RESUMO
PURPOSE: Medulloblastoma (MB) is a malignant brain disease in young children. The overall survival of MB patients is disappointing due to absence of effective therapeutics and this could be attributed to the lack of molecular mechanism underlying MB. FHOD3 was an important gene during cardio-genesis and was reported to promote cell migration in cancer. However, its role in MB is not clear to date. METHODS: RT-qPCR and IHC analysis were used to determine expression of FHOD3. Survival curve was drawn by K-M analysis. FHOD3 was knocked down by RNAi technology. The effects of FHOD3 on medulloblastoma cells were determined by CCK-8 assay, colony formation assay, transwell assay and FACs analysis. RESULTS: FHOD3 expression increased by 1.5 fold in tumor tissues compared to the control and IHC analysis further confirmed strong expression of FHOD3 in medulloblastoma tissues. Then higher FHOD3 expression was associated with shorter survival time in MB patients (13.0 months versus 43.8 months). In medulloblastoma cells such as Daoy and D283med, FHOD3 also displayed abundant expression. When FHOD3 was knocked down, the ability of cell proliferation and colony formation was reduced over greatly. The capability of cell migration and invasion was also inhibited significantly. However, cell apoptotic rate increased significantly reversely. Mechanistically, the phosphorylation level of RhoA, ROCK1, and LIMK1 was decreased when FHOD3 was knocked down but increased reversely when FHOD3 was over-expressed in Daoy cells. CONCLUSIONS: FHOD3 was associated with overall survival time in medulloblastoma patients and was essential to cell proliferation, growth and survival in medulloblastoma and might regulates activation of RhoA/ROCK1/LIMK1 signaling pathway.
Assuntos
Neoplasias Cerebelares/metabolismo , Forminas/metabolismo , Quinases Lim/metabolismo , Meduloblastoma/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Apoptose , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Cerebelares/mortalidade , Pré-Escolar , Feminino , Forminas/genética , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Fosforilação , Transdução de Sinais , Ensaio Tumoral de Célula-TroncoRESUMO
BACKGROUND: Age is closely related to the efficacy of treatment for non-small cell lung cancer (NSCLC) patients. Latest clinical trials have proved the better overall survival (OS) for the use of immune checkpoint inhibitors verse chemotherapy in NSCLC patients. However, we had no clear idea of the efficacy of them in elderly patients. So we conducted a meta-analysis to compare the efficacy of immune checkpoint inhibitors for NSCLC patients of different age groups and summarized overall treatment-related adverse events. MATERIALS AND METHODS: PubMed, EMBASE, Web of Science and the Cochrane Library were searched for all clinical trials in NSCLC until 30th of April 2019. Eligible studies included randomized controlled trials (RCTs) comparing immune checkpoint inhibitors with chemotherapy in NSCLC patients. The hazard ratio (HRs) and 95% confidence intervals (CIs) of OS, progression-free survival or adverse events (AEs) were used. RESULTS: A total of 4994 patients from 8 RCTs were included. Immune checkpoint inhibitors significantly prolonged the OS (HR, 0.73; 95% CI, 0.61-0.89) versus chemotherapy in NSCLC patients who were less than 65 years old. Also, they prolonged the OS (HR, 0.74; 95% CI, 0.59-0.93) in NSCLC patients who were more than 65 years old. However, there was no statistical significance of OS (HR, 0.87; 95% CI, 0.57-1.30) among NSCLC patients who were more than 75 years old. It also showed that the single use of immune checkpoint inhibitors had fewer all-grade AEs. CONCLUSION: Regardless of the NSCLC patients who were less or more than 65 years, immune checkpoint inhibitors could achieve better OS than chemotherapy. But there was no significant difference when NSCLC patients who were more than 75 years old. Older patient should be offered immune therapies if it is possible and the mechanism in old age treatment should be further studied.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Fatores Etários , Idoso , Antineoplásicos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Taxa de SobrevidaRESUMO
Microsatellite markers were isolated using dual-suppression-PCR for the endangered species Excentrodendron hsienmu (Tiliaceae) to evaluate the genetic diversity and population structure of this species. A total of 11 polymorphic microsatellite loci were characterized in E. hsienmu. The number of alleles per locus ranged from 2 to 9, with an average of 5.27. The expected heterozygosity value ranged from 0.053 to 0.780, with an average of 0.568 and the observed heterozygosity value ranged from 0 to 0.595, with an average of 0.268. The polymorphic information content value ranged from 0.051 to 0.740, with an average of 0.521. These newly designed markers will be of great potential significance and profound influence in future research related to the genetic diversity, population structure, and patterns of gene flow of this species, which will contribute to the implementation of conservation and management strategies for this species.
Assuntos
Repetições de Microssatélites , Tiliaceae/genética , Alelos , DNA de Plantas/genética , Espécies em Perigo de Extinção , Loci Gênicos , Variação Genética , Heterozigoto , Polimorfismo GenéticoRESUMO
We investigated the synergistic effect of bone morphogenetic protein 9 (BMP9) and transforming growth factor (TGF)-b in the transformation of mesenchymal stem cells into osteoblasts. We evaluated the effect of BMP9 and TGF-b on the induction of osteoblast formation. Mitogen-activated protein kinase (MAPK) pathway-related proteins such as p38, extracellular receptor kinase 1/2, and c-Jun N-terminal kinase (JNK) were analyzed. The interactions between TGF-Smad and BMP-MAPK were also studied. BMP9 alone induced the differentiation of mesenchymal stem cells (MSCs) into osteoblasts and enhanced phosphorylation of p38, extracellular receptor kinase 1/2, and JNK. TGF-b alone failed to induce transformation, but could increase the effect of BMP9. In this process the activation of Smad resulted in activation of the JNK pathway in the MAPK pathway. BMP9 induced osteogenesis of MSC differentiation through the MAKP pathway, while TGF-b contributed to BMP9 enhancement through the Smad-JNK pathway.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Fator 2 de Diferenciação de Crescimento/farmacologia , Osteoblastos/citologia , Fator de Crescimento Transformador beta/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Osteoblastos/efeitos dos fármacos , Osteoblastos/enzimologia , Osteopontina/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
AIM: To evaluate the therapeutic effects of domestic chicken collagen type II (CCII) on rat osteoarthritis (OA) and analyze concomitant changes in the level of Matrix metalloproteinase (MMP)-13, MMP-9, Cathepsin K and their mRNA as well as the tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA in articular cartilage of osteoarthritic rats. METHODS: Osteoarthritis models were surgically induced. Morphology of articular cartilage was done by haematoxylin and eosin staining and Mankin score was calculated, immunohistochemistry of MMP-13, MMP-9 and Cathepsin K was done by ABC method while the mRNA level for MMP-13, MMP-9, cathepsin K as well as TIMP-1 was evaluated by RT-PCR method. RESULTS: Oral administration of CCII reduced the morphological changes of osteoarthritic cartilage (shown by Mankin score), decreased levels of MMP-13, MMP-9, cathepsin K as well as their mRNA in articular cartilage from osteoarthritic rats while it exhibited no effect on TIMP-1 mRNA. CONCLUSION: Oral CCII reduced articular cartilage degradation of osteoarthritic rats and may probably be a potent drug candidate for OA treatment.
Assuntos
Cartilagem Articular/patologia , Colágeno Tipo II/uso terapêutico , Osteoartrite/tratamento farmacológico , Animais , Catepsina K , Catepsinas/efeitos dos fármacos , Galinhas , Indicadores Básicos de Saúde , Imuno-Histoquímica , Metaloproteinase 13 da Matriz/efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Modelos Animais , Osteoartrite/fisiopatologia , RNA Mensageiro , Ratos , Ratos Wistar , Inibidor Tecidual de Metaloproteinase-1/efeitos dos fármacosRESUMO
AIM: To evaluate the therapeutic effects of domestic chicken collagen type II (CCII) on rat osteoarthritis (OA) and analyze concomitant changes in the level of Matrix metalloproteinase (MMP)-13, MMP-9, Cathepsin K and their mRNA as well as the tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA in articular cartilage of osteoarthritic rats. METHODS: Osteoarthritis models were surgically induced. Morphology of articular cartilage was done by haematoxylin and eosin staining and Mankin score was calculated, immunohistochemistry of MMP-13, MMP-9 and Cathepsin K was done by ABC method while the mRNA level for MMP-13, MMP-9, cathepsin K as well as TIMP-1 was evaluated by RT-PCR method. RESULTS: Oral administration of CCII reduced the morphological changes of osteoarthritic cartilage (shown by Mankin score), decreased levels of MMP-13, MMP-9, cathepsin K as well as their mRNA in articular cartilage from osteoarthritic rats while it exhibited no effect on TIMP-1 mRNA. CONCLUSION: Oral CCII reduced articular cartilage degradation of osteoarthritic rats and may probably be a potent drug candidate for OA treatment.
Objetivo: Evaluar los efectos terapéuticos del colágeno de pollo doméstico de tipo II (CPII) en la osteoartritis de ratas (OA) y analizar los cambios concomitantes en el nivel de metaloproteinasa de la matriz (MMP-13). MMP-9, catepsina K y su mRNA, así como el inhibidor tisular de la metalopro-teinasa de la matriz (TIMP)-1 mRNA en el cartílago articular de ratas osteoartríticas. Métodos: Modelos osteoartríticos fueron obtenidos mediante inducción quirúrgica. La morfología del cartílago articular se realizó mediante tinción H-E, y se calculó la puntuación de Mankin. Se realizó la inmunohistoquímica de MMP-13, MMP-9 y catepsina K mediante el método ABC, en tanto que el nivel de mRNA para MMP-13, MMP-9, y catepsina K así como el TIMP-1, fue evaluado mediante el método RT-PCR. Resultados: La administración oral de CPII redujo los cambios morfológicos del cartílago osteo-artrítico (mostrado por la puntuación Mankin), disminuyó los niveles de MMP-13, MMP-9, catepsina K así como su mRNA en cartílago articular de las ratas osteoartríticas mientras que no mostró efecto sobre TIMP-1 mRNA. Conclusión: El CP oral redujo la degradación del cartílago articular de las ratas osteoartríticas y puede ser probablemente candidato a un medicamento potente para el tratamiento de la OA.
Assuntos
Animais , Ratos , Cartilagem Articular/patologia , Colágeno Tipo II/uso terapêutico , Osteoartrite/tratamento farmacológico , Imuno-Histoquímica , Modelos Animais , Catepsinas/efeitos dos fármacos , Galinhas , Indicadores Básicos de Saúde , Inibidor Tecidual de Metaloproteinase-1/efeitos dos fármacos , /efeitos dos fármacos , Metaloproteinase 9 da Matriz/efeitos dos fármacos , Osteoartrite/fisiopatologia , RNA Mensageiro , Ratos WistarRESUMO
By formalizing the relation among components and 'borrowing information' among them, Bayes and empirical Bayes methods can produce more valid, efficient and informative statistical evaluations than those based on traditional methods. In addition, Bayesian structuring of complicated models and goals guides development of appropriate statistical approaches and generates summaries which properly account for sampling and modelling uncertainty. Computing innovations enable implementation of complex and relevant models, thereby substantially increasing the role of Bayes/empirical Bayes methods in important statistical assessments. Policy-relevant statistical assessments involve synthesis of information from a set of related components such as medical clinics, geographic regions or research studies. Typical assessments include inference for individual parameters, synthesis over the collection of components (for example, the parameter histogram) and comparisons among parameters (for example, ranks). The relative importance of these goals depends on the context. Bayesian structuring provides a guide to valid inference. For example, while posterior means are the 'obvious' and optimal estimates for individual components under squared error loss, their empirical distribution function (EDF) is underdispersed and never valid for estimating the EDF of the true, underlying parameters. Effective histogram estimates result from optimizing a loss function based in a distance between the histogram and its estimate. Similarly, ranking observed data usually produces poor estimates and ranking posterior means can be inappropriate. Effective estimates should be based on a loss function that caters directly to ranks. Using examples of 'borrowing information', shrinkage and the variance/bias trade-off we motivate Bayes and empirical Bayes analysis. Then, we outline the formal approach and discuss 'triple-goal' estimates with values that when ranked produce optimal ranks, for which the EDF is an optimal estimate of the parameter EDF and such that the values themselves are effective estimates of co-ordinate-specific parameters. We use basic models and data analysis examples to highlight the conceptual and structural issues.