RESUMO
OBJECTIVE: Persistence of leukemic cells after induction therapy has been shown to correlate with poor survival in acute myeloid leukemia (AML). In this study, we tested if human mesenchymal stromal cells (hMSCs) have protective effects on leukemic cells undergoing chemotherapy. METHODS: Persistent disease was used as marker to identify cases with therapy-resistant leukemic cells in 95 patients with AML. Immunophenotyping, cell cycle, and apoptosis assays were assessed by flow cytometry. AML coculture studies were performed with hMSC of healthy donors. RESULTS: Samples from patients with persistent disease had increased fractions of CD34+ CD38- and quiescent leukemic cells. Comparison of sample series collected at time points of diagnosis and blast persistence showed a relative therapy resistance of quiescent leukemic cells. Consistent with these observations, relapsed disease always displayed higher proportions of quiescent cells compared to samples of first diagnosis suggesting that quiescence is an important therapy escape mechanism of resistant cells. Co-culture studies demonstrated that hMSC protect leukemic cells from the effect of AraC treatment by enriching for quiescent cells, mimicking the effects observed in patients. This effect was even detectable when no direct stromal contact was established. CONCLUSIONS: Our data suggest that hMSC contribute to quiescence and therapy resistance of persistent AML cells.
Assuntos
Comunicação Celular , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais , Linhagem Celular Tumoral , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Pessoa de Meia-Idade , Mutação , Células-Tronco Neoplásicas/efeitos dos fármacos , Prognóstico , Falha de Tratamento , Adulto JovemRESUMO
Background: As the most common female malignancy, the incidence and mortality of endometrial carcinoma (EC) continue to increase worldwide. The effects of traditional standard therapy are limited; thus, novel therapeutic strategies urgently need to be developed. We sought to provide prospective targeting insights into EC therapeutics by comprehensively examining and confirming the biological molecular characterization of EC genes. Methods: The molecular characterization of EC genes was integrated and analyzed using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx) databases. The differentially expressed genes (DEGs) were identified, and the abnormal expression of some core cell-cycle proteins in the EC specimens was determined by examining and integrating the TCGA and GTEx data. The enriched signaling pathways involved in tumor progression were also examined. Results: Immunohistochemical staining data from the Human Protein Atlas database showed that the differential expression levels of the cyclin dependent kinase inhibitor 2A (CDKN2A) and tyrosine threonine kinase (TTK) molecules, and the high messenger ribonucleic acid (RNA) levels of CDKN2A and TTK were associated with a poor prognosis in EC patients. High TTK expression was also significantly correlated with the tumor progression associated signaling pathways, such as the cell-cycle, nucleolus, and RNA processing pathways. The inhibition of TTK expression by a TTK inhibitor (NTRC0066-0) significantly suppressed the proliferation of the EC cells and synergistically increased the sensitivity of the EN and AN3-CA EC cell lines. Conclusions: The findings suggest that the TTK inhibitor could be used in EC therapy. This study highlighted the potential predictive role of TTK molecules and showed that TTK molecules might serve as prospective targets for EC therapy.
RESUMO
Relapse of acute myeloid leukemia (AML) has a very poor prognosis and remains a common cause of treatment failure in patients with this disease. AML relapse is partially driven by the chemoresistant nature of leukemia stem cells (LSCs), which remains poorly understood, and our study aimed at elucidating the underlying mechanism. Accumulating evidences show that long noncoding RNAs (lncRNAs) play a crucial role in AML development. Herein, the lncRNA, LINC00152, was identified to be highly expressed in CD34+ LSCs and found to regulate the self-renewal of LSCs derived from AML patients. Importantly, LINC00152 upregulation was correlated with the expression of 16 genes within a 17-gene LSC biomarker panel, which contributed to the accurate prediction of initial therapy resistance in AML. Knockdown of LINC00152 markedly increased the drug sensitivity of leukemia cells. Furthermore, LINC00152 expression was found to be correlated with poly (ADP-ribose) polymerase 1 (PARP1) expression in AML, whereas LINC00152 knockdown significantly decreased the expression of PARP1. Upregulation of LINC00152 or PARP1 was associated with poor prognosis in AML patients. Collectively, these data highlight the importance and contribution of LINC00152 in the regulation of self-renewal and chemoresistance of LSCs in AML.
RESUMO
Pancreatic cancer is a common cause of worldwide cancer-related mortality with a poor 5-year survival rate. Aldehyde dehydrogenase (ALDH) activity is a possible marker for malignant stem cells in solid organ systems, including the pancreas, and N,N-diethylaminobenzaldehyde (DEAB) is able to inhibit ALDH activity. In the present study, the role of DEAB in the treatment of pancreatic cancer cells and the potential underlying mechanisms were investigated. The ALDH activities of pancreatic cancer cell lines treated with or without DEAB were analyzed by an ALDEFLUOR™ assay. The Cell Counting Kit-8 and colony formation assays, and cell cycle analysis were used to evaluate the viability, colony-forming ability and cell quiescence of cell lines under DEAB treatment, respectively. DEAB and/or gemcitabine-induced cell apoptosis was assessed by flow cytometry. DEAB reduced ALDH activity and inhibited the proliferation, colony-forming ability and cell quiescence of pancreatic cancer cell lines. Compared with respective controls, DEAB alone and the combination of gemcitabine and DEAB significantly decreased cell viability and increased cell apoptosis. Moreover, reverse transcription-PCR and western blotting were used to measure the expressions of B cell lymphoma 2 (Bcl2) associated X protein (Bax) and Bcl2 mRNA and protein. The anti-cancer effect of DEAB was associated with upregulation of Bax expression. Therefore, targeting ALDH with DEAB may be a potential therapeutic choice for pancreatic cancer, demonstrating a synergic effect with gemcitabine.
RESUMO
OBJECTIVE: To investigate the clinical and laboratorial features of primary myelofibrosis (PMF) patients treated in our hospital, to analyze the risk factors influancing survival, and to compare several prognostic scoring systems. METHODS: parameters about clinical and laboratorial features were taken from medical documents at diagnosis, univariate analysis was conducted by Kaplan-Meier method, the survival data were compared with Log-rank test, and a COX model was used for multivariate analyses. RESULTS: In our center the anemia and JAK2V617F mutation were more common, while the abnormal karyotype was less common, the constitutional symptoms, splenomegaly, Hb level < 100 g/L and LDH are adverse factors for survival in univariate analysis. Constitutional symptoms and Plt count < 100 × 10(9)/L are adverse factors of survival according to multivariate analysis. CONCLUSION: The anemia is more frequent in Chinese patients. Constitutional symptoms and Plt count < 100 × 10(9)/L are independent risk factors for survival. LILLI, modified IPSS, modified DIPSS are suitable to our data.
Assuntos
Cariótipo Anormal , Mielofibrose Primária , Povo Asiático , Humanos , Janus Quinase 2 , Mutação , Prognóstico , Fatores de RiscoRESUMO
The classic BCR-ABL negative myeloproliferative neoplasm (MPN) comprise polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). These three disorders are characterized by stem cell-derived clonal myeloproliferation and presence of somatic mutations. The WHO diagnostic criteria for the classic BCR-ABL negative MPN has been revised in the 2008 edition by incorporating new information about their molecular pathogenesis. Robust prognostic system for PMF has already done, and those for PV and ET are under discussion. Treatment with novel drugs is promising, and allo-stem cell transplantation (allo-ASCT) is the only curative treatment for myelofibrosis, however, the patient selection and management before transplant have been discussed for a long time.