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
Lycii Radicis Cortex(LRC)is a medicinal and food homologous plant with various pharmacological activities,including anti-tumor effects.This study explores the anti-tumor effect of LRC on non-small cell lung cancer(NSC...Lycii Radicis Cortex(LRC)is a medicinal and food homologous plant with various pharmacological activities,including anti-tumor effects.This study explores the anti-tumor effect of LRC on non-small cell lung cancer(NSCLC)and its molecular mechanism using mice bearing Lewis lung carcinoma cells.LRC significantly suppressed the growth of NSCLC.Besides,RNA sequencing of mice tumors and hematoxylin&eosin and immunofluorescence staining revealed that LRC promoted the infiltration of T lymphocytes,specifically GZMB~+CD8~+T lymphocytes,in tumor tissues.The Gene Set Enrichment Analysis of spleen RNA indicated that LRC up-regulated PD-1-downstream pathways,suggesting that LRC exerted its effects through the PDL1/PD-1 pathway.Further experiments revealed that LRC interacted with PD-L1,blocking PD-L1/PD-1 binding and thus restoring the T cell killing activity on tumor cells.Together,these results support using LRC as healthy food to improve anti-tumor immunity in patients with NSCLC.展开更多
BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a ...BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.展开更多
Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC case...Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC cases.Despite advancements in targeted therapies and localized treatments,the 5-year survival rate remains low,indicating limited efficacy of current approaches.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has brought new hope for patients with PLC.However,the liver's unique immune microenvironment presents significant challenges to the effectiveness of immunotherapy in HCC.This article reviews recent research developments in liver cancer immunotherapy,focusing on ICIs,combination therapies,emerging treatments,and prospective future directions.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
Glioblastoma(GBM)is one of the most aggressive and treatment-resistant brain cancers.Despite years of research and clinical trials,especially using immune checkpoint inhibitors,therapeutic gains remain minimal[1,2].A ...Glioblastoma(GBM)is one of the most aggressive and treatment-resistant brain cancers.Despite years of research and clinical trials,especially using immune checkpoint inhibitors,therapeutic gains remain minimal[1,2].A recent study published in Nature by Faust Akl and colleagues begins to lift the veil on this mystery,uncovering a previously unknown mechanism of immune evasion in GBM[3].展开更多
Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tum...Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.展开更多
Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitor...Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitors have emerged as a key strategy in cancer treatment.However,anti-programmed cell death 1/programmed death ligand 1 therapies,one of the main immunotherapeutic approaches,only elicit a response in only approximately 20%of advanced HCC.This suggests that there may be other immune checkpoints playing important roles in HCC immunotherapy.Recent studies have highlighted Signal regulatory protein alpha(SIRPα)is a phagocytic checkpoint in macrophages and other immune cells,as a promising novel therapeutic target in tumor immunotherapy.This review summarizes current progress on SIRPαin HCC and identifies key challenges for future related research.展开更多
CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upre...CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upregulation of various inhibitory receptors and significant shifts in both transcriptional and epigenetic profiles,thus ultimately leading to inadequate tumor control.Therapeutic strategies aimed at reversing CD8^(+)T cell exhaustion have the potential to rejuvenate immune responses and enhance treatment efficacy.This review compiles current knowledge regarding the molecular mechanisms underlying CD8^(+)T cell exhaustion,including the roles of immune checkpoint molecules,the tumor microenvironment,metabolic reprogramming,transcription factors,and epigenetic modifications.Emerging therapeutic approaches designed to combat CD8^(+)T cell exhaustion are evaluated,with emphasis on the modulation of immune checkpoints;targeting of metabolic and transcriptional changes;and exploration of other innovative strategies,such as epigenetic editing and engineered CAR-T cells.Importantly,we expand the exhaustion concept to immune cells beyond CD8^(+)T cells,such as CD4^(+)T cells,natural killer cells,and myeloid populations,thereby highlighting the broader implications of systemic immunosuppression in the cancer context.Finally,we propose avenues for future research aimed at further elucidating the factors and molecular mechanisms associated with CD8^(+)T cell exhaustion,thereby underscoring the critical need for strategies aimed at reversing this state to improve outcomes in cancer immunotherapy.展开更多
As a rising immune checkpoint on tumor cells,CD24 is closely related to tumorigenesis and progression.CD24 can directly regulate the malignant behavior of tumor cells and indirectly inhibit the function of immune cell...As a rising immune checkpoint on tumor cells,CD24 is closely related to tumorigenesis and progression.CD24 can directly regulate the malignant behavior of tumor cells and indirectly inhibit the function of immune cells in the meantime,which promotes the immune escape of tumor cells,induces cancer invasion and causes poor prognosis.The basic principle of cancer treatment is to induce cell death and inhibit cell survival.Resistance to chemoradiotherapy is a critical challenge in oncology,which limits the effectiveness of anti-cancer treatments.Many studies have shown a strong association between CD24 and chemoradiotherapy resistance in tumor cells,but the specific mechanism remains unclear.Understanding the mechanisms that CD24 induces chemoradiotherapy resistance may allow us to develop new promising therapeutic strategies to enhance the efficacy of chemoradiotherapy and improve clinical outcomes in the treatment of cancer patients.In this review,we summarized the basic characteristics and functions of CD24,as well as its role in the development of cancer.We focused on the resistance to radiotherapy and chemotherapy mediated by CD24,deciphered fundamental mechanisms and introduced existing clinical studies,with an attempt to propose potential solutions for future explorations.展开更多
Objective To investigate the combined effects of thymidine phosphorylase(TYMP)and sine oculis homeobox homologue 1(Six1)on the tumor microenvironment and their role in promoting metastasis in gastric cancer(GC).Method...Objective To investigate the combined effects of thymidine phosphorylase(TYMP)and sine oculis homeobox homologue 1(Six1)on the tumor microenvironment and their role in promoting metastasis in gastric cancer(GC).Methods A total of 674 GC patients who underwent surgical resection were enrolled.Correlations between TYMP/Six1 expression and the clinicopathological characteristics and overall survival of patients were analysed.The expression of TYMP,Six1 and vascular endothelial growth factor C(VEGFc)was quantified via immunohistochemistry and quantitative real-time polymerase chain reaction.Cell transfection,wound-healing assays and bioinformatics analyses were used to explore the potential underlying mechanisms involved.Results Compared with the other groups,the Six1+/TYMP+patients exhibited poor differentiation,advanced tumor stage,a higher rate of lymphatic vessel invasion and shorter survival.Additionally,the protein expression of TYMP and Six1 was positively correlated with the VEGFc level.A significant increase in VEGFc expression was observed in cells transfected with TYMP,Six1,and TYMP/Six1 vectors.The results of the wound-healing assay indicated that the synergistic effect of TYMP and Six1 enhanced the migratory ability of GC cells.Furthermore,bioinformatics analysis revealed that TYMP and Six1 were positively correlated with immunosuppressive immune cell subsets and elevated the expression of inhibitory immune checkpoints in GC.Conclusions The combination of TYMP and Six1 is a good predictive and prognostic biomarker for GC.This combination enhances the expression of VEGFc,facilitates the invasion of GC cells,and may be linked to inhibitory immune cells and the tumor immune microenvironment.展开更多
Megakaryocytes and hepatocytes are unique cells in mammals that undergo polyploidization through endomitosis in terminal differentiation.Many polyploidization regulators and underlying mechanisms have been reported,mo...Megakaryocytes and hepatocytes are unique cells in mammals that undergo polyploidization through endomitosis in terminal differentiation.Many polyploidization regulators and underlying mechanisms have been reported,most of which are tightly coupled with development,organogenesis,and cell differentiation.However,the nature of endomitosis,which involves successful entry into and exit from mitosis without complete cytokinesis,has not yet been fully elucidated.We highlight that endomitosis is a new cell fate in the cell cycle,and tetraploidy is a critical stage at the bifurcation of cell fate decision.This review summarizes the recent research progress in this area and provides novel insights into how cells manipulate mitosis toward endomitosis.Endomitotic cells can evade the tetraploidy restrictions and proceed to multiple rounds of the cell cycle.This knowledge not only deepens our understanding of endomitosis as a fundamental biological process but also offers new perspectives on the physiological and pathophysiological implications of polyploidization.展开更多
One of the most prevalent malignant tumors worldwide,stomach cancer still has a high incidence and fatality rate in China,and the number of young people developing early-onset gastric cancer is steadily increasing.The...One of the most prevalent malignant tumors worldwide,stomach cancer still has a high incidence and fatality rate in China,and the number of young people developing early-onset gastric cancer is steadily increasing.The 5-year survival rate of stomach cancer is typically 30%–35%,the prognosis is bad,the patients’quality of life is low,and the progression of advanced gastric cancer cannot be effectively managed despite the use of surgical surgery,chemotherapy,and other medicines.We urgently need molecular biomarkers with high specificity and sensitivity to increase the early gastric cancer detection rate,extend patient survival,and improve patient quality of life.The initial diagnosis of gastric cancer primarily depends on gastroscopy and biopsy,and invasive procedures cause significant discomfort to patients.Similar to this,treating advanced and metastatic stomach cancer is a pressing issue that requires attention.More and more immune checkpoint molecules have been discovered,and corresponding inhibitors are gradually being applied to clinical diagnosis and treatment.Recently,some non-coding RNAs have begun to be used as new targets for the treatment of gastric cancer.Some non-coding RNAs are highly present in the serum or urine of gastric cancer patients and can be used as diagnostic markers or prognostic indicators.Many clinical trials targeting non-coding RNAs have also shown good therapeutic effects.In general,targeting non-coding RNAs has shown good therapeutic effects.The biomarkers for gastric cancer detection and treatment are reviewed in this article,focusing on the new non-coding RNAs used in diagnosis,prognosis,and treatment.Patients with stomach cancer should have access to more precise and efficient diagnosis and treatment choices as a result of ongoing technological advancements and thorough research.展开更多
Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs sele...Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs selectively target different receptors comprising programmed cell death-1 receptor,programmed cell death-ligand 1 receptor,and cytotoxic T lymphocyte antigen 4 receptor.The widespread utilization of ICIs over the past several years,however,is frequently accompanied by immune-related adverse events(irAEs)that substantially impact the patient’s quality of life,particularly those affecting the digestive system,including both the upper and lower gastrointestinal tract.Based on a literature search covering databases such as PubMed,Web of Science,Embase,and the Cochrane Library,we present an insight into primary gastrointestinal irAEs,with a special focus on endoscopic manifestations.Additionally,we analyze data regarding the pathogenetic mechanisms,diagnostic approaches,histological characteristics,and proposed therapeutic interventions for managing irAEs involving the gastrointestinal tract.展开更多
BACKGROUND The optimal sequencing of immune checkpoint inhibitor(ICI)and brain radiotherapy in the management of brain metastasis from non-small cell lung cancer(NSCLC)is unclear.AIM To evaluate the survival of concur...BACKGROUND The optimal sequencing of immune checkpoint inhibitor(ICI)and brain radiotherapy in the management of brain metastasis from non-small cell lung cancer(NSCLC)is unclear.AIM To evaluate the survival of concurrent ICI and consolidation ICI in NSCLC patients treated with brain radiotherapy.METHODS We retrospectively analyzed NSCLC patients treated with brain radiotherapy and ICI.Treatment response and survival were estimated.The cox proportional hazards regression model was utilized to investigate the association between overall survival and clinical variables.RESULTS There were 54 patients in concurrent ICI and radiotherapy group,and 62 individuals treated with radiotherapy followed by consolidation ICI.The objective response rates were similar between the two group.The median progression free survival was significantly high in the concurrent ICI group compared with consolidation ICI group(9.56 months vs 8.15 months,P=0.038).In addition,the median overall survival was 22.08 months in the concurrent ICI group,clearly longer than that in the consolidation group(13.24 months,P=0.009).CONCLUSION In NSCLC patients with brain metastases,our analyses suggested that radio therapy concurrent with ICI was associated with significant benefit compared with radiotherapy followed by consolidation ICI.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supported by Natural Science Foundation of Guangdong Province,China(2022A1515011575)National Natural Science Foundation of China,China(81873154)President Foundation of Integrated Hospital of Traditional Chinese Medicine,Southern Medical University,China(1202103010)。
文摘Lycii Radicis Cortex(LRC)is a medicinal and food homologous plant with various pharmacological activities,including anti-tumor effects.This study explores the anti-tumor effect of LRC on non-small cell lung cancer(NSCLC)and its molecular mechanism using mice bearing Lewis lung carcinoma cells.LRC significantly suppressed the growth of NSCLC.Besides,RNA sequencing of mice tumors and hematoxylin&eosin and immunofluorescence staining revealed that LRC promoted the infiltration of T lymphocytes,specifically GZMB~+CD8~+T lymphocytes,in tumor tissues.The Gene Set Enrichment Analysis of spleen RNA indicated that LRC up-regulated PD-1-downstream pathways,suggesting that LRC exerted its effects through the PDL1/PD-1 pathway.Further experiments revealed that LRC interacted with PD-L1,blocking PD-L1/PD-1 binding and thus restoring the T cell killing activity on tumor cells.Together,these results support using LRC as healthy food to improve anti-tumor immunity in patients with NSCLC.
文摘BACKGROUND Gastric cancer(GC)is one of the most common malignancies worldwide,and Helicobacter pylori(HP)infection is a well-established risk factor for its development.Programmed death-ligand 1(PD-L1)expression is a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in cancer treatment.While HP infection and PD-L1 expression in GC may be linked,the relationship between them remains unclear,in part because there have been conflicting results reported from various studies.AIM To perform a meta-analysis to assess the relationship between HP and PD-L1 expression in patients with GC.METHODS A systematic literature review was conducted using PubMed,Embase,Cochrane Library,and Web of Science databases.Observational studies that examined the association between HP infection and PD-L1 expression in patients with GC were included.Odds ratios and 95%confidence intervals were calculated to estimate the association.Heterogeneity was assessed using Cochrane’s Q test and I²statistic.A random-effects model was used due to significant heterogeneity across studies.RESULTS Fourteen studies involving a total of 3069 patients with GC were included.The pooled analysis showed a significant association between HP infection and increased PD-L1 expression in GC tissues(odd ratio=1.69,95%confidence interval:1.24-2.29,P<0.001,I^(2)=59%).Sensitivity analyses confirmed the robustness of these findings.Subgroup analyses did not show significant variation based on geographic region,sample size,or method of PD-L1 assessment.Publication bias was minimal,as shown by funnel plots and Egger’s regression test.CONCLUSION HP infection is associated with increased PD-L1 expression in GC,suggesting that HP status may influence the response to programmed cell death protein 1/PD-L1 blockade therapy.
文摘Primary liver cancer(PLC)is a prevalent malignancy with high incidence and mortality rates globally.Hepatocellular carcinoma(HCC),primarily resulting from hepatitis B virus infections in Asia,constitutes most PLC cases.Despite advancements in targeted therapies and localized treatments,the 5-year survival rate remains low,indicating limited efficacy of current approaches.The advent of immunotherapy,particularly immune checkpoint inhibitors(ICIs),has brought new hope for patients with PLC.However,the liver's unique immune microenvironment presents significant challenges to the effectiveness of immunotherapy in HCC.This article reviews recent research developments in liver cancer immunotherapy,focusing on ICIs,combination therapies,emerging treatments,and prospective future directions.
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.
文摘Glioblastoma(GBM)is one of the most aggressive and treatment-resistant brain cancers.Despite years of research and clinical trials,especially using immune checkpoint inhibitors,therapeutic gains remain minimal[1,2].A recent study published in Nature by Faust Akl and colleagues begins to lift the veil on this mystery,uncovering a previously unknown mechanism of immune evasion in GBM[3].
基金Supported by 2021 Key Topic of Qinghai Provincial Health System–Guiding Plan Topic,No.2021-WJZDX-43.
文摘Currently,the use of immune checkpoint inhibitors(ICIs)has shown notable clinical efficacy in treating various malignant tumors,significantly improving patient prognosis.However,while ICIs enhance the body’s anti-tumor effects,they can also trigger immune-related adverse events(irAEs),with ICI-associated colitis being one of the more prevalent forms.This condition can disrupt treatment,necessitate drug discontinuation,and adversely affect therapeutic outcomes.In severe cases,irAEs may even become life-threatening.A recent case report by Hong et al highlights the importance of vigilance for ICI-associated colitis in patients experiencing symptoms such as diarrhea and abdominal pain,which can arise both during and even after completion of ICI treatment.Early identification,multidisciplinary management,and continuous monitoring of patients are essential steps to further improve outcomes.
基金Supported by the National Key Sci-Tech Special Project of China,No.2018ZX10302207the Beijing Natural Science Foundation,No.7222191+3 种基金the Beijing Natural Science Foundation,No.7244426the Fundamental Research Funds for the Central Universities,Peking University,No.PKU2024XGK005the Peking University Medicine Seed Fund for Interdisciplinary Research,No.BMU2021MX007 and No.BMU2022MX001Fundamental Research Funds for the Central Universities,Peking University People’s Hospital Scientific Research Development Funds,No.RDY2020-06 and No.RDJ2022-14.
文摘Hepatocellular carcinoma(HCC)is a primary malignant tumor of the liver and one of the most common malignant tumors,as well as the third leading cause of cancer-related death.In recent years,immune checkpoint inhibitors have emerged as a key strategy in cancer treatment.However,anti-programmed cell death 1/programmed death ligand 1 therapies,one of the main immunotherapeutic approaches,only elicit a response in only approximately 20%of advanced HCC.This suggests that there may be other immune checkpoints playing important roles in HCC immunotherapy.Recent studies have highlighted Signal regulatory protein alpha(SIRPα)is a phagocytic checkpoint in macrophages and other immune cells,as a promising novel therapeutic target in tumor immunotherapy.This review summarizes current progress on SIRPαin HCC and identifies key challenges for future related research.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82171810)the Program of Shandong Provincial Scientific and Technological Development of Traditional Chinese Medicine(Grant No.M-2023210)。
文摘CD8^(+)T cell exhaustion,a critical challenge in the immune response to cancer,is characterized by a profound decline in the functionality of effector CD8^(+)T cells.This state of exhaustion is accompanied by the upregulation of various inhibitory receptors and significant shifts in both transcriptional and epigenetic profiles,thus ultimately leading to inadequate tumor control.Therapeutic strategies aimed at reversing CD8^(+)T cell exhaustion have the potential to rejuvenate immune responses and enhance treatment efficacy.This review compiles current knowledge regarding the molecular mechanisms underlying CD8^(+)T cell exhaustion,including the roles of immune checkpoint molecules,the tumor microenvironment,metabolic reprogramming,transcription factors,and epigenetic modifications.Emerging therapeutic approaches designed to combat CD8^(+)T cell exhaustion are evaluated,with emphasis on the modulation of immune checkpoints;targeting of metabolic and transcriptional changes;and exploration of other innovative strategies,such as epigenetic editing and engineered CAR-T cells.Importantly,we expand the exhaustion concept to immune cells beyond CD8^(+)T cells,such as CD4^(+)T cells,natural killer cells,and myeloid populations,thereby highlighting the broader implications of systemic immunosuppression in the cancer context.Finally,we propose avenues for future research aimed at further elucidating the factors and molecular mechanisms associated with CD8^(+)T cell exhaustion,thereby underscoring the critical need for strategies aimed at reversing this state to improve outcomes in cancer immunotherapy.
基金supported by Health Commission of Hubei Province Scientific Research Project(No.WJ2023M068)Leading Discipline of Oncology Construction Project of Zhongnan Hospital of Wuhan University(No.XKJS202005)+8 种基金Youth Interdisciplinary Special Fund of Zhongnan Hospital of Wuhan University(No.ZNQNJC2022003)Knowledge Innovation Program of Wuhan-Shuguang Project(No.2023020201020510)Translational Medicine and Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University(ZNJC202322)Fundamental Research Funds for the Central Universities(Wuhan University,Clinical Medicine+X,2042024YXB017)Hubei Province Chinese Medicine Research Project(ZY2023Q015)Natural Science Foundation of Hubei Province(2023A FB665)Medical Young Talents Program of Hubei Province,Wuhan Young Medical Talents Training Project to L.-L.Bu,Youth Fund of the National Natural Science Foundation of China(82001644)Medical Young Talents Program of Hubei Province(7020206)“Dawn of Scientific and Technological Innovation”Program of Wuhan(703030804).
文摘As a rising immune checkpoint on tumor cells,CD24 is closely related to tumorigenesis and progression.CD24 can directly regulate the malignant behavior of tumor cells and indirectly inhibit the function of immune cells in the meantime,which promotes the immune escape of tumor cells,induces cancer invasion and causes poor prognosis.The basic principle of cancer treatment is to induce cell death and inhibit cell survival.Resistance to chemoradiotherapy is a critical challenge in oncology,which limits the effectiveness of anti-cancer treatments.Many studies have shown a strong association between CD24 and chemoradiotherapy resistance in tumor cells,but the specific mechanism remains unclear.Understanding the mechanisms that CD24 induces chemoradiotherapy resistance may allow us to develop new promising therapeutic strategies to enhance the efficacy of chemoradiotherapy and improve clinical outcomes in the treatment of cancer patients.In this review,we summarized the basic characteristics and functions of CD24,as well as its role in the development of cancer.We focused on the resistance to radiotherapy and chemotherapy mediated by CD24,deciphered fundamental mechanisms and introduced existing clinical studies,with an attempt to propose potential solutions for future explorations.
基金supported by the National Natural Science Foundation of China(No.81602104).
文摘Objective To investigate the combined effects of thymidine phosphorylase(TYMP)and sine oculis homeobox homologue 1(Six1)on the tumor microenvironment and their role in promoting metastasis in gastric cancer(GC).Methods A total of 674 GC patients who underwent surgical resection were enrolled.Correlations between TYMP/Six1 expression and the clinicopathological characteristics and overall survival of patients were analysed.The expression of TYMP,Six1 and vascular endothelial growth factor C(VEGFc)was quantified via immunohistochemistry and quantitative real-time polymerase chain reaction.Cell transfection,wound-healing assays and bioinformatics analyses were used to explore the potential underlying mechanisms involved.Results Compared with the other groups,the Six1+/TYMP+patients exhibited poor differentiation,advanced tumor stage,a higher rate of lymphatic vessel invasion and shorter survival.Additionally,the protein expression of TYMP and Six1 was positively correlated with the VEGFc level.A significant increase in VEGFc expression was observed in cells transfected with TYMP,Six1,and TYMP/Six1 vectors.The results of the wound-healing assay indicated that the synergistic effect of TYMP and Six1 enhanced the migratory ability of GC cells.Furthermore,bioinformatics analysis revealed that TYMP and Six1 were positively correlated with immunosuppressive immune cell subsets and elevated the expression of inhibitory immune checkpoints in GC.Conclusions The combination of TYMP and Six1 is a good predictive and prognostic biomarker for GC.This combination enhances the expression of VEGFc,facilitates the invasion of GC cells,and may be linked to inhibitory immune cells and the tumor immune microenvironment.
基金supported by the National Natural Science Foundation of China(Nos.32270643,91957109,and 81870427).
文摘Megakaryocytes and hepatocytes are unique cells in mammals that undergo polyploidization through endomitosis in terminal differentiation.Many polyploidization regulators and underlying mechanisms have been reported,most of which are tightly coupled with development,organogenesis,and cell differentiation.However,the nature of endomitosis,which involves successful entry into and exit from mitosis without complete cytokinesis,has not yet been fully elucidated.We highlight that endomitosis is a new cell fate in the cell cycle,and tetraploidy is a critical stage at the bifurcation of cell fate decision.This review summarizes the recent research progress in this area and provides novel insights into how cells manipulate mitosis toward endomitosis.Endomitotic cells can evade the tetraploidy restrictions and proceed to multiple rounds of the cell cycle.This knowledge not only deepens our understanding of endomitosis as a fundamental biological process but also offers new perspectives on the physiological and pathophysiological implications of polyploidization.
基金funded by the National Key Research and Development Project,grant number 2021YFE0192100Natural Science Foundation of Hunan Province,grant numbers 2021JJ30694,2023JJ30529+4 种基金Innovation and Entrepreneurship Training Program for College Students in Hunan Province,grant number S202210555254Key Projects of Hunan Provincial Education Department,grant number 21A0285Natural Science Foundation of Hunan Provincial and Municipal Co-Funding,grant number 2022JJ50029Key Projects of Shaoyang Science and Technology Bureau,grant number 2021GZ031Innovation and Entrepreneurship Training Program for College Students of the University of South China,grant numbers D202405212006326156,D202405210948392932,D202405211329047648,D202405221955420827.
文摘One of the most prevalent malignant tumors worldwide,stomach cancer still has a high incidence and fatality rate in China,and the number of young people developing early-onset gastric cancer is steadily increasing.The 5-year survival rate of stomach cancer is typically 30%–35%,the prognosis is bad,the patients’quality of life is low,and the progression of advanced gastric cancer cannot be effectively managed despite the use of surgical surgery,chemotherapy,and other medicines.We urgently need molecular biomarkers with high specificity and sensitivity to increase the early gastric cancer detection rate,extend patient survival,and improve patient quality of life.The initial diagnosis of gastric cancer primarily depends on gastroscopy and biopsy,and invasive procedures cause significant discomfort to patients.Similar to this,treating advanced and metastatic stomach cancer is a pressing issue that requires attention.More and more immune checkpoint molecules have been discovered,and corresponding inhibitors are gradually being applied to clinical diagnosis and treatment.Recently,some non-coding RNAs have begun to be used as new targets for the treatment of gastric cancer.Some non-coding RNAs are highly present in the serum or urine of gastric cancer patients and can be used as diagnostic markers or prognostic indicators.Many clinical trials targeting non-coding RNAs have also shown good therapeutic effects.In general,targeting non-coding RNAs has shown good therapeutic effects.The biomarkers for gastric cancer detection and treatment are reviewed in this article,focusing on the new non-coding RNAs used in diagnosis,prognosis,and treatment.Patients with stomach cancer should have access to more precise and efficient diagnosis and treatment choices as a result of ongoing technological advancements and thorough research.
文摘Treatment with immune checkpoint inhibitors(ICIs)is an innovative therapy for managing certain types of malignancy and has the potential to improve overall patient survival significantly.The most widely used ICIs selectively target different receptors comprising programmed cell death-1 receptor,programmed cell death-ligand 1 receptor,and cytotoxic T lymphocyte antigen 4 receptor.The widespread utilization of ICIs over the past several years,however,is frequently accompanied by immune-related adverse events(irAEs)that substantially impact the patient’s quality of life,particularly those affecting the digestive system,including both the upper and lower gastrointestinal tract.Based on a literature search covering databases such as PubMed,Web of Science,Embase,and the Cochrane Library,we present an insight into primary gastrointestinal irAEs,with a special focus on endoscopic manifestations.Additionally,we analyze data regarding the pathogenetic mechanisms,diagnostic approaches,histological characteristics,and proposed therapeutic interventions for managing irAEs involving the gastrointestinal tract.
文摘BACKGROUND The optimal sequencing of immune checkpoint inhibitor(ICI)and brain radiotherapy in the management of brain metastasis from non-small cell lung cancer(NSCLC)is unclear.AIM To evaluate the survival of concurrent ICI and consolidation ICI in NSCLC patients treated with brain radiotherapy.METHODS We retrospectively analyzed NSCLC patients treated with brain radiotherapy and ICI.Treatment response and survival were estimated.The cox proportional hazards regression model was utilized to investigate the association between overall survival and clinical variables.RESULTS There were 54 patients in concurrent ICI and radiotherapy group,and 62 individuals treated with radiotherapy followed by consolidation ICI.The objective response rates were similar between the two group.The median progression free survival was significantly high in the concurrent ICI group compared with consolidation ICI group(9.56 months vs 8.15 months,P=0.038).In addition,the median overall survival was 22.08 months in the concurrent ICI group,clearly longer than that in the consolidation group(13.24 months,P=0.009).CONCLUSION In NSCLC patients with brain metastases,our analyses suggested that radio therapy concurrent with ICI was associated with significant benefit compared with radiotherapy followed by consolidation ICI.
