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  • 1
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    SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival (2012)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2012-11-16
    Description: Among spliceosome component mutations, those involving SF3B1 are most frequent in myelodysplastic syndromes with ring sideroblasts (MDS-RS; ~ 75% incidence) and SRSF2 in chronic myelomonocytic leukemia (~ 28% incidence). We recently reported on the lack of prognostic significance for SF3B1 mutations in both MDS-RS and primary myelofibrosis (PMF). In the current study, we examined the prevalence and prognostic relevance of SRSF2 mutations in PMF. Among 187 patients screened, 32 (17%) harbored SRSF2 monoallelic mutations affecting residue P95. Significant associations were demonstrated between SRSF2 mutations and advanced age ( P 〈 .01), IDH mutations ( P 〈 .01), and higher DIPSS-plus risk category ( P = .03). SRSF2 mutations were associated with shortened overall ( P 〈 .01) and leukemia-free ( P 〈 .01) survival; the adverse effect on survival was independent of DIPSS-plus ( P = .01; HR = 1.9; 95% CI, 1.1-3.0) and IDH mutations ( P 〈 .01; HR = 2.3; 95% CI, 1.4-3.8). In conclusion, SRSF2 mutations are relatively common in PMF, cluster with IDH mutations, and are independently predictive of poor outcome.
    Keywords: Free Research Articles, Myeloid Neoplasia, Brief Reports, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 2
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    Spontaneous coronary artery dissection during hematopoietic stem cell infusion (2013)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2013-11-08
    Keywords: Transplantation
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 3
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    Unusual sequence effects on nucleotide excision repair of arylamine lesions: DNA bending/distortion as a primary recognition factor (2013)
    Oxford University Press
    Details
    Publication Date: 2013-01-20
    Description: The environmental arylamine mutagens are implicated in the etiology of various sporadic human cancers. Arylamine-modified dG lesions were studied in two fully paired 11-mer duplexes with a -G*C N - sequence context, in which G* is a C8-substituted dG adduct derived from fluorinated analogs of 4-aminobiphenyl (FABP), 2-aminofluorene (FAF) or 2-acetylaminofluorene (FAAF), and N is either dA or dT. The FABP and FAF lesions exist in a simple mixture of ‘stacked’ (S) and ‘B-type’ (B) conformers, whereas the N -acetylated FAAF also samples a ‘wedge’ (W) conformer. FAAF is repaired three to four times more efficiently than FABP and FAF. A simple A- to -T polarity swap in the G*C A /G*C T transition produced a dramatic increase in syn -conformation and resulted in 2- to 3-fold lower nucleotide excision repair (NER) efficiencies in Escherichia coli . These results indicate that lesion-induced DNA bending/thermodynamic destabilization is an important DNA damage recognition factor, more so than the local S/B-conformational heterogeneity that was observed previously for FAF and FAAF in certain sequence contexts. This work represents a novel 3'-next flanking sequence effect as a unique NER factor for bulky arylamine lesions in E. coli .
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Conformational and thermodynamic properties modulate the nucleotide excision repair of 2-aminofluorene and 2-acetylaminofluorene dG adducts in the NarI sequence (2012)
    Oxford University Press
    Details
    Publication Date: 2012-05-13
    Description: Nucleotide excision repair (NER) is a major repair pathway that recognizes and corrects various lesions in cellular DNA. We hypothesize that damage recognition is an initial step in NER that senses conformational anomalies in the DNA caused by lesions. We prepared three DNA duplexes containing the carcinogen adduct N -(2'-deoxyguanosin-8-yl)-7-fluoro-2-acetylaminofluorene (FAAF) at G 1 , G 2 or G 3 of Nar I sequence (5'-CCG 1 G 2 CG 3 CC-3'). Our 19 F-NMR/ICD results showed that FAAF at G 1 and G 3 prefer syn S- and W-conformers, whereas anti B-conformer was predominant for G 2 . We found that the repair of FAAF occurs in a conformation-specific manner, i.e. the highly S/W-conformeric G 3 and -G 1 duplexes incised more efficiently than the B-type G 2 duplex (G 3 ~G 1 〉 G 2 ). The melting and thermodynamic data indicate that the S- and W-conformers produce greater DNA distortion and thermodynamic destabilization. The N -deacetylated N -(2'-deoxyguanosin-8-yl)-7-fluoro-2-aminofluorene (FAF) adducts in the same Nar I sequence are repaired 2- to 3-fold less than FAAF: however, the incision efficiency was in order of G 2 ~G 1 〉 G 3 , a reverse trend of the FAAF case. We have envisioned the so-called N -acetyl factor as it could raise conformational barriers of FAAF versus FAF. The present results provide valuable conformational insight into the sequence-dependent UvrABC incisions of the bulky aminofluorene DNA adducts.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    Prognostic irrelevance of ring sideroblast percentage in World Health Organization-defined myelodysplastic syndromes without excess blasts (2012)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publication Date: 2012-06-15
    Description: The presence of ≥ 15% bone marrow (BM) ring sideroblasts (RS) and 〈 5% blasts is required for a diagnosis of refractory anemia with ring sideroblasts. We examined the phenotypic and prognostic relevance of this "15%" RS threshold in 200 patients with myelodysplastic syndromes (MDS) without excess blasts and with ≥ 1% RS. The impact of RS% was assessed both as a continuous and categorical variable: 〈 5% (n = 56), 5%-14% (n = 32), 15%-50% (n = 79), and 〉 50% (n = 33). RS% correlated ( P 〈 .05) directly with age, platelet count, transfusion dependency, BM cellularity, and mutant SF3B1 and inversely with hemoglobin level, multilineage dysplasia, and high-risk karyotype; but did not correlate with IDH mutations. At a median follow-up of 33 months, 156 (73%) deaths and 24 (12%) leukemic transformations were documented. Neither univariate nor multivariable analysis showed significant effect for RS% on overall or leukemia-free survival, suggesting the limited prognostic value of quantifying BM RS in MDS.
    Keywords: Free Research Articles, Myeloid Neoplasia, Brief Reports, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
    Published by American Society of Hematology (ASH)
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  • 6
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    Lomofungin and dilomofungin: inhibitors of MBNL1-CUG RNA binding with distinct cellular effects (2014)
    Oxford University Press
    Details
    Publication Date: 2014-06-03
    Description: Myotonic dystrophy type 1 (DM1) is a dominantly inherited neuromuscular disorder resulting from expression of RNA containing an expanded CUG repeat (CUG exp ). The pathogenic RNA is retained in nuclear foci. Poly-(CUG) binding proteins in the Muscleblind-like (MBNL) family are sequestered in foci, causing misregulated alternative splicing of specific pre-mRNAs. Inhibitors of MBNL1-CUG exp binding have been shown to restore splicing regulation and correct phenotypes in DM1 models. We therefore conducted a high-throughput screen to identify novel inhibitors of MBNL1-(CUG) 12 binding. The most active compound was lomofungin, a natural antimicrobial agent. We found that lomofungin undergoes spontaneous dimerization in DMSO, producing dilomofungin, whose inhibition of MBNL1–(CUG) 12 binding was 17-fold more potent than lomofungin itself. However, while dilomofungin displayed the desired binding characteristics in vitro , when applied to cells it produced a large increase of CUG exp RNA in nuclear foci, owing to reduced turnover of the CUG exp transcript. By comparison, the monomer did not induce CUG exp accumulation in cells and was more effective at rescuing a CUG exp -induced splicing defect. These results support the feasibility of high-throughput screens to identify compounds targeting toxic RNA, but also demonstrate that ligands for repetitive sequences may have unexpected effects on RNA decay.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors (2014)
    Oxford University Press
    Details
    Publication Date: 2014-12-18
    Description: Background This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity. Patients and methods A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle. Results Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug–drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%). Conclusions This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.
    Print ISSN: 0923-7534
    Electronic ISSN: 1569-8041
    Topics: Medicine
    Published by Oxford University Press
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