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1.
Life Sci ; 248: 117465, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105707

RESUMO

BACKGROUND: Severe peripheral nerve injury leads to skeletal muscle atrophy and impaired limb function that is not sufficiently improved by existing treatments. Fibroblast growth factor 6 (FGF6) is involved in tissue regeneration and is dysregulated in denervated rat muscles. However, the way that FGF6 affects skeletal muscle repair after peripheral nerve injury has not been fully elucidated. METHODS: In this study, we investigated the role of FGF6 in the regeneration of denervated muscles using myoblast cells and an in vivo model of peripheral nerve injury. RESULTS: FGF6 promoted the viability and migration of C2C12 and primary myoblasts in a dose-dependent manner through FGFR1-mediated upregulation of cyclin D1. Low concentrations of FGF6 promoted myoblast differentiation through FGFR4-mediated activation of ERK1/2, which upregulated expression of MyHC, MyoD, and myogenin. FGFR-1, FGFR4, MyoD, and myogenin were not upregulated when FGF6 expression was inhibited in myoblasts by shRNA-mediated knockdown. Injection of FGF6 into denervated rat muscles enhanced the MyHC-IIb muscle fiber phenotype and prevented muscular atrophy. CONCLUSION: These findings indicate that FGF6 reduces skeletal muscle atrophy by relying on the ERK1/2 mechanism and enhances the conversion of slow muscle to fast muscle fibers, thereby promoting functional recovery of regenerated skeletal muscle after innervation.


Assuntos
Fator 6 de Crescimento de Fibroblastos/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Músculo Esquelético/metabolismo , Traumatismos dos Nervos Periféricos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Regeneração/genética , Animais , Diferenciação Celular , Linhagem Celular , Movimento Celular , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Fator 6 de Crescimento de Fibroblastos/antagonistas & inibidores , Fator 6 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Denervação Muscular/métodos , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Proteína MyoD/genética , Proteína MyoD/metabolismo , Mioblastos/metabolismo , Mioblastos/patologia , Miogenina/genética , Miogenina/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/patologia , Cultura Primária de Células , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Nervo Isquiático/lesões
2.
Nat Chem Biol ; 16(3): 267-277, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31959966

RESUMO

A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that is thermodynamically disadvantaged because of an electrostatic repulsion between enzyme and substrate kinases. Under physiological conditions, the energetic gain resulting from ligand-induced dimerization of extracellular domains overcomes this opposing clash, stabilizing the A-loop-transphosphorylating dimer. A unique pathogenic fibroblast growth factor receptor gain-of-function mutation promotes formation of the complex responsible for phosphorylation of A-loop tyrosines by eliminating this repulsive force. We show that asymmetric complex formation induces a more phosphorylatable A-loop conformation in the substrate kinase, which in turn promotes the active state of the enzyme kinase. This explains how quantitative differences in the stability of ligand-induced extracellular dimerization promotes formation of the intracellular A-loop-transphosphorylating asymmetric complex to varying extents, thereby modulating intracellular kinase activity and signaling intensity.


Assuntos
Domínio AAA/fisiologia , Proteínas Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Domínio AAA/genética , Domínio Catalítico , Dimerização , Ativação Enzimática , Humanos , Ligantes , Fosforilação , Ligação Proteica , Conformação Proteica , Proteínas Tirosina Quinases/fisiologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/fisiologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Tirosina/química
3.
J Environ Pathol Toxicol Oncol ; 38(3): 217-227, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679309

RESUMO

BACKGROUND: Natural active components have been reported to serve as adjuvant medications in the clinical practice of cancer therapeutics. However, the antineoplastic roles of atractylenolide III (ATL) are rarely reported. In the present study, we assessed the functions of ATL combined with docetaxel in gastric cancer cells. METHODS: Cell viability and cytotoxic activity were evaluated using CCK-8 and LDH-based cytotoxicity assays, respectively. Protein expression levels were measured by western blotting analysis. Annexin V-FITC/PI staining was used to evaluate cell apoptosis using flow cytometry. RESULTS: AGS and SGC-7901 cell viability was significantly inhibited in ATL combined with docetaxel group compared with docetaxel treatment alone. The levels of LDH, apoptosis rate, and the ratio of BAX to Bcl-2 were significantly elevated in combination treatment group compared to docetaxel treatment alone. Intriguingly, docetaxel combined with ATL resulted in a significant decrease in FGFR1, FGFR2, and FGFR4 protein expression compared with docetaxel treatment alone. Knockout of FGFR1, -2, and -4 exhibited a similar role of medications to inhibit growth and induce apoptosis in AGS and SGC-7901 cells. CONCLUSIONS: ATL and docetaxel treatment performed the synergistic effects on the inhibition of growth and induction of apoptosis in gastric cancer cells, and the underlying mechanism was mediated, at least partially, through the inhibition of FGFR1, -2, and -4.


Assuntos
Antineoplásicos/farmacologia , Docetaxel/farmacologia , Lactonas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Sesquiterpenos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias Gástricas/tratamento farmacológico
4.
Zhonghua Xue Ye Xue Za Zhi ; 40(10): 848-852, 2019 Oct 14.
Artigo em Chinês | MEDLINE | ID: mdl-31775485

RESUMO

Objective: To investigate the clinic-pathological features, diagnosis and treatment of 8p11 myeloproliferative syndrome (EMS) . Methods: Five patients diagnosed as EMS from Jan 2014 to May 2018 at Blood Disease Hospital, Chinese Academy of Medical Sciences were enrolled. The clinical manifestations, laboratory characteristics, treatment and outcome of these patients were summarized. Results: The peripheral blood leukocyte count of 5 patients with EMS increased significantly, accompanied with an elevated absolute eosinophils value (the average as 18.89×10(9)/L) . The hypercellularity of myeloid cells was common in bone marrow, always with the elevated proportion of eosinophils (the average as 17.24%) , but less than 5% of blast cells. The chromosome karyotype of the 5 cases differed from each other, but presenting with the same rearrangement of FGFR1 gene by fluorescence in situ hybridization technology. The average interval between onset and diagnosis was 4.8 months with a median survival of only 14 months. Conclusion: EMS was a rare hematologic malignancy with poor prognosis and short survival. It was commonly to be misdiagnosed. Analysis of cytogenetics and molecular biology were helpful for early diagnosis.


Assuntos
Eosinofilia , Neoplasias Hematológicas/genética , Doenças Linfáticas/genética , Transtornos Mieloproliferativos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Cromossomos Humanos Par 8 , Eosinofilia/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Transtornos Mieloproliferativos/genética , Translocação Genética
5.
Am J Case Rep ; 20: 1566-1571, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31649234

RESUMO

BACKGROUND Encephalocraniocutaneous lipomatosis is a rare neurocutaneous disorder characterized by cutaneous, ocular, and central nervous system anomalies; its molecular etiology was recently identified. This report describes the surgical treatment and genetic characterization of a giant ocular lipodermoid cyst secondary to encephalocraniocutaneous lipomatosis. CASE REPORT An 11-year-old girl with past medical history of absence seizures presented with a reddish protruding mass in her right eye involving the temporal conjunctiva and the peripheral temporal cornea; eyelid closure was not possible due to mass protrusion. She also presented skin tags at the level of the external canthus and 3 alopecic areas at the level of the scalp compatible with nevus psiloliparus. No family history was reported. A dermoid cyst was suspected and excisional biopsy was performed under general anesthesia. A large conjunctival and lamellar corneoscleral resection was done, followed by a corneal tectonic graft. Molecular analysis was carried out, including PCR and Sanger sequencing on DNA obtained from the mass. After surgery, the patient achieved complete eyelid closure, reduction of ocular surface symptoms, and improved aesthetic appearance. Histological analysis confirmed a lipodermoid cyst; genetic tests confirmed a mosaic activating mutation in FGFR1 (c.1638C>A, p.Asn546Lys). The diagnosis was encephalocraniocutaneous lipomatosis. CONCLUSIONS ECCL is a rare condition; an accurate diagnosis comprising clinical and genetic aspects can facilitate the monitoring of possible complications, improve the multidisciplinary treatment, and provide valuable information for future therapy developments. In this case, the patient's quality of life improved significantly, ocular symptoms disappeared, and a good esthetic appearance was achieved.


Assuntos
Cisto Dermoide/genética , Cisto Dermoide/cirurgia , Oftalmopatias/diagnóstico , Oftalmopatias/genética , Neoplasias Oculares/genética , Neoplasias Oculares/cirurgia , Lipomatose/diagnóstico , Lipomatose/genética , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Biópsia , Criança , Transplante de Córnea , Análise Mutacional de DNA , Cisto Dermoide/etiologia , Oftalmopatias/complicações , Neoplasias Oculares/etiologia , Feminino , Humanos , Lipomatose/complicações , Síndromes Neurocutâneas/complicações , Reação em Cadeia da Polimerase , Convulsões/etiologia
6.
Mol Med Rep ; 20(4): 3959-3967, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485617

RESUMO

Fibroblast growth factor receptor 1 (FGFR1) signaling has been reported to contribute to the carcinogenic progression of various cancer types. Previous studies have demonstrated that FGFR1 expression is increased in non­small cell lung cancer (NSCLC) and promotes cancer cell metastasis. However, the molecular mechanisms underlying increased FGFR1 expression in NSCLC remains largely unknown. In the current study, microRNA (miR)­497 levels were observed to be inversely correlated with FGFR1 expression in tumor samples from patients with NSCLC. In the NSCLC cell line A549, miR­497 overexpression inhibited cell proliferation and migration. Increased expression of miR­497 led to a reduction in FGFR1 expression, at the mRNA and protein levels. In addition, transfection of miR­497 mimics inactivated the protein kinase B (AKT) and c­Jun N­terminal kinase (JNK) signaling pathways, as reduced matrix metallopeptidase 26 expression; all of which are regulated by FGFR1. Using TargetScan software, FGFR1 was also identified as a predicted target gene of miR­497, and a dual luciferase reporter assay confirmed that miR­497 directly regulated FGFR1. Transfection of a recombinant FGFR1 overexpression vector reversed miR­497 mimic­induced arrest of cell growth and migration in A549 cells. In conclusion, the results of the present study identified miR­497 as a potential tumor suppressor gene in NSCLC that may function via repressing FGFR1 expression, and AKT and JNK signaling.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Células A549 , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia
7.
BMC Med Genet ; 20(1): 149, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477042

RESUMO

BACKGROUND: Rotator cuff disease is a widespread musculoskeletal pathology and a major cause of shoulder pain. Studies on familial predisposition suggest that genetic plays a role in the pathogenesis of rotator cuff disease. Several genes are responsible for rotator cuff disease. The aim of this study was to perform a systematic review on genetic association between rotator cuff disease and genes variations. METHODS: A systematic review of the literature was performed, in accordance with the PRISMA guidelines. PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar databases were searched comprehensively using the keywords: "Rotator cuff", "Gene", "Genetic", "Predisposition", "Single-nucleotide polymorphism" and "Genome-wide association". RESULTS: 8 studies investigating genes variations associated with rotator cuff tears were included in this review. 6 studies were case-control studies on candidate genes and 2 studies were GWASs. A significant association between SNPs and rotator cuff disease was found for DEFB1, FGFR1, FGFR3, ESRRB, FGF10, MMP-1, TNC, FCRL3, SASH1, SAP30BP, rs71404070 located next to cadherin8. Contradictory results were reported for MMP-3. CONCLUSION: Further investigations are warranted to identify complete genetic profiles of rotator cuff disease and to clarify the complex interaction between genes, encoded proteins and environment. This may lead to individualized strategies for prevention and treatment of rotator cuff disease. LEVEL OF EVIDENCE: Level IV, Systematic Review.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla , Lesões do Manguito Rotador/genética , Caderinas/genética , Bases de Dados Factuais , Fator 10 de Crescimento de Fibroblastos/genética , Humanos , Metaloproteinase 1 da Matriz/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptores Estrogênicos/genética , Receptores Imunológicos/genética , Manguito Rotador , Tenascina/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , beta-Defensinas/genética
8.
Gene ; 717: 144047, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31421190

RESUMO

BACKGROUND: Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways play important roles in the formation of the blood vascular system and nervous system across animal phyla. We have earlier reported VEGF and FGF from Hydra vulgaris Ind-Pune, a cnidarian with a defined body axis, an organized nervous system and a remarkable ability of regeneration. We have now identified three more components of VEGF and FGF signaling pathways from hydra. These include FGF-1, FGF receptor 1 (FGFR-1) and VEGF receptor 2 (VEGFR-2) with a view to deciphering their possible roles in regeneration. METHODS: In silico analysis of proteins was performed using Clustal omega, Swiss model, MEGA 7.0, etc. Gene expression was studied by whole mount in situ hybridization. VEGF and FGF signaling was inhibited using specific pharmacological inhibitors and their effects on head regeneration were studied. RESULTS: Expression patterns of the genes indicate a possible interaction between FGF-1 and FGFR-1 and also VEGF and VEGFR-2. Upon treatment of decapitated hydra with pharmacological inhibitor of FGFR-1 or VEGFR-2 for 48 h, head regeneration was delayed in treated as compared to untreated, control regenerates. When we studied the expression of head specific genes HyBra1 and HyKs1 and tentacle specific gene HyAlx in control and treated regenerates using whole mount in situ hybridization, expression of all the three genes was found to be adversely affected in treated regenerates. CONCLUSIONS: The results suggest that VEGF and FGF signaling play important roles in regeneration of hypostome and tentacles in hydra.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Cabeça/fisiologia , Hydra/fisiologia , Regeneração/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Simulação por Computador , Fator 1 de Crescimento de Fibroblastos/química , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Hydra/efeitos dos fármacos , Indóis/farmacologia , Domínios Proteicos , Pirróis/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais , Homologia Estrutural de Proteína , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
PLoS Genet ; 15(7): e1008254, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31276493

RESUMO

The mouse organ of Corti, housed inside the cochlea, contains hair cells and supporting cells that transduce sound into electrical signals. These cells develop in two main steps: progenitor specification followed by differentiation. Fibroblast Growth Factor (FGF) signaling is important in this developmental pathway, as deletion of FGF receptor 1 (Fgfr1) or its ligand, Fgf20, leads to the loss of hair cells and supporting cells from the organ of Corti. However, whether FGF20-FGFR1 signaling is required during specification or differentiation, and how it interacts with the transcription factor Sox2, also important for hair cell and supporting cell development, has been a topic of debate. Here, we show that while FGF20-FGFR1 signaling functions during progenitor differentiation, FGFR1 has an FGF20-independent, Sox2-dependent role in specification. We also show that a combination of reduction in Sox2 expression and Fgf20 deletion recapitulates the Fgfr1-deletion phenotype. Furthermore, we uncovered a strong genetic interaction between Sox2 and Fgf20, especially in regulating the development of hair cells and supporting cells towards the basal end and the outer compartment of the cochlea. To explain this genetic interaction and its effects on the basal end of the cochlea, we provide evidence that decreased Sox2 expression delays specification, which begins at the apex of the cochlea and progresses towards the base, while Fgf20-deletion results in premature onset of differentiation, which begins near the base of the cochlea and progresses towards the apex. Thereby, Sox2 and Fgf20 interact to ensure that specification occurs before differentiation towards the cochlear base. These findings reveal an intricate developmental program regulating organ of Corti development along the basal-apical axis of the cochlea.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Órgão Espiral/citologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Fatores de Transcrição SOXB1/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Técnicas de Inativação de Genes , Masculino , Camundongos , Órgão Espiral/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais
10.
Gastroenterology ; 157(5): 1413-1428.e11, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31352001

RESUMO

BACKGROUND & AIMS: Obesity is a risk factor for pancreatic cancer. In mice, a high-fat diet (HFD) and expression of oncogenic KRAS lead to development of invasive pancreatic ductal adenocarcinoma (PDAC) by unknown mechanisms. We investigated how oncogenic KRAS regulates the expression of fibroblast growth factor 21, FGF21, a metabolic regulator that prevents obesity, and the effects of recombinant human FGF21 (rhFGF21) on pancreatic tumorigenesis. METHODS: We performed immunohistochemical analyses of FGF21 levels in human pancreatic tissue arrays, comprising 59 PDAC specimens and 45 nontumor tissues. We also studied mice with tamoxifen-inducible expression of oncogenic KRAS in acinar cells (KrasG12D/+ mice) and fElasCreERT mice (controls). KrasG12D/+ mice were placed on an HFD or regular chow diet (control) and given injections of rhFGF21 or vehicle; pancreata were collected and analyzed by histology, immunoblots, quantitative polymerase chain reaction, and immunohistochemistry. We measured markers of inflammation in the pancreas, liver, and adipose tissue. Activity of RAS was measured based on the amount of bound guanosine triphosphate. RESULTS: Pancreatic tissues of mice expressed high levels of FGF21 compared with liver tissues. FGF21 and its receptor proteins were expressed by acinar cells. Acinar cells that expressed KrasG12D/+ had significantly lower expression of Fgf21 messenger RNA compared with acinar cells from control mice, partly due to down-regulation of PPARG expression-a transcription factor that activates Fgf21 transcription. Pancreata from KrasG12D/+ mice on a control diet and given injections of rhFGF21 had reduced pancreatic inflammation, infiltration by immune cells, and acinar-to-ductal metaplasia compared with mice given injections of vehicle. HFD-fed KrasG12D/+ mice given injections of vehicle accumulated abdominal fat, developed extensive inflammation, pancreatic cysts, and high-grade pancreatic intraepithelial neoplasias (PanINs); half the mice developed PDAC with liver metastases. HFD-fed KrasG12D/+ mice given injections of rhFGF21 had reduced accumulation of abdominal fat and pancreatic triglycerides, fewer pancreatic cysts, reduced systemic and pancreatic markers of inflammation, fewer PanINs, and longer survival-only approximately 12% of the mice developed PDACs, and none of the mice had metastases. Pancreata from HFD-fed KrasG12D/+ mice given injections of rhFGF21 had lower levels of active RAS than from mice given vehicle. CONCLUSIONS: Normal acinar cells from mice and humans express high levels of FGF21. In mice, acinar expression of oncogenic KRAS significantly reduces FGF21 expression. When these mice are placed on an HFD, they develop extensive inflammation, pancreatic cysts, PanINs, and PDACs, which are reduced by injection of FGF21. FGF21 also reduces the guanosine triphosphate binding capacity of RAS. FGF21 might be used in the prevention or treatment of pancreatic cancer.


Assuntos
Células Acinares/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Transformação Celular Neoplásica/metabolismo , Dieta Hiperlipídica , Fatores de Crescimento de Fibroblastos/metabolismo , Neoplasias Intraductais Pancreáticas/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células Acinares/patologia , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/prevenção & controle , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Regulação para Baixo , Fatores de Crescimento de Fibroblastos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Transgênicos , Mutação , PPAR gama/genética , PPAR gama/metabolismo , Cisto Pancreático/genética , Cisto Pancreático/metabolismo , Cisto Pancreático/patologia , Neoplasias Intraductais Pancreáticas/genética , Neoplasias Intraductais Pancreáticas/patologia , Neoplasias Intraductais Pancreáticas/prevenção & controle , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/prevenção & controle , Pancreatite/genética , Pancreatite/metabolismo , Pancreatite/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
11.
Oncogene ; 38(37): 6399-6413, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31324888

RESUMO

Evolved resistance to tyrosine kinase inhibitor (TKI)-targeted therapies remains a major clinical challenge. In epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC), failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with initially surviving drug-tolerant persister cells, which can seed bona fide genetic mechanisms of resistance to EGFR TKIs. While therapeutic approaches targeting fully resistant cells, such as those harboring an EGFRT790M mutation, have been developed, a clinical strategy for preventing the emergence of persister cells remains elusive. Using mesenchymal cell lines derived from biopsies of patients who progressed on EGFR TKI as surrogates for persister populations, we performed whole-genome CRISPR screening and identified fibroblast growth factor receptor 1 (FGFR1) as the top target promoting survival of mesenchymal EGFR mutant cancers. Although numerous previous reports of FGFR signaling contributing to EGFR TKI resistance in vitro exist, the data have not yet been sufficiently compelling to instigate a clinical trial testing this hypothesis, nor has the role of FGFR in promoting the survival of persister cells been elucidated. In this study, we find that combining EGFR and FGFR inhibitors inhibited the survival and expansion of EGFR mutant drug-tolerant cells over long time periods, preventing the development of fully resistant cancers in multiple vitro models and in vivo. These results suggest that dual EGFR and FGFR blockade may be a promising clinical strategy for both preventing and overcoming EMT-associated acquired drug resistance and provide motivation for the clinical study of combined EGFR and FGFR inhibition in EGFR-mutated NSCLCs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares , Inibidores de Proteínas Quinases/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/genética , Receptores ErbB/genética , Receptores ErbB/fisiologia , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Mutação , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Pathol Int ; 69(6): 372-377, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31218776

RESUMO

Glioneuronal tumor (GNT) is a rare central nervous system neoplasm composed of glial and neuronal components. Making the specific diagnosis of GNT can be challenging due to histopathological and genetical similarities among some GNTs and low-grade gliomas. We report a case of GNT with rosette-forming glioneuronal tumor, dysembryoplastic neuroepithelial tumor, and pilocytic astrocytoma-like morphology harboring FGFR1 mutation. A 16-year-old female presented with absence seizures. Magnetic resonance imaging revealed a right temporal lobe mass with multinodular enhancement by gadolinium administration. The tumor was mostly composed of oligodendrocyte-like cells (OLCs) with variable perinuclear haloes. Abundant Rosenthal fibers and eosinophilic granular bodies were identified. Neither mitotic figures nor areas of necrosis were seen. Focal neurocytic rosette features, involving ring-like arrays of OLCs around eosinophilic cores, were observed. Direct sequencing showed a missense mutation in FGFR1 K656E, whereas FGFR1 N546K, PIK3CA, and BRAF V600E were intact. KIAA1549-BRAF fusion was not detected by fluorescence in situ hybridization analysis.


Assuntos
Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Epilepsia/patologia , Glioma/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adolescente , Astrocitoma/complicações , Astrocitoma/diagnóstico , Astrocitoma/genética , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/genética , Epilepsia/diagnóstico , Epilepsia/etiologia , Feminino , Glioma/complicações , Glioma/diagnóstico , Glioma/genética , Humanos , Mutação/genética
13.
Pediatr Blood Cancer ; 66(10): e27897, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31250523

RESUMO

We report two patients with leukaemia driven by the rare CNTRL-FGFR1 fusion oncogene. This fusion arises from a t(8;9)(p12;q33) translocation, and is a rare driver of biphenotypic leukaemia in children. We used RNA sequencing to report novel features of expressed CNTRL-FGFR1, including CNTRL-FGFR1 fusion alternative splicing. From this knowledge, we designed and tested a Droplet Digital PCR assay that detects CNTRL-FGFR1 expression to approximately one cell in 100 000 using fusion breakpoint-specific primers and probes. We also utilised cell-line models to show that effective tyrosine kinase inhibitors, which may be included in treatment regimens for this disease, are only those that block FGFR1 phosphorylation.


Assuntos
Proteínas de Ciclo Celular/genética , Leucemia/genética , Leucemia/terapia , Terapia de Alvo Molecular/métodos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Humanos , Lactente , Masculino , Fusão Oncogênica , Proteínas de Fusão Oncogênica/genética , Reação em Cadeia da Polimerase/métodos , Inibidores de Proteínas Quinases/uso terapêutico
14.
Poult Sci ; 98(11): 5691-5699, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237331

RESUMO

Targeting fibroblast growth factor 23 (FGF-23) signaling pathway is of interest in controlling body phosphate metabolism. This study investigated the effect of anti-fibroblast growth factor receptor 1 (FGFR1, major FGF-23 receptor in the kidney) antibodies on phosphate metabolism. White Leghorn laying hens (65-wk-old) were vaccinated with either a FGFR1 peptide vaccine (five 8-amino-acid peptides were selected, CrZ-1:LPEDPRWE, CrZ-2:LDKDKPNR, CrZ-3:RRPPGMEY, CrZ-4:GSPYPGVP, and CrZ-5:RMDKPSNC) or adjuvant control. At peak antibody titer, hens were artificially inseminated. Chicks from control-vaccinated hens were fed either a non-phytate phosphorus (nPP) sufficient (nPP = 0.45%, positive control) or deficient (nPP = 0.20%, negative control) diet, while chicks from each of the FGFR1 peptide vaccinated hens were fed with the above nPP-deficient diet, for 14 D. When compared to control hens, plasma phosphate in CrZ-1, CrZ-2, CrZ-3, CrZ-4, and CrZ-5 vaccinated hens were decreased by 33, 30, 24, 20, and 26%, respectively (P < 0.05); egg weight in CrZ-2 and CrZ-5 vaccinated hens were increased by 6 and 7%, respectively (P < 0.05); egg production in CrZ-3, CrZ-4, and CrZ-5 vaccinated hens tended to decrease (P = 0.085; decreased by 14, 15, and 13%, respectively). When compared to positive control, chicks from all other groups had decreased body weight gain (BWG) and feed intake (FI) during 1 to 14 D, and had decreased plasma phosphate, tibiotarsus ash, and 24-h phosphorus excretion on day 14. When compared to negative control, BWG of CrZ-1, CrZ-2, CrZ-3, and CrZ-4 antibody chicks were decreased by 23, 28, 26, and 20%, respectively (P < 0.05); FI of CrZ-1, CrZ-2, and CrZ-3 antibody chicks were decreased by 15, 15, and 18%, respectively (P < 0.05); plasma phosphate of CrZ-5 antibody chicks were decreased by 26% (P < 0.05); plasma FGF-23 levels of CrZ-4 antibody chicks were increased by 18% (P < 0.05); tibiotarsus ash content of CrZ-2, CrZ-3, and CrZ-4 antibody chicks were decreased by 20, 20, and 21%, respectively (P < 0.05). In conclusion, anti-FGFR1 peptide antibodies decreased egg production of hens and growth performance of their progeny chicks probably by activating FGF-23 signaling and stimulating FGF-23 production.


Assuntos
Proteínas Aviárias/genética , Galinhas/fisiologia , Fatores de Crescimento de Fibroblastos/genética , Fosfatos/metabolismo , Fósforo na Dieta/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Animais , Anticorpos/imunologia , Proteínas Aviárias/metabolismo , Galinhas/genética , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Óvulo/fisiologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/genética
15.
Genes Chromosomes Cancer ; 58(10): 731-736, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31066955

RESUMO

Conventional osteosarcoma is the most common primary malignancy of bone. This group of neoplasms is subclassified according to specific histological features, but hitherto there has been no correlation between subtype, treatment, and prognosis. By in-depth genetic analyses of a chondroblastoma-like osteosarcoma, we detect a genetic profile that is distinct from those previously reported in benign and malignant bone tumors. The overall genomic copy number profile was less complex than that typically associated with conventional osteosarcoma, and there was no activating point mutation in any of H3F3A, H3F3B, IDH1, IDH2, BRAF, or GNAS. Instead, we found a homozygous CDKN2A deletion, a DMD microdeletion and an FN1-FGFR1 gene fusion. The latter alteration has been described in phosphaturic mesenchymal tumor. This tumor type shares some morphological features with chondroblastoma-like osteosarcoma and we cannot rule out that the present case actually represents an FN1-FGFR1 positive malignant phosphaturic mesenchymal tumor of bone without osteomalacia.


Assuntos
Neoplasias Ósseas/genética , Condroblastoma/genética , Deleção de Genes , Mesenquimoma/genética , Fusão Oncogênica , Osteossarcoma/genética , Neoplasias Ósseas/patologia , Condroblastoma/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Distrofina/genética , Fibronectinas/genética , Homozigoto , Humanos , Masculino , Mesenquimoma/metabolismo , Pessoa de Meia-Idade , Osteossarcoma/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética
16.
Biomed Res Int ; 2019: 5086297, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31032349

RESUMO

Bone marrow mesenchymal stem cells undergo differentiation to different lineages with different efficiencies when induced by different factors. We added a bFGF-chitosan controlled release system (bFGF-CCRS) as an inducer into conditioned medium to facilitate the oriented differentiation of BMSCs into neural lineage cells (eventually mature neurons); furthermore, we synchronized BMSCs to the G0/G1 phase via serum starvation to observe the effect of the inducer on the differentiation direction and efficiency. The nonsynchronized group, chitosan alone (not loaded with bFGF) group, soluble bFGF group, and conditioned medium group served as controls, and we observed the dynamic process of differentiation of BMSCs into neural lineage cells at different time points after the beginning of coculture. We analyzed the binding patterns of bFGF and chitosan and assayed the expression differences of key factors (FGFR1, ERK, and c-fos) and molecular switches (BTG2) that regulate the transformation from cell proliferation to differentiation. We also investigated the potential molecular mechanism of BMSC differentiation into neural lineage cells at a high percentage when induced by bFGF-CCRS.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Animais , Células da Medula Óssea/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quitosana/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas Imediatamente Precoces/genética , Células-Tronco Mesenquimais/citologia , Proteína Quinase 3 Ativada por Mitógeno/genética , Células-Tronco Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Supressoras de Tumor/genética
17.
Int J Oncol ; 54(6): 2211-2221, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942425

RESUMO

Emerging reports have revealed that several microRNAs (miRNAs) are abnormally expressed in non­small cell lung cancer (NSCLC). miRNAs have been identified as oncogenes or tumor suppressors, and regulate various biological processes including oncogenesis and development. miR­802 is dysregulated in multiple types of human cancer, and exerts tumor­suppressive or promoting roles. However, the expression levels and functional roles of miR­802 in NSCLC remain largely unknown. In the present study, miR­802 expression was demonstrated to be decreased in NSCLC tissues and cell lines. A low miR­802 expression was significantly correlated with the tumor stage, lymph node metastasis and brain metastasis in NSCLC patients. Restoring miR­802 expression inhibited NSCLC cell proliferation and colony formation, induced cell apoptosis, decreased cell migration and invasion in vitro, and hindered in vivo tumor growth. Mechanistically, fibroblast growth factor receptor 1 (FGFR1) was confirmed as the target gene of miR­802 in NSCLC cells. In addition, FGFR1 silencing mimicked the tumor­suppressing roles of miR­802 upregulation in NSCLC cells. Furthermore, rescue experiments revealed that FGFR1 reintroduction rescued the miR­802­induced inhibition of the malignant phenotypes in NSCLC cells. Notably, miR­802 was able to deactivate the phosphoinositide 3­kinase (PI3K)/AKT serine/threonine kinase (Akt)/mammalian target of rapamycin (mTOR) pathway in NSCLC cells in vitro and in vivo. Overall, these results demonstrated that miR­802 could downregulate FGFR1 expression, thereby deactivating the PI3K/Akt/mTOR pathway and inhibiting the malignant development of NSCLC. Thus, miR­802 may be a therapeutic candidate for patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , MicroRNAs/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Linhagem Celular Tumoral , Regulação para Baixo/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinase/metabolismo , Pneumonectomia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Pediatr Dent ; 41(2): 132-135, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30992111

RESUMO

Purpose: The purpose of this study was to determine if dental ages are more advanced in overweight children and influenced by genetic variation. Methods: Panoramic radiographs from 577 children were obtained. For performing genetic studies, an additional 236 subjects had panoramic radiographs and whole saliva samples collected. Genotyping of IGF, FGF, and FGFR markers was done. Dental age was determined in 177 patients utilizing Demerjian's method and panoramic radiographs. Skeletal maturation was determined in 28 patients using Baccetti's cervical vertebral maturation method on lateral cephalograms. PLINK was used to test for over-representation of alleles. Results: FGF7, FGF10, and FGF13 were significantly associated with obesity (P = 0.02). When dental age was considered, overweight and obese children are more likely to have dental ages more advanced than their chronological ages (P = 0.05). An excess of heterozygotes of FGF18 rs4073716 was found in children with dental age more advanced than their chronological age (P=0.04). Conclusions: Overweight and obese children have dental ages more advanced than their chronological ages, and this occurrence may be influenced by genetic variation in FGF18.


Assuntos
Determinação da Idade pelos Dentes , Variação Genética , Obesidade Pediátrica , Radiografia Panorâmica , Dente/crescimento & desenvolvimento , Determinação da Idade pelo Esqueleto , Índice de Massa Corporal , Vértebras Cervicais/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Fatores de Crescimento de Fibroblastos/genética , Marcadores Genéticos , Humanos , Masculino , Pennsylvania , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor IGF Tipo 2/genética
19.
Mol Genet Genomic Med ; 7(5): e625, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30891959

RESUMO

BACKGROUND: Postzygotic KRAS, HRAS, NRAS, and FGFR1 mutations result in a group of mosaic RASopathies characterized by related developmental anomalies in eye, skin, heart, and brain. These oculocutaneous disorders include oculoectodermal syndrome (OES) encephalo-cranio-cutaneous lipomatosis (ECCL), and Schimmelpenning-Feuerstein-Mims syndrome (SFMS). Here, we report the results of the clinical and molecular characterization of a novel cohort of patients with oculocutaneous mosaic RASopathies. METHODS: Two OES, two ECCL, and two SFMS patients were ascertained in the study. In addition, two subjects with unilateral isolated epibulbar dermoids were also enrolled. Molecular analysis included PCR amplification and Sanger sequencing of KRAS, HRAS, NRAS, and FGFR1 genes in DNA obtained from biopsies (skin/epibulbar dermoids), buccal mucosa, and blood leukocytes. Massive parallel sequencing was employed in two cases with low-level mosaicism. RESULTS: In DNA from biopsies, mosaicism for pathogenic variants, including KRAS p.Ala146Thr in two OES subjects, FGFR1 p.Asn546Lys and KRAS p.Ala146Val in ECCL patients, and KRAS p.Gly12Asp in both SFMS patients, was demonstrated. No mutations were shown in DNA from conjunctival lesions in two subjects with isolated epibubar dermoids. CONCLUSION: Our study allowed the expansion of the clinical spectrum of mosaic RASopathies and supports that mosaicism for recurrent mutations in KRAS and FGFR1 is a commonly involved mechanism in these rare oculocutaneous anomalies.


Assuntos
Cisto Dermoide/genética , Displasia Ectodérmica/genética , Oftalmopatias/genética , Lipomatose/genética , Síndromes Neurocutâneas/genética , Nevo Sebáceo de Jadassohn/genética , Fenótipo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Cisto Dermoide/patologia , Displasia Ectodérmica/patologia , Oftalmopatias/patologia , GTP Fosfo-Hidrolases/genética , Humanos , Lipomatose/patologia , Proteínas de Membrana/genética , Mosaicismo , Síndromes Neurocutâneas/patologia , Nevo Sebáceo de Jadassohn/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética
20.
Nat Commun ; 10(1): 1373, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30914635

RESUMO

Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of circulating tumor DNA (ctDNA) in 34 patients after progression on CDK4/6 inhibitors identified FGFR1/2 amplification or activating mutations in 14/34 (41%) post-progression specimens. Finally, ctDNA from patients enrolled in MONALEESA-2, the registration trial of ribociclib, showed that patients with FGFR1 amplification exhibited a shorter progression-free survival compared to patients with wild type FGFR1. Thus, we propose breast cancers with FGFR pathway alterations should be considered for trials using combinations of ER, CDK4/6 and FGFR antagonists.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , DNA Tumoral Circulante/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Aminopiridinas/administração & dosagem , Aminopiridinas/farmacologia , Animais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fulvestranto/administração & dosagem , Fulvestranto/farmacologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células MCF-7 , Camundongos , Mutação , Naftalenos/farmacologia , Piperazinas/farmacologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Purinas/administração & dosagem , Purinas/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Quinoxalinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores Estrogênicos/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
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