A distinct epigenetic signature at targets of a leukemia protein

BACKGROUND: Human myelogenous leukemia characterized by either the non random t(8; 21)(q22; q22) or t(16; 21)(q24; q22) chromosome translocations differ for both their biological and clinical features. Some of these features could be consequent to differential epigenetic transcriptional deregulation at AML1 targets imposed by AML1-MTG8 and AML1-MTG16, the fusion proteins deriving from the two translocations. Preliminary findings showing that these fusion proteins lead to transcriptional downregulation of AML1 targets, marked by repressive chromatin changes, would support this hypothesis. Here we show that combining conventional global gene expression arrays with the power of bioinformatic genomic survey of AML1-consensus sequences is an effective strategy to identify AML1 targets whose transcription is epigenetically downregulated by the leukemia-associated AML1-MTG16 protein. RESULTS: We interrogated mouse gene expression microarrays with probes generated either from 32D cells infected with a retroviral vector carrying AML1-MTG16 and unable of granulocyte differentiation and proliferation in response to the granulocyte colony stimulating factor (G-CSF), or from 32D cells infected with the cognate empty vector. From the analysis of differential gene expression alone (using as criteria a p value < 0.01 and an absolute fold change > 3), we were unable to conclude which of the 37 genes downregulated by AML1-MTG16 were, or not, direct AML1 targets. However, when we applied a bioinformatic approach to search for AML1-consensus sequences in the 10 Kb around the gene transcription start sites, we closed on 17 potential direct AML1 targets. By focusing on the most significantly downregulated genes, we found that both the AML1-consensus and the transcription start site chromatin regions were significantly marked by aberrant repressive histone tail changes. Further, the promoter of one of these genes, containing a CpG island, was aberrantly methylated. CONCLUSION: This study shows that a leukemia-associated fusion protein can impose a distinct epigenetic repressive signature at specific sites in the genome. These findings strengthen the conclusion that leukemia-specific oncoproteins can induce non-random epigenetic changes

Exome-wide analysis of the discovehr cohort reveals novel candidate pharmacogenomic variants for clinical pharmacogenomics

Recent advances in next-generation sequencing technology have led to the production of an unprecedented volume of genomic data, thus further advancing our understanding of the role of genetic variation in clinical pharmacogenomics. In the present study, we used whole exome sequencing data from 50,726 participants, as derived from the DiscovEHR cohort, to identify pharmacogenomic variants of potential clinical relevance, according to their occurrence within the PharmGKB database. We further assessed the distribution of the identified rare and common pharmacogenomics variants amongst different GnomAD subpopulations. Overall, our findings show that the use of publicly available sequence data, such as the DiscovEHR dataset and GnomAD, provides an opportunity for a deeper understanding of genetic variation in pharmacogenes with direct implications in clinical pharmacogenomics

The human homologue of the yeast mitochondrial AAA metalloprotease Yme1p complements a yeast yme1 disruptant

AbstractIn yeast, three AAA superfamily metalloproteases (Yme1p, Afg3p and Rca1p) are localized to the mitochondrial inner membrane where they perform roles in the assembly and turnover of the respiratory chain complexes. We have investigated the function of the proposed human orthologue of yeast Yme1p, encoded by the YME1L gene on chromosome 10p. Transfection of both HEK-293EBNA and yeast cells with a green fluorescent protein-tagged YME1L cDNA confirmed mitochondrial targeting. When expressed in a yme1 disruptant yeast strain, YME1L restored growth on glycerol at 37°C. We propose that YME1L plays a phylogenetically conserved role in mitochondrial protein metabolism and could be involved in mitochondrial pathologies

Implementing a multidisciplinary psychotropic medication review among nursing home residents with dementia:a process evaluation

OBJECTIVES: Before drawing conclusions on the contribution of an effective intervention to daily practice and initiating dissemination, its quality and implementation in daily practice should be optimal. The aim of this process evaluation was to study these aspects alongside a randomized controlled trial investigating the effects of a multidisciplinary biannual medication review in long-term care organizations (NTR3569). DESIGN: Process evaluation with multiple measurements. SETTING: Thirteen units for people with dementia in six long-term care organizations in the Netherlands. PARTICIPANTS: Physicians, pharmacists, and nursing staff of participating units. INTERVENTION: The PROPER intervention is a structured and biannually repeated multidisciplinary medication review supported by organizational preparation and education, evaluation, and guidance. MEASUREMENTS: Web-based questionnaires, interviews, attendance lists of education sessions, medication reviews and evaluation meetings, minutes, evaluation, and registration forms. RESULTS: Participation rates in education sessions (95%), medication reviews (95%), and evaluation meetings (82%) were high. The intervention's relevance and feasibility and applied implementation strategies were highly rated. However, the education sessions and conversations during medication reviews were too pharmacologically oriented for several nursing staff members. Identified barriers to implementation were required time, investment, planning issues, and high staff turnover; facilitators were the positive attitude of professionals toward the intervention, the support of higher management, and the appointment of a local implementation coordinator. CONCLUSION: Implementation was successful. The commitment of both higher management and professionals was an important factor. This may partly have been due to the subject being topical; Dutch long-term-care organizations are pressed to lower inappropriate psychotropic drug use

A Novel Text-Mining Approach for Retrieving Pharmacogenomics Associations From the Literature

Text mining in biomedical literature is an emerging field which has already been shown to have a variety of implementations in many research areas, including genetics, personalized medicine, and pharmacogenomics. In this study, we describe a novel text-mining approach for the extraction of pharmacogenomics associations. The code that was used toward this end was implemented using R programming language, either through custom scripts, where needed, or through utilizing functions from existing libraries. Articles (abstracts or full texts) that correspond to a specified query were extracted from PubMed, while concept annotations were derived by PubTator Central. Terms that denote a Mutation or a Gene as well as Chemical compound terms corresponding to drug compounds were normalized and the sentences containing the aforementioned terms were filtered and preprocessed to create appropriate training sets. Finally, after training and adequate hyperparameter tuning, four text classifiers were created and evaluated (FastText, Linear kernel SVMs, XGBoost, Lasso, and Elastic-Net Regularized Generalized Linear Models) with regard to their performance in identifying pharmacogenomics associations. Although further improvements are essential toward proper implementation of this text-mining approach in the clinical practice, our study stands as a comprehensive, simplified, and up-to-date approach for the identification and assessment of research articles enriched in clinically relevant pharmacogenomics relationships. Furthermore, this work highlights a series of challenges concerning the effective application of text mining in biomedical literature, whose resolution could substantially contribute to the further development of this field

Molecular data show conserved DNA locations distinguishing lung cancer subtypes and regulation of immune genes

Introduction: Non-small-cell lung cancer exhibits a range of transcriptional and epigenetic patterns that not only define distinct phenotypes, but may also govern immune related genes, which have a major impact on survival. Methods: We used open-source RNA expression and DNA methylation data of the Cancer Genome Atlas with matched non-cancerous tissue to evaluate whether these pretreatment molecular patterns also influenced genes related to the immune system and overall survival. Results: The distinction between lung adenocarcinoma and squamous c

Can the PROPER intervention reduce psychotropic drug prescription in nursing home residents with dementia?:Results of a cluster-randomized controlled trial

Objectives:To evaluate the effect of the PROPER intervention in nursing home residents with dementia on the prevalence of psychotropic drug use and neuropsychiatric symptoms.Design:A cluster-randomized controlled design with two parallel groups (intervention versus usual care) and assessments at 0, 6, 12, and 18 months.Setting:Thirty-one dementia special care units within 13 long-term care organizations in the Netherlands.Participants:Three hundred eighty nursing home residents with dementiaIntervention:The PROPER intervention consisted of a structured and repeated multidisciplinary medication review, supported by education and continuous evaluation.Measurements:Prescriptions of antipsychotics, antidepressants, anxiolytics, and hypnotics, and occurrence of neuropsychiatric symptoms.Results:The prescription of any type of psychotropic drugs increased in the intervention group, and decreased in the control group, with an estimated difference of 3.9 percentage points per 6 months (p = 0.01). Effects for the individual drug groups were minor (differences of 1.6 percentage points and below per 6 months) and not statistically significant. The occurrence of neuropsychiatric symptoms remained stable in both the intervention and control groups during the follow-up of 18 months.Conclusions:The PROPER intervention failed to demonstrate effectiveness in reducing the prevalence of psychotropic drugs. It may be interesting to enrich the intervention with components that address personal attitudes and communication between nursing home professionals, not only with respect to the prescription of psychotropic drugs, but also to neuropsychiatric symptoms

Improving psychotropic drug prescription in nursing home patients with dementia:design of a cluster randomized controlled trial

Background: Neuropsychiatric symptoms are highly prevalent in nursing home patients with dementia. Despite modest effectiveness and considerable side effects, psychotropic drugs are frequently prescribed for these neuropsychiatric symptoms. This raises questions whether psychotropic drugs are appropriately prescribed. The aim of the PROPER (PRescription Optimization of Psychotropic drugs in Elderly nuRsing home patients with dementia) II study is to investigate the efficacy of an intervention for improving the appropriateness of psychotropic drug prescription in nursing home patients with dementia.Methods/design: The PROPER II study is a multi-center cluster randomized controlled, pragmatic trial using parallel groups. It has a duration of eighteen months and four six-monthly assessments. Six nursing homes will participate in the intervention and six will continue care as usual. The nursing homes will be located throughout the Netherlands, each participating with two dementia special care units with an average of fifteen patients per unit, resulting in 360 patients. The intervention consists of a structured and repeated multidisciplinary medication review supported by education and continuous evaluation. It is conducted by pharmacists, physicians, and nurses and consists of three components: 1) preparation and education, 2) conduct, and 3) evaluation/guidance. The primary outcome is the proportion of patients with appropriate psychotropic drug use. Secondary outcomes are the overall frequency of psychotropic drug use, neuropsychiatric symptoms, quality of life, activities of daily living, psychotropic drug side effects and adverse events (including cognition, comorbidity, and mortality). Besides, a process analysis on the intervention will be carried out.Discussion: This study is expected to improve the appropriateness of psychotropic drug prescription for neuropsychiatric symptoms in nursing home patients with dementia by introducing a structured and repeated multidisciplinary medication review supported by education and continuous evaluation.</p

The tissue-specific aspect of genome-wide DNA methylation in newborn and placental tissues: Implications for epigenetic epidemiologic studies

Epigenetic programming is essential for lineage differentiation, embryogenesis and placentation in early pregnancy. In epigenetic association studies, DNA methylation is often examined in DNA derived from white blood cells, although its validity to other tissues of interest remains questionable. Therefore, we investigated the tissue specificity of epigenome-wide DNA methylation in newborn and placental tissues. Umbilical cord white blood cells (UC-WBC, n = 25), umbilical cord blood mononuclear cells (UC-MNC, n = 10), human umbilical vein endothelial cells (HUVEC, n = 25) and placental tissue (n = 25) were obtained from 36 uncomplicated pregnancies. Genome-wide DNA methylation was measured by the Illumina HumanMethylation450K BeadChip. Using UC-WBC as a reference tissue, we identified 3595 HUVEC tissue-specific differentially methylated regions (tDMRs) and 11,938 placental tDMRs. Functional enrichment analysis showed that HUVEC and placental tDMRs were involved in embryogenesis, vascular development and regulation of gene expression. No tDMRs were identified in UC-MNC. In conclusion, the extensive amount of genome-wide HUVEC and placental tDMRs underlines the relevance of tissue-specific approaches in future epigenetic association studies, or the use of validated representative tissues for a certain disease of interest, if available. To this purpose, we herewith provide a relevant dataset of paired, tissue-specific, genome-wide methylation measurements in newborn tissues