Abstract Purpose Diabetes mellitus (DM) is the second most common comorbidity in myelodysplastic syndromes (MDS). The purpose of the study was to investigate the clinical characteristics of MDS patients with DM. Methods A retrospective analysis was performed on the clinical data of 890 MDS patients with or without DM. Clinical data, including genetic changes, overall survival (OS), leukemia-free survival (LFS) and infection, were analyzed. Results Among 890 patients, 184 (20.7%) had DM. TET2 and SF3B1 mutations occurred more frequently in the DM group than those in the non-DM group ( p = 0.0092 and p = 0.0004, respectively). Besides, DM was an independent risk factor for infection (HR 2.135 CI 1.451–3.110, p = 0.000) in MDS. Compared to non-DM patients, MDS patients with DM had poor OS and LFS ( p = 0.0002 and p = 0.0017, respectively), especially in the lower-risk group. While in multivariate analysis, DM did not retain its prognostic significance and the prognostic significance of infection was maintained (HR 2.488 CI 1.749–3.538, p = 0.000). Conclusions MDS patients with DM have an inferior prognosis which may due to higher infection incidence, with TET2 and SF3B1 mutations being more frequent in those cases.
Abstract 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.
Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 ( ROBO1 ) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42 , a member of the Rho–guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1 -deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42 .
Neural precursor cells (NPCs) are a group of cells with self-renewal and multi-differentiation potential. MicroRNAs are required for neurogenesis in the central nervous system (CNS). Recent reports suggest that miR-1224 is important in human CNS diseases. However, its function in neurogenesis of brain development is unclear. The current study demonstrated the essential while developing the neocortex. The results showed that miR-1224 facilitated more NPCs to differentiate into neurons and oligodendrocytes while suppressing astrocyte differentiation. Conversely, inhibition of miR-1224 enhances the self-renewal ability and apoptosis of NPCs. The role of miR-1224 in the developing neocortex was examined by performing in-utero electroporation in vivo. It was observed that depletion impeded upper-layer Cux1
Abstract Purpose: Diabetes mellitus (DM) is the second most common comorbidity in myelodysplastic syndromes (MDS). The purpose of the study was to investigate the clinical characteristics of MDS patients with DM. Methods: A retrospective analysis was performed on the clinical data of 958 MDS patients with and without DM. Clinical data, including genetic changes, overall survival (OS), leukemia-free survival (LFS) and infection, were analyzed. Results: Among 958 patients, 202 (21.1%) had DM. TET2 and SF3B1 mutations occurred more frequently in the DM group than in the non-DM group (p = 0.0124 and p = 0.0009, respectively). Compared to non-DM patients, MDS patients with DM had poor OS and LFS (p < 0.0001 and p = 0.0003, respectively), especially in the lower-risk group. In multivariate analysis, DM independently predicted OS (HR 1.369 CI 1.078-1.738, p = 0.010). Meanwhile, DM was an independent risk factor for bacterial infection (HR 2.055 CI 1.415-2.984, p = 0.000) and fungal infection (HR 2.146 CI 1.422-3.238, p = 0.000) in MDS. Conclusions: MDS patients with DM have an inferior prognosis and higher infection incidence, with TET2 and SF3B1 mutations being more frequent in those cases.
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.
Despite 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. We 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. Patients 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. High 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.
Objective: To investigate the abnormalities of iron metabolism parameters, the prevalence and risk factors of iron overload and clinical characteristics of patients with myelodysplastic syndromes(MDS). Methods: Retrospective investigation was used to observe abnormal iron metabolism parameters and clinical characteristics of newly diagnosed 94 MDS patients in our center from June 2015 to March 2016. Results: Of 94 patients, 71(75.53%)had a hemoglobin level of less than 100 g/L at diagnosis. Iron overload was observed in 52(55.32%)of 94 MDS patients, in which a higher prevalence of iron overload was observed in low risk groups(IPSS low/Int-1 risk groups)than higher risk groups(Int-2/high risk groups). Higher levels of serum iron(SI)[36.5(8.5-64.7)mmol/L vs 25.2(3.7-45.3)mmol/L, P<0.01], transferrin saturation(TSAT)[43.5(12.2-77.2)% vs 53.4(14.8-97.5)%, P <0.01]and serum ferritin(SF)were observed in iron overload group. No differences of labile cellular iron(LCI)and reactive oxygen species(ROS)were observed between two groups(P=0.88, P=0.06). As the results of clinical complication of iron overload, alanine aminotransferase(ALT)[25(3-158)U/L vs 16(5-80)U/L, P=0.03]and type B natriuretic peptide precursor(proBNP)[190(6-4281)ng/L vs 84(12-2 275)ng/L, P= 0.05]levels were increased in iron overload group. There was no significant difference in iron metabolism parameters between patients with refractory anemia(RARS)and non RARS patients(P>0.05). Both frequency and volume of RBC transfusion had a significant effect on all iron metabolism parameters(SI, TSAT and SF)(P <0.01)except LCI and ROS. Excluded the patients with history of blood transfusion and SF levels over 1 000 μg/L, higher levels of LCI were mainly observed in dysplastic erythropoiesis and increased bone marrow erythroblasts ratio groups(P<0.01, P<0.05). Conclusion: The main cause of iron overload in MDS is chronic transfusion therapy. Both frequency and intensity of transfusion regimen have a main effect on iron metabolism parameters. LCI levels are mainly increased in newly diagnosed patients with the abnormalities of iron metabolism and have a stronger association with dysplastic erythropoiesis and increased bone marrow erythroblasts ratio. As the toxic fraction of iron and its negative impact on MDS, iron overload monitoring and chelation treatment decision can also be supported by LCI.
Monosomic karyotype (MK) has recently been associated with poor prognosis of myelodysplastic syndromes (MDS). The objective of the current study was to investigate the prevalence and spectrum of autosomal monosomies in an unselected cohort of patients with known or suspected MDS by using retrospective analysis. The results showed that bone marrow cytogenetic studies (1532 cases) were performed between 2004 and 2012, and an abnormal karyotype was found in 538 cases (35.1%). In the 538 cases, 202 (37.5%) cases had autosomal monosomies including sole (n = 47, 23.3%), part of two (n = 33, 21.3%) or more (n = 122, 78.7%) anomalies. Almost all 22 autosomes were involved, but monosomy 7 was by far the most frequent, constituting 66.1% of all isolated monosomies and the highest fraction of those with two or more abnormalities. Other recurrent sole monosomies included chromosomes 20 (15.0%) and 13 (8.5%). Monosomy 13 (12.5%), 18 (8.3%), 20 (6.3%), 17 (7.3%), 21 (5.2%), 5 (5.2%) and 12 (5.2%) were also recurrent in the setting of 3 abnormalities. Bone marrow histology and clinical information were reviewed in all cases with isolated monosomy; associated clinical phenotypes were found in RCMD (n = 20, 13 were -7), RAEB (n = 12, 11 were -7), RA (n = 9, 3 were -7) and chronic myelomonocytic leukemia (CMML, n = 6, 4 were -7) cases. Sole monosomy 20 (n = 7, RA 3 case and RCMD 4 cases) was not detected in RAEB or CMML cases. It is concluded that the presence of at least 1 autosomal monosomy was documented in approximately 37.5% of all abnormal cases, which has potential impact on a more than trivial fraction of patients with MDS. The preponderance of monosomy 7 implicates a pathogenetic role for haploinsufficiency of genes associated with chromosome 7. The rarity of sole monosomy involving other chromosomes other than 7, 20, and 13 suggests that haploinsufficiency involving entire chromosomes is detrimental to cell survival, unless their effect is overcome by the presence of other genetic changes that are often associated with additional chromosomal abnormalities. The observation is consistent with the usually favorable prognostic profile associated with sole monosomy 20.
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