DNA Methylation of Tumor Suppressive miRNAs in Non-Hodgkin’s Lymphomas

published_or_final_versio

The safety and efficacy of mesenchymal stem cells for prevention or regeneration of intervertebral disc degeneration: a systematic review

General Posters: abstract no. GP86INTRODUCTION: Mesenchymal stem cells (MSCs) have been used to halt the progression or regenerate the disc with hopes to prevent or treat discogenic back pain. However, the safety and efficacy of the use of MSCs for such treatment in animal and human models at short and long term assessment (i.e. greater than 48 weeks) have not been systematically addressed. This study addressed a systematic review of comparative controlled studies addressing the use of MSCs to that of no treatment/saline for the treatment of disc degeneration. METHODS: Online databases were extensively searched. Controlled trials in animal models and humans were eligible for inclusion. Trial design, MSC characteristics, injection method, disc assessment, outcome intervals, and complication events were assessed. Validity of each study was assessed addressing trial design. Two individuals independently addressed the aforementioned. RESULTS: Twenty-two animal studies were included. No human comparative controlled trials were reported. All three types of MSCs (i.e. derived from bone marrow, synovial and adipose tissue) showed successful inhibition of disc degeneration progression. From three included studies, bone marrow derived MSC showed superior quality of disc repair when compared to other treatments, including TGF-β1, NP bilaminar co-culture and axial distraction regimen. However, osteophyte development was reported in two studies as potential complication of MSC transplantation. CONCLUSIONS: Based on animal models, the current evidence suggests that in the short-term MSC transplantation is safe and effective in halting disc degeneration; however, additional and larger studies are needed to assess the long-term regenerative effects and potential complications. Inconsistency in methodological design and outcome parameters prevent any robust conclusions. In addition, randomized controlled trials in humans are needed to assess the safety and efficacy of such therapy.published_or_final_versio

Whole exome sequencing identifies novel mutations in relapsed or refractory acute promyelocytic leukaemia failing treatment with oral arsenic trioxide

Conference abstracts will be published in Haematologica in the near futurepostprin

The safety and efficacy of mesenchymal stem cells for prevention or regeneration of intervertebral disc degeneration: a systematic review

S221 - Scientific session: Stem-cell technologies: no. A15

Epigenetic inactivation of the MIR34B/C in multiple myeloma

We postulated that MIR34B/C, a direct transcriptional target of TP53, might be inactivated by promoter hypermethylation in multiple myeloma (MM). MIR34B/C promoter methylation was studied in 8 normal marrow controls, 8 MM cell lines, 95 diagnostic, and 23 relapsed/progressed MMsamples by methylation-specific PCR. MIR34B/C was methylated in 6 (75.0%) MM cell lines but not normal controls. 5-Aza-2′-deoxycytidine led to MIR34B/C promoter demethylation and MIR34B reexpression. Moreover, restoration of MIR34B led to reduced cellular proliferation and enhanced apoptosis of myeloma cells. In primary samples, methylation of MIR34B/C occurred in 5.3% at diagnosis and 52.2% at relapse/disease progression (P < .001). In 12 MM patients with paired samples at diagnosis and relapse/progression, MIR34B/C methylation was acquired in 6 at relapse/progression. In conclusion, MIR34B/C is a tumor suppressor in myeloma. Hypermethylation of MIR34B/C is tumor-specific. Frequent MIR34B/C hypermethylation during relapse/progression but not at diagnosis implicated a role of MIR34B/C hypermethylation in myeloma relapse/progression. © 2011 by The American Society of Hematology.link_to_subscribed_fulltex

A systematic review of the safety and efficacy of mesenchymal stem cells for disc degeneration: insights and future directions for regenerative therapeutics

Intervertebral disc degeneration is associated with low back pain. Mesenchymal stem cells (MSCs) have been used to "regenerate" the disc. The aim of this study was to perform a systematic review of comparative controlled studies assessing the safety and efficacy of using MSCs in animal in disc regeneration. Literature databases were extensively searched. Trial design, MSC sources, injection method, disc assessment, outcome intervals, and complication events were assessed. Validity of each study was performed. Twenty-four animal studies were included with 20.8% of the studies reporting randomization of groups. The studies represented 862 discs that were injected with MSCs and 1,603 discs as controls. All three types of MSCs (i.e. bone marrow, synovial and adipose tissue) showed successful inhibition of disc degeneration. Bone marrow-derived MSCs demonstrated superior quality of repair compared with other non-MSC treatments. A 2.7% overall complication rate was noted, whereby complications were noted only in rabbits. Overall, evidence suggested that MSCs increased disc space height in the majority of animal models. This is the first systematic review to assess the safety and efficacy of MSC for the treatment of disc degeneration. Short-term MSC transplantation is safe and effective; however, additional, larger and higher-quality studies are needed to assess the long-term safety and efficacy. Inconsistency in methodological design and outcome parameters prevent any robust conclusions. Recommendations are further made to improve efficacy, reduce potential complications, and standardize techniques for future studies

Next-Generation Sequencing with a 54-Gene Panel Identifies Unique Mutational Profile and Prognostic Markers in Chinese Patients with Myelofibrosis

634. Myeloproliferative Syndromes: Clinical: Poster I: no. 1638Introduction and objectives: Myelofibrosis (MF) has the worst outcome amongst various myeloproliferative neoplasms. Its prognosis is determined by clinicopathologic features and mutations in key driver genes. An increasing number of gene mutations involving various biological pathways in myeloid malignancies has been discovered. The prognostic significance of these mutations have not been clearly defined. In this study, we aim to describe the genomic characteristic in a large cohort of MF patients and identify clinical and molecular predictors of outcome. Methods: We evaluated the genetic profile of 101 patients with MF (primary, N=70; secondary, N=30) using next-generation sequencing with a 54-gene panel comprising: ABL1, ASXL1, ATRX, BCOR, BCORL1, BRAF, CALR, CBL, CBLB, CBLC, CDKN2A, CEBPA, CSF3R, CUX1, DNMT3A, ETV6, EZH2, FBXW7, FLT3, GATA1, GATA2, GNAS, HRAS, IDH1, IDH2, IKZF1, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, MPL, MYD88, NOTCH1, NPM1, NRAS, PDGFRA, PHF6, PTEN, PTPN11, RAD21, RUNX1, SETBP1, SF3B1, SMC1A, SMC3, SRSF2, STAG2, TET2, TP53, U2AF1, WT1, ZRSR2. Multivariate cox regression analysis was used to determine prognostic factors for overall survival (OS) and leukemia-free survival (LFS). Results: We identified mutations in 39 genes implicated in myeloid malignancies (Figure 1A). 96 patients (95%) with MF had a mutation in 1 or more genes: 14 patients (13.9%) had 1 mutation, 38 patients (37.6%) had 2 mutations, 18 patients (17.8%) had 3 mutations, 15 patients (14.9%) had 4 mutations, 7 patients (6.9%) had 5 mutations and 4 patients (4%) had 6 or more mutations. TET2/JAK2V617F (16 patients, 15.9%), ASXL1/JAK2V617F (12 patients, 11.9%) and ASXL1/CALR (10 patients, 9.9%) were the most frequently co-mutated genes (Figure 1B). Other JAK2 variants occurred concomitantly with JAK2V617F in 10 patients (9.9%) and CALR mutations in 4 patients (4%) mutations. Other frequently concomitant mutations included CUX1/JAK2V617F (6 patients, 5.9%), EZH2/JAK2V617F (6 patients, 5.9%), RUNX1/JAK2V617F (5 patients, 5%), SF3B1/JAK2V617F (5 patients, 5%), SETBP1/JAK2V617F (4 patients, 4%) and ZRSR2/JAK2V617F (4 patients, 4%). The median follow-up of the cohort was 49 (1-256) months. The 5-year and 10-year OS were 66.3% and 35.4%. The 5-year and 10-year LFS of were 84% and 63.3%. There were no statistically significant differences in OS and LFS between primary and secondary MF. Significant negative prognostic indicators were identified on multivariate analysis, including male gender (P=0.044), age > 65 years (P=0.044), Hb < 10g/dL (P=0.001), mutated CUX1 (P=0.003) and mutated TP53 (P=0.043) for OS, and Hb < 10g/dL (P=0.007), mutated TP53 (P=0.043) and mutated IDH2 (P=0.001) for LFS. In primary MF, inferior prognostic indicators included male gender (P=0.031), Hb < 10g/dL (P=0.002), platelet count < 100 x 109/L (P=0.021), mutated TET2 (P=0.011) and mutated CUX1 (P=0.011) for OS; and Hb < 10g/dL (P=0.027), mutated RUNX1 (P=0.019) and mutated DNMT3A (P=0.004) for LFS. In JAK2V617F positive MF, inferior prognostic indicators included mutated ASXL1 (P=0.006) and mutated SRSF2 (P<0.001) for OS; and mutated U2AF1 (P=0.037) for LFS. Conclusion: Our study demonstrated unique molecular profiles and prognostic predictors of outcome in Chinese patients with MF