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1.
Eur J Med Chem ; 180: 15-27, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31299584

RESUMO

Six series of 4-(benzo[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methylpyridin-2-yl)- pyrazoles 18a-d, 19a-d, 22a-d and 3(5)-(6-methylpyridin-2-yl)-4-(thieno[3,2,-c]- pyridin-2-yl)pyrazoles 20a-d, 21a-d, 23c, 23d have been synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38α mitogen activated protein (MAP) kinase inhibitory activities in enzymatic assays. Among these compounds, the most active compound, 22c, inhibited ALK5 phosphorylation with an IC50 value of 0.030 µM in the enzymatic assay. Compound 22c showed four-fold more potent activity against ALK5 kinase than the clinical candidate, compound LY-2157299. The selectivity index of 22c against p38α MAP kinase is 235, which is much higher than that of LY-2157299 (4) and equally selective to that of EW-7197 (218). Compound 22c effectively suppressed protein and mRNA expression of collagen I and α-SMA in TGF-ß-induced LX-2 human hepatic stellate cell (HSC), this result shows that compound 22c has the ability to inhibit the activation of HSC. Compound 22c is expected to be a preclinical candidate for the treatment of hepatic fibrosis.


Assuntos
Desenho de Drogas , Fibrose/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Fibrose/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Relação Estrutura-Atividade
2.
Int J Mol Sci ; 20(12)2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31207955

RESUMO

It is well established that smoking has detrimental effects on bone integrity and is a preventable risk factor for metabolic bone disorders. Following orthopedic surgeries, smokers frequently show delayed fracture healing associated with many complications, which results in prolonged hospital stays. One crucial factor responsible for fracture repair is the recruitment and differentiation of mesenchymal stem cells (MSCs) at early stages, a mechanism mediated by transforming growth factor ß (TGF-ß). Although it is known that smokers frequently have decreased TGF-ß levels, little is known about the actual signaling occurring in these patients. We investigated the effect of cigarette smoke on TGF-ß signaling in MSCs to evaluate which step in the pathway is affected by cigarette smoke extract (CSE). Single-cell-derived human mesenchymal stem cell line (SCP-1 cells) were treated with CSE concentrations associated with smoking up to 20 cigarettes a day. TGF-ß signaling was analyzed using an adenovirus-based reporter assay system. Primary cilia structure and downstream TGF-ß signaling modulators (Smad2, Smad3, and Smad4) were analyzed by Western blot and immunofluorescence staining. CSE exposure significantly reduced TGF-ß signaling. Intriguingly, we observed that protein levels of phospho-Smad2/3 (active forms) as well as nuclear translocation of the phospho-Smad3/4 complex decreased after CSE exposure, phenomena that affected signal propagation. CSE exposure reduced the activation of TGF-ß modulators under constitutive activation of TGF-ß receptor type I (ALK5), evidencing that CSE affects signaling downstream of the ALK5 receptor but not the binding of the cytokine to the receptor itself. CSE-mediated TGF-ß signaling impaired MSC migration, proliferation, and differentiation and ultimately affected endochondral ossification. Thus, we conclude that CSE-mediated disruption of TGF-ß signaling in MSCs is partially responsible for delayed fracture healing in smokers.


Assuntos
Doenças Ósseas Metabólicas/etiologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Transdução de Sinais , Poluição por Fumaça de Tabaco/efeitos adversos , Fator de Crescimento Transformador beta/metabolismo , Diferenciação Celular , Linhagem Celular , Movimento Celular , Proliferação de Células , Cílios/efeitos dos fármacos , Cílios/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Proteínas Smad/metabolismo
3.
BMC Cancer ; 19(1): 405, 2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035970

RESUMO

BACKGROUND: Wilms' tumor is also called nephroblastoma and is the most common pediatric renal cancer. Several genetic and epigenetic factors have been found to account for the development of Wilms' tumor. MiRNAs play important roles in this tumorigenic process. In the present study, we aimed to investigate the role of miR-140-5p in nephroblastoma by identifying its targets, as well as its underlying molecular mechanism of action. METHODS: The miRNA expression profile of nephroblastoma samples was investigated and the targets of miR-140-5p were predicted and validated using the miRNA luciferase reporter method. Moreover, the roles of miR-140-5p in regulating nephroblastoma cell proliferation, migration and cell cycle were analyzed by the CCK8, migration and flow cytometry assays, respectively. The downstream protein of the direct target of miR-140-5p was also identified. RESULTS: miR-140-5p was downregulated in Wilms' tumor tissues, whereas in the nephroblastoma cell lines G401 and WT-CLS1 that exhibited high levels of miRNA-140-5p, inhibition of cellular proliferation and metastasis were noted as well as cell cycle arrest at the G1/S phase. TGFBRI and IGF1R were identified as direct target genes for miRNA-140-5p. In addition, SMAD2/3 and p-AKT were regulated by TGFBRI and IGF1R separately and participated in the miRNA-140-5p regulatory network. Ectopic expression of TGFBR1 and IGF-1R could abrogate the inhibitory effect of miR-140-5p. CONCLUSION: We demonstrated that miRNA-140-5p participates in the progression of Wilms' tumor by targeting the TGFBRI/SMAD2/3 and the IGF-1R/AKT signaling pathways.


Assuntos
Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Transdução de Sinais/genética , Tumor de Wilms/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Criança , Progressão da Doença , Regulação para Baixo , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptores de Somatomedina/genética , Receptores de Somatomedina/metabolismo , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Tumor de Wilms/metabolismo , Tumor de Wilms/patologia
4.
Nat Commun ; 10(1): 1665, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971692

RESUMO

Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes remain to be systemically identified for lung cancer. Through the genome-wide screening of tumor-suppressive transcription factors, we demonstrate here that GATA4 functions as an essential tumor suppressor in lung cancer in vitro and in vivo. Ectopic GATA4 expression results in lung cancer cell senescence. Mechanistically, GATA4 upregulates multiple miRNAs targeting TGFB2 mRNA and causes ensuing WNT7B downregulation and eventually triggers cell senescence. Decreased GATA4 level in clinical specimens negatively correlates with WNT7B or TGF-ß2 level and is significantly associated with poor prognosis. TGFBR1 inhibitors show synergy with existing therapeutics in treating GATA4-deficient lung cancers in genetically engineered mouse model as well as patient-derived xenograft (PDX) mouse models. Collectively, our work demonstrates that GATA4 functions as a tumor suppressor in lung cancer and targeting the TGF-ß signaling provides a potential way for the treatment of GATA4-deficient lung cancer.


Assuntos
Fator de Transcrição GATA4/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Proteínas Wnt/metabolismo , Células A549 , Animais , Senescência Celular/genética , Regulação para Baixo , Feminino , Fator de Transcrição GATA4/genética , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/genética , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Regulação para Cima , Proteínas Wnt/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cell Mol Life Sci ; 76(15): 3005-3018, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31006037

RESUMO

The accumulation of intracellular ß-amyloid peptide (Aß) is important pathological characteristic of Alzheimer's disease (AD). However, the exact underlying molecular mechanism remains to be elucidated. Here, we reported that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a long n on-coding RNA, exhibits repressed expression in the early stage of AD and its down-regulation declines neuroglial cell mediating Aß clearance via inhibiting expression of endocytosis-related genes. We find that NEAT1 is associated with P300/CBP complex and its inhibition affects H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) located nearby to the transcription start site of many genes, including endocytosis-related genes. Interestingly, NEAT1 inhibition down-regulates H3K27Ac but up-regulates H3K27Cro through repression of acetyl-CoA generation. NEAT1 also mediates the binding between STAT3 and H3K27Ac but not H3K27Cro. Therefore, the decrease of H3K27Ac and/or the increase of H3K27Cro declines expression of multiple related genes. Collectively, this study first reveals the different roles of H3K27Ac and H3K27Cro in regulation of gene expression and provides the insight of the epigenetic regulatory mechanism of NEAT1 in gene expression and AD pathology.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , RNA Longo não Codificante/metabolismo , Acetilcoenzima A/metabolismo , Acetilação/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Animais , Caveolina 2/antagonistas & inibidores , Caveolina 2/genética , Caveolina 2/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Camundongos , Camundongos Transgênicos , Neuroglia/citologia , Neuroglia/metabolismo , Fragmentos de Peptídeos/farmacologia , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
6.
Eur J Pharmacol ; 852: 58-67, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30807748

RESUMO

Hypertrophic scar (HPS) is a manifestation of abnormal tissue repair, representing excessive extracellular matrix production and abnormal function of fibroblasts, for which no satisfactory treatment is available at present. Here we identified a natural product of flavonoid, dihydromyricetin, could effectively attenuate HPS formation. We showed that local intradermal injection of dihydromyricetin (50 µM) reduced the gross scar area, cross-sectional size of the scar and the scar elevation index in a mechanical load-induced mouse model. In addition, dihydromyricetin treatment also markedly decreased collagen density of the scar tissue. Furthermore, both in vitro and in vivo study both demonstrated that dihydromyricetin inhibited the proliferation, activation, contractile and migration abilities of hypertrophic scar-derived fibroblasts (HSFs) but did not affect HSFs apoptosis. Western blot analysis revealed that dihydromyricetin could down-regulate the phosphorylation of Smad2 and Smad3 of TGF-ß signaling. Such bioactivity of dihydromyricetin may result from its selective binding to the catalytic region of activin receptor-like kinase 5 (ALK5), as suggested by the molecular docking study and kinase binding assay (12.26 µM). Above all, dihydromyricetin may prove to be a promising agent for the treatment of HPS and other fibroproliferative disorders.


Assuntos
Cicatriz Hipertrófica/tratamento farmacológico , Flavonóis/farmacologia , Terapia de Alvo Molecular , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Adolescente , Adulto , Animais , Biocatálise , Proliferação de Células/efeitos dos fármacos , Cicatriz Hipertrófica/metabolismo , Cicatriz Hipertrófica/patologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Flavonóis/metabolismo , Flavonóis/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Conformação Proteica , Receptor do Fator de Crescimento Transformador beta Tipo I/química , Proteína Smad2/metabolismo , Proteína Smad3/efeitos dos fármacos , Adulto Jovem
7.
J Pharm Pharmacol ; 71(6): 988-995, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30809816

RESUMO

OBJECTIVES: TGF-ß through hyperelongation of glycosaminoglycan (GAG) chains leads to binding of low-density lipoproteins to the proteoglycans. The vasoactive peptide, endothelin-1 (ET-1), plays a key role in the development of atherosclerosis. This study addressed the question whether ET-1 by activating the Rho kinase and cytoskeletal rearrangement can transactivate the TGF-ß receptor leading to phosphorylation of the transcription factor Smad2 and increased expression of the GAG chain synthesizing enzyme such as chondroitin synthase-1 (CHSY-1) in bovine aortic endothelial cells (BAECs). METHODS: In this study, intermediates in ET-1-induced Smad2C phosphorylation and the protein level of CHSY-1 were identified and quantified by Western blotting. KEY FINDINGS: Endothelin-1 caused time-dependent phosphorylation of Smad2C which was inhibited in the presence of the endothelin B receptor antagonist, BQ788. The response to ET-1 was inhibited by the Rho/ROCK kinase antagonist, Y27632 and by cytochalasin D, an inhibitor of actin polymerization but the ET-1-mediated pSmad2C was not inhibited by the matrix metalloproteinase (MMP) inhibitor, GM6001. ET-1 increased CHSY-1 protein level, which was inhibited in the presence of BQ788, cytochalasin D and Y27632. CONCLUSIONS: Endothelin-1 signalling via the ETB receptor utilizes cytoskeletal rearrangement and Rho kinase but not MMPs leading to TßRI transactivation signalling and phosphorylation of Smad2C and through this pathway increased the level of CHSY-1.


Assuntos
Células Endoteliais/metabolismo , Endotelina-1/metabolismo , N-Acetilgalactosaminiltransferases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Amidas/farmacologia , Animais , Aorta/citologia , Western Blotting , Bovinos , Células Cultivadas , Citocalasina D/farmacologia , Oligopeptídeos/farmacologia , Fosforilação/fisiologia , Piperidinas/farmacologia , Piridinas/farmacologia , Receptor de Endotelina B/efeitos dos fármacos , Receptor de Endotelina B/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Fatores de Tempo , Ativação Transcricional/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Quinases Associadas a rho/metabolismo
8.
Int J Oncol ; 54(1): 128-138, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30387848

RESUMO

MicroRNAs (miRNAs or miRs) have recently emerged as key regulators of various types of cancer, including non­small cell lung cancer (NSCLC). The disrupted expression of miRNAs is associated with tumorigenesis and metastasis; however, the underlying mechanisms remain unclear. In this study, we demonstrate that miR­98­5p is downregulated in NSCLC and that miR­98­5p deficiency is associated with an advanced clinical stage and metastasis. A dual­luciferase reporter assay was performed to confirm that transforming growth factor beta receptor 1 (TGFBR1), a key stimulator of tumor proliferation and metastasis, was a direct target of miR­98­5p. miR­98­5p overexpression resulted in the downregulation of TGFBR1 and the suppression of the viability, proliferation, migration and invasion of A549 and H1299 cells. Furthermore, miR­98­5p was demonstrated to be an efficient suppressor of tumor growth in an A549 subcutaneous xenograft tumor mouse model. Finally, miR­98­5p overexpression exerted a significant anti­metastatic effect in a mouse model of pulmonary metastasis. On the whole, the results of the present study suggest that miR­98­5p/TGFBR1 may serve as promising targets for NSCLC therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Regiões 3' não Traduzidas , Células A549 , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Transplante de Neoplasias
9.
Prostate ; 79(1): 31-43, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30155899

RESUMO

BACKGROUND: Prostate cancer progression is navigated by the androgen receptor (AR) and transforming-growth factor-ß (TGF-ß) signaling. We previously demonstrated that aberrant TGF-ß signaling accelerates prostate tumor progression in a transgenic mouse model of prostate cancer via effects on epithelial-mesenchymal transition (EMT), driving castration-resistant prostate cancer (CRPC). METHODS: This study examined the antitumor effect of the combination of TGF-ß receptor I (TßRI) inhibitor, galunisertib, and FDA-approved antiandrogen enzalutamide, in our pre-clinical model. Age-matched genotypically characterized DNTGFßRII male mice were treated with either galunisertib and enzalutamide, in combination or as single agents in three "mini"-trials and the effects on tumor growth, phenotypic EMT, and actin cytoskeleton were evaluated. RESULTS: Galunisertib in combination with enzalutamide significantly suppressed prostate tumor growth, by increasing apoptosis and decreasing cell proliferation of tumor cell populations compared to the inhibitor as a monotherapy (P < 0.05). The combination treatment dramatically reduced cofilin levels, actin cytoskeleton regulator, compared to single agents. Treatment with galunisertib targeted nuclear Smad4 protein (intracellular TGF-ß effector), but had no effect on nuclear AR. Consequential to TGF-ß inhibition there was an EMT reversion to mesenchymal-epithelial transition (MET) and re-differentiation of prostate tumors. Elevated intratumoral TGF-ß1 ligand, in response to galunisertib, was blocked by enzalutamide. CONCLUSION: Our results provide novel insights into the therapeutic value of targeting TGF-ß signaling to overcome resistance to enzalutamide in prostate cancer by phenotypic reprogramming of EMT towards tumor re-differentiation and cytoskeleton remodeling. This translational work is significant in sequencing TGF-ß blockade and antiandrogens to optimize therapeutic response in CRPC.


Assuntos
Antineoplásicos/administração & dosagem , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/administração & dosagem , Quinolinas/administração & dosagem , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Animais , Sinergismo Farmacológico , Transição Epitelial-Mesenquimal/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Feniltioidantoína/administração & dosagem , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo
10.
PLoS One ; 13(12): e0209417, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30550590

RESUMO

Uterine gland development, also known as adenogenesis, is a key uterine morphogenic process indispensable for normal uterine function and fertility. Our earlier studies have reported that overactivation of TGFB receptor 1 (TGFBR1) in the mouse uterus using progesterone receptor (Pgr)-Cre recombinase causes female infertility, defective decidualization, and reduced uterine gland formation, a developmental milestone of postnatal uterus. To understand mechanisms that underpin the disrupted uterine gland formation in mice with sustained activation of TGFBR1, we raised the question of whether early postnatal adenogenesis was compromised in these mice. Experiments were designed using mice with constitutive activation of TGFBR1 driven by Pgr-Cre to determine the timing of adenogenic defects and potential mechanisms associated with dysregulation of adenogenic genes, luminal epithelial cell proliferation and endometrial fibrotic changes. Uterine tissues from mice with constitutive activation of TGFBR1 were collected during the critical time window of adenogenesis and analyzed together with age-matched controls. Multiple approaches including immunohistochemistry, immunofluorescence, Trichrome staining, quantitative real-time PCR, western blot, conditional knockout and human endometrial cell culture were utilized. TGFBR1 activation in the mouse uterus suppressed adenogenesis during postnatal uterine development, concomitant with the aberrant differentiation of uterine stromal cells. Analysis of transcript expression of WNT pathway components revealed dysregulation of adenogenesis-associated genes. Notably, the adenogenic defects occurred in spite of the increased proliferation of uterine luminal epithelial cells, accompanied by increased expression of genes associated with fibrotic changes. Moreover, the adenogenic defects were alleviated in mice where TGFBR1 was activated in presumably half of the complement of uterine cells. Our results suggest that altered differentiation of endometrial stromal cells and formation of stromal compartment promote adenogenic defects.


Assuntos
Células Epiteliais/fisiologia , Infertilidade Feminina/etiologia , Transdução de Sinais/fisiologia , Células Estromais/fisiologia , Útero/embriologia , Animais , Diferenciação Celular , Linhagem Celular , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Organogênese , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptores de Progesterona/genética , Fator de Crescimento Transformador beta/metabolismo , Útero/citologia , Útero/fisiologia
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