58-year-old Chinese woman presented with a mass in right renal pelvis incidentally detected by ultrasonography(Fig.1A).No positive signs were found by physical examination,and urinalysis was also normal.Enhanced compu...58-year-old Chinese woman presented with a mass in right renal pelvis incidentally detected by ultrasonography(Fig.1A).No positive signs were found by physical examination,and urinalysis was also normal.Enhanced computed tomography(CT)of abdomen displayed a polycystic mass of 2.3 cm2.1 cm1.6 cm in right sinus renalis(Fig.1B and C)with ample blood perfusion in arterial phase(Fig.1B)and less perfusion in venous phase(Fig.1C).展开更多
CD8+T cells within the tumor microenvironment(TME)are often functionally impaired,which limits their ability to mount effective anti-tumor responses.However,the molecular mechanisms behind this dysfunction remain inco...CD8+T cells within the tumor microenvironment(TME)are often functionally impaired,which limits their ability to mount effective anti-tumor responses.However,the molecular mechanisms behind this dysfunction remain incompletely understood.Here,we identified valosin-containing protein(VCP)as a key regulator of CD8+T cells suppression in hepatocellular carcinoma(HCC).Our findings reveal that VCP suppresses the activation,expansion,and cytotoxic capacity of CD8+T cells both in vitro and in vivo,significantly contributing to the immunosuppressive nature of the TME.Mechanistically,VCP stabilizes the expression of glycerol-3-phosphate dehydrogenase 1-like protein(GPD1L),leading to the accumulation of glycerol-3-phosphate(G3P),a downstream metabolite of GPD1L.The accumulated G3P diffuses into the TME and directly interacts with SRC-family tyrosine kinase LCK,a critical component of the T-cell receptor(TCR)signaling pathway in CD8+T cells.This interaction heightens the phosphorylation of Tyr505,a key inhibitory residue,ultimately reducing LCK activity and impairing downstream TCR signaling.Consequently,CD8+T cells lose their functional capacity,diminishing their ability to fight against HCC.Importantly,we demonstrated that targeting VCP in combination with anti-PD1 therapy significantly suppresses HCC tumor growth and restores the anti-tumor function of CD8+T cells,suggesting synergistic therapeutic potential.These findings highlight a previously unrecognized mechanism involving VCP and G3P in suppressing T-cell-mediated immunity in the TME,positioning VCP as a promising upstream target for enhancing immunotherapy in HCC.展开更多
Knowledge graphs(KGs)express relationships between entity pairs,and many real-life problems can be formulated as knowledge graph reasoning(KGR).Conventional approaches to KGR have achieved promising performance but st...Knowledge graphs(KGs)express relationships between entity pairs,and many real-life problems can be formulated as knowledge graph reasoning(KGR).Conventional approaches to KGR have achieved promising performance but still have some drawbacks.On the one hand,most KGR methods focus only on one phase of the KG lifecycle,such as KG completion or refinement,while ignoring reasoning over other stages,such as KG extraction.On the other hand,traditional KGR methods,broadly categorized as symbolic and neural,are unable to balance both scalability and interpretability.To resolve these two problems,we take a more comprehensive perspective of KGR with regard to the whole KG lifecycle,including KG extraction,completion,and refinement,which correspond to three subtasks:knowledge extraction,relational reasoning,and inconsistency checking.In addition,we propose the implementation of KGR using a novel neural symbolic framework,with regard to both scalability and interpretability.Experimental results demonstrate that our proposed methods outperform traditional neural symbolic models.展开更多
文摘58-year-old Chinese woman presented with a mass in right renal pelvis incidentally detected by ultrasonography(Fig.1A).No positive signs were found by physical examination,and urinalysis was also normal.Enhanced computed tomography(CT)of abdomen displayed a polycystic mass of 2.3 cm2.1 cm1.6 cm in right sinus renalis(Fig.1B and C)with ample blood perfusion in arterial phase(Fig.1B)and less perfusion in venous phase(Fig.1C).
基金supported by the following source.National Key R&D Program of China(Grant No.2019YFA0709300)Noncommunicable Chronic Diseases-National Science and Technology Major Project(Grant No.2023ZD0507500)+7 种基金National Natural Science Foundation of China(Grant Nos.U19A2008,81972307,82102705,82272787,82373232,and 82473189)Natural Science Foundation of Anhui Province(2208085J47,2408085QH255)Provincial Key R&D Program of Anhui Province(202204295107020025,202204295107020022)The Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB0940201)Scientific Research Project of Anhui Provincial Department of Education(Grant No.2022AH030125)Beijing Xisike Clinical Oncology Research Foundation(Grant No.Y-JS2019-014).Research Funds of Centre for Leading Medicine and Advanced Technologies of IHM(Grant No.2023IHM01031)USTC Research Funds of the Double First-Class Initiative(YD9110002048,YD9110002050,and YD9110002068)Program for Innovative Research Team of The First Affiliated Hospital of USTC(CXGG01).
文摘CD8+T cells within the tumor microenvironment(TME)are often functionally impaired,which limits their ability to mount effective anti-tumor responses.However,the molecular mechanisms behind this dysfunction remain incompletely understood.Here,we identified valosin-containing protein(VCP)as a key regulator of CD8+T cells suppression in hepatocellular carcinoma(HCC).Our findings reveal that VCP suppresses the activation,expansion,and cytotoxic capacity of CD8+T cells both in vitro and in vivo,significantly contributing to the immunosuppressive nature of the TME.Mechanistically,VCP stabilizes the expression of glycerol-3-phosphate dehydrogenase 1-like protein(GPD1L),leading to the accumulation of glycerol-3-phosphate(G3P),a downstream metabolite of GPD1L.The accumulated G3P diffuses into the TME and directly interacts with SRC-family tyrosine kinase LCK,a critical component of the T-cell receptor(TCR)signaling pathway in CD8+T cells.This interaction heightens the phosphorylation of Tyr505,a key inhibitory residue,ultimately reducing LCK activity and impairing downstream TCR signaling.Consequently,CD8+T cells lose their functional capacity,diminishing their ability to fight against HCC.Importantly,we demonstrated that targeting VCP in combination with anti-PD1 therapy significantly suppresses HCC tumor growth and restores the anti-tumor function of CD8+T cells,suggesting synergistic therapeutic potential.These findings highlight a previously unrecognized mechanism involving VCP and G3P in suppressing T-cell-mediated immunity in the TME,positioning VCP as a promising upstream target for enhancing immunotherapy in HCC.
基金funded by National Natural Science Foundation of China(Grant no.91846204 and U19B2027)National Key Research and Development Program of China(Grant no.2018YFB1402800).
文摘Knowledge graphs(KGs)express relationships between entity pairs,and many real-life problems can be formulated as knowledge graph reasoning(KGR).Conventional approaches to KGR have achieved promising performance but still have some drawbacks.On the one hand,most KGR methods focus only on one phase of the KG lifecycle,such as KG completion or refinement,while ignoring reasoning over other stages,such as KG extraction.On the other hand,traditional KGR methods,broadly categorized as symbolic and neural,are unable to balance both scalability and interpretability.To resolve these two problems,we take a more comprehensive perspective of KGR with regard to the whole KG lifecycle,including KG extraction,completion,and refinement,which correspond to three subtasks:knowledge extraction,relational reasoning,and inconsistency checking.In addition,we propose the implementation of KGR using a novel neural symbolic framework,with regard to both scalability and interpretability.Experimental results demonstrate that our proposed methods outperform traditional neural symbolic models.
