Pre‐eclampsia is a hypertensive disease of pregnancy characterized by new‐onset hypertension, with either proteinuria and/or organ dysfunction. Pre‐eclampsia is a leading cause of maternal morbidity and mortality; however, the underlying cellular and molecular mechanisms are not well understood. There is consensus that the underlying mechanism(s) resulting in pre‐eclampsia is centered around abnormal placentation, inadequate spiral‐artery remodeling, and deficiency in trophoblast invasion, resulting in impaired maternal blood flow to the placenta and a release of signals and/or inflammatory mediators into maternal circulation triggering the systemic manifestations of pre‐eclampsia. ER stress, resulting in impaired autophagy and placental release of aggregated proteins, may also confer systemic stress to maternal organs in pre‐eclampsia. Extracellular vesicles (EVs), lipid‐bilayer enclosed structures containing macromolecules including proteins, miRNA, and other important nucleotides, have been suggested to play an important role in this maternal‐fetal communication. Circulating EVs are present in greater quantity in the plasma of pre‐eclampsia subjects compared to normal pregnancy, and the placental derived EVs have been shown to have altered protein and RNA cargo. In this review, we will focus on EVs and their role in pre‐eclampsia, specifically their role in immune responses, inflammation, altered angiogenesis, and endothelial dysfunction.
Background Preterm birth is a significant clinical problem and an enormous burden on society, affecting one in eight pregnant women and their newborns. Despite decades of research, the molecular mechanism underlying its pathogenesis remains unclear. Many studies have shown that preterm birth is associated with health risks across the later life course. The “fetal origins” hypothesis postulates that adverse intrauterine exposures are associated with later disease susceptibility. Our recent studies have focused on the placental epigenome at term. We extended these studies to genome-wide placental DNA methylation across a wide range of gestational ages. We applied methylation dependent immunoprecipitation/DNA sequencing (MeDIP-seq) to 9 placentas with gestational age from 25 weeks to term to identify differentially methylated regions (DMRs). Results Enrichment analysis revealed 427 DMRs with nominally significant differences in methylation between preterm and term placentas ( p < 0.01) and 21 statistically significant DMRs after multiple comparison correction (FDR p < 0.05), of which 62% were hypo-methylated in preterm placentas vs term placentas. The majority of DMRs were in distal intergenic regions and introns. Significantly enriched pathways identified by Ingenuity Pathway Analysis (IPA) included Citrulline-Nitric Oxide Cycle and Fcy Receptor Mediated Phagocytosis in macrophages. The DMR gene set overlapped placental gene expression data, genes and pathways associated evolutionarily with preterm birth. Conclusion These studies form the basis for future studies on the epigenetics of preterm birth, “fetal programming” and the impact of environment exposures on this important clinical challenge. Electronic supplementary material The online version of this article (10.1186/s12881-019-0835-6) contains supplementary material, which is available to authorized users.
High-throughput sequencing produces an extraordinary amount of genomic data that is organized into a number of high-dimension datasets. Accordingly, visualization of genomic data has become essential for quality control, exploration, and data interpretation. The Variant Call Format (VCF) is a text file format generated during the variant calling process that contains genomic information and locations of variants in a group of sequenced samples. The current workflow for visualization of genomic variant data from VCF files requires use of a combination of existing tools. Here, we describe VIVA (VIsualization of VAriants), a command line utility and Jupyter Notebook based tool for evaluating and sharing genomic data for variant analysis and quality control of sequencing experiments from VCF files. VIVA combines the functionality of existing tools into a single command to interactively evaluate and share genomic data, as well as create publication quality graphics.
Understanding the genetic contribution(s) to the risk of preterm birth may lead to the development of interventions for treatment, prediction and prevention. Twin studies suggest heritability of preterm birth is 36–40%. Large epidemiological analyses support a primary maternal origin for recurrence of preterm birth, with little effect of paternal or fetal genetic factors. We exploited an “extreme phenotype” of preterm birth to leverage the likelihood of genetic discovery. We compared variants identified by targeted sequencing of women with 2–3 generations of preterm birth with term controls without history of preterm birth. We used a meta-genomic, bi-clustering algorithm to identify gene sets coordinately associated with preterm birth. We identified 33 genes including 217 variants from 5 modules that were significantly different between cases and controls. The most frequently identified and connected genes in the exome library were IGF1, ATM and IQGAP2. Likewise, SOS1, RAF1 and AKT3 were most frequent in the haplotype library. Additionally, SERPINB8, AZU1 and WASF3 showed significant differences in abundance of variants in the univariate comparison of cases and controls. The biological processes impacted by these gene sets included: cell motility, migration and locomotion; response to glucocorticoid stimulus; signal transduction; metabolic regulation and control of apoptosis.
These NCCN Guidelines for Distress Management discuss the identification and treatment of psychosocial problems in patients with cancer. All patients experience some level of distress associated with a cancer diagnosis and the effects of the disease and its treatment regardless of the stage of disease. Clinically significant levels of distress occur in a subset of patients, and identification and treatment of distress are of utmost importance. The NCCN Distress Management Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights describe updates to the NCCN Distress Thermometer (DT) and Problem List, and to the treatment algorithms for patients with trauma- and stressor-related disorders.
BackgroundRuns of homozygosity (ROH) are consecutive homozygous genotypes, which may result from population inbreeding or consanguineous marriages. ROH enhance the expression of recessive traits.MethodsWe mapped ROH in a case control study of women delivering at term compared to women delivering at or before 34 weeks gestation. Gene sets known to be important in risk of preterm birth were examined for their overlap with identified ROH segments.ResultsWhile we found no evidence of increased burden of ROH or copy number variations in mothers delivering at or before 34 weeks compared to term, we identified 424 genome-wide 50 kb segments with significant difference in abundance of overlapping ROH segments in cases versus controls, p<0.05. These regions overlap 199 known genes. We found preterm birth associated genes (CXCR4, MYLK, PAK1) and genes shown to have an evolutionary link to preterm (CXCR4, PPP3CB, C6orf57, DUSP13, and SLC25A45) with significant differences in abundance of overlapping ROH blocks in cases versus controls, p<0.001.ConclusionWe conclude, while we found no significant burden of runs of homozygosity, we did identify genomic regions with significantly greater abundance of ROH blocks in women delivering preterm that overlapped genes known to be involved in preterm birth.
Preeclampsia is one of the most common causes of fetal and maternal morbidity and mortality in the world. We built a Database for Preeclampsia (dbPEC) consisting of the clinical features, concurrent conditions, published literature and genes associated with Preeclampsia. We included gene sets associated with severity, concurrent conditions, tissue sources and networks. The published scientific literature is the primary repository for all information documenting human disease. We used semantic data mining to retrieve and extract the articles pertaining to preeclampsia-associated genes and performed manual curation. We deposited the articles, genes, preeclampsia phenotypes and other supporting information into the dbPEC. It is publicly available and freely accessible. Previously, we developed a database for preterm birth (dbPTB) using a similar approach. Using the gene sets in dbPTB, we were able to successfully analyze a genome-wide study of preterm birth including 4000 women and children. We identified important genes and pathways associated with preterm birth that were not otherwise demonstrable using genome-wide approaches. dbPEC serves not only as a resources for genes and articles associated with preeclampsia, it is a robust source of gene sets to analyze a wide range of high-throughput data for gene set enrichment analysis.Database URL: http://ptbdb.cs.brown.edu/dbpec/
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