No abstract

Novel sequencing designs are necessary to supplement the recognized knowledge of myelodysplastic syndrome (MDS)-related genomic alterations. In this study, we sequenced 28 target genes in 320 Chinese MDS patients but obtained 77.2% of recall factors and 82.8% of genetic abnormalities (including karyotype abnormalities). In addition to known relationships among mutations, some specific chromosomal abnormalities were found to link to specific gene mutations. Trisomy 8 tended to be linked to U2AF1 and ZRSR2 mutations, and 20q- exhibited higher SRSF2/WT1 and U2AF1 mutation frequency. Chromosome 7 involvement accounted for up to 50% of RUNX1 mutations and 37.5% of SETBP1 mutations. Patients carrying a complex karyotype were prone to present TP53 mutations (36.1%). However, individuals with normal karyotypes rarely possessed mutations in the TP53, RUNX1 and U2AF1. Moreover, DNMT3A, TP53, SRSF2, STAG2, ROBO1/2 and WT1 predicted poor survival and high AML transformation. By integrating these predictors into international prognostic scoring system (IPSS) or revised IPSS, we built a set of mutation-based prognostic risk models. These models could layer different degrees of risk in patients more satisfactorily. In summary, this sequencing design was able to detect a number of gene mutations and could be used to stratify patients with varied prognostic risk.

We determined the biological and prognostic significance of five recurrent genetic aberrations in Chinese patients with myelodysplastic syndromes (MDS). A total of 304 Chinese MDS patients were screened for known mutations in five genes (ASXL1, U2AF1, SF3B1, SRSF2, and EZH2) using next-generation sequencing. Of these, 97 patients (31.9 %) harbored at least one mutation in the five genes, and patients harboring these mutations had distinct clinical features. Incidence ratios for mutations in ASXL1, U2AF1, SF3B1, SRSF2, and EZH2 were 11.8, 8.6, 8.2, 4.3, and 3.6 %, respectively. Patients with U2AF1, SRSF2, and EZH2 mutations more commonly had high-risk than low-risk subtypes, while SF3B1 mutations were frequently confirmed in MDS subtypes with increased ring sideroblasts. Cases with ASXL1 mutations had a higher percentage of complex karyotypes, while U2AF1 mutations were more common in patients with trisomy 8 or 20q deletions. Notably, among 124 patients with a normal karyotype, 48 (38.7 %) had at least one mutation. Patients with U2AF1 or SRSF2 mutations had significantly shorter overall survival (OS) times compared with patients without these mutations (U2AF1 mutations: median OS, 18 vs 54 months, p = 0.032; SRSF2 mutations: median OS 11 vs 54 months, p = 0.005, respectively). Multivariate analysis showed that the presence of SRSF2 mutations was an independent unfavorable prognostic factor for OS (hazard ratio 2.039; 95 % confidence interval 1.040-4.000; p = 0.038). These data suggest that mutations in epigenetic modification and splicesome genes are common in Chinese patients with MDS, while mutations in U2AF1 and SRSF2 appear to predict an unfavorable prognosis.

Background To identify the performance of contrast‐enhanced spectral mammography (CESM) and magnetic resonance imaging (MRI) for breast cancer diagnosis by pooling the open published data. Methods A systematic review of studies relevant to CESM and MRI in the diagnosis of breast cancer were screened in the electronic databases of Pubmed, EMBASE, the Cochrane Library, Web of Science, Google scholar and CNKI. The methodical quality of the included publications was evaluated by the quality assessment of diagnostic accuracy studies‐2 (QUADAS‐2). The diagnostic sensitivity, specificity and area under the ROC curve (AUC) were pooled and the true positive (TP), false positive (FP), false negative (FN) and true negative (TN) of the original studies were calculated. Results A total of 13 diagnostic publications were identified and included in the meta‐analysis. Of those included, five were retrospective studies and the remaining eight were prospective work. The combined data indicating the pooled sensitivity and specificity of CESM and MRI were 0.97 (95% CI: 0.95–0.98), 0.66 (95% CI: 0.59–0.71), 0.97 (95% CI: 0.95–0.98),and 0.52 (95% CI: 0.46–0.58), respectively. The pooled +LR and –LR for CESM were 2.70 (95% CI: 1.57–4.65), 0.06 (95% CI: 0.04–0.09), and 2.01 (95% CI: 1.78–2.26), 0.08 (95% CI: 0.05–0.11) for MRI, respectively. For the diagnostic odds ratio (DOR), the pooled results of CESM and MRI were 60.15 (95% CI: 24.72–146.37) and 31.34 (95% CI: 19.61–50.08), respectively. The AUC of the symmetric receiver operating characteristic curve (SROC) was 0.9794 and 0.9157 for CESM and MRI, respectively, calculated using the Moses model in the diagnosis of breast cancer. Conclusions Both CESM and MRI are effective methods for the detection of breast cancer with high diagnostic sensitivity. The diagnostic performance of CESM appears to be more effective than MRI.

The progressive mechanism underlying myelodysplastic syndrome remains unknown. Here we identify ROBO1 and ROBO2 as novel progression-related somatic mutations using whole-exome and targeted sequencing in 6 of 16 (37.5%) paired MDS patients with disease progression. Further deep sequencing detects 20 (10.4%) patients with ROBO mutations in a cohort of 193 MDS patients. In addition, copy number loss and loss of heterogeneity (LOH) of ROBO1 and ROBO2 are frequently observed in patients with progression or carrying ROBO mutations. In in vitro experiments, overexpression of ROBO1 or ROBO2 produces anti-proliferative and pro-apoptotic effects in leukaemia cells. However, this effect was lost in ROBO mutants and ROBO-SLIT2 signalling is impaired. Multivariate analysis shows that ROBO mutations are independent factors for predicting poor survival. These findings demonstrate a novel contribution of ROBO mutations to the pathogenesis of MDS and highlight a key role for ROBO-SLIT2 signalling in MDS disease progression.

Rigosertib has demonstrated therapeutic activity for patients with high-risk myelodysplastic syndrome (MDS) in clinical trials. However, the role of rigosertib in MDS has not been thoroughly characterized. In this study, we found out that rigosertib induced apoptosis, blocked the cell cycle at the G2/M phase and subsequently inhibited the proliferation of CD34+ cells from MDS, while it minimally affected the normal CD34+ cells. Further studies showed that rigosertib acted via the activation of the P53 signaling pathway. Bioinformatics analysis based on gene expression profile and flow cytometry analysis revealed the abnormal activation of the Akt-PI3K, Jak-STAT and Wnt pathways in high-grade MDS, while the p38 MAPK, SAPK/JNK and P53 pathways were abnormally activated in low-grade MDS. Rigosertib could markedly inhibit the activation of the Akt-PI3K and Wnt pathways, whereas it activated the SAPK/JNK and P53 pathways in high-grade MDS. A receptor tyrosine kinase phosphorylation array demonstrated that rigosertib could increase the activation of RET and PDGFR-β while reducing the activation of Tie2 and VEGFR2 in MDS cells. Taken together, these data indicate that rigosertib is a selective and promising anti-tumor agent that could ameliorate multiple dysregulated signaling transduction pathways in high-grade MDS.

Background Atherosclerosis (AS), which characterized with the accumulation of lipids on the vessel wall, is the pathological basis of many cardiovascular diseases (CVD) and seriously threatens human health. Resveratrol (RES) has been reported to be benefit for AS treatment. This research aimed to observe the effects of RES on AS induced by high-fat diet (HFD) and LPS in ApoE−/− mice and investigate the underlying mechanism. Methods ApoE−/− mice were fed with HFD companied with LPS to induce AS and RES was administrated for 20 weeks. Splenic CD4+ T cells were cultured and treated with anti-CD3/CD28 together with LPS, and RES was added. Serum lipids and the atherosclerotic areas of aortas were detected. The activation of CD4+ T cells were investigated both in vivo and in vitro and the expression of DNA methyltransferases (Dnmt) in CD4+ T cells were measured. Results In vivo, administration of RES prevented HFD and LPS induced dysfunction of serum lipids including TC (total cholesterol), TG (triglyceride), LDL-C (low density lipoprotein cholesterol) and HDL-C (high density lipoprotein cholesterol), ameliorated the thickened coronary artery wall and decreased the areas of atherosclerotic lesion on aortas. Besides, RES decreased the number of CD4+ T cells in peripheral blood, decreased the expression of CD25 and CD44, but not affected the expression of L-selectin (CD62L). In vitro, RES decreased the expression of Ki67, CD25 and CD44 in CD4+ T cells. Moreover, RES increased the secretion of IL-2, IL-10 and TGF-β1, decreased IL-6. In addition, RES decreased both the mRNA and protein level of Dnmt1 and Dnmt3b in CD4+ T cells. Conclusion These results indicated that RES ameliorated AS induced by HFD companied with LPS in ApoE−/− mice, inhibited the proliferation and activation of CD4+ T cells and regulated the expression of Dnmt1 and Dnmt3b.

BackgroundDespite the efficacy of decitabine treatment in myelodysplastic syndrome (MDS), no definite predictor of response is known. In this study, we investigated whether the expression levels of human equilibrative nucleoside transporter 1 (hENT1), hENT2, deoxycytidine kinase (DCK) and cytidine deaminase (CDA) genes could predict response to decitabine in MDS.MethodsWe performed quantitative real-time PCR in marrow mononuclear cells to examine the expression of hENT1, hENT2, DCK, and CDA prior to therapy in 98 MDS patients initially treated with decitabine. Response and overall survival of patients treated with decitabine were analyzed according to gene expression levels. HENT1 knockdown was performed by shRNA in the SKM-1 cell line, and the effect of this on the demethylation ability of decitabine on long interspersed nucleotide element 1 (LINE1) was investigated.ResultsPatients responding to decitabine presented with significantly higher hENT1 expression levels than non-responders (p = 0.004). Overall response, complete response, and cytogenetic complete response rate in patients with high hENT1 expression (79.4, 41.3, and 43.8 %) were significantly higher than those in patients with low hENT1 expression (48.6, 20.0, and 5.9 %, respectively) (p = 0.004, 0.033, and 0.006, respectively). In higher-risk MDS, patients with high hENT1 expression showed prolonged survival compared with those with low hENT1 expression (22.0 vs 14.0 months; p = 0.027). However, the expression levels of hENT2, DCK, and CDA did not affect response rate. Knockdown of hENT1 in SKM-1 cells weakened the demethylation effect on LINE1 induced by decitabine.ConclusionsHigh expression of hENT1 appears to predict a good response to decitabine and a prolonged survival in higher-risk MDS patients treated with decitabine. HENT1 expression knockdown weakens the demethylation effect of decitabine.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0817-9) contains supplementary material, which is available to authorized users.