DNMT3A mutations are associated with poor prognosis in acute myeloid leukemia (AML), but the stability of this mutation during the clinical course remains unclear. In the present study of 500 patients with de novo AML, DNMT3A mutations were identified in 14% of total patients and in 22.9% of AML patients with normal karyotype. DNMT3A mutations were positively associated with older age, higher WBC and platelet counts, intermediate-risk and normal cytogenetics, FLT3 internal tandem duplication, and NPM1, PTPN11, and IDH2 mutations, but were negatively associated with CEBPA mutations. Multivariate analysis demonstrated that the DNMT3A mutation was an independent poor prognostic factor for overall survival and relapse-free survival in total patients and also in normokaryotype group. A scoring system incorporating the DNMT3A mutation and 8 other prognostic factors, including age, WBC count, cytogenetics, and gene mutations, into survival analysis was very useful in stratifying AML patients into different prognostic groups (P < .001). Sequential study of 138 patients during the clinical course showed that DNMT3A mutations were stable during AML evolution. In conclusion, DNMT3A mutations are associated with distinct clinical and biologic features and poor prognosis in de novo AML patients. Furthermore, the DNMT3A mutation may be a potential biomarker for monitoring of minimal residual disease. (Blood. 2012;119(2):559-568)

The impact of WT1 mutations in acute myeloid leukemia (AML) is not completely settled. We aimed to determine the clinical implication of WT1 mutation in 470 de novo non-M3 AML patients and its stability during the clinical course. WT1 mutations were identified in 6.8% of total patients and 8.3% of younger patients with normal karyotype (CN-AML). The WT1 mutation was closely associated with younger age (P < .001), French-AmericanBritish M6 subtype (P ‫؍‬ .006), and t(7; 11)(p15;p15) (P ‫؍‬ .003). Multivariate analysis demonstrated that the WT1 mutation was an independent poor prognostic factor for overall survival and relapse-free survival among total patients and the CN-AML group. A scoring system incorporating WT1 mutation, NPM1/FLT3-ITD, CEBPA mutations, and age into survival analysis proved to be very useful to stratify CN-AML patients into different prognostic groups (P < .001). Sequential analyses were performed on 133 patients.

The loss of overlying enamel or cementum exposes dentinal tubules and increases the risk of several dental diseases, such as dentin hypersensitivity (causing sharp pain and anxiety), caries, and pulp inflammation. This paper presents a fast-reacting, more reliable and biocompatible biomaterial that effectively occludes exposed dentinal tubules by forming a biomimetic crystalline dentin barrier. To generate this biomaterial, a gelatin-templated mesoporous silica biomaterial (CaCO3@mesoporous silica, CCMS) containing nanosized calcium carbonate particles is mixed with 30% H3PO4 at a 1/1 molar ratio of Ca/P (denoted as CCMS-HP), which enables Ca2+ and PO4(3-)/HPO4(2-) ions to permeate the dentinal tubules and form dicalcium phosphate dihydrate (DCPD), tricalcium phosphate (TCP) or hydroxyapatite (HAp) crystals at a depth of approximately 40 μm (sub-μ-CT and nano-SEM/EDS examinations). In vitro biocompatibility tests (WST-1 and lactate dehydrogenase) and ALP assays show high cell viability and mineralization ability in a transwell dentin disc model treated with CCMS-HP (p<0.05). The in vivo efficacy and biocompatibility analyses of the biomaterial in an animal model reveal significant crystal growth (DCPD, TCP or HAp-like) and no pulp irritation after 70 days (p<0.05). The developed CCMS-HP holds great promise for treating exposed dentin by growing biomimetic crystals within dentinal tubules. These findings demonstrate that the mesoporous silica biomaterials presented here have great potential for serving as both a catalyst and carrier in the repair or regeneration of dental hard tissue.

Mutations in splicing factor (SF) genes are frequently detected in myelodysplastic syndrome, but the prognostic relevance of these genes mutations in acute myeloid leukemia (AML) remains unclear. In this study, we investigated mutations of three SF genes, SF3B1, U2AF1 and SRSF2, by Sanger sequencing in 500 patients with de novo AML and analysed their clinical relevance. SF mutations were identified in 10.8% of total cohort and 13.2% of those with intermediate-risk cytogenetics. SF mutations were closely associated with RUNX1, ASXL1, IDH2 and TET2 mutations. SF-mutated AML patients had a significantly lower complete remission rate and shorter disease-free survival (DFS) and overall survival (OS) than those without the mutation. Multivariate analysis demonstrated that SFmutation was an independent poor prognostic factor for DFS and OS. A scoring system incorporating SF mutation and ten other prognostic factors was proved very useful to risk-stratify AML patients. Sequential study of paired samples showed that SF mutations were stable during AML evolution. In conclusion, SF mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression. These mutations may be potential targets for novel treatment and biomarkers for disease monitoring in AML.

No abstract

Current information about clinical significance of IDH mutations in myelodysplastic syndromes (MDS), their association with other genetic alterations and the stability during disease progression is limited. In this study, IDH mutations were identified in 4.6% of 477 patients with MDS based on the FAB classification and in 2.2 % of 368 patients based on the 2008 WHO classification. IDH mutations were closely associated with older age, higher platelet counts, and mutations of DNMT3A (36.4% vs. 8.7%, P < 0.001), ASXL1 (47.6% vs. 22.0%, P 5 0.007), and SRSF2 (45.5% vs. 11.8%, P < 0.001). IDH2 mutation was a poor prognostic factor for overall survival in patients with lower-risk MDS, based on international prognosis scoring system (IPSS), FAB classification, WHO classification, or revised IPSS (all P Ϲ 0.001), but not in higher-risk groups. Sequential studies in 151 patients demonstrated that all IDH-mutated patients retained the same mutation during disease evolution while none of the IDH-wild patients acquired a novel mutation during follow-ups. In conclusion, IDH mutation is a useful biomarker for risk stratification of patients with lower-risk MDS. IDH mutations are stable during the clinical course. The mutation, in association with other genetic alterations, may play a role in the development, but not progression of MDS.

An ideal material has yet to be discovered that can completely treat dentin hypersensitivity; however, calcium phosphate precipitation has exhibited potential value for the treatment of dentin hypersensitivity by the occlusion of dentinal tubules. We hypothesized that a novel mesoporous silica biomaterial (nano CaO@mesoporous silica, NCMS) containing nano-sized calcium oxide particles mixed with 30% phosphoric acid can efficiently occlude dentinal tubules and significantly reduce dentin permeability, even with the presence of pulpal pressure. This highly supersaturated Ca(2+)-and HPO(4)(2-)ion-containing NCMS paste was brushed onto dentin surfaces, and the ions diffused deeply into the dentinal tubules and formed a CaHPO(4).2H(2)O precipitation with a depth of 100 microm. The results of the dentin permeability tests showed that the novel mesoporous material exhibited a significant reduction in dentin permeability (p < 0.05), even under simulated pulpal pressure, as compared with our previously developed material, DP-bioglass, and a commercial desensitizing material, Seal & Protect.

The purpose of our study was to re-evaluate the effects of surface treatment on the bond strength of repaired methacrylate-based dental composite materials including nanofillers (Ceram X, Dentsply). The microtensile bond strengths were measured before or after thermo-mechanical fatigue simulation. The treatments were as follows: (1)No treatment (negative control), (2)Bonding agent, (3) Acetone, (4)Acetone+Bonding agent, (5)Silane, (6)Silane+Bonding agent. In the digitized SEM image of the polished aged specimens without any surface treatment, the percentage of the visible fillers relative to the whole image was calculated. Before and after fatigue, no significant differences could be observed among the different pretreatment groups. Fatigue increased the microtensile strength values of Acetone and Silane groups. The digitized SEM image reveals that 11.5% of the exposed surface could be identified as uncovered filler surface. None of surface treatments (acetone, silane and bonding agent) contributed to increase the tensile strength of repaired composite samples including nanofillers.