Acute myeloid leukemia (AML) represents an aggressive hematopoietic malignancy with a prognosis inferior to that of other leukemias. Recent targeted therapies offer new opportunities to achieve better treatment outcomes. However, due to the complex heterogeneity of AML, its prognosis remains dismal. In this study, we first identified the correlation between high expression of BRD4 and overall survival of patients with AML. Targeted degradation of BRD2, BRD3, and BRD4 proteins by dBET1, a proteolysis-targeting chimera (PROTAC) against the bromodomain and extra-terminal domain (BET) family members, showed cytotoxic effects on Kasumi (AML1-ETO), NB4 (PML-RARa), THP-1 (MLL-AF9), and MV4-11 (MLL-AF4) AML cell lines representing different molecular subtypes of AML. Furthermore, we determined that dBET1 treatment arrested cell cycling and enhanced apoptosis and c-MYC was identified as the downstream target. Collectively, our results indicated that dBET1 had broad anti-cancer effects on AML cell lines with different molecular lesions and provided more benefits to patients with AML.
Surgical stress initiates a series of host hormone, metabolism and immune responses, which predominantly affect the homeostatic mechanism of patients with major surgery. B7-H3 is a co-stimulatory molecule and has been shown to participate in both adaptive and innate immune responses. In this study we evaluated the clinical significance of plasma B7-H3 levels in pediatric patients with different types of operation and degrees of surgical stress. A total of 48 children received pediatric general and cardiac surgery were recruited into this study. Based on the surgical stress scoring, children were divided into moderate stress (n = 14) and severe stress (n = 34) groups. Plasma B7-H3 levels were assessed at selected time points: before surgery, immediately after surgery, at day 1, day 3, and day 7 after surgery. Correlations between plasma B7-H3 levels and surgical stress scores were also examined. Plasma B7-H3 levels were significantly decreased in all 48 pediatric patients after surgery compared to the B7-H3 level before surgery (p < 0.01). Children with general surgery showed significant decreases in plasma B7-H3 immediately after surgery, and at day 3 and day 7 after surgery (p < 0.05, p < 0.01), whereas children with cardiac surgery showed reduced plasma B7-H3 immediately after surgery and at day 3 after surgery (p < 0.05). Plasma B7-H3 in cardiac surgery group was dropped much lower than that in general surgery group at day 1 (p < 0.05) and day 3 (p < 0.01) after surgery. Significantly reduced plasma B7-H3 was observed in the severe stress group, but not in the moderate stress group, immediately after surgery and at day 3 after surgery (p < 0.05), and severe stress group had significantly lower plasma B7-H3 levels than moderate stress group at day 1, day 3, and day 7 after surgery (p < 0.05). Furthermore, plasma B7-H3 levels at day 1 (p = 0.01) and day 3 (p = 0.025) after surgery correlated negatively with surgical stress scores. Plasma B7-H3 levels were decreased significantly in children subjected to pediatric general and cardiac surgery, which is closely associated with the severity of surgical stress. The negative correlation of plasma B7-H3 levels at day 1 and day 3 after surgery with surgical stress scoring implicates that the plasma B7-H3 level might be a useful biomarker for monitoring stress intensity during pediatric surgery.
Abstract Neuroblastoma is a unique malignancy in infants often presenting with either localized or metastatic disease. The study was carried out to explore the risk stratification of the poor prognosis for patients underwent surgical treatment. 60 patients diagnosed with neuroblastoma were primarily enrolled in the study from April 2008 to April 2016. All the patients underwent surgical treatment and received 5-year follow-up. Clinical variables, including age, International Neuroblastoma Staging System (INSS) stage, tumor size and site, histology, and MYCN status were retrospectively analyzed, and EFS was chosen as the endpoint. The median age of patients was 8.2 months and average follow-up period was 40.2 ± 8.6 months. Among 60 patients, complete remission was achieved in 35 patients and partial remission in 14 subjects. Poor prognosis including patient death and tumor progression were overserved in 11 patients. Cox multifactor regression analysis revealed that age, histology and MYCN status had significant prognostic effect on event-free survival (EFS) rate for neuroblastoma patients underwent surgical treatment. In our study, we identified a series of prognostic factors including age, histology, and MYCN status predicting the prognosis of neuroblastoma patients after surgical treatment.
The purpose of this study was to investigate invasion and metastasis related genes in gastric cancer. The transwell migration assay was used to select a highly invasive sub-line from minimally invasive parent gastric cancer cells, and gene expression was compared using a microarray. MMP28 upregulation was confirmed using qRT-PCR. MMP28 immunohistochemistry was performed in normal and gastric cancer specimens. Invasiveness and tumor formation of stable cells overexpressing MMP28 were tested in vitro and in vivo. MMP28 was overexpressed in the highly invasive sub-cell line. Immunohistochemistry revealed MMP28 expression was markedly increased in gastric carcinoma relative to normal epithelia, and was significantly associated with depth of tumor invasion, lymph node metastasis and poorer overall survival. Ectopic expression of MMP28 indicated MMP28 promoted tumor cell invasion in vitro and increased gastric carcinoma metastasis in vivo. This study indicates MMP28 is frequently overexpressed during progression of gastric carcinoma, and contributes to tumor cell invasion and metastasis. MMP28 may be a novel therapeutic target for prevention and treatment of metastases in gastric cancer.
Distraction osteogenesis (DO) is a bone regeneration technique used to treat maxillofacial disorders, fracture nonunion, and large bone defects. It is well known for its amazing regenerative potential, but an extended consolidation period limits its clinical use. The interaction between the nervous system and bone regeneration has attracted great attention in recent years. Sema3A is a key axonal chemorepellent which has been proved to have bone-protective effects. In this article, we try to improve DO by local administration of Sema3A and explore the possible mechanisms. Forty wildtype, male, adult mice were divided into two groups after tibia osteotomy surgery. Sema3A or Saline was daily injected transcutaneous into the center of the distraction zone during the consolidation period. Micro-CT images were taken at 4, 6,8 and 10 weeks post-surgery; vascular density and biomechanical testing were performed at 10 weeks post-surgery. We also set up in vitro vessel growth assay to evaluate the effect of Sema3A on angiogenesis. Compared with the Saline group, Sema3A treatment significantly accelerated bone regeneration, improved angiogenesis and callus’ biomechanical strength. At 10 weeks post-surgery, compared with the Saline group, the BV/TV, BMD, TMD increased by about 23%, 22%, 18% respectively, vascular density increased by about 49% in the Sema3A group. Histological images and western-blot showed decreased expression of VEGF-A and increased expression of Ang-1 at 4 weeks post-surgery in the Sema3A group. In vitro, Sema3A suppressed VEGF-induced angiogenesis but had little effect on Ang-induced angiogenesis. Conclusion: Sema3A could accelerate bone regeneration and improve angiogenesis during DO.
Acute myeloid leukemia (AML) is a myeloid neoplasm makes up 7.6% of hematopoietic malignancies. Super-enhancers (SEs) represent a special group of enhancers, which have been reported in multiple cell types. In this study, we explored super-enhancer profiling through ChIP-Seq analysis of AML samples and AML cell lines, followed by functional analysis.ChIP-seq analysis for H3K27ac was performed in 11 AML samples, 7 T-ALL samples, 8 B-ALL samples, and in NB4 cell line. Genes and pathways affected by GNE-987 treatment were identified by gene expression analysis using RNA-seq. One of the genes associated with super-enhancer and affected by GNE-987 treatment was LYL1 basic helix-loop-helix family member (LYL1). shRNA mediated gene interference was used to down-regulate the expression of LYL1 in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells.We identified a total of 200 genes which were commonly associated with super-enhancers in ≧10 AML samples, and were found enriched in regulation of transcription. Using the BRD4 inhibitor GNE-987, we assessed the dependence of AML cells on transcriptional activation for growth and found GNE-987 treatment predominantly inhibits cell growth in AML cells. Moreover, 20 candidate genes were selected by super-enhancer profile and gene expression profile and among which LYL1 was observed to promote cell growth and survival in human AML cells.In summary, we identified 200 common super-enhancer-associated genes in AML samples, and a series of those genes are cancer genes. We also found GNE-987 treatment downregulates the expression of super-enhancer-associated genes in AML cells, including the expression of LYL1. Further functional analysis indicated that LYL1 is required for AML cell growth and survival. These findings promote understanding of AML pathophysiology and elucidated an important role of LYL1 in AML progression.
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