Surficial geologic map of the Des Moines Lobe of Iowa, Phase 5: Polk County

https://ir.uiowa.edu/igs_ofm/1030/thumbnail.jp

Association between DNMT3A Mutations and Prognosis of Adults with <i>De Novo</i> Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

<div><p>Background</p><p>DNA methyltransferase 3A (DNMT3A) mutations were considered to be independently associated with unfavorable prognosis in adults with de novo acute myeloid leukemia (AML), however, there are still debates on this topic. Here, we aim to further investigate the association between DNMT3A mutations and prognosis of patients with AML.</p> <p>Methods</p><p>Eligible studies were identified from several data bases including PubMed, Embase, Web of Science, ClinicalTrials and the Cochrane Library (up to June 2013). The primary endpoint was overall survival (OS), while relapse-free survival (RFS) and event-free survival (EFS) were chosen as secondary endpoints. If possible, we would pool estimate effects (hazard ratio [HR] with 95% confidence interval[CI]) of outcomes in random and fixed effects models respectively.</p> <p>Results</p><p>That twelve cohort studies with 6377 patients exploring the potential significance of DNMT3A mutations on prognosis were included. Patients with DNMT3A mutations had slightly shorter OS (HR = 1.60; 95% CI, 1.31–1.95; P<0.001), as compared to wild-type carriers. Among the patients younger than 60 years of age, DNMT3A mutations predicted a worse OS (HR = 1.84; 95% CI, 1.36–2.50; P<0.001). In addition, mutant DNMT3A predicted inferior OS (HR = 2.30; 95% CI, 1.78–2.97; P = 0.862) in patients with unfavorable genotype abnormalities. Similar results were also found in some other subgroups. However, no significant prognostic value was found on OS (HR = 1.40; 95% CI, 0.98–1.99; P = 0.798) in the favorable genotype subgroup. Similar results were found on RFS and EFS under different conditions.</p> <p>Conclusions</p><p>DNMT3A mutations have slightly but significantly poor prognostic impact on OS, RFS and EFS of adults with de novo AML in total population and some specific subgroups.</p> </div

Outcome of subgroups in a random effects model.

<p>N.of S., number of studies;</p><p>D+/−, indicates ratio of number of patients with mutant DNMT3A to patients with wild-type DNMT3A;</p><p>—, reflects there is no corresponding data presented; Abbreviations: mt, mutation; wt, wild type.</p

Data_Sheet_1_Bioinformatic and Functional Analysis of a Key Determinant Underlying the Substrate Selectivity of the Al Transporter, Nrat1.docx

<p>Nrat1 is a member of the natural resistance-associated macrophage protein (Nramp) family of metal ion transporters in all organisms. Different from other Nramp members capable of transporting divalent metals, Nrat1 specifically transports trivalent aluminum (Al) ion. However, molecular mechanism underlying the Al transport selectivity of Nrat1 remains unknown. Here, we performed structure-function analyses of Nrat1 and other Nramp members to gain insights into the determinants of ion selectivity. A phylogenetic analysis showed that plant Nramp transporters could be divided into five groups. OsNrat1 was found in one of the individual clades and clustered with SbNrat1 and ZmNrat1 on the evolutionary tree. Structural modeling revealed that Nrat1 transporters adopted a common LeuT fold shared by many Nramp-family transporters that likely employed an identical transport mechanism. Sequence alignment and evolutionary conservation analysis of amino acids identified a metal-permeation pathway of Nrat1 centered at the metal binding site. The metal binding site of Nrat1 was characterized by two conserved sequence motifs, i.e., the Asp-Pro-Ser-Asn motif (motif A) and the Ala-Ile-Ile-Thr motif (motif B). Replacement of the Ala-Met-Val-Met motif B of the OsNramp3 manganese (Mn) transporter to that of Nrat1 resulted in a partial gain of Al transport activity and a total loss of Mn in yeast. Conversely, substitution of the motif B of OsNrat1 with that of OsNramp3 altered the Al transport activity. These observations indicated the metal binding site, particularly the motif B, as a key determinant of Al selectivity of Nrat1.</p

Confunnel with filled studies from metatrim:

<p>mutant DNMT3A versus wild-type DNMT3A in a random effects model. The pooled HR on overall survival from 12 published studies is robust and the heterogeneity mainly results from unpublished studies.</p

Forest plot of the HR for overall survival of all AML patients.

<p>DNMT3A mutations versus wild-type DNMT3A. I–V Overall: the pooled HR with 95% CI using a fixed effects model; D+L Overall: the pooled HR with 95% CI using a random effects model.</p

Outcome of subgroups in a fixed effects model.

<p>N.of S., number of studies;</p><p>D+/−, indicates ratio of number of patients with mutant DNMT3A to patients with wild-type DNMT3A;</p><p>—, reflects there is no corresponding data presented; Abbreviations: mt, mutation; wt, wild type.</p

Forest plot of the HRs for relapse-free or event-free survival of AML patients.

<p>DNMT3A mutations versus wild-type DNMT3A. I–V Subtotal represented the pooled HRs with 95% CIs using a fixed effects model; D+L Subtotal represented the pooled HR with 95% CI using a random effects model.</p

PRISMA flow diagram for study review and inclusion.

<p>PRISMA flow diagram for study review and inclusion.</p

Funnel plots illustrated significant asymmetry on HR for overall survival of all patients.

<p>Studies were distributed asymmetrically and suggested biases exist.</p