A checkpointing scheme for relevant distributed real-time tasks which can be scheduled as a DAG is proposed. A typical algorithm, OSA, is selected for DAG scheduling. A new methods based a new structure, Scheduled Clu...A checkpointing scheme for relevant distributed real-time tasks which can be scheduled as a DAG is proposed. A typical algorithm, OSA, is selected for DAG scheduling. A new methods based a new structure, Scheduled Cluster Tree, is presented to calculate the slack time of each task in the task cluster. In the checkpointing scheme, the optimal checkpoint intervals which minimize the approximated failure probability are derived formally and validated experimentally. The complexity of approximated failure probability is quite small compared with that of the exact probability. Meanwhile, the consistency of the checkpointing is discussed also.展开更多
The reliability of high-performance computing(HPC)is essential for program execution stability.However,as the hardware fault rate constantly increases,fault-tolerance techniques such as Checkpoint/Restart(C/R)introduc...The reliability of high-performance computing(HPC)is essential for program execution stability.However,as the hardware fault rate constantly increases,fault-tolerance techniques such as Checkpoint/Restart(C/R)introduce significant system overhead.This paper proposes Program Error Resilience-Aware Checkpointing Mechanism(ResCheckpointer)to mitigate the overhead of the C/R mechanism.The primary motivation of ResCheckpointer is that we observe that crash proneness(i.e.,the probability of the program crashing after fault occurrence)varies significantly among inter-and intra-HPC programs,which prompts us to flexibly adjust checkpoint intervals for further C/R overhead optimization.Specifically,we first construct the graph neural network(GNN)based learning paradigms to excavate the complex error propagation and effect mechanisms hidden within the HPC program’s execution flow,and propose Crash-Predictor for efficiently predicting programs’crash proneness.Based on this,we build ResCheckpointer,which equips an intelligent checkpoint interval setting strategy for HPC programs,i.e.,denser for the crash proneness stage while sparser for the error resilience stage.Experimental results show that ResCheckpointer can achieve up to 55.37%C/R cost reduction compared with the baseline C/R mechanism.展开更多
Network of workstations (NOW) now becomes one of the main trends of parallel computing. But for long-running scientific programs, it needs effective fault tolerance for its changing property. Checkpointing and rollbac...Network of workstations (NOW) now becomes one of the main trends of parallel computing. But for long-running scientific programs, it needs effective fault tolerance for its changing property. Checkpointing and rollback recovery is a solution to this problem. First the main problems upon rollback recovery are discussed, the different checkpointing techniques for NOW are analyzed, and then the design and implementation of ChaRM (checkpoint-based rollback recovery and process migration) system are described. The comparison of three coordinated checkpointing systems is given.展开更多
A consistent checkpointing algorithm with short freezing time (SFT) is presented in this paper. It supports fault-tolerance in distributed systems. The algorithm has shorter freezing time, lower overhead, and simplici...A consistent checkpointing algorithm with short freezing time (SFT) is presented in this paper. It supports fault-tolerance in distributed systems. The algorithm has shorter freezing time, lower overhead, and simplicity of recovery. To make checkpoint time shorter, a special control message (Munblock) is used to ensure that a process can respond the checkpoint event quickly at any given time. Moreover, main memory algorithm is used to improve the concurrency of checkpointing. By using SFT, the freezing time resulted by checkpointing is less than 0.03s. Furthermore, the control message number of SFT is only O(n).展开更多
In this papert the hard problem of the thorough garbage collection in uncoordinated Checkpointing algorithms is studied. After introduction of the traditional garbage collecting scheme, with which only obsolete checkp...In this papert the hard problem of the thorough garbage collection in uncoordinated Checkpointing algorithms is studied. After introduction of the traditional garbage collecting scheme, with which only obsolete checkpoints can be discarded, it is shown that this kind of traditional method may fail to discard any checkpoint in some special cases, and it is necessary and urgent to find a thorough garbage collecting method, with which all the checkpoints useless for any future rollback-recovery including the obsolete ones can be discarded. Then, the Thorough Garbage Collection Theorem is proposed and proved, which ensures the feasibility of the thorough garbage collection, and gives the method to calculate the set of the useful checkpoints as well.展开更多
Background:Exercise exerts tumor-suppressive effects across multiple malignancies,partly through exerkines—exercise-induced secreted factors with immunomodulatory and metabolic functions.However,the prognostic releva...Background:Exercise exerts tumor-suppressive effects across multiple malignancies,partly through exerkines—exercise-induced secreted factors with immunomodulatory and metabolic functions.However,the prognostic relevance of exerkines across cancer types remains unclear,and the molecular determinants of exercise responsiveness are poorly defined.Methods:We systematically profiled 183 curated exerkine-related genes across 33 cancer types from The Cancer Genome Atlas(TCGA)using non-negative matrix factorization(NMF)to define molecular subtypes.Prognostic significance was evaluated via Kaplan-Meier analysis.For five cancers with consistent survival divergence(LGG,KIRC,LUAD,PAAD,ACC),we developed an Exerkine Prognostic Index(EPI)using LASSO Cox regression and validated its predictive performance through time-dependent ROC analysis.Immune cell infiltration(CIBERSORT),stromal/immune scores(ESTIMATE),and immune checkpoint expression were assessed to characterize immune landscape differences between EPI subgroups.Results:Exerkine-based NMF clustering identified prognostically distinct subtypes in 25 cancers.The EPI robustly stratified patients into high-and low-risk groups with significant differences in overall survival(p<0.001).High-EPI subgroups were associated with elevated infiltration of immunosuppressive cells(e.g.,Tregs,M0 macrophages),altered immune/stromal scores,and differential expression of immune checkpoints such as PD-L1 and CTLA4 in a cancer-type-specific manner.Discussion:Our findings reveal that exerkine expression patterns capture biologically and clinically relevant heterogeneity across cancers.The EPI provides a robust molecular tool to stratify patients by prognosis and immune contexture,offering insights into differential exercise responsiveness.Conclusions:Exerkines represent promising biomarkers for risk stratification and precision-guided exercise interventions in oncology.展开更多
Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop met...Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.展开更多
BACKGROUND Chemotherapy with an immune checkpoint inhibitor is one of the standard regimens for treating advanced gastric cancer(AGC).Ascites and peritoneal dissemination are common complications and poor prognostic f...BACKGROUND Chemotherapy with an immune checkpoint inhibitor is one of the standard regimens for treating advanced gastric cancer(AGC).Ascites and peritoneal dissemination are common complications and poor prognostic factors of AGC;however,reports regarding its efficacy and safety in patients with AGC and massive ascites are limited.AIM To evaluate the safety and efficacy of nivolumab combined with chemotherapy in patients with AGC and ascites.METHODS We retrospectively collected clinical data from 124 patients with AGC who received chemotherapy plus nivolumab as first-line treatment from July 2017 to December 2024.Based on computed tomography scans,massive or moderate ascites were classified as high ascites burden(HAB),whereas mild or no ascites were classified as low ascites burden.RESULTS Ascites was detected in 47 patients(38%);26(21%)were classified into the HAB group.Patients in the HAB group exhibited a significantly poorer performance status,a higher prevalence of diffuse-type histology,and lower programmed cell death ligand 1(PD-L1)expression.Combination therapy with FOLFOX and neutropenia was significantly more common in the HAB group.Progression-free survival(PFS)(4.4 months vs 9.3 months,P=0.0012)and overall survival(OS)(7.3 months vs 21.2 months,P<0.0001)were significantly poorer in the HAB group.However,an improvement in ascites was observed in 61.5%of patients in the HAB group.PD-L1 expression did not correlate with either PFS or OS in the HAB group.CONCLUSION Nivolumab plus chemotherapy demonstrated modest efficacy and acceptable toxicity in patients with AGC and HAB.展开更多
Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its s...Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].展开更多
Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neu...Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.展开更多
Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenv...Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenvatinib and everolimus represents a viable option,and the present review aimed to summarize its activity,effectiveness,and safety.Methods:A systematic review of the literature was conducted using PubMed,targeting studies published between 2018 and 2025.Eligible studies included English-language prospective and retrospective trials reporting survival outcomes in mRCC patients treated with lenvatinib and everolimus after at least one ICI-containing regimen.Results:Nine studies met the inclusion criteria,encompassing a total of 441 patients.The lenvatinib and everolimus combination was primarily used in the third and subsequent lines of therapy.Median overall survival ranged from 7.5 to 24.5 months,while median progression-free survival was more consistent,between 6.1 and 6.7 months,except for one study reporting 12.9 months.Objective response rates varied widely(14.0%–55.7%).Adverse events of grade≥3 did not exceed the expected rate,with diarrhoea and proteinuria as the most reported events.Dose reductions and treatment discontinuations due to toxicity occurred but were generally lower than in prior pivotal trials.Conclusions:Real-world evidence suggests that lenvatinib and everolimus represent an effective and safe option after ICI failure in mRCC patients.Nevertheless,the lack of randomized phase III trials and the heterogeneity of existing studies highlight the need for more robust prospective research to guide post-ICI therapeutic strategies.展开更多
Anti-programmed cell death protein 1(PD-1)or its ligand(PD-L1)are immune checkpoint inhibitors(ICIs)that have revolutionized cancer therapy.However,the efficacy of anti-PD-1 and anti-PD-L1 is limited by resistance and...Anti-programmed cell death protein 1(PD-1)or its ligand(PD-L1)are immune checkpoint inhibitors(ICIs)that have revolutionized cancer therapy.However,the efficacy of anti-PD-1 and anti-PD-L1 is limited by resistance and inter-individual variability.In recent years increasing evidence has highlighted the pivotal role of the gut microbiota in modulating the response to PD-1/PD-L1 immunotherapy.Extensive preclinical studies have demonstrated that commensal microbes can increase the efficacy of PD-1/PD-L1 blockade through multiple mechanisms,including the production of metabolites,such as short-chain fatty acids(SCFAs),tryptophan derivatives,and extracellular polysaccharides that remodel the tumor microenvironment,as well as the activation of immune pathways involving dendritic cells,CD8+T cells,and M1 macrophages to increase antitumor immunity.Moreover,clinical studies have shown that fecal microbiota transplantation(FMT)and targeted probiotic interventions show promise for improving the response to PD-1/PD-L1 therapy,while reducing the risk of immune-related adverse events(irAEs).This review systematically explores the multifaceted regulatory roles of the commensal microbiota in PD-1/PD-L1 therapy and examines the preclinical prospects of microbiota-based personalized immunotherapeutic strategies.The integration of multiomics technologies,synthetic biology,and precise microbiota interventions may further optimize PD-1/PD-L1 immunotherapy and offer novel insights into antitumor immune modulation.展开更多
When applied to mobile computing systems,checkpoint protocols for distributed computing systems would face many new challenges, such as low wireless bandwidth, frequent disconnections, and lack of stable storage at mo...When applied to mobile computing systems,checkpoint protocols for distributed computing systems would face many new challenges, such as low wireless bandwidth, frequent disconnections, and lack of stable storage at mobile hosts. This paper proposes a novel checkpoint protocol to effectively reduce the coordinating overhead. By using a communication vector, only a few processes participate in the checkpointing event. During checkpointing, the scheme can save the time used to trace the dependency tree by sending checkpoint requests to dependent processes at once. In addition, processes are non- blocking in this scheme, since the inconsistency is resolved by the piggyback technique. Hence the unnecessary and orphan messages can be avoided. Compared with the traditional coordinated checkpoint approach, the proposed non-blocking algorithm obtains a minimal number of processes to take checkpoints. It also reduces the checkpoint latency, which brings less overhead to mobile host with limited resources.展开更多
Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor i...Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.展开更多
Hepatocellular carcinoma(HCC)is a highly aggressive malignancy,largely driven by an immunosuppres-sive tumor microenvironment(TME)that facilitates tumor growth,immune escape,and resistance to therapy.Although immunoth...Hepatocellular carcinoma(HCC)is a highly aggressive malignancy,largely driven by an immunosuppres-sive tumor microenvironment(TME)that facilitates tumor growth,immune escape,and resistance to therapy.Although immunotherapy—particularly immune checkpoint inhibitors(ICIs)—has transformed the therapeutic landscape by restoring T cell-mediated anti-tumor responses,their clinical benefit as monotherapy remains suboptimal.This limitation is primarily attributed to immunosuppressive components within the TME,including tumor-associated macrophages,regulatory T cells(Tregs),and myeloid-derived suppressor cells(MDSCs).To address these challenges,combination strategies have been explored,such as dual checkpoint blockade targeting programmed cell death protein 1(PD-1),programmed death-ligand 1(PD-L1),and cytotoxic T-lymphocyte-associated antigen 4(CTLA-4),as well as synergistic use of ICIs with anti-angiogenic agents or TME-targeted interventions.These approaches have shown encouraging potential in enhancing immune efficacy.This review outlines the complex crosstalk between the TME and immunotherapeutic responses in HCC,emphasizing how combination regimens may overcome immune resistance.Furthermore,we discuss the remaining hurdles,including therapeutic resistance and immune-related adverse events,and propose future directions involving TME-associated biomarkers and individualized treatment strategies to improve patient outcomes.展开更多
BACKGROUND Gastric cancer is a leading global cause of cancer mortality,with poor survival in locally advanced stages.While immune checkpoint inhibitors(ICIs)like sintilimab have improved outcomes in advanced disease,...BACKGROUND Gastric cancer is a leading global cause of cancer mortality,with poor survival in locally advanced stages.While immune checkpoint inhibitors(ICIs)like sintilimab have improved outcomes in advanced disease,their role as neoadjuvant therapy remains understudied.This study investigates sintilimab combined with nabpaclitaxel/S-1 as preoperative treatment for locally advanced gastric cancer(LAGC),addressing an unmet need for effective neoadjuvant strategies.AIM To explore the efficacy and safety of combination treatment with sintilimab and nab-paclitaxel plus S-1 as neoadjuvant therapy for LAGC.METHODS Clinical data from 82 patients diagnosed with LAGC,who underwent preoperative treatment and surgery between April 2020 and December 2022,were included.Patients were divided into 2 groups according to treatment regimen:ICI(sintilimab+nab-paclitaxel+S-1);and non-ICI(nab-paclitaxel+S-1).Imaging and pathological efficacy,intra-and postoperative conditions,molecular subtypes,short-term survival outcomes,and safety were compared between the 2 groups.RESULTS Imaging evaluation of therapeutic efficacy revealed that the inclusion of ICI yielded a significantly higher complete response rate(13.2%vs 0.0%;P=0.048),and objective response rate(69.8%vs 31.0%,P=0.001)compared with non-ICI treatment.Pathological evaluation revealed that the ICI group exhibited a significantly higher pathological complete response rate(13.2%vs 0.0%;P=0.048)and major pathological response rate(35.8%vs 13.8%;P=0.041)than those in the non-ICI group.The two-year disease-free survival rate in the ICI group was greater than that in the non-ICI group(83.0%vs 55.2%;P=0.043).The use of ICI did not increase the incidence of adverse reactions(47.2%vs 41.4%;P=0.614)or perioperative adverse events(18.9%vs 13.8%;P=0.761).CONCLUSION The combination of sintilimab with nab-paclitaxel+S-1 for neoadjuvant treatment of LAGC improved efficacy in patients without increasing adverse drug reactions and perioperative adverse events,suggesting that this treatment regimen is safe and feasible.展开更多
In the past decade,immunotherapies targeting cytotoxic T-lymphocyte antigen-4(CTLA-4),programmed cell death 1(PD-1),and PD-1 ligand(PD-L1)have been approved for solid tumors.However,some patients demonstrate suboptima...In the past decade,immunotherapies targeting cytotoxic T-lymphocyte antigen-4(CTLA-4),programmed cell death 1(PD-1),and PD-1 ligand(PD-L1)have been approved for solid tumors.However,some patients demonstrate suboptimal clinical outcomes due to resistance.The tumor microenvironment(TME)significantly affects the efficiency of immunotherapy by mediating interactions between tumor and non-tumor cells,including dendritic cells,T cells,B cells,macrophages,neutrophils,NK cells,and myeloid-derived suppressor cells(MDSCs).These non-tumor cells often exhibit two phenotypes with altered functions,and tumor cells drives their transition towards tumor promotion through tumor-education.Tumor-educated cells(TECs)are cells influenced by tumor cells,which acquire immune-suppressive phenotypes and promote tumor progression through resistance to anticancer therapies.These cells undergo modifications in response to signals from the tumor,which can influence their roles in tumor progression.Their dynamic interactions with tumor cells contribute to the reshaping of the TME,facilitating cancer growth and immune modulation.This review summarizes research on TECs in TME,explores mechanisms related to tumor education,and discusses their role in tumor progression and immunotherapy resistance.Additionally,potential therapeutic approaches targeting these cells are also reviewed,which may complement current treatment strategies.展开更多
文摘A checkpointing scheme for relevant distributed real-time tasks which can be scheduled as a DAG is proposed. A typical algorithm, OSA, is selected for DAG scheduling. A new methods based a new structure, Scheduled Cluster Tree, is presented to calculate the slack time of each task in the task cluster. In the checkpointing scheme, the optimal checkpoint intervals which minimize the approximated failure probability are derived formally and validated experimentally. The complexity of approximated failure probability is quite small compared with that of the exact probability. Meanwhile, the consistency of the checkpointing is discussed also.
基金supported by the National Key Research and Development Program of China under Grant No.2023YFB4502304the National Natural Science Foundation of China under Grant Nos.62272190 and 62302190.
文摘The reliability of high-performance computing(HPC)is essential for program execution stability.However,as the hardware fault rate constantly increases,fault-tolerance techniques such as Checkpoint/Restart(C/R)introduce significant system overhead.This paper proposes Program Error Resilience-Aware Checkpointing Mechanism(ResCheckpointer)to mitigate the overhead of the C/R mechanism.The primary motivation of ResCheckpointer is that we observe that crash proneness(i.e.,the probability of the program crashing after fault occurrence)varies significantly among inter-and intra-HPC programs,which prompts us to flexibly adjust checkpoint intervals for further C/R overhead optimization.Specifically,we first construct the graph neural network(GNN)based learning paradigms to excavate the complex error propagation and effect mechanisms hidden within the HPC program’s execution flow,and propose Crash-Predictor for efficiently predicting programs’crash proneness.Based on this,we build ResCheckpointer,which equips an intelligent checkpoint interval setting strategy for HPC programs,i.e.,denser for the crash proneness stage while sparser for the error resilience stage.Experimental results show that ResCheckpointer can achieve up to 55.37%C/R cost reduction compared with the baseline C/R mechanism.
基金Project supported by the National "863" High-tech Program of China.
文摘Network of workstations (NOW) now becomes one of the main trends of parallel computing. But for long-running scientific programs, it needs effective fault tolerance for its changing property. Checkpointing and rollback recovery is a solution to this problem. First the main problems upon rollback recovery are discussed, the different checkpointing techniques for NOW are analyzed, and then the design and implementation of ChaRM (checkpoint-based rollback recovery and process migration) system are described. The comparison of three coordinated checkpointing systems is given.
基金the National Natural Science Foundation of China !69673012
文摘A consistent checkpointing algorithm with short freezing time (SFT) is presented in this paper. It supports fault-tolerance in distributed systems. The algorithm has shorter freezing time, lower overhead, and simplicity of recovery. To make checkpoint time shorter, a special control message (Munblock) is used to ensure that a process can respond the checkpoint event quickly at any given time. Moreover, main memory algorithm is used to improve the concurrency of checkpointing. By using SFT, the freezing time resulted by checkpointing is less than 0.03s. Furthermore, the control message number of SFT is only O(n).
文摘In this papert the hard problem of the thorough garbage collection in uncoordinated Checkpointing algorithms is studied. After introduction of the traditional garbage collecting scheme, with which only obsolete checkpoints can be discarded, it is shown that this kind of traditional method may fail to discard any checkpoint in some special cases, and it is necessary and urgent to find a thorough garbage collecting method, with which all the checkpoints useless for any future rollback-recovery including the obsolete ones can be discarded. Then, the Thorough Garbage Collection Theorem is proposed and proved, which ensures the feasibility of the thorough garbage collection, and gives the method to calculate the set of the useful checkpoints as well.
基金supported by Beijing Sport University Graduate Innovation Programme(2024013).
文摘Background:Exercise exerts tumor-suppressive effects across multiple malignancies,partly through exerkines—exercise-induced secreted factors with immunomodulatory and metabolic functions.However,the prognostic relevance of exerkines across cancer types remains unclear,and the molecular determinants of exercise responsiveness are poorly defined.Methods:We systematically profiled 183 curated exerkine-related genes across 33 cancer types from The Cancer Genome Atlas(TCGA)using non-negative matrix factorization(NMF)to define molecular subtypes.Prognostic significance was evaluated via Kaplan-Meier analysis.For five cancers with consistent survival divergence(LGG,KIRC,LUAD,PAAD,ACC),we developed an Exerkine Prognostic Index(EPI)using LASSO Cox regression and validated its predictive performance through time-dependent ROC analysis.Immune cell infiltration(CIBERSORT),stromal/immune scores(ESTIMATE),and immune checkpoint expression were assessed to characterize immune landscape differences between EPI subgroups.Results:Exerkine-based NMF clustering identified prognostically distinct subtypes in 25 cancers.The EPI robustly stratified patients into high-and low-risk groups with significant differences in overall survival(p<0.001).High-EPI subgroups were associated with elevated infiltration of immunosuppressive cells(e.g.,Tregs,M0 macrophages),altered immune/stromal scores,and differential expression of immune checkpoints such as PD-L1 and CTLA4 in a cancer-type-specific manner.Discussion:Our findings reveal that exerkine expression patterns capture biologically and clinically relevant heterogeneity across cancers.The EPI provides a robust molecular tool to stratify patients by prognosis and immune contexture,offering insights into differential exercise responsiveness.Conclusions:Exerkines represent promising biomarkers for risk stratification and precision-guided exercise interventions in oncology.
文摘Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.
文摘BACKGROUND Chemotherapy with an immune checkpoint inhibitor is one of the standard regimens for treating advanced gastric cancer(AGC).Ascites and peritoneal dissemination are common complications and poor prognostic factors of AGC;however,reports regarding its efficacy and safety in patients with AGC and massive ascites are limited.AIM To evaluate the safety and efficacy of nivolumab combined with chemotherapy in patients with AGC and ascites.METHODS We retrospectively collected clinical data from 124 patients with AGC who received chemotherapy plus nivolumab as first-line treatment from July 2017 to December 2024.Based on computed tomography scans,massive or moderate ascites were classified as high ascites burden(HAB),whereas mild or no ascites were classified as low ascites burden.RESULTS Ascites was detected in 47 patients(38%);26(21%)were classified into the HAB group.Patients in the HAB group exhibited a significantly poorer performance status,a higher prevalence of diffuse-type histology,and lower programmed cell death ligand 1(PD-L1)expression.Combination therapy with FOLFOX and neutropenia was significantly more common in the HAB group.Progression-free survival(PFS)(4.4 months vs 9.3 months,P=0.0012)and overall survival(OS)(7.3 months vs 21.2 months,P<0.0001)were significantly poorer in the HAB group.However,an improvement in ascites was observed in 61.5%of patients in the HAB group.PD-L1 expression did not correlate with either PFS or OS in the HAB group.CONCLUSION Nivolumab plus chemotherapy demonstrated modest efficacy and acceptable toxicity in patients with AGC and HAB.
文摘Dear Editor,Lymphocyte activation gene 3(LAG3),the third established target for immune checkpoint blockade therapy,suppresses T cell function by binding to major histocompatibility complex classⅡ(MHCⅡ).Despite its significant therapeutic potential in cancer immunotherapy and the substantial attention it has received from academia and industry,the molecular mechanisms of LAG3-mediated immunosuppression remain poorly understood,primarily because of its unique ligand-binding characteristics and intracellular domains[1].
基金Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),project numbers 324633948 and 409784463(DFG grants Hi 678/9-3 and Hi 678/10-2,FOR2953)to HHBundesministerium für Bildung und Forschung-BMBF,project number 16LW0463K to HT.
文摘Microglia are the resident macrophages of the central nervous system.They act as the first line of defense against pathogens and play essential roles in neuroinflammation and tissue repair after brain insult or in neurodegenerative and demyelinating diseases(Borst et al.,2021).Together with infiltrating monocyte-derived macrophages,microglia also play a critical role for brain tumor development,since immunosuppressive interactions between tumor cells and tumor-associated microglia and macrophages(TAM)are linked to malignant progression.This mechanism is of particular relevance in glioblastoma(GB),the deadliest form of brain cancer with a median overall survival of less than 15 months(Khan et al.,2023).Therefore,targeting microglia and macrophage activation is a promising strategy for therapeutic interference in brain disease.
文摘Background:While the treatment of metastatic renal cell carcinoma(mRCC)is evolving due to immune checkpoint inhibitors(ICIs),optimal strategies for later lines of therapy have yet to be defined.The combination of lenvatinib and everolimus represents a viable option,and the present review aimed to summarize its activity,effectiveness,and safety.Methods:A systematic review of the literature was conducted using PubMed,targeting studies published between 2018 and 2025.Eligible studies included English-language prospective and retrospective trials reporting survival outcomes in mRCC patients treated with lenvatinib and everolimus after at least one ICI-containing regimen.Results:Nine studies met the inclusion criteria,encompassing a total of 441 patients.The lenvatinib and everolimus combination was primarily used in the third and subsequent lines of therapy.Median overall survival ranged from 7.5 to 24.5 months,while median progression-free survival was more consistent,between 6.1 and 6.7 months,except for one study reporting 12.9 months.Objective response rates varied widely(14.0%–55.7%).Adverse events of grade≥3 did not exceed the expected rate,with diarrhoea and proteinuria as the most reported events.Dose reductions and treatment discontinuations due to toxicity occurred but were generally lower than in prior pivotal trials.Conclusions:Real-world evidence suggests that lenvatinib and everolimus represent an effective and safe option after ICI failure in mRCC patients.Nevertheless,the lack of randomized phase III trials and the heterogeneity of existing studies highlight the need for more robust prospective research to guide post-ICI therapeutic strategies.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82222058,82425046,and 82273142).
文摘Anti-programmed cell death protein 1(PD-1)or its ligand(PD-L1)are immune checkpoint inhibitors(ICIs)that have revolutionized cancer therapy.However,the efficacy of anti-PD-1 and anti-PD-L1 is limited by resistance and inter-individual variability.In recent years increasing evidence has highlighted the pivotal role of the gut microbiota in modulating the response to PD-1/PD-L1 immunotherapy.Extensive preclinical studies have demonstrated that commensal microbes can increase the efficacy of PD-1/PD-L1 blockade through multiple mechanisms,including the production of metabolites,such as short-chain fatty acids(SCFAs),tryptophan derivatives,and extracellular polysaccharides that remodel the tumor microenvironment,as well as the activation of immune pathways involving dendritic cells,CD8+T cells,and M1 macrophages to increase antitumor immunity.Moreover,clinical studies have shown that fecal microbiota transplantation(FMT)and targeted probiotic interventions show promise for improving the response to PD-1/PD-L1 therapy,while reducing the risk of immune-related adverse events(irAEs).This review systematically explores the multifaceted regulatory roles of the commensal microbiota in PD-1/PD-L1 therapy and examines the preclinical prospects of microbiota-based personalized immunotherapeutic strategies.The integration of multiomics technologies,synthetic biology,and precise microbiota interventions may further optimize PD-1/PD-L1 immunotherapy and offer novel insights into antitumor immune modulation.
基金the Postdoctoral Science Foundation (No. 20060390461)the Basic Research Foundation of Harbin Engineering University (Nos. HEUF040806,HEUFT05009, and HEUFP05020)
文摘When applied to mobile computing systems,checkpoint protocols for distributed computing systems would face many new challenges, such as low wireless bandwidth, frequent disconnections, and lack of stable storage at mobile hosts. This paper proposes a novel checkpoint protocol to effectively reduce the coordinating overhead. By using a communication vector, only a few processes participate in the checkpointing event. During checkpointing, the scheme can save the time used to trace the dependency tree by sending checkpoint requests to dependent processes at once. In addition, processes are non- blocking in this scheme, since the inconsistency is resolved by the piggyback technique. Hence the unnecessary and orphan messages can be avoided. Compared with the traditional coordinated checkpoint approach, the proposed non-blocking algorithm obtains a minimal number of processes to take checkpoints. It also reduces the checkpoint latency, which brings less overhead to mobile host with limited resources.
基金supported by the National Key Research and Development Program of China(No.2022YFE0102100)the National Natural Science Foundation of China(Nos.U22A20307 and 81930041)。
文摘Dysfunction of anti-tumor immune responses is crucial for cancer progression. Immune checkpoint blockade(ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified;some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration(FDA) for clinical treatment. However, limited responses and immune-related adverse events(ir AEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.
基金supported by Guangdong Basic and Applied Basic Research Foundation(2024A1515012993)the Project of Hunan Provincial Health Commission(No.D202303078877).
文摘Hepatocellular carcinoma(HCC)is a highly aggressive malignancy,largely driven by an immunosuppres-sive tumor microenvironment(TME)that facilitates tumor growth,immune escape,and resistance to therapy.Although immunotherapy—particularly immune checkpoint inhibitors(ICIs)—has transformed the therapeutic landscape by restoring T cell-mediated anti-tumor responses,their clinical benefit as monotherapy remains suboptimal.This limitation is primarily attributed to immunosuppressive components within the TME,including tumor-associated macrophages,regulatory T cells(Tregs),and myeloid-derived suppressor cells(MDSCs).To address these challenges,combination strategies have been explored,such as dual checkpoint blockade targeting programmed cell death protein 1(PD-1),programmed death-ligand 1(PD-L1),and cytotoxic T-lymphocyte-associated antigen 4(CTLA-4),as well as synergistic use of ICIs with anti-angiogenic agents or TME-targeted interventions.These approaches have shown encouraging potential in enhancing immune efficacy.This review outlines the complex crosstalk between the TME and immunotherapeutic responses in HCC,emphasizing how combination regimens may overcome immune resistance.Furthermore,we discuss the remaining hurdles,including therapeutic resistance and immune-related adverse events,and propose future directions involving TME-associated biomarkers and individualized treatment strategies to improve patient outcomes.
基金Supported by the Wu Jieping Medical Fund,No.320.6750.2022-09-14the Climbing Fund of PhD Workstation,Zhangzhou Affiliated Hospital of Fujian Medical University,No.PDB202412。
文摘BACKGROUND Gastric cancer is a leading global cause of cancer mortality,with poor survival in locally advanced stages.While immune checkpoint inhibitors(ICIs)like sintilimab have improved outcomes in advanced disease,their role as neoadjuvant therapy remains understudied.This study investigates sintilimab combined with nabpaclitaxel/S-1 as preoperative treatment for locally advanced gastric cancer(LAGC),addressing an unmet need for effective neoadjuvant strategies.AIM To explore the efficacy and safety of combination treatment with sintilimab and nab-paclitaxel plus S-1 as neoadjuvant therapy for LAGC.METHODS Clinical data from 82 patients diagnosed with LAGC,who underwent preoperative treatment and surgery between April 2020 and December 2022,were included.Patients were divided into 2 groups according to treatment regimen:ICI(sintilimab+nab-paclitaxel+S-1);and non-ICI(nab-paclitaxel+S-1).Imaging and pathological efficacy,intra-and postoperative conditions,molecular subtypes,short-term survival outcomes,and safety were compared between the 2 groups.RESULTS Imaging evaluation of therapeutic efficacy revealed that the inclusion of ICI yielded a significantly higher complete response rate(13.2%vs 0.0%;P=0.048),and objective response rate(69.8%vs 31.0%,P=0.001)compared with non-ICI treatment.Pathological evaluation revealed that the ICI group exhibited a significantly higher pathological complete response rate(13.2%vs 0.0%;P=0.048)and major pathological response rate(35.8%vs 13.8%;P=0.041)than those in the non-ICI group.The two-year disease-free survival rate in the ICI group was greater than that in the non-ICI group(83.0%vs 55.2%;P=0.043).The use of ICI did not increase the incidence of adverse reactions(47.2%vs 41.4%;P=0.614)or perioperative adverse events(18.9%vs 13.8%;P=0.761).CONCLUSION The combination of sintilimab with nab-paclitaxel+S-1 for neoadjuvant treatment of LAGC improved efficacy in patients without increasing adverse drug reactions and perioperative adverse events,suggesting that this treatment regimen is safe and feasible.
基金supported by the NIH/NCI grants(No.P01CA257907)the Educational Department of Hunan Province for Excellent Youth Scholars(No.23B0011)。
文摘In the past decade,immunotherapies targeting cytotoxic T-lymphocyte antigen-4(CTLA-4),programmed cell death 1(PD-1),and PD-1 ligand(PD-L1)have been approved for solid tumors.However,some patients demonstrate suboptimal clinical outcomes due to resistance.The tumor microenvironment(TME)significantly affects the efficiency of immunotherapy by mediating interactions between tumor and non-tumor cells,including dendritic cells,T cells,B cells,macrophages,neutrophils,NK cells,and myeloid-derived suppressor cells(MDSCs).These non-tumor cells often exhibit two phenotypes with altered functions,and tumor cells drives their transition towards tumor promotion through tumor-education.Tumor-educated cells(TECs)are cells influenced by tumor cells,which acquire immune-suppressive phenotypes and promote tumor progression through resistance to anticancer therapies.These cells undergo modifications in response to signals from the tumor,which can influence their roles in tumor progression.Their dynamic interactions with tumor cells contribute to the reshaping of the TME,facilitating cancer growth and immune modulation.This review summarizes research on TECs in TME,explores mechanisms related to tumor education,and discusses their role in tumor progression and immunotherapy resistance.Additionally,potential therapeutic approaches targeting these cells are also reviewed,which may complement current treatment strategies.
