脑胶质瘤是颅内最常见的肿瘤,治疗形势严峻,其治疗疗效和预后差异巨大。如何实现脑胶质瘤的个体化治疗,提高治疗成功率,是目前临床上亟待解决的问题。前期研究发现,IDH基因突变是预测低级别胶质瘤(LGG)预后的一个关键因子。IDH突变患者...脑胶质瘤是颅内最常见的肿瘤,治疗形势严峻,其治疗疗效和预后差异巨大。如何实现脑胶质瘤的个体化治疗,提高治疗成功率,是目前临床上亟待解决的问题。前期研究发现,IDH基因突变是预测低级别胶质瘤(LGG)预后的一个关键因子。IDH突变患者的预后要明显好于IDH野生型患者。然而,目前IDH突变影响LGG预后的具体机制仍不明了。通过对TCGA和GEO等公用数据库中LGG数据集的挖掘,我们发现IDH突变能够显著下调GNG基因的表达(RSEM 1247.50 vs 891.15,P=1.55×10-3)。而GNG基因则与LGG患者的总生存期和药物敏感性显著关联。GNG高表达的LGG患者的生存期要显著短于低表达的患者(P=1.73×10-4,HR=3.30)。而在LGG采用替莫唑胺治疗的疾病进展患者(PD)中,GNG的表达要显著高于非疾病进展患者(CR+PR+SD)(RSEM 1709.98 vs 1076.09,P=5.00×10-3)。进一步分析显示,IDH突变能够显著上调GNG基因启动子区域1甲基化位点的甲基化程度(Beta 0.64 vs0.78,P=4.50×10-5),而该甲基化位点的甲基化程度与GNG的m RNA表达呈负相关(P<1.00×10-6,r=-0.69)。这些结果表明IDH突变可能通过影响GNG基因启动子甲基化而影响其表达,进而改变LGG患者的化疗预后。目前,我们正进一步开展机制实验验证这一结果。本研究为阐明脑胶质瘤预后个体差异发生机制提供了一定的科学依据。展开更多
针对社会设施的动态选址问题,本文提出一种基于需求密度感知和Growing Neural Gas Networks (GNG)的设施动态选址方案。该方法主要有以下三方面,第一、对区域进行划分;第二、获取区域的资源需求密度,并对低密度区域进行过滤;第三:基于...针对社会设施的动态选址问题,本文提出一种基于需求密度感知和Growing Neural Gas Networks (GNG)的设施动态选址方案。该方法主要有以下三方面,第一、对区域进行划分;第二、获取区域的资源需求密度,并对低密度区域进行过滤;第三:基于区域的需求密度对有限的信息资源进行合理分配。本文方法与Kmeans进行了对比,实验结果表明所提方法可有效对区域需求进行拓扑感知,并可对有限的可移动设施进行合理性规划。展开更多
Therapeutic targeting FOxO3A(a forkhead transcription factor)represents a prom-ising strategy to suppress acute myeloid leukemia(AML).However,the effective inhibitors that target FOXO3A are lacking and the adaptive re...Therapeutic targeting FOxO3A(a forkhead transcription factor)represents a prom-ising strategy to suppress acute myeloid leukemia(AML).However,the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOxO3A depletion on AML cells.Here,we show that FOxO3A deficiency induces a compensa-tory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance.Mitochondrial metabolism acts downstream of mTOR to provoke activa-tion of JNK/c-JUN via reactive oxygen species(ROS).At the molecular level,FOXO3A directly binds to the promoter of G protein gamma subunit 7(GNG7)and preserves its expression,while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR.Consequently,combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML.Through a structure-based virtual screening,we report one potent small-molecule FOxO3A inhibitor(Gardenoside)that exhibits a strong effect of anti-FOXO3A DNA binding.Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model.These results demonstrate that mTOR can mediate adaptive resistance to FOxO3A inhibition and validate a combinatorial approach for treating AML.展开更多
The N^(6)-methyladenosine(m^(6)A)modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs....The N^(6)-methyladenosine(m^(6)A)modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs.Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder(MDD),a common neuropsychiatric disorder with an unclear aetiology.Here,we found that the levels of the circular RNA HECW2(circHECW2)were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress(CUS)mouse model.Notably,the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS.Furthermore,we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP,leading to an increase in Gng4 expression via m^(6)A modifications.Our findings provide functional insight into the correlation between circHECW2 and m^(6)A methylation,suggesting that circHECW2 may represent a potential target for MDD treatment.展开更多
文摘脑胶质瘤是颅内最常见的肿瘤,治疗形势严峻,其治疗疗效和预后差异巨大。如何实现脑胶质瘤的个体化治疗,提高治疗成功率,是目前临床上亟待解决的问题。前期研究发现,IDH基因突变是预测低级别胶质瘤(LGG)预后的一个关键因子。IDH突变患者的预后要明显好于IDH野生型患者。然而,目前IDH突变影响LGG预后的具体机制仍不明了。通过对TCGA和GEO等公用数据库中LGG数据集的挖掘,我们发现IDH突变能够显著下调GNG基因的表达(RSEM 1247.50 vs 891.15,P=1.55×10-3)。而GNG基因则与LGG患者的总生存期和药物敏感性显著关联。GNG高表达的LGG患者的生存期要显著短于低表达的患者(P=1.73×10-4,HR=3.30)。而在LGG采用替莫唑胺治疗的疾病进展患者(PD)中,GNG的表达要显著高于非疾病进展患者(CR+PR+SD)(RSEM 1709.98 vs 1076.09,P=5.00×10-3)。进一步分析显示,IDH突变能够显著上调GNG基因启动子区域1甲基化位点的甲基化程度(Beta 0.64 vs0.78,P=4.50×10-5),而该甲基化位点的甲基化程度与GNG的m RNA表达呈负相关(P<1.00×10-6,r=-0.69)。这些结果表明IDH突变可能通过影响GNG基因启动子甲基化而影响其表达,进而改变LGG患者的化疗预后。目前,我们正进一步开展机制实验验证这一结果。本研究为阐明脑胶质瘤预后个体差异发生机制提供了一定的科学依据。
文摘针对社会设施的动态选址问题,本文提出一种基于需求密度感知和Growing Neural Gas Networks (GNG)的设施动态选址方案。该方法主要有以下三方面,第一、对区域进行划分;第二、获取区域的资源需求密度,并对低密度区域进行过滤;第三:基于区域的需求密度对有限的信息资源进行合理分配。本文方法与Kmeans进行了对比,实验结果表明所提方法可有效对区域需求进行拓扑感知,并可对有限的可移动设施进行合理性规划。
基金supported by the Chongqing Science Fund for Distinguished Young Scholars,China(C(STB2022NSCQJQX0032)National Science Foundation of China(No.81970100,82170115 and 81700135)the Doctor Research Project of Chongqing,China(No.CSTB2022BSXMJCX0005)。
文摘Therapeutic targeting FOxO3A(a forkhead transcription factor)represents a prom-ising strategy to suppress acute myeloid leukemia(AML).However,the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOxO3A depletion on AML cells.Here,we show that FOxO3A deficiency induces a compensa-tory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance.Mitochondrial metabolism acts downstream of mTOR to provoke activa-tion of JNK/c-JUN via reactive oxygen species(ROS).At the molecular level,FOXO3A directly binds to the promoter of G protein gamma subunit 7(GNG7)and preserves its expression,while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR.Consequently,combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML.Through a structure-based virtual screening,we report one potent small-molecule FOxO3A inhibitor(Gardenoside)that exhibits a strong effect of anti-FOXO3A DNA binding.Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model.These results demonstrate that mTOR can mediate adaptive resistance to FOxO3A inhibition and validate a combinatorial approach for treating AML.
基金This work was supported by grants from the Science and Technology Innovation 2030-Major Project of the Ministry of Science and Technology of China(2021ZD0202904/2021ZD0202900)the National Science Fund Distinguished Young Scholars(82025033,China)+4 种基金the National Natural Science Foundation of China(82230115,82273914,81903591,82372024,82003733)the Natural Science Foundation of Jiangsu Province(BK20200358,China)ZhiShan Scholar Program of Southeast University(2242022R40059 and 2242021R40023,China)the Jiangsu Provincial Key Laboratory of Critical Care Medicine(JSKLCCM-2022-02-008,China)the Open Project Program of the Key Laboratory of Developmental Genes and Human Diseases of the Ministry of Education(LDGHD202304,China).
文摘The N^(6)-methyladenosine(m^(6)A)modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs.Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder(MDD),a common neuropsychiatric disorder with an unclear aetiology.Here,we found that the levels of the circular RNA HECW2(circHECW2)were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress(CUS)mouse model.Notably,the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS.Furthermore,we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP,leading to an increase in Gng4 expression via m^(6)A modifications.Our findings provide functional insight into the correlation between circHECW2 and m^(6)A methylation,suggesting that circHECW2 may represent a potential target for MDD treatment.
