Treosulfan Versus Busulfan-based Conditioning in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-analysis.

It is unclear whether there is a difference in outcomes with treosulfan or busulfan-based conditioning in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). We reviewed the evidence on this topic through a systematic review and meta-analysis, the comparison between treosulfan and busulfan-based conditioning in pediatric patients undergoing HSCT for instance. Six studies were included. Meta-analysis showed that there was no difference in the incidence of acute graft versus host disease (odds ratio [OR]: 0.96; 95% CI: 0.57, 1.61), grade II to IV acute graft versus host disease (OR: 1.19; 95% CI: 0.83, 1.72), chronic GVHD (OR: 1.18; 95% CI: 0.70, 2.00), and veno-occlusive disease (OR: 0.92; 95% CI: 0.22, 3.85) between treosulfan and busulfan groups. Pooled analysis indicated marginally better survival with treosulfan-based conditioning (OR: 1.57; 95% CI: 1.00, 2.44), however, these results were unstable on sensitivity analysis. A meta-analysis found no difference in transplant-related mortality (OR: 0.70; 95% CI: 0.34, 1.42) between the two groups. Retrospective data from a heterogenous population indicates that there is no difference in the rate of GVHD after treosulfan versus busulfan-based conditioning for pediatric HSCT. A marginal improvement in survival was noted with treosulfan but the results remained unstable. Future randomized controlled trials are needed to provide better evidence.

MiR-16-5p suppresses breast cancer proliferation by targeting ANLN.

BACKGROUND: In recent years, gene expression-based analysis has been used for disease biomarker discovery, providing ways for better diagnosis, leading to improvement of clinical treatment efficacy. This study aimed to explore the role of miR-16-5p and ANLN in breast cancer (BC). METHODS: Cohort datasets of BC were obtained from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) and analyzed by bioinformatics tools. qRT-PCR and western blotting were applied to validate ANLN and its protein expression. A dual-luciferase reporter assay was used to prove the regulatory relationship of miR-16-5p and ANLN. Finally, MTT, wound healing, Transwell invasion and flow cytometry analyses of the cell cycle and apoptosis were performed to assess cell proliferation, migration, invasion, cell cycle and apoptosis, respectively. RESULTS: A total of 195 differentially expressed genes (DEGs) and 50 overlapping microRNAs (miRNAs) were identified. Among these DEGs and miRNAs, ANLN, associated with poor overall survival in BC, overlapped in the GSE29431, GSE42568, TCGA and GEPIA2 databases. Moreover, ANLN was highly expressed, while miR-16-5p was lower in BC cells than in breast epithelial cells. Then, we confirmed that ANLN was directly targeted by miR-16-5p in BC cells. Over-expression of miR-16-5p and knock-down of ANLN remarkably inhibited cell proliferation and migration as well as cell invasion, arrested the cells in G2/M phase and induced apoptosis in BC cells. CONCLUSIONS: These findings suggest that miR-16-5p restrains proliferation, migration and invasion while affecting cell cycle and promotes apoptosis by regulating ANLN, thereby providing novel candidate biomarkers for the diagnosis and treatment of BC.

Lithium chloride inhibits cell survival, overcomes drug resistance, and triggers apoptosis in multiple myeloma via activation of the Wnt/ß-catenin pathway.

Multiple myeloma (MM) is an extremely malignant plasma cell disease, which is still incurable due to its drug resistance. Lithium chloride (LiCl) functions in many pathological processes, including bipolar disorder, acute brain injuries, and chronic neurodegenerative diseases, but its antagonistic role in MM progression has not been reported thus far. In this study, we found that LiCl inhibited MM cell proliferation and induced MM cell cycle G2/M phase arrest in a dose-dependent manner. Moreover, LiCl overcomes bortezomib (BTZ)-mediated resistance in MM cells and induces apoptosis in BTZ-resistant cells. Our data preliminarily indicate that LiCl induces MM cell apoptosis via activating the Wnt/ß-catenin signaling pathway. Overall, our results define LiCl as an inducer of MM cell apoptosis and unveil a crosstalk between BTZ and LiCl in facilitating cell apoptosis.

Lysines 207 and 325 methylation of WDR5 catalyzed by SETD6 promotes breast cancer cell proliferation and migration.

Accumulating evidence has revealed that the methylation of lysines on nonhistones by histone lysine methyltransferases (HMTs) is crucial for regulating tumo-rigenesis and metastasis. However, whether the methy-lation of lysines on HMT complex components occurs and has functions in cancer progression is less well understood. WD repeat domain 5 (WDR5) is a core component of an HMT complex named mixed lineage leukemia (MLL)/Suppressor of Variegation, Enhancer of Zeste, and Trithorax 1 (SET1). In the present study, it was reported that lysines 207 and 325 (K207 and K325, respectively) of WDR5 were monomethylated by SET­domain­containing protein methyltransferase 6. Disrupting the methylation of K207/K325 via a K207R/K325R double­site mutation attenuated the WDR5 promotion of breast cancer cell proliferation and migration. Methylation of K207/K325 on WDR5 partially contributed to maintaining global histone tri­methylation of lysine 4 on histone H3 levels, but did not affect MLL/SET1 complex assembly. These results further understanding of a potential post­translational modification of WDR5, and imply that the methylation of lysines on HMT complex components is crucial for regulating human carcinogenesis.

[Effects of HDAC Inhibitor Scriptaid on IM9 Cell Line and Its Mechanism].

OBJECTIVE: To study the effect of HDAC inhibitor Scriptaid on multiple myeloma IM9 cells and preliminarily clarify the mechanism of Scriptaid-induced cell apoptosis. METHODS: The cell viability, cell cycle and cell apoptosis were measured by CCK8 assay and flow cytometry respectively, the relative target gene expression levels were detected by RT-PCR, the effect of Scriptaid on p21 promoter activity was detected by using luciferase reporter assay. RESULTS: Scriptaid inhibited IM9 cell viability in a dose-dependent manner. Scriptaid induced IM9 cell cycle arrest at G2/M phase in a dose-dependent manner. Scriptaid triggered IM9 cell apoptosis was obviously, the mRNA levels of apoptosis-related proteins Caspase 9, Caspase 3 and PARP1 were also activated. The apoptosis-associated factors BAD, PTEN and p21 increased following treatment with different dose of Scriptaid, meanwhile, p21 promoter activity was also activated significantly. CONCLUSION: HDAC inhibitor Scriptaid can promote IM9 cell apoptosis by transcriptional activation of p21 promoter in concentration-dependent manner.

Scriptaid inhibits cell survival, cell cycle, and promotes apoptosis in multiple myeloma via epigenetic regulation of p21.

Multiple myeloma (MM) is an extremely serious plasma cell malignancy. Despite the recent introduction of chemotherapies such as bortezomib and lenalidomide, it remains an incurable disease due to the high rate of relapse and the development of drug resistance. Epigenetic regulation is closely related to MM progression, but the epigenetic modification mechanism of MM cell apoptosis has remained unclear. As a novel histone deacetylase inhibitor (HDACi), Scriptaid's possible roles in MM progression have not been explored. Herein, we found that Scriptaid decreased several human MM cell viabilities in a dose-dependent manner. Scriptaid was also able to dose dependently and significantly induce MM cell cycle arrest at the G2/M phase. Moreover, Scriptaid facilitates p21 transcriptional activities by mediating H3Ac gene-activated modification, eventually leading to MM cell apoptosis. Overall, our results show that Scriptaid is an inducer of MM cell death, suggesting the possibility for Scriptaid-mediated therapeutics to cure refractory/relapsed MM.

Histone deacetylase inhibitor NaBut suppresses cell proliferation and induces apoptosis by targeting p21 in multiple myeloma.

Multiple myeloma (MM) is an extremely serious hematological malignancy that remains incurable due to chemotherapy resistance. Epigenetic regulation is closely associated with progression of MM. Histone deacetylase inhibitor NaBut functions in various physiologic processes, including inflammation and differentiation. Its' possible roles in MM progression have not been explored. In this report, NaBut decreased survival of several human MM cell lines in a dose- and time-dependent manner. NaBut could also lead to cell cycle arrest at the G2/M phase in a dose-dependent manner. NaBut inhibited bortezomib-resistant cell proliferation in dose- and time-dependent manners, and NaBut was likely to induce partly bortezomib-resistant MM cell death. Moreover, NaBut induced MM cell apoptosis via transcriptional activation of p21. Overall, our results implicate NaBut as a potential therapeutic drug for MM.