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1.
Mol Cancer Ther ; 15(12): 2936-2945, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27765852

RESUMO

The development of new antiandrogens, such as enzalutamide, or androgen synthesis inhibitors like abiraterone has improved patient outcomes in the treatment of advanced prostate cancer. However, due to the development of drug resistance and tumor cell survival, a majority of these patients progress to the refractory state of castration-resistant prostate cancer (CRPC). Thus, newer therapeutic agents and a better understanding of their mode of action are needed for treating these CRPC patients. We demonstrated previously that targeting the Binding Function 3 (BF3) pocket of the androgen receptor (AR) has great potential for treating patients with CRPC. Here, we explore the functional activity of this site by using an advanced BF3-specific small molecule (VPC-13566) that was previously reported to effectively inhibit AR transcriptional activity and to displace the BAG1L peptide from the BF3 pocket. We show that VPC-13566 inhibits the growth of various prostate cancer cell lines, including an enzalutamide-resistant cell line, and reduces the growth of AR-dependent prostate cancer xenograft tumors in mice. Importantly, we have used this AR-BF3 binder as a chemical probe and identified a co-chaperone, small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA), as an important AR-BF3 interacting partner. Furthermore, we used this AR-BF3-directed small molecule to demonstrate that inhibition of AR activity through the BF3 functionality can block translocation of the receptor into the nucleus. These findings suggest that targeting the BF3 site has potential clinical importance, especially in the treatment of CRPC and provide novel insights on the functional role of the BF3 pocket. Mol Cancer Ther; 15(12); 2936-45. ©2016 AACR.


Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Proteínas de Transporte/metabolismo , Domínios e Motivos de Interação entre Proteínas , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/química , Animais , Benzamidas , Biomarcadores Tumorais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ligação Proteica/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Receptores Androgênicos/química , Transdução de Sinais/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Chem Biol ; 21(11): 1476-85, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25459660

RESUMO

There has been a resurgence of interest in the development of androgen receptor (AR) inhibitors with alternative modes of action to overcome the development of resistance to current therapies. We demonstrated previously that one promising strategy for combatting mutation-driven drug resistance is to target the Binding Function 3 (BF3) pocket of the receptor. Here we report the development of a potent BF3 inhibitor, 3-(2,3-dihydro-1H-indol-2-yl)-1H-indole, which demonstrates excellent antiandrogen potency and anti-PSA activity and abrogates the androgen-induced proliferation of androgen-sensitive (LNCaP) and enzalutamide-resistant (MR49F) PCa cell lines. Moreover, this compound effectively reduces the expression of AR-dependent genes in PCa cells and effectively inhibits tumor growth in vivo in both LNCaP and MR49F xenograft models. These findings provide evidence that targeting the AR BF3 pocket represents a viable therapeutic approach to treat patients with advanced and/or resistant prostate cancer.


Assuntos
Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Receptores Androgênicos/química , Antagonistas de Androgênios/uso terapêutico , Animais , Benzamidas , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Indóis/uso terapêutico , Masculino , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/toxicidade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Estrutura Terciária de Proteína , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transplante Heterólogo
3.
Pharmaceuticals (Basel) ; 6(5): 623-33, 2013 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-24276170

RESUMO

Hypertension represents a major risk factor for cardiovascular events, associating with vascular hypertrophy and dysfunction in resistance vessels. Clevidipine is a novel antihypertensive drug working as a selective calcium channel antagonist with an ultra-short half-life that lowers arterial blood pressure by reducing systemic arterial resistance. The aim was to assess the effect of clevidipine on the hypertrophic vessels of profilin1 hypertensive transgenic mice compared to sodium nitroprusside (SNP) and labetalol using wire myograph techniques. The effects of clevidipine, SNP and labetalol on the hypertrophic vessels were studied on mesenteric arterial function from 8 profilin1 hypertrophic mice and eight non-transgenic controls. Our results showed a significant difference between the effects of the three drugs on the hypertrophic mesenteric arteries of transgenic profilin1 mice compared to the non-transgenic controls. The half maximal effective concentration (EC50) of clevidipine, SNP and labetalol in profilin1 mice (1.90 ± 0.05, 0.97 ± 0.07, 2.80 ± 0.05 nM, respectively) were significantly higher than the EC50 in non-transgenic controls (0.91 ± 0.06, 0.32 ± 0.06, 0.80 ± 0.09 nM, respectively). Moreover, the increase in the EC50 for clevidipine (2-fold) to produce the same effect on both normal and hypertrophic arteries was less than that of SNP (3-fold) and labetalol (3.5-fold). Therefore, we concluded clevidipine exhibited the lowest dose shift to relax the hypertrophic vessels compared to SNP and labetalol in the profilin1 hypertrophic animal mouse model.

4.
Mol Cancer Ther ; 12(11): 2425-35, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23939374

RESUMO

The human androgen receptor plays a major role in the development and progression of prostate cancer and represents a well-established drug target. All clinically approved androgen receptor antagonists possess similar chemical structures and exhibit the same mode of action on the androgen receptor. Although initially effective, resistance to these androgen receptor antagonists usually develops and the cancer quickly progresses to castration-resistant and metastatic states. Yet even in these late-stage patients, the androgen receptor is critical for the progression of the disease. Thus, there is a continuing need for novel chemical classes of androgen receptor antagonists that could help overcome the problem of resistance. In this study, we implemented and used the synergetic combination of virtual and experimental screening to discover a number of new 10-benzylidene-10H-anthracen-9-ones that not only effectively inhibit androgen receptor transcriptional activity, but also induce almost complete degradation of the androgen receptor. Of these 10-benzylidene-10H-anthracen-9-one analogues, a lead compound (VPC-3033) was identified that showed strong androgen displacement potency, effectively inhibited androgen receptor transcriptional activity, and possesses a profound ability to cause degradation of androgen receptor. Notably, VPC-3033 exhibited significant activity against prostate cancer cells that have already developed resistance to the second-generation antiandrogen enzalutamide (formerly known as MDV3100). VPC-3033 also showed strong antiandrogen receptor activity in the LNCaP in vivo xenograft model. These results provide a foundation for the development of a new class of androgen receptor antagonists that can help address the problem of antiandrogen resistance in prostate cancer.


Assuntos
Antagonistas de Receptores de Andrógenos/química , Antagonistas de Receptores de Andrógenos/farmacologia , Antracenos/química , Antracenos/farmacologia , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/metabolismo , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Antracenos/metabolismo , Antracenos/uso terapêutico , Benzamidas , Compostos de Benzilideno/metabolismo , Compostos de Benzilideno/uso terapêutico , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Bases de Dados Factuais , Modelos Animais de Doenças , Células HeLa , Humanos , Masculino , Camundongos Nus , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Med Chem ; 56(3): 1136-48, 2013 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-23301637

RESUMO

The human androgen receptor (AR) is a proven therapeutic target in prostate cancer. All current antiandrogens, such as Bicalutamide, Flutamide, Nilutamide, and Enzalutamide, target the buried hydrophobic androgen binding pocket of this protein. However, effective resistance mechanisms against these therapeutics exist such as mutations occurring at the target site. To overcome these limitations, the surface pocket of the AR called binding function 3 (BF3) was characterized as an alternative target for small molecule therapeutics. A number of AR inhibitors directly targeting the BF3 were previously identified by us ( J. Med. Chem. 2011 . 54 , 8563 ). In the current study, based on the prior results, we have developed structure-activity relationships that allowed designing a series of 2-((2-phenoxyethyl)thio)-1H-benzimidazole and 2-((2-phenoxyethyl)thio)-1H-indole as lead BF3 inhibitors. Some of the developed BF3 ligands demonstrated significant antiandrogen potency against LNCaP and Enzalutamide-resistant prostate cancer cell lines.


Assuntos
Benzimidazóis/metabolismo , Receptores Androgênicos/metabolismo , Benzimidazóis/química , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Masculino , Estrutura Molecular , Antígeno Prostático Específico/metabolismo
6.
PLoS One ; 7(8): e42500, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22936985

RESUMO

The pathways inducing the critical transition from compensated hypertrophy to cardiac dilation and failure remain poorly understood. The goal of our study is to determine the role of Rac-induced signaling in this transition process. Our previous results showed that Thyroxin (T4) treatment resulted in increased myocardial Rac expression in wild-type mice and a higher level of expression in Zea maize RacD (ZmRacD) transgenic mice. Our current results showed that T4 treatment induced physiologic cardiac hypertrophy in wild-type mice, as demonstrated by echocardiography and histopathology analyses. This was associated with significant increases in myocardial Rac-GTP, superoxide and ERK1/2 activities. Conversely, echocardiography and histopathology analyses showed that T4 treatment induced dilated cardiomyopathy along with compensatory cardiac hypertrophy in ZmRacD mice. These were linked with further increases in myocardial Rac-GTP, superoxide and ERK1/2 activities. Additionally, there were significant increases in caspase-8 expression and caspase-3 activity. However, there was a significant decrease in p38-MAPK activity. Interestingly, inhibition of myocardial Rac-GTP activity and superoxide generation with pravastatin and carvedilol, respectively, attenuated all functional, structural, and molecular changes associated with the T4-induced cardiomyopathy in ZmRacD mice except the compensatory cardiac hypertrophy. Taken together, T4-induced ZmRacD is a novel mouse model of dilated cardiomyopathy that shares many characteristics with the human disease phenotype. To our knowledge, this is the first study to show graded Rac-mediated O(2)·(-) results in cardiac phenotype shift in-vivo. Moreover, Rac-mediated O(2)·(-) generation, cardiomyocyte apoptosis, and myocardial fibrosis seem to play a pivotal role in the transition from cardiac hypertrophy to cardiac dilation and failure. Targeting Rac signaling could represent valuable therapeutic strategy not only in saving the failing myocardium but also to prevent this transition process.


Assuntos
Apoptose/efeitos dos fármacos , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Fibrose/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Tiroxina/toxicidade , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Western Blotting , Carbazóis/uso terapêutico , Cardiomegalia/induzido quimicamente , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Carvedilol , Ecocardiografia , Feminino , Fibrose/induzido quimicamente , Masculino , Camundongos , Camundongos Transgênicos , Pravastatina/uso terapêutico , Propanolaminas/uso terapêutico , Vasodilatadores/uso terapêutico , Proteínas rac de Ligação ao GTP/genética
7.
Am J Physiol Heart Circ Physiol ; 301(3): H868-80, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21622832

RESUMO

Rac1-GTPase activation plays a key role in the development and progression of cardiac remodeling. Therefore, we engineered a transgenic mouse model by overexpressing cDNA of a constitutively active form of Zea maize Rac gene (ZmRacD) specifically in the hearts of FVB/N mice. Echocardiography and MRI analyses showed cardiac hypertrophy in old transgenic mice, as evidenced by increased left ventricular (LV) mass and LV mass-to-body weight ratio, which are associated with relative ventricular chamber dilation and systolic dysfunction. LV hypertrophy in the hearts of old transgenic mice was further confirmed by an increased heart weight-to-body weight ratio and histopathology analysis. The cardiac remodeling in old transgenic mice was coupled with increased myocardial Rac-GTPase activity (372%) and ROS production (462%). There were also increases in α(1)-integrin (224%) and ß(1)-integrin (240%) expression. This led to the activation of hypertrophic signaling pathways, e.g., ERK1/2 (295%) and JNK (223%). Pravastatin treatment led to inhibition of Rac-GTPase activity and integrin signaling. Interestingly, activation of ZmRacD expression with thyroxin led to cardiac dilation and systolic dysfunction in adult transgenic mice within 2 wk. In conclusion, this is the first study to show the conservation of Rho/Rac proteins between plant and animal kingdoms in vivo. Additionally, ZmRacD is a novel transgenic model that gradually develops a cardiac phenotype with aging. Furthermore, the shift from cardiac hypertrophy to dilated hearts via thyroxin treatment will provide us with an excellent system to study the temporal changes in cardiac signaling from adaptive to maladaptive hypertrophy and heart failure.


Assuntos
Hipertrofia Ventricular Esquerda/enzimologia , Miocárdio/enzimologia , Proteínas de Plantas/metabolismo , Disfunção Ventricular Esquerda/enzimologia , Função Ventricular Esquerda , Remodelação Ventricular , Proteínas rac1 de Ligação ao GTP/metabolismo , Envelhecimento , Sequência de Aminoácidos , Análise de Variância , Animais , Ecocardiografia , Genótipo , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Integrina alfa1/metabolismo , Integrina beta1/metabolismo , Sistema de Sinalização das MAP Quinases , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Mutação , Miocárdio/patologia , Cadeias Pesadas de Miosina/genética , Fenótipo , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/genética , Pravastatina/farmacologia , Regiões Promotoras Genéticas , Superóxidos/metabolismo , Tiroxina/farmacologia , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/genética , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/genética , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/genética
8.
J Cardiovasc Pharmacol ; 57(5): 550-8, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21326111

RESUMO

Hypertension represents a major risk factor for cardiovascular diseases. We have developed a novel transgenic mouse model by overexpressing the cDNA of human profilin1 in the blood vessels of transgenic mice, which led to vascular hypertrophy and hypertension. We assessed the effects of losartan, amlodipine, or atenolol on vascular hypertrophy-associated hypertension, by treating the profilin1 transgenic mice for 4 weeks. Our myograph results showed improvement in the contraction response toward phenylephrine and in the relaxation response toward acetylcholine and sodium nitrite in losartan- and amlodipine-treated profilin1 mice. Western blot analyses using mesenteric arteries of losartan- and amlodipine-treated profilin1 mice showed significant decreases in their signaling, respectively, as follows: the expression of α1 integrin (104% and 93%) and ß1 integrin (116% and 109%); p-ERK1/2 (149% and 130%) and p-JNK (171% and 137%); the phospho-myosin light chain 20 (117% and 150%); and the ROCKII expression (125% and 180%). Conversely, there were significant increases in the endothelial nitric oxide synthase expression (82% and 80%) and activation (p-endothelial nitric oxide synthase) (78% and 76%). On the other hand, atenolol-treated profilin1 mice showed no significant change in all measured parameters. In conclusion, the profilin1 gene may represent a new therapeutic target in the treatment of vascular hypertrophy-associated hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Artérias Mesentéricas/efeitos dos fármacos , Profilinas/genética , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Western Blotting , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Hipertensão/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos , Camundongos Transgênicos , Cadeias Leves de Miosina/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Quinases Associadas a rho/metabolismo
9.
Am J Physiol Heart Circ Physiol ; 298(6): H2112-20, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20400688

RESUMO

Increased mechanical stress/hypertension in the vessel wall triggers the hypertrophic signaling pathway, resulting in structural remodeling of vasculature. Vascular hypertrophy of resistance vessels leads to reduced compliance and elevation of blood pressure. We showed before that increased expression of profilin1 protein in the medial layer of the aorta induces stress fiber formation, triggering the hypertrophic signaling resulting in vascular hypertrophy and, ultimately, hypertension in older mice. Our hypothesis is that profilin1 induced vascular hypertrophy in resistance vessels, which led to elevation of blood pressure, both of which contributed to the modulation of vascular function. Our results showed significant increases in the expression of alpha(1)- and beta(1)-integrins (280 + or - 6.3 and 325 + or - 7.4%, respectively) and the activation of the Rho/Rho-associated kinase (ROCK) II pathway (260 and 350%, respectively, P < 0.05) in profilin1 mesenteric arteries. The activation of Rho/ROCK led to the inhibition of endothelial nitric oxide synthase expression (39 + or - 5.4%; P < 0.05) and phosphorylation (35 + or - 4.5%; P < 0.05) but also an increase in myosin light chain 20 phosphorylation (372%, P < 0.05). There were also increases in hypertrophic signaling pathways in the mesenteric arteries of profilin1 mice such as phospho-extracellular signal-regulated kinase 1/2 and phospho-c-Jun NH(2)-terminal kinase (312.15 and 232.5%, respectively, P < 0.05). Functional analyses of mesenteric arteries toward the vasoactive drugs were assessed using wire-myograph and showed significant increases in the vascular responses of profilin1 mesenteric arteries toward phenylephrine, but significant decreases in response toward ROCK inhibitor Y-27632, ACh, sodium nitrite, and cytochalasin D. The changes in vascular responses in the mesenteric arteries of profilin1 mice are due to vascular hypertrophy and the elevation of blood pressure in the profilin1 transgenic mice.


Assuntos
Hipertensão/metabolismo , Hipertensão/fisiopatologia , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/patologia , Músculo Liso Vascular/fisiopatologia , Profilinas/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Hipertensão/etiologia , Hipertrofia/complicações , Hipertrofia/metabolismo , Hipertrofia/patologia , Integrina alfa1/metabolismo , Integrina beta1/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Músculo Liso Vascular/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fenilefrina/farmacologia , Profilinas/genética , Transdução de Sinais/fisiologia , Vasoconstritores/farmacologia , Quinases Associadas a rho/metabolismo
10.
J Biol Chem ; 282(52): 37632-9, 2007 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-17942408

RESUMO

We have overexpressed either the cDNA of human profilin 1 or expressed the mutant (88R/L) in the blood vessels of transgenic FVB/N mice. Reverse transcription-PCR indicated selective overexpression of profilin 1 and 88R/L in vascular smooth muscle cells. Polyproline binding showed increased profilin 1 and 88R/L proteins in transgenic mice compared with control (~30%, p < 0.05). Rhodamine-phalloidin staining revealed increase stress fiber formation in vascular smooth muscle cells of profilin 1 compared with 88R/L and control. Hematoxylin and eosin staining showed clear signs of vascular hypertrophy in the aorta of profilin 1 mice versus 88R/L and control. However, there were no differences between 88R/L and control mice. Western blotting confirmed the activation of the hypertrophic signaling cascades in aortas of profilin 1 mice. Phospho-ERK1/2 was significantly higher in profilin 1 than 88R/L and control (512.3 and 361.7%, respectively, p < 0.05). Profilin 1 mice had significant increases in phospho-JNK as compared with 88R/L and control (371.4 and 346%, respectively, p < 0.05). However, there were no differences between 88R/L and control mice in both kinases. There was a significant increase in ROCK II kinase in the aorta of profilin 1 mice compared with controls (>400%, p < 0.05). Tail cuff and circadian monitoring of blood pressure showed significant increases in systolic and mean arterial blood pressures of profilin 1 mice starting at age 6 months compared with controls (~25 mm Hg, p < 0.05). These results suggest that increased actin polymerization in blood vessels triggers activation of the hypertrophic signaling cascades and results in elevation of blood pressure at advanced age.


Assuntos
Regulação da Expressão Gênica , Hipertensão/genética , Hipertrofia/genética , Profilinas/biossíntese , Profilinas/genética , Actinas/química , Animais , Aorta/metabolismo , Valva Aórtica/citologia , Pressão Sanguínea , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Transgênicos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Modelos Biológicos , Miócitos de Músculo Liso/citologia , Transdução de Sinais
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