid hurting others inadvertently when speaking and how to achieve successful conversations. Moreover, it can help practitioners to find some sound methods to combine speech and humanity together to make them harmonious in the long run.
基金This work is partially sponsored by National Key R&D Program of China(No.2019YFB2101700)National Science Foundation of China(No.62172297,No.61902276)+1 种基金the Key Research and Development Project of Sichuan Province(No.2021YFSY0012)Tianjin Intelligent Manufacturing Special Fund Project(No.20211097,No.20201159).
文摘Cryptojacking is a type of resource embezzlement attack,wherein an attacker secretly executes the cryptocurrency mining program in the target host to gain profits.It has been common since 2017,and in fact,it once became the greatest threat to network security.To better prove the attack ability the harm caused by cryptojacking,this paper proposes a new covert browser-based mining attack model named Delay-CJ,this model was deployed in a simulation environment for evaluation.Based on the general framework of cryptojacking,Delay-CJ adds hybrid evasion detection techniques and applies the delayed execution strategy specifically for video websites in the prototype implementation.The results show that the existing detection methods used for testing may become invalid as result of this model.In view of this situation,to achieve a more general and robust detection scheme,we built a cryptojacking detection system named CJDetector,which is based on cryptojacking process features.Specifically,it identifies malicious mining by monitoring CPU usage and analyzing the function call information.This system not only effectively detects the attack in our example but also has universal applicability.The recognition accuracy of CJDetector reaches 99.33%.Finally,we tested the web pages in Alexa 50K websites to investigate cryptojacking activity in the real network.We found that although cryptojacking is indeed on the decline,it remains a part of network security threats that cannot be ignored.
基金funding from the National Science Foundation of China(31930016)the Peking-Tsinghua Center for Life Sciences+4 种基金ZW received funding from the State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases(2024KF00001)the National Science Foundation of China(82350119)CCW received funding from the Talent Introduction Funds from the Chinese Academy of Medical Science(2022-RC310-10)the National Science Foundation of China(32150005)the Research Funds from Health@InnoHK Program,launched by the Innovation Technology Commission of the Hong Kong Special Administrative Region.
文摘Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites.In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer cells.We found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells.The coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX complex.Additionally,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells.Through our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells.Moreover,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.
文摘Toxoplasma gondii is a protozoan of worldwide distribution and the agent of toxoplasmosis.It is estimated that 30%–50%of the world population could be infected with this parasite.Although the infection in immunocompetent individuals is mostly asymptomatic,the disease in immunosuppressed and pregnant is a risk condition.As a member of the phylum Apicomplexa,T.gondii has an obligatory intracellular lifestyle;therefore,invading a host cell and establishing it inside a parasitophorous vacuole(PV)are mandatories for the survival of this parasite.The construction of a perfect intracellular niche for T.gondii requires the secretion of an arsenal of proteins from unique secretory organelles.These proteins will remodel the vacuolar environment and the host cell organization and functions,allowing the parasite to access essential nutrients and stay“invisible”inside a host cell.In the present review,we will discuss the main steps involved in the PV formation and its differentiation to tissue cyst,focusing mainly on the strategies employed in the acquisition of nutrients and proteins involved in host cell modification.
基金supported by the Science Foundation of Fujian Province of China(2019J01596).
文摘Circulating tumor cells(CTCs)are neoplastic cells that are detached from primary tumors and enter circulation.Enumeration and characterization of CTCs are of significance in cancer diagnosis,prognosis,and treatment monitoring.CTC survival in the bloodstream is a limiting step for the development of metastases in distant organs.Recent technological advances,especially in single-cell molecular analyses have uncovered heterogeneous CTC survival mechanisms.Undergoing epithelial-to-mesenchymal transition(EMT),increasing stem cell-like properties,and forming cell clusters enable CTCs to adapt to the harsh microenvironment of the circulation.Expressing and releasing several immunosuppressive molecules help CTCs escape from anti-cancer immune mechanisms.This review article summarizes the biological characteristics of CTCs and focuses on the recent understanding of the mechanisms by which CTCs survive in circulation.Additionally,the clinical and therapeutic implications of CTCs are discussed.
基金This work was supported by the National Natural Science Foundation of China(No.52202438).
文摘This paper presents a novel evasion guidance law for hypersonic morphing vehicles,focusing on determining the optimized wing's unfolded angle to promote maneuverability based on an intelligent algorithm.First,the pursuit-evasion problem is modeled as a Markov decision process.And the agent's action consists of maneuver overload and the unfolded angle of wings,which is different from the conventional evasion guidance designed for fixed-shape vehicles.The reward function is formulated to ensure that the miss distances satisfy the prescribed bounds while minimizing energy consumption.Then,to maximize the expected cumulative reward,a residual learning method is proposed based on proximal policy optimization,which integrates the optimal evasion for linear cases as the baseline and trains to optimize the performance for nonlinear engagement with multiple pursuers.Therefore,offline training guarantees improvement of the constructed evasion guidance law over conventional ones.Ultimately,the guidance law for online implementation includes only analytical calculations.It maps from the confrontation state to the expected angle of attack and the unfolded angle while retaining high computational efficiency.Simulations show that the proposed evasion guidance law can utilize the change of unfolded angle to extend the maximum overload capability.And it surpasses conventional maneuver strategies by ensuring better evasion efficacy and higher energy efficiency.