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1.
Bioorg Med Chem Lett ; 107: 129769, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38670537

RESUMO

Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178).


Assuntos
Proliferação de Células , Quinase 4 Dependente de Ciclina , Inibidores de Proteínas Quinases , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Animais , Descoberta de Drogas , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Dose-Resposta a Droga , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Ratos , Ensaios de Seleção de Medicamentos Antitumorais , Avaliação Pré-Clínica de Medicamentos
2.
Sensors (Basel) ; 21(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34283149

RESUMO

Implicit authentication mechanisms are expected to prevent security and privacy threats for mobile devices using behavior modeling. However, recently, researchers have demonstrated that the performance of behavioral biometrics is insufficiently accurate. Furthermore, the unique characteristics of mobile devices, such as limited storage and energy, make it subject to constrained capacity of data collection and processing. In this paper, we propose an implicit authentication architecture based on edge computing, coined Edge computing-based mobile Device Implicit Authentication (EDIA), which exploits edge-based gait biometric identification using a deep learning model to authenticate users. The gait data captured by a device's accelerometer and gyroscope sensors is utilized as the input of our optimized model, which consists of a CNN and a LSTM in tandem. Especially, we deal with extracting the features of gait signal in a two-dimensional domain through converting the original signal into an image, and then input it into our network. In addition, to reduce computation overhead of mobile devices, the model for implicit authentication is generated on the cloud server, and the user authentication process also takes place on the edge devices. We evaluate the performance of EDIA under different scenarios where the results show that i) we achieve a true positive rate of 97.77% and also a 2% false positive rate; and ii) EDIA still reaches high accuracy with limited dataset size.


Assuntos
Identificação Biométrica , Aprendizado Profundo , Computadores de Mão , Marcha , Privacidade
3.
Environ Sci Pollut Res Int ; 31(15): 22410-22430, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38407706

RESUMO

Realizing the coordination between the economic and environmental systems through a green growth model is an important goal for China to enter the high-quality development stage. Meanwhile, financial technology (fintech) is rapidly developing in China. To explore the relationship between the two, this research uses panel data from 276 cities in China from 2011 to 2022 and empirically tests through constructing econometric models and machine learning algorithms. The empirical result shows that fintech has an impact on green growth. Specifically, there is a U-shaped relationship between fintech and green growth, meaning that before a certain stage, fintech may have a certain inhibitory effect on green growth. After fintech exceeds a certain development level, it will promote the improvement of green growth. Further mediation tests show that innovation plays a mediating role in the impact of fintech on green growth. Additionally, this research also conducts consistency tests based on different criteria including the location, scale, and financial development level of cities. Based on the research findings, policy suggestions are proposed in this paper to promote the development of fintech and stimulate the growth of the green economy. Overall, our research sheds more light on the fintech-green growth linkage and provides new insights into comprehending the role of fintech in advancing towards a low-carbon economy.


Assuntos
Algoritmos , Carbono , Modelos Econométricos , China , Cidades , Aprendizado de Máquina , Desenvolvimento Econômico
5.
Sci Signal ; 11(547)2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206136

RESUMO

The Hippo signaling pathway regulates organ size and plays critical roles in maintaining tissue growth, homeostasis, and regeneration. Dysregulated in a wide spectrum of cancers, in mammals, this pathway is regulated by two key effectors, YAP and TAZ, that may functionally overlap. We found that TAZ promoted liver inflammation and tumor development. The expression of TAZ, but not YAP, in human liver tumors positively correlated with the expression of proinflammatory cytokines. Hyperactivated TAZ induced substantial myeloid cell infiltration into the liver and the secretion of proinflammatory cytokines through a TEAD-dependent mechanism. Furthermore, tumors with hyperactivated YAP and TAZ had distinct transcriptional signatures, which included the increased expression of inflammatory cytokines in TAZ-driven tumors. Our study elucidated a previously uncharacterized link between TAZ activity and inflammatory responses that influence tumor development in the liver.


Assuntos
Proteínas de Ligação a DNA/genética , Inflamação/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/genética , Fígado/metabolismo , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/genética , Fatores de Transcrição/genética , Animais , Proteínas de Ciclo Celular , Citocinas/genética , Citocinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica/métodos , Via de Sinalização Hippo , Humanos , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos C57BL , Mutação , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição de Domínio TEA , Transativadores , Fatores de Transcrição/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Transplante Heterólogo
6.
Oncotarget ; 7(5): 5461-9, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26701727

RESUMO

Hepatocellular carcinoma (HCC) is the fifth most common type of cancers worldwide. However, current therapeutic approaches for this epidemic disease are limited, and its 5-year survival rate hasn't been improved in the past decades. Patient-derived xenograft (PDX) tumor models have become an excellent in vivo system for understanding of disease biology and drug discovery. In order to identify new therapeutic targets for HCC, whole-exome sequencing (WES) was performed on more than 60 HCC PDX models. Among them, four models exhibited protein-altering mutations in JAK1 (Janus Kinase 1) gene. To explore the transforming capability, these mutations were then introduced into HEK293FT and Ba/F3 cells. The results demonstrated that JAK1S703I mutation was able to activate JAK-STAT (Signal Transducer and Activator of Transcription) signaling pathway and drive cell proliferation in the absence of cytokine stimulation in vitro. Furthermore,the sensitivity to the treatment of a JAK1/2 inhibitor, ruxolitinib, was observed in JAK1S703I mutant PDX model, but not in other non-activating mutant or wild type models. Pharmacodynamic analysis showed that phosphorylation of STAT3 in the Ruxolitinib-treated tumor tissues was significantly suppressed. Collectively, our results suggested that JAK1S703I is an activating mutation for JAK-STAT signaling pathway in vitro and in vivo, and JAK-STAT pathway might represent a new therapeutic approach for HCC treatment. Monotherapy using a more potent and specific JAK1 inhibitor and combinatory therapy should be further explored in JAK1 mutant PDX models.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Janus Quinase 1/genética , Neoplasias Hepáticas/tratamento farmacológico , Mutação/genética , Pirazóis/farmacologia , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Apoptose , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células , Feminino , Humanos , Janus Quinase 1/antagonistas & inibidores , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nitrilas , Fosforilação , Pirimidinas , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/genética , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Oncotarget ; 6(24): 20160-76, 2015 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-26062443

RESUMO

Lack of clinically relevant tumor models dramatically hampers development of effective therapies for hepatocellular carcinoma (HCC). Establishment of patient-derived xenograft (PDX) models that faithfully recapitulate the genetic and phenotypic features of HCC becomes important. In this study, we first established a cohort of 65 stable PDX models of HCC from corresponding Chinese patients. Then we showed that the histology and gene expression patterns of PDX models were highly consistent between xenografts and case-matched original tumors. Genetic alterations, including mutations and DNA copy number alterations (CNAs), of the xenografts correlated well with the published data of HCC patient specimens. Furthermore, differential responses to sorafenib, the standard-of-care agent, in randomly chosen xenografts were unveiled. Finally, in the models expressing high levels of FGFR1 gene according to the genomic data, FGFR1 inhibitor lenvatinib showed greater efficacy than sorafenib. Taken together, our data indicate that PDX models resemble histopathological and genomic characteristics of clinical HCC tumors, as well as recapitulate the differential responses of HCC patients to the standard-of-care treatment. Overall, this large collection of PDX models becomes a clinically relevant platform for drug screening, biomarker discovery and translational research in preclinical setting.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Animais , Carcinoma Hepatocelular/patologia , Variações do Número de Cópias de DNA , Modelos Animais de Doenças , Feminino , Expressão Gênica , Genômica , Humanos , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Ensaios Antitumorais Modelo de Xenoenxerto
8.
PLoS One ; 8(8): e71697, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23977114

RESUMO

The protein TIN2 is a member of telomere-binding protein complex that serves to cap and protect mammalian chromosome ends. As a number of proteins in this complex are phosphorylated in a cell cycle-dependent manner, we investigated whether TIN2 is modified by phosphorylation as well. We performed phospho-proteomic analysis of human TIN2, and identified two phosphorylated residues, serines 295 and 330. We demonstrated that both these sites were phosphorylated during mitosis in human cells, as detected by Phos-tag reagent and phosphorylation-specific antibodies. Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase RSK2. Specifically, phosphorylation of TIN2 at both these residues was increased upon expression of RSK2 and reduced by an inhibitor of the RSK family of kinases. Moreover, RSK2 phosphorylated TIN2 in vitro. The identification of these specifically timed post-translational events during the cell cycle suggests a potential mitotic regulation of TIN2 by phosphorylation.


Assuntos
Ciclo Celular , Proteínas de Ligação a Telômeros/metabolismo , Sequência de Aminoácidos , Anticorpos Fosfo-Específicos/metabolismo , Ciclo Celular/efeitos dos fármacos , Células HeLa , Humanos , Espectrometria de Massas , Mitose/efeitos dos fármacos , Dados de Sequência Molecular , Nocodazol/farmacologia , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , Pteridinas/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Proteínas de Ligação a Telômeros/química
9.
Mol Cell Biol ; 32(8): 1387-95, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22331467

RESUMO

Human telomeres are DNA-protein complexes that cap and protect the ends of chromosomes. The protein PinX1 associates with telomeres through an interaction with the resident double-stranded telomere-binding protein TRF1. PinX1 also binds to and inhibits telomerase, the enzyme responsible for complete replication of telomeric DNA. We now report that endogenous PinX1 associates with telomeres primarily at mitosis. Moreover, knockdown of PinX1 caused delayed mitotic entry and reduced the accumulation of TRF1 on telomeres during this stage of the cell cycle. Taking these findings together, we suggest that one function of PinX1 is to stabilize TRF1 during mitosis, perhaps to promote transition into M phase of the cell cycle.


Assuntos
Mitose/fisiologia , Telômero/metabolismo , Proteína 1 de Ligação a Repetições Teloméricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Apoptose/genética , Proteínas de Ciclo Celular , Células HeLa , Humanos , Ligação Proteica , Homeostase do Telômero , Proteína 1 de Ligação a Repetições Teloméricas/genética , Proteínas Supressoras de Tumor/genética
10.
PLoS One ; 3(8): e2890, 2008 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-18682832

RESUMO

Fsp27, a member of the Cide family proteins, was shown to localize to lipid droplet and promote lipid storage in adipocytes. We aimed to understand the biological role of Fsp27 in regulating adipose tissue differentiation, insulin sensitivity and energy balance. Fsp27(-/-) mice and Fsp27/lep double deficient mice were generated and we examined the adiposity, whole body metabolism, BAT and WAT morphology, insulin sensitivity, mitochondrial activity, and gene expression changes in these mouse strains. Furthermore, we isolated mouse embryonic fibroblasts (MEFs) from wildtype and Fsp27(-/-) mice, followed by their differentiation into adipocytes in vitro. We found that Fsp27 is expressed in both brown adipose tissue (BAT) and white adipose tissue (WAT) and its levels were significantly elevated in the WAT and liver of leptin-deficient ob/ob mice. Fsp27(-/-) mice had increased energy expenditure, lower levels of plasma triglycerides and free fatty acids. Furthermore, Fsp27(-/-)and Fsp27/lep double-deficient mice are resistant to diet-induced obesity and display increased insulin sensitivity. Moreover, white adipocytes in Fsp27(-/-) mice have reduced triglycerides accumulation and smaller lipid droplets, while levels of mitochondrial proteins, mitochondrial size and activity are dramatically increased. We further demonstrated that BAT-specific genes and key metabolic controlling factors such as FoxC2, PPAR and PGC1alpha were all markedly upregulated. In contrast, factors inhibiting BAT differentiation such as Rb, p107 and RIP140 were down-regulated in the WAT of Fsp27(-/-) mice. Remarkably, Fsp27(-/-) MEFs differentiated in vitro show many brown adipocyte characteristics in the presence of the thyroid hormone triiodothyronine (T3). Our data thus suggest that Fsp27 acts as a novel regulator in vivo to control WAT identity, mitochondrial activity and insulin sensitivity.


Assuntos
Tecido Adiposo Marrom/fisiologia , Tecido Adiposo/fisiologia , Camundongos Knockout/genética , Mitocôndrias/genética , Proteínas/genética , Tecido Adiposo/patologia , Tecido Adiposo Marrom/patologia , Animais , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Insulina/fisiologia , Leptina/deficiência , Leptina/genética , Camundongos , Camundongos Obesos/genética , Mitocôndrias/metabolismo , Fenótipo , Magreza/genética
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