This survey analyzes two national pharmacovigilance databases in order to determine the major adverse reactions observed with the use of cholinesterase inhibitors in dementia. We conducted a statistical analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) and the Canada Vigilance Adverse Reaction Database (CVARD) concerning the side effects of cholinesterase inhibitors. The statistics calculated for each adverse event were the frequency and the reporting odds ratios (ROR). A total of 9877 and 2247 reports were extracted from the FAERS and CVARD databases, respectively. A disproportionately higher frequency of reports of death as an adverse event for rivastigmine, compared to the other acetylcholinesterase inhibiting drugs, was observed in both the FAERS (ROR = 3.42; CI95% = 2.94–3.98; P<0.0001) and CVARD (ROR = 3.67; CI95% = 1.92–7.00; P = 0.001) databases. While cholinesterase inhibitors remain to be an important therapeutic tool against Alzheimer’s disease, the disproportionate prevalence of fatal outcomes with rivastigmine compared with alternatives should be taken into consideration.
Key Points
Targeted DNAm profiling of MDS patient bone marrow mononuclear cells identifies several distinct DNAm clusters. Clusters enrich for specific genetic lesions and show differences in survival independent of clinical prognostic scoring systems..
Meloidogyne incognita is an economically important plant parasitic nematode. Here we demonstrate substantial variation in the invasiveness of four M. incognita populations relative to tomato. Infective (J2) stage transcriptomes reveal significant variation in the expression of proteincoding and non-coding RNAs between populations. We identify 33 gene expression markers (GEMs) that correlate with invasiveness, and which map to genes with predicted roles in host-finding and invasion, including neuropeptides, ion channels, GPCRs, cell wall-degrading enzymes and microRNAs. These data demonstrate a surprising diversity in microRNA complements between populations, and identify GEMs for invasiveness of M. incognita for the first time.
11Meloidogyne incognita is an economically important plant parasitic nematode. Here we 12 demonstrate substantial variation in the invasiveness of four M. incognita populations relative to 13 tomato. Infective (J2) stage transcriptomes reveal significant variation in the expression of protein-14 coding and non-coding RNAs between populations. We identify 33 gene expression markers (GEMs) 15 that correlate with invasiveness, and which map to genes with predicted roles in host-finding and 16 invasion, including neuropeptides, ion channels, GPCRs, cell wall-degrading enzymes and microRNAs. 17These data demonstrate a surprising diversity in microRNA complements between populations, and 18 identify GEMs for invasiveness of M. incognita for the first time. 19 20
DNA methyltransferase inhibitors (DNMTI) like 5-Azacytidine (5-Aza) are the only disease-modifying drugs approved for the treatment of higher-risk myelodysplastic syndromes (MDS), however less than 50% of patients respond, and there are no predictors of response with clinical utility. Somatic mutations in the DNA methylation regulating gene tet-methylcytosine dioxygenase 2 (TET2) are associated with response to DNMTIs, however the mechanisms responsible for this association remain unknown. Using bisulfite padlock probes, mRNA sequencing, and hydroxymethylcytosine pull-down sequencing at several time points throughout 5-Aza treatment, we show that TET2 loss particularly influences DNA methylation (5mC) and hydroxymethylation (5hmC) patterns at erythroid gene enhancers and is associated with downregulation of erythroid gene expression in the human erythroleukemia cell line TF-1. 5-Aza disproportionately induces expression of these down-regulated genes in TET2KO cells and this effect is related to dynamic 5mC changes at erythroid gene enhancers after 5-Aza exposure. We identified differences in remethylation kinetics after 5-Aza exposure for several types of genomic regulatory elements, with distal enhancers exhibiting longer-lasting 5mC changes than other regions. This work highlights the role of 5mC and 5hmC dynamics at distal enhancers in regulating the expression of differentiation-associated gene signatures, and sheds light on how 5-Aza may be more effective in patients harboring TET2 mutations.
Implications:
TET2 loss in erythroleukemia cells induces hypermethylation and impaired expression of erythroid differentiation genes which can be specifically counteracted by 5-Azacytidine, providing a potential mechanism for the increased efficacy of 5-Aza in TET2-mutant patients with MDS.
Visual Overview:
http://mcr.aacrjournals.org/content/molcanres/19/3/451/F1.large.jpg.
<p>A) Dose-response curve of wild-type TF1 cell viability for three different lengths of 5-Aza treatments (1 dose per day for a total length of treatment between 1 and 3 days). Points represent replicates per condition, shaded region corresponds to 95% confidence band estimated by 4 parameter logistic regression model (EC50 and slope as parameter and lower bounded at zero; modeled with R package "drc"). B) Dose-response of DNMT1 downregulation 24 hours after the indicated 5-Aza dose. C) Time course of DNMT1 downregulation following the indicated dosage schedules.</p>
<p>Cells were treated with 100uM L-AA or vehicle 24hrs before DNA isolation. A) 5hmC dot blot for L-AA treated or untreated Cells. B) Standard curve of 5hmC densitometric signal vs. pmol (calculated from 5hmC standard with known 5hmC amount). C) Quantification of dot blot signal for TET2-WT and KO cells +/- L-AA.</p>
<div>Abstract<p>DNA methyltransferase inhibitors (DNMTI) like 5-Azacytidine (5-Aza) are the only disease-modifying drugs approved for the treatment of higher-risk myelodysplastic syndromes (MDS), however less than 50% of patients respond, and there are no predictors of response with clinical utility. Somatic mutations in the DNA methylation regulating gene <i>tet-methylcytosine dioxygenase 2</i> (<i>TET2</i>) are associated with response to DNMTIs, however the mechanisms responsible for this association remain unknown. Using bisulfite padlock probes, mRNA sequencing, and hydroxymethylcytosine pull-down sequencing at several time points throughout 5-Aza treatment, we show that <i>TET2</i> loss particularly influences DNA methylation (5mC) and hydroxymethylation (5hmC) patterns at erythroid gene enhancers and is associated with downregulation of erythroid gene expression in the human erythroleukemia cell line TF-1. 5-Aza disproportionately induces expression of these down-regulated genes in TET2KO cells and this effect is related to dynamic 5mC changes at erythroid gene enhancers after 5-Aza exposure. We identified differences in remethylation kinetics after 5-Aza exposure for several types of genomic regulatory elements, with distal enhancers exhibiting longer-lasting 5mC changes than other regions. This work highlights the role of 5mC and 5hmC dynamics at distal enhancers in regulating the expression of differentiation-associated gene signatures, and sheds light on how 5-Aza may be more effective in patients harboring <i>TET2</i> mutations.</p>Implications:<p>TET2 loss in erythroleukemia cells induces hypermethylation and impaired expression of erythroid differentiation genes which can be specifically counteracted by 5-Azacytidine, providing a potential mechanism for the increased efficacy of 5-Aza in TET2-mutant patients with MDS.</p>Visual Overview:<p><a href="http://mcr.aacrjournals.org/content/molcanres/19/3/451/F1.large.jpg" target="_blank">http://mcr.aacrjournals.org/content/molcanres/19/3/451/F1.large.jpg</a>.</p></div>
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