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1.
IEEE Trans Cybern ; 52(8): 7624-7633, 2022 Aug.
Article in English | MEDLINE | ID: mdl-33301413

ABSTRACT

Diagnosing the fault as early as possible is significant to guarantee the safety and reliability of the high-speed train. Incipient fault always makes the monitored signals deviate from their normal values, which may lead to serious consequences gradually. Due to the obscure early stage symptoms, incipient faults are difficult to detect. This article develops a stacked generalization (stacking)-based incipient fault diagnosis scheme for the traction system of high-speed trains. To extract the fault feature from the faulty data signals, which are similar to the normal ones, the extreme gradient boosting (XGBoost), random forest (RF), extra trees (ET), and light gradient boosting machine (LightGBM) are chosen as the base estimators in the first layer of the stacking. Then, the logistic regression (LR) is taken as the meta estimator in the second layer to integrate the results from the base estimators for fault classification. Thanks to the generalization ability of stacking, the incipient fault diagnosis performance of the proposed stacking-based method is better than that of the single model (XGBoost, RF, ET, and LightGBM), although they can be used to detect the incipient faults, separately. Moreover, to find out the optimal hyperparameters of the base estimators, a swarm intelligent optimization algorithm, pigeon-inspired optimization (PIO), is employed. The proposed method is tested on a semiphysical platform of the CRH2 traction system in CRRC Zhuzhou Locomotive Company Ltd. The results show that the fault diagnosis rate of the proposed scheme is over 96%.


Subject(s)
Algorithms , Traction , Logistic Models , Reproducibility of Results
2.
J Med Chem ; 64(15): 10878-10889, 2021 08 12.
Article in English | MEDLINE | ID: mdl-34279092

ABSTRACT

MyD88 gene mutation has been identified as one of the most prevalent driver mutations in the activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). The published literature suggests that interleukin-1 receptor-associated kinase 1 (IRAK1) is an essential gene for ABC DLBCL harboring MyD88 mutation. Importantly, the scaffolding function of IRAK1, rather than its kinase activity, is required for tumor cell survival. Herein, we present our design, synthesis, and biological evaluation of a novel series of potent and selective IRAK1 degraders. One of the most potent compounds, Degrader-3 (JNJ-1013), effectively degraded cellular IRAK1 protein with a DC50 of 3 nM in HBL-1 cells. Furthermore, JNJ-1013 potently inhibited IRAK1 downstream signaling pathways and demonstrated strong anti-proliferative effects in ABC DLBCL cells with MyD88 mutation. This work suggests that IRAK1 degraders have the potential for treating cancers that are dependent on the IRAK1 scaffolding function.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Lymphoma, Large B-Cell, Diffuse/drug therapy , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Interleukin-1 Receptor-Associated Kinases/metabolism , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity Relationship
3.
Cancer Res ; 73(8): 2587-97, 2013 Apr 15.
Article in English | MEDLINE | ID: mdl-23400593

ABSTRACT

MDM2 negatively regulates p53 stability and many human tumors overproduce MDM2 as a mechanism to restrict p53 function. Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy. RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies. RG7112 binds MDM2 with high affinity (K(D) ~ 11 nmol/L), blocking its interactions with p53 in vitro. A crystal structure of the RG7112-MDM2 complex revealed that the small molecule binds in the p53 pocket of MDM2, mimicking the interactions of critical p53 amino acid residues. Treatment of cancer cells expressing wild-type p53 with RG7112 activated the p53 pathway, leading to cell-cycle arrest and apoptosis. RG7112 showed potent antitumor activity against a panel of solid tumor cell lines. However, its apoptotic activity varied widely with the best response observed in osteosarcoma cells with MDM2 gene amplification. Interestingly, inhibition of caspase activity did not change the kinetics of p53-induced cell death. Oral administration of RG7112 to human xenograft-bearing mice at nontoxic concentrations caused dose-dependent changes in proliferation/apoptosis biomarkers as well as tumor inhibition and regression. Notably, RG7112 was highly synergistic with androgen deprivation in LNCaP xenograft tumors. Our findings offer a preclinical proof-of-concept that RG7112 is effective in treatment of solid tumors expressing wild-type p53.


Subject(s)
Antineoplastic Agents/pharmacology , Imidazolines/pharmacology , Neoplasms/metabolism , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Signal Transduction/drug effects , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Caspases/metabolism , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Disease Models, Animal , Female , Humans , Imidazolines/chemistry , Mice , Molecular Docking Simulation , Neoplasms/pathology , Protein Binding/drug effects , Protein Stability/drug effects , Proto-Oncogene Proteins c-mdm2/chemistry , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Burden/drug effects , Tumor Suppressor Protein p53/chemistry , Xenograft Model Antitumor Assays
4.
Proc Natl Acad Sci U S A ; 109(29): 11788-93, 2012 Jul 17.
Article in English | MEDLINE | ID: mdl-22745160

ABSTRACT

Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.


Subject(s)
Apoptosis/physiology , Hydantoins/pharmacology , Models, Molecular , Nuclear Proteins/antagonists & inhibitors , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Tumor Suppressor Protein p53/metabolism , Apoptosis/drug effects , Blotting, Western , Cell Cycle Proteins , Cell Line, Tumor , Crystallization , Dimerization , Fluorescence Resonance Energy Transfer , Humans , Nuclear Magnetic Resonance, Biomolecular , Nuclear Proteins/chemistry , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins c-mdm2/chemistry , Signal Transduction/drug effects , Signal Transduction/physiology , Tetrazolium Salts , Thiazoles
5.
Mol Cancer ; 10: 49, 2011 May 03.
Article in English | MEDLINE | ID: mdl-21539745

ABSTRACT

BACKGROUND: Hormone therapy is the standard of care for newly diagnosed or recurrent prostate cancers. It uses anti-androgen agents, castration, or both to eliminate cancer promoting effect of testicular androgen. The p53 tumor suppressor controls a major pathway that can block cell proliferation or induce apoptosis in response to diverse forms of oncogenic stress. Activation of the p53 pathway in cancer cells expressing wild-type p53 has been proposed as a novel therapeutic strategy and recently developed MDM2 antagonists, the nutlins, have validated this in preclinical models of cancer. The crosstalk between p53 and androgen receptor (AR) signaling suggest that p53 activation could augment antitumor outcome of androgen ablation in prostate cancer. Here, we test this hypothesis in vitro and in vivo using the MDM2 antagonist, nutlin-3 and the p53 wild-type prostate cancer cell line, LNCaP. RESULTS: Using charcoal-stripped serum as a cellular model of androgen deprivation, we show an increased apoptotic effect of p53 activation by nutlin-3a in the androgen-dependent LNCaP cells and to a lesser extent in androgen-independent but responsive 22Rv1 cell line. This effect is due, at least in part, to an enhanced downregulation of AR expression by activated p53. In vivo, androgen deprivation followed by two weeks of nutlin administration in LNCaP-bearing nude mice led to a greater tumor regression and dramatically increased survival. CONCLUSIONS: Since majority of prostate tumors express wild-type p53, its activation by MDM2 antagonists in combination with androgen depletion may offer an efficacious new approach to prostate cancer therapy.


Subject(s)
Cell Proliferation/drug effects , Imidazoles/pharmacology , Piperazines/pharmacology , Prostatic Neoplasms/drug therapy , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Androgens/metabolism , Androgens/pharmacology , Animals , Apoptosis/drug effects , Blotting, Western , Cell Line, Tumor , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice , Mice, Nude , MicroRNAs/genetics , Mutation , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Proto-Oncogene Proteins c-mdm2/metabolism , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Xenograft Model Antitumor Assays
6.
Mol Cancer Res ; 7(9): 1497-509, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19737973

ABSTRACT

Cellular senescence is a stress-induced state of irreversible growth arrest thought to act as a barrier to cancer development. The p53 tumor suppressor is a critical mediator of senescence and recent in vivo studies have suggested that p53-induced senescence may contribute to tumor clearance by the immune system. Recently developed MDM2 antagonists, the nutlins, are effective p53 activators and potent antitumor agents in cells with functional apoptotic pathways. However, they only block cell cycle progression in cancer cells with compromised p53 apoptotic signaling. We use nutlin-3a as a selective probe to study the role of p53 activation in senescence using a panel of eight epithelial cancer cell lines and primary epithelial cells. Our results reveal that the MDM2 antagonist can induce a senescence-like state in all tested cell lines, but it is reversible and cells resume proliferation upon drug removal and normalization of p53 control. Retinoblastoma family members (pRb, p107, and p130) previously implicated in gene silencing during fibroblasts senescence were found down-regulated in cells with nutlin-induced senescence-like phenotype, suggesting a mechanism for its reversibility. Therefore, selective p53 pathway activation is insufficient for induction of true senescence in epithelial cells in vitro. However, elevated expression of several inflammatory cytokines in cancer cells with nutlin-induced senescence-like phenotype suggests a possible in vivo benefit of p53-activating therapies.


Subject(s)
Cell Cycle/drug effects , Cellular Senescence/drug effects , Imidazoles/pharmacology , Neoplasms/pathology , Piperazines/pharmacology , Tumor Suppressor Protein p53/metabolism , Apoptosis/drug effects , Apoptosis/physiology , Cell Cycle/physiology , Cell Growth Processes/drug effects , Cell Growth Processes/physiology , Cell Line, Tumor , Cellular Senescence/physiology , Cytokines/biosynthesis , Down-Regulation , Epithelial Cells/drug effects , Epithelial Cells/pathology , HCT116 Cells , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Phenotype , Retinoblastoma Protein/metabolism , Signal Transduction/drug effects
7.
Cell Cycle ; 7(11): 1604-12, 2008 Jun 01.
Article in English | MEDLINE | ID: mdl-18520179

ABSTRACT

The p53 tumor suppressor is a powerful growth suppressive and pro-apoptotic molecule frequently inactivated in human cancer. Many tumors overproduce its negative regulator MDM2, a specific p53 ubiquitin ligase and transcriptional inhibitor, to disable p53 function. Therefore, p53 activation by inhibiting MDM2 has been proposed as a novel strategy for cancer therapy in tumors expressing wild-type p53. Recently developed small-molecule p53-MDM2 binding inhibitors, the nutlins, selectively activate p53 function and induce cell cycle arrest and apoptosis in cancer cells. By stabilizing p53, nutlins also elevate the cellular level of its transcriptional target MDM2. Here, we present evidence that nutlin-induced MDM2 retains its ubiquitin ligase activity and contributes to the anti-tumor activity of p53-MDM2 binding inhibitors by facilitating the degradation of another p53 inhibitor, MDMX. MDM2 and MDMX levels were analyzed in a panel of 12 randomly selected solid tumor cell lines. In the presence of nutlin-3, MDM2 increased in all and MDMX decreased in most of the cell lines. MDMX was resistant to nutlin-induced degradation in 2/12 cell lines. In these cells, MDMX appears to be a major suppressor of the apoptotic response to p53 activation although this effect was only partially p53-dependent. Doxorubicin facilitated MDMX degradation through DNA damage response pathways and restored their sensitivity to nutlin, suggesting that combination therapy may be an effective way to overcome nutlin resistance in cancers with MDMX aberrations.


Subject(s)
Apoptosis/physiology , Gene Expression Regulation, Neoplastic/physiology , Imidazoles/pharmacology , Nuclear Proteins/metabolism , Piperazines/pharmacology , Proto-Oncogene Proteins c-mdm2/metabolism , Proto-Oncogene Proteins/metabolism , Signal Transduction/physiology , Tumor Suppressor Protein p53/metabolism , Cell Cycle Proteins , Cell Line, Tumor , DNA Primers/genetics , Doxorubicin/pharmacology , Humans , Immunoblotting , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , RNA, Small Interfering/genetics , Reverse Transcriptase Polymerase Chain Reaction
8.
Nat Struct Mol Biol ; 14(3): 215-23, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17310253

ABSTRACT

Many features of the cancer cell phenotype emerge as a result of cooperation between multiple oncogenic mutations. Here we show that activated Ras(V12) and loss of p53 function can cooperate to promote cell motility, a feature closely associated with cancer progression to malignancy. Our analysis indicates that Ras(V12) and loss of p53 synergistically induce RhoA activity, revealing a previously unknown role for p53 in tumor suppression. p53 prevents activation of RhoA and thus induction of cell motility by Ras(V12) through a simple signaling circuit, which integrates multiple inputs that converge on RhoA. Our data suggest that p53 suppresses cancer progression to malignancy by modulating the quality of Ras signaling.


Subject(s)
Cell Movement , Neoplasms/metabolism , Neoplasms/pathology , Tumor Suppressor Protein p53/metabolism , ras Proteins/metabolism , rhoA GTP-Binding Protein/metabolism , Animals , Cell Line, Tumor , Colon/cytology , Colon/pathology , Down-Regulation/genetics , Enzyme Activation , GTPase-Activating Proteins/metabolism , Humans , Mice , Models, Biological , Mutant Proteins/metabolism , Phosphotyrosine/metabolism , Protein Transport , Tumor Suppressor Protein p53/deficiency , Up-Regulation/genetics , rhoA GTP-Binding Protein/genetics
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