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

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

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

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

PRISMA flow diagram for study review and inclusion.

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

The Combination of Quantitative Proteomics and Systems Genetics Analysis Reveals that PTN Is Associated with Sleep-Loss-Induced Cognitive Impairment

Sleep loss is associated with cognitive dysfunction. However, the detailed mechanisms remain unclear. In this study, we established a para-chlorophenylalanine (PCPA)-induced insomniac mouse model with impaired cognitive function. Mass-spectrometry-based proteomics showed that the expression of 164 proteins was significantly altered in the hippocampus of the PCPA mice. To identify critical regulators among the potential markers, a transcriptome-wide association screening was performed in the BXD mice panel. Among the candidates, the expression of pleiotrophin (Ptn) was significantly associated with cognitive functions, indicating that Ptn-mediates sleep-loss-induced cognitive impairment. Gene co-expression analysis further revealed the potential mechanism by which Ptn mediates insomnia-induced cognitive impairment via the MAPK signaling pathway; that is, the decreased secretion of Ptn induced by insomnia leads to reduced binding to Ptprz1 on the postsynaptic membrane with the activation of the MAPK pathway via Fos and Nr4a1, further leading to the apoptosis of neurons. In addition, Ptn is genetically trans-regulated in the mouse hippocampus and implicated in neurodegenerative diseases in human genome-wide association studies. Our study provides a novel biomarker for insomnia-induced cognitive impairment and a new strategy for seeking neurological biomarkers by the integration of proteomics and systems genetics