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1.
Ann Hematol ; 98(9): 2073-2080, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31201514

RESUMO

Patients with primary refractory or early relapsed acute myeloid leukemia (AML) have a dismal prognosis, and the treatment options for these patients are limited. The present study retrospectively examined the efficacy and toxicities of the combination of cladribine 5 mg/m2 per day and intermediate-dose cytarabine 1 g/m2 per day for 5 days and granulocyte colony-stimulating factor (G-CSF) as a salvage treatment in 36 patients with relapsed/refractory AML. Among these, 32 patients had de novo AML, and the remaining 4 patients had secondary AML. The median age for the study cohort was 45.8 years. According to the European LeukemiaNet prognostic index, 5 patients had favorable risk, 18 had intermediate risk, and 11 had poor risk. The complete remission was achieved in 58% of the patients with tolerable toxicities. Fifteen patients underwent stem cell transplantation later. Patients who underwent allogeneic hematopoietic stem cell transplantation had a significantly improved 1-year overall survival compared with those who did not (73% vs. 29%, P < 0.001). The results suggested that, as a salvage regimen, modified cladribine, cytarabine, and G-CSF were effective and well tolerated for patients with relapsed/refractory AML, especially for patients who underwent subsequent stem cell transplantation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Terapia de Salvação , Adulto , Idoso , Aloenxertos , Cladribina/administração & dosagem , Citarabina/administração & dosagem , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Leucemia Mieloide Aguda/sangue , Masculino , Pessoa de Meia-Idade , Indução de Remissão
2.
Cancer Med ; 8(8): 3981-3991, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31150156

RESUMO

Osteosarcoma is the most common type of primary malignant tumor of skeletal with poor prognosis in children and adolescents. Accumulating evidence indicates that CBX2 is overexpressed in multiple human neoplasm and play a critical role in tumorigenesis and progression. However, its functional role and upstream regulation mechanism in osteosarcoma remain unknown. In the present study, tissue microarray (TMA) analysis was performed to determine the association between CBX2 expression and clinical prognosis of osteosarcoma patients by immunohistochemistry. We also investigated the functional role of CBX2 using small interfering RNA (siRNA) in vitro and in vivo. Additionally, we confirmed the direct binding between CBX2 and let-7a via qPCR, western blot and luciferase reporter assay. We found that CBX2 is dramatically upregulated in osteosarcoma tissues and high CBX2 expression was correlated with metastasis, recurrence, and chemotherapy response, as well as unfavorable prognosis in patients with osteosarcoma. Similar results were observed in a sarcoma cohort from The Cancer Genome Atlas (TCGA) dataset. Further experiments revealed that CBX2 knockdown significantly impeded osteosarcoma cell proliferation and invasion ability in vitro, and suppressed the tumor growth in tumor xenografts model. Mechanistically, we confirmed that CBX2 is a functional target of miRNA let-7a. Overexpression of let-7a inhibits osteosarcoma cell proliferation, which was reversed by CBX2 overexpression. Taken together, our study demonstrates that let-7a/CBX2 plays a crucial role in osteosarcoma progression. CBX2 could serve as a promising prognostic biomarker and potential therapeutic target for osteosarcoma patients.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30290990

RESUMO

BACKGROUND: microRNA-139 (miR-139) is dysregulated in various types of tumors and plays a key role in carcinogenesis. miR-139 may be used as a diagnostic and prognostic biomarker of cancers. However, the data from the literature are not consistent. The present study aimed to verify the prognostic and diagnostic values of miR-139 in solid tumors. DATA SOURCES: PubMed, Web of Science and Embase databases were searched and publications from January 2011 to August 2017 were included. We used Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database to further validate this meta-analysis. RESULTS: Eight individual studies from seven articles were included. Pooled analyses showed that low miR-139 expression was related to worse overall survival (OS) [hazard ratio (HR) = 2.27; 95% confidence intervals (CI): 1.74-2.95; P < 0.001] in solid tumors, including hepatocellular carcinoma (HCC) and glioblastoma multiforme (GBM), consisting with the results of TCGA. However, our results of CRC showed that low miR-139 expression was associated with poor OS which was contradictory with the results in TCGA database and need larger samples to validate the phenomenon; whereas for CRC patients, high miR-139 expression predicted poor RFS, which was in good accordance with TCGA results. The results of 27 microarrays from GEO database showed that miR-139 expression levels were lower in tumor tissues compared to adjacent non-tumor tissues or healthy tissues. Decreased miR-139 expression was also significantly correlated with poor differentiation grade (OR = 3.57; 95% CI: 1.44-8.85; P = 0.006). However, the combined data indicated that no associations between miR-139 expression and the following parameters such as age (pooled OR = 1.50; 95% CI: 0.69-3.24; P = 0.304), gender (pooled OR = 0.92; 95% CI: 0.56-1.51; P = 0.738), tumor size (pooled OR = 1.51; 95% CI: 0.69-3.31; P = 0.298), late tumor-node-metastasis stage (pooled OR = 1.63; 95% CI: 0.99-2.68; P = 0.057) and lymph-node-metastasis (pooled OR = 0.66; 95% CI: 0.34-1.28; P = 0.222). CONCLUSIONS: Low miR-139 expression was related to poor prognosis in HCC and GBM, which could be regarded as a potential prognostic biomarker. However, its precise functional role in CRC still need to be further investigated through larger samples and multicenter studies.

4.
Sci Rep ; 7(1): 15260, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29116110

RESUMO

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

5.
Sci Rep ; 7(1): 2894, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28588271

RESUMO

Patients with secondary acute myeloid leukemia (sAML) arising from myelodysplastic syndromes have a poor prognosis marked by an increased resistance to chemotherapy. An urgent need exists for adjuvant treatments that can enhance or replace current therapeutic options. Here we show the potential of LB100, a small-molecule protein phosphatase 2 A (PP2A) inhibitor, as a monotherapy and chemosensitizing agent for sAML using an in-vitro and in-vivo approach. We demonstrate that LB100 decreases cell viability through caspase activation and G2/M cell-cycle arrest. LB100 enhances daunorubicin (DNR) cytotoxicity resulting in decreased xenograft volumes and improved overall survival. LB100 profoundly upregulates miR-181b-1, which we show directly binds to the 3' untranslated region of Bcl-2 mRNA leading to its translational inhibition. MiR-181b-1 ectopic overexpression further diminishes Bcl-2 expression leading to suppression of sAML cell growth, and enhancement of DNR cytotoxicity. Our research highlights the therapeutic potential of LB100, and provides new insights into the mechanism of LB100 chemosensitization.

6.
Zhonghua Xue Ye Xue Za Zhi ; 35(11): 1009-12, 2014 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-25417880

RESUMO

OBJECTIVE: To investigate the expression level and regulation mechanism of miR-720 as well as the association of miR-720 expression with leukemia biological characteristics. METHODS: Expression and promoter methylation of miR-720 were determined by quantitive PCR and pyrosequencing in 38 patients with AML and 20 normal controls. Lentivirous-mediated miR-702 overexpression was constructed in AML cell line kasumi-1. The cell proliferation, apoptosis, cycle, colony formation, migration and P53-mediated apoptosis pathway were determined. RESULTS: AML patients showed significantly lower miR-720 expression compared with normal controls (0.69±0.09 vs 3.00±0.46, P<0.01); The methylation level of miR-720 promoter region in AML patients were significantly higher than normal controls [(75.56±2.35)% vs (47.65±2.78)%, P<0.01]. miR-720 overexpression in kasumi-1 cells induced significantly increased cell apoptosis (P=0.017), elevated apoptosis sensitivity to etoposide (P=0.004), and reduced cell proliferation (P<0.01). miR-720 overexpression also induced reduced colony formation (P=0.005), cell cycle arrest in G(1)/G(0) phase and decreased migration ability in kasumi-1 cells. In addition, overexpression of miR-720 significantly induced increased cell apoptosis-related proteins including P53 and Bax, and activation of NF-κB signal transduction pathway. After kasumi-1 cells were treated with 1uM decitabine for 48 hours, miR-720 promoter methylation reduced significantly, and miR-720 expression significantly increased. CONCLUSION: The expression of miR-720 in AML patients reduced significantly, and DNA methylation-mediated epigenetic silencing of miR-720 contributed to maintain the malignant characteristics of AML.


Assuntos
Metilação de DNA , Epigênese Genética , Leucemia Mieloide Aguda/genética , MicroRNAs/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Leucemia Mieloide Aguda/patologia , Regiões Promotoras Genéticas
7.
J Transl Med ; 12: 167, 2014 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-24923330

RESUMO

BACKGROUND: The methylation inhibitor 5-Aza-2'-deoxycytidine (decitabine, DAC) has a great therapeutic value for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). But decitabine monotherapy was associated with a relatively low rate of complete remission in AML and MDS. We aimed to investigate the effect of several anti-leukemia drugs in combination with decitabine on the proliferation of myeloid leukemia cells, to select the most efficient combination group and explore the associated mechanisms of these combination therapies. METHODS: Cell proliferation was tested by MTT assay and CFU-GM assay. Cell apoptosis was evaluated by Annexin V and PI staining in cell culture, TUNEL assay and transmission electron microscopy in animal study. MicroPET was used to imaging the tumor in mouse model. Molecular studies were conducted using microarray expression analysis, which was used to explore associated pathways, and real-time quantitative reverse transcription-PCR, western blot and immunohistochemistry, used to assess regulation of Wnt/ß-catenin pathway. Statistical significance among groups was determined by one-way ANOVA analysis followed by post hoc Bonferroni's multiple comparison test. RESULTS: Among five anti-leukemia agents in combining with decitabine, the sequential combination of decitabine and idarubicin induced synergistic cell death in U937 cells, and this effect was verified in HEL, SKM-1 cells and AML cells isolated from AML patients. Importantly, tumor growth inhibition in this sequential combination was found to be higher than in single agent or controls in vivo. Moreover, sequential combination of the two agents induced apoptosis and depression of the Wnt/ß-catenin pathway in both AML cell culture and animal studies. CONCLUSIONS: The findings demonstrated that sequentially combination of decitabine and idarubicin had synergistic anti-leukemia effects. These effects were mainly attributed to demethylation of Wnt/ß-catenin pathway inhibitors and downregulation of Wnt/ß-catenin pathway nuclear targets.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Núcleo Celular/metabolismo , Regulação para Baixo , Proteínas Wnt/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Azacitidina/administração & dosagem , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Proliferação de Células/efeitos dos fármacos , Decitabina , Sinergismo Farmacológico , Humanos , Idarubicina/administração & dosagem , Idarubicina/farmacologia , Marcação In Situ das Extremidades Cortadas , Leucemia/patologia , Metilação , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células U937 , Proteínas Wnt/metabolismo
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