As one of the hallmarks of cancer,metabolic reprogramming leads to cancer progression,and targeting glycolytic enzymes could be useful strategies for cancer therapy.By screening a small molecule library consisting of ...As one of the hallmarks of cancer,metabolic reprogramming leads to cancer progression,and targeting glycolytic enzymes could be useful strategies for cancer therapy.By screening a small molecule library consisting of 1320 FDA-approved drugs,we found that penfluridol,an antipsychotic drug used to treat schizophrenia,could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma(ESCC).Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol.By using drug affinity responsive target stability(DARTS)technology and proteomics,we identified phosphofructokinase,liver type(PFKL),a key enzyme in glycolysis,as a direct target of penfluridol.Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells,illustrating that PFKL is essential for the bioactivity of penfluridol.High PFKL expression is correlated with advanced stages and poor survival of ESCC patients,and silencing of PFKL significantly suppressed tumor growth.Mechanistically,direct binding of penfluridol and PFKL inhibits glucose consumption,lactate and ATP production,leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner.Taken together,PFKL is a potential prognostic biomarker and therapeutic target in ESCC,and penfluridol may be a new therapeutic option for management of this lethal disease.展开更多
Neural architecture search(NAS)plays an important role in many computer vision tasks.However,the high computational cost of forward and backward propagations during the search,process restricts its practical applicati...Neural architecture search(NAS)plays an important role in many computer vision tasks.However,the high computational cost of forward and backward propagations during the search,process restricts its practical application.In this paper,we present the search process as a multi-armed bandit problem,where we take into account the uncertainty caused by the contradiction between the huge search space and limited number of trials.Bandit NAS optimizes the trade-off between exploitation and exploration for a highly efficient search.Specifically,we sampled from a set of operations in one trial,where each operation was weighted by its trial performance and a bias to allow operations with less training to be selected.We further reduced the search space by abandoning the operation with the lowest potential,significantly reducing the search cost.Experimental results on the CIFAR-10 dataset show that the resulting architecture achieves the most advanced precision with a search speed approximately two times faster than that of partially connected differentialble architecture search.On ImageNet,we attained the most advanced top-1 accuracy of 75.3%with a search time of 1.8 GPU days.展开更多
基金supported by National Natural Science Foundation of China(31961160727,81773085,and 81973339)National Key Research and Development Program of China(2017YFA0505100)Guangdong Natural Science Research Grant International joint project(2021A0505030035,China)。
文摘As one of the hallmarks of cancer,metabolic reprogramming leads to cancer progression,and targeting glycolytic enzymes could be useful strategies for cancer therapy.By screening a small molecule library consisting of 1320 FDA-approved drugs,we found that penfluridol,an antipsychotic drug used to treat schizophrenia,could inhibit glycolysis and induce apoptosis in esophageal squamous cell carcinoma(ESCC).Gene profiling and Ingenuity Pathway Analysis suggested the important role of AMPK in action mechanism of penfluridol.By using drug affinity responsive target stability(DARTS)technology and proteomics,we identified phosphofructokinase,liver type(PFKL),a key enzyme in glycolysis,as a direct target of penfluridol.Penfluridol could not exhibit its anticancer property in PFKL-deficient cancer cells,illustrating that PFKL is essential for the bioactivity of penfluridol.High PFKL expression is correlated with advanced stages and poor survival of ESCC patients,and silencing of PFKL significantly suppressed tumor growth.Mechanistically,direct binding of penfluridol and PFKL inhibits glucose consumption,lactate and ATP production,leads to nuclear translocation of FOXO3a and subsequent transcriptional activation of BIM in an AMPK-dependent manner.Taken together,PFKL is a potential prognostic biomarker and therapeutic target in ESCC,and penfluridol may be a new therapeutic option for management of this lethal disease.
基金supported by the National Natural Science Foundation of China (Grant No.62076016)。
文摘Neural architecture search(NAS)plays an important role in many computer vision tasks.However,the high computational cost of forward and backward propagations during the search,process restricts its practical application.In this paper,we present the search process as a multi-armed bandit problem,where we take into account the uncertainty caused by the contradiction between the huge search space and limited number of trials.Bandit NAS optimizes the trade-off between exploitation and exploration for a highly efficient search.Specifically,we sampled from a set of operations in one trial,where each operation was weighted by its trial performance and a bias to allow operations with less training to be selected.We further reduced the search space by abandoning the operation with the lowest potential,significantly reducing the search cost.Experimental results on the CIFAR-10 dataset show that the resulting architecture achieves the most advanced precision with a search speed approximately two times faster than that of partially connected differentialble architecture search.On ImageNet,we attained the most advanced top-1 accuracy of 75.3%with a search time of 1.8 GPU days.
