MicroRNAs (miRNAs) are small (~22 nucleotide) non-coding RNAs whose altered expression has been associated with various types of cancers, including leukemia. In the present study, we conducted a quantitative PCR (qPCR) analysis of expression of 23 human precursor miRNAs in bone marrow specimens of 85 Chinese primary leukemia patients, including 53 acute myeloid leukemia (AML) and 32 acute lymphoblastic leukemia (ALL) cases. We show that 16 miRNAs were differentially expressed between AMLs and ALLs; Of them, eight were previously reported (i.e., miR-23a, miR-27a/b, miR-128a, miR-128b, miR-221, miR-222, miR-223, and let-7b) and eight were newly identified (i.e., miR-17, miR-20a, miR-29a/c, miR-29b, miR-146a, miR-150, miR-155, and miR-196b). More importantly, through correlating miRNA expression signatures with outcome of patients, we further show that expression signatures of a group of miRNAs are associated with overall survival of patients. Of them, three (i.e., miR-146a, miR-181a/c, and miR-221), five (i.e., miR-25, miR-26a, miR-29b, miR-146a, and miR-196b), and three (i.e., miR-26a, miR-29b, and miR-146a) miRNAs are significantly associated with overall survival (P<0.05) of the 32 ALL, 53 AML, and 40 non-M3 AML patients, respectively. Particularly, the expression signature of miR-146a is significantly inversely correlated with overall survival of both ALL and AML patients. The prognostic significance of miR-146a in AML has been confirmed further in an independent study of 61 Chinese new AML patient samples. We also identified 622 putative target genes of miR-146a that are predicted by at least three out of the five major prediction programs (i.e., TragetScan, PicTar, miRanda, miRBase Targets, and PITA); Through gene ontology analysis, we found that these genes were particularly enriched (2–9 fold higher than expected by chance) in the GO categories of “negative regulation of biology processes”, “negative regulation of cellular processes”, “apoptosis”, and “cell cycle”, which may be related to the association of miR-146a with poor survival.
Abstract:Objective: Gorham-Stout syndrome (GSS) is a rare disorder of uncertain etiology and unpredictable prognosis. This study aims to present a comprehensive understanding of this rare entity. Methods: A literature search in PubMed and three Chinese databases was performed to screen histologically proven GSS cases among Chinese residents in the mainland. We analyzed the patients' clinical characteristics, the value of different treatment modalities and their influence on the clinical outcome. Results: Sixty-seven cases were finally enrolled. There were 43 men (64.2%) and 24 women (35.8%). The mean age at diagnosis was 28 years (1.5-71 years). The most common clinical symptoms included pain (n=40, 59.7%), functional impairment (n=13, 19.4%), and swelling (n=12, 17.9%). The radiographic presentation of 37 cases (55.2%) was disappearance of a portion of the bone. The others presented as radiolucent foci in the intramedullary or subcortical regions. A total of 42 cases provided data on therapy, these included surgery (n=27, 40.3%), radiation therapy (n=6, 9.0%), surgery combined with radiation therapy (n=2, 3.0%), and medicine therapy (n=7, 10.4%). For 30 of these 42 cases, follow-up data were available: 21 cases had the disorder locally controlled and 9 had a symptom progression. Fortunately, the disease is not fatal in the majority of cases. Conclusions: GSS has no specific symptoms and it should be taken into consideration when an unclear massive osteolysis occurs. The efficacies of different treatment modalities are still unpredictable and further research is required to assess the values of different treatments.
Chidamide, a novel histone deacetylase (HDAC) inhibitor, induces antitumor effects in various types of cancer. The present study aimed to evaluate the cytotoxic effect of chidamide on multiple myeloma and the underlying mechanisms involved. Viability of multiple myeloma cells upon chidamide treatment was determined by the Cell Counting Kit-8 assay. Apoptosis induction and cell cycle alteration were detected by flow cytometry. Specific apoptosis-associated proteins and cell cycle proteins were evaluated by western blot analysis. Chidamide suppressed cell viability in a time- and dose-dependent manner. Chidamide treatment markedly suppressed the expression of type I HDACs and further induced the acetylation of histones H3 and H4. In addition, it promoted G 0 /G 1 arrest by decreasing cyclin D1 and c-myc expression, and increasing phosphorylated-cellular tumor antigen p53 and cyclin-dependent kinase inhibitor 1 (p21) expression in a dose-dependent manner. Treatment with chidamide induced cell apoptosis by upregulating the apoptosis regulator Bax/B-cell lymphoma 2 ratio in a caspase-dependent manner. In addition, the combination of chidamide with bortezomib, a proteasome inhibitor widely used as a therapeutic agent for multiple myeloma, resulted in enhanced inhibition of cell viability. In conclusion, chidamide induces a marked antimyeloma effect by inducing G 0 /G 1 arrest and apoptosis via a caspase-dependent pathway. The present study provides evidence for the clinical application of chidamide in multiple myeloma.
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