Explore the vast range of titles available.

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53 , FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1 , the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia. Analysis of genomic and clinical features of acute erythroid leukemia in comparison to other myeloid disorders supports its distinct classification, defines subgroups and suggests therapeutic vulnerabilities.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway ( GNAS , PRKAR1A ) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2 , and several loss-of-function fusions in tumor suppressor genes PTCH1 , SUFU and NCOR1 . Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention. Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

Race and ethnicity are consequential constructs when it comes to exposure to air pollution. Persistent environmental racial/ethnic inequalities call for attention to identifying the factors that maintain them. We examined associations between racial residential segregation and racial/ethnic inequalities in exposure to three types of air pollutants. Using data from the Panel Study of Income Dynamics (1990–2011), the U.S. Census (1990–2010), and the Environmental Protection Agency, we tested the independent and joint contributions of race/ethnicity and metropolitan-level residential segregation on individual levels of exposure to air pollution nationwide. We found that racial and ethnic minorities were exposed to significantly higher levels of air pollution compared to Whites. The difference between minorities and Whites in exposure to all three types of air pollution was most pronounced in metropolitan areas with high levels of residential segregation. The environmental inequities observed in this study call for public health and policy initiatives to ameliorate the sources of racial/ethnic gaps in pollution exposure. Given the links between the physical environment and health, addressing such uneven environmental burdens may be a promising way to improve population health and decrease racial/ethnic inequalities therein.

The pregnancy complication preeclampsia (PE), which occurs in approximately 3% to 8% of human pregnancies, is characterized by placental pathologies that can lead to significant fetal and maternal morbidity and mortality. Currently, the only known cure is delivery of the placenta. As the etiology of PE remains unknown, it is vital to find models to study this common syndrome. Here we show that matrix metalloproteinase-9 (MMP9) deficiency causes physiological and placental abnormalities in mice, which mimic features of PE. As with the severe cases of this syndrome, which commence early in gestation, MMP9-null mouse embryos exhibit deficiencies in trophoblast differentiation and invasion shortly after implantation, along with intrauterine growth restriction or embryonic death. Reciprocal embryo transfer experiments demonstrated that embryonic MMP9 is a major contributor to normal implantation, but maternal MMP9 also plays a role in embryonic trophoblast development. Pregnant MMP9-null mice bearing null embryos exhibited clinical features of PE as VEGF dysregulation and proteinuria accompanied by preexisting elevated blood pressure and kidney pathology. Thus, our data show that fetal and maternal MMP9 play a role in the development of PE and establish the MMP9-null mice as a much-needed model to study the clinical course of this syndrome.

IntroductionModerate acute malnutrition (MAM) causes substantial child morbidity and mortality, accounting for 4.4% of deaths and 6.0% of disability-adjusted life years (DALY) lost among children under 5 each year. There is growing consensus on the need to provide appropriate treatment of MAM, both to reduce associated morbidity and mortality and to halt its progression to severe acute malnutrition. We estimated health outcomes, costs and cost-effectiveness of four dietary supplements for MAM treatment in children 6–35 months of age in Mali.MethodsWe conducted a cluster-randomised MAM treatment trial to describe nutritional outcomes of four dietary supplements for the management of MAM: ready-to-use supplementary foods (RUSF; PlumpySup); a specially formulated corn–soy blend (CSB) containing dehulled soybean flour, maize flour, dried skimmed milk, soy oil and a micronutrient pre-mix (CSB++; Super Cereal Plus); Misola, a locally produced, micronutrient-fortified, cereal–legume blend (MI); and locally milled flour (LMF), a mixture of millet, beans, oil and sugar, with a separate micronutrient powder. We used a decision tree model to estimate long-term outcomes and calculated incremental cost-effectiveness ratios (ICERs) comparing the health and economic outcomes of each strategy.ResultsCompared to no MAM treatment, MAM treatment with RUSF, CSB++, MI and LMF reduced the risk of death by 15.4%, 12.7%, 11.9% and 10.3%, respectively. The ICER was US$9821 per death averted (2015 USD) and US$347 per DALY averted for RUSF compared with no MAM treatment.ConclusionMAM treatment with RUSF is cost-effective across a wide range of willingness-to-pay thresholds.Trial registrationNCT01015950.

The onset of adolescence is associated with an increased tendency to engage in risky behaviors and a developmental shift toward peers that contributes to increased prioritization for learning about and achieving social status. There is relatively little understanding about the specific links between these adolescent-typical phenomena, particularly regarding their neural underpinnings. Based on existing models that suggest the role of puberty in promoting adolescent status-seeking and risk-taking tendencies, we investigated the relation of pubertal hormones with behavioral and neural responses to status-relevant social information in the context of risk taking. We used a probabilistic decision task in which 11- to 13-year-old girls chose to take a risk, or not, while receiving either social rank or monetary performance feedback. While feedback type did not differentially influence risk-taking behavior, whole-brain imaging results showed that activation in the anterior insula was increased for risk taking in the social rank feedback condition compared to the monetary feedback condition. This heightened activation was more pronounced in girls with higher estradiol levels. These findings suggest that brain processes involved in adolescent risky decisions may be influenced by the desire for social-status enhancement and provide preliminary evidence for the role of pubertal hormones in enhancing this adolescent-typical social sensitivity.

People are exposed to phthalates through their wide use as plasticizers and in personal care products. Many phthalates are endocrine disruptors and have been associated with adverse health outcomes. However, knowledge gaps exist in understanding the molecular mechanisms associated with the effects of exposure in early and late pregnancy. In this study, we examined the relationship of eleven urinary phthalate metabolites with isoprostane, an established marker of oxidative stress, among pregnant Mexican-American women from an agricultural cohort. Isoprostane levels were on average 20% higher at 26 weeks than at 13 weeks of pregnancy. Urinary phthalate metabolite concentrations suggested relatively consistent phthalate exposures over pregnancy. The relationship between phthalate metabolite concentrations and isoprostane levels was significant for the sum of di-2-ethylhexyl phthalate and the sum of high molecular weight metabolites with the exception of monobenzyl phthalate, which was not associated with oxidative stress at either time point. In contrast, low molecular weight metabolite concentrations were not associated with isoprostane at 13 weeks, but this relationship became stronger later in pregnancy (p-value = 0.009 for the sum of low molecular weight metabolites). Our findings suggest that prenatal exposure to phthalates may influence oxidative stress, which is consistent with their relationship with obesity and other adverse health outcomes.

Recent genome- and epigenome-wide studies demonstrate that the DNA methylation is controlled in part by genetics, highlighting the importance of integrating genetic and epigenetic data. To better understand molecular mechanisms affecting gene expression, we used the candidate susceptibility gene paraoxonase 1 (PON1) as a model to assess associations of PON1 genetic polymorphisms with DNA methylation and arylesterase activity, a marker of PON1 expression. PON1 has been associated with susceptibility to obesity, cardiovascular disease, and pesticide exposure. In this study, we assessed DNA methylation in 18 CpG sites located along PON1 shores, shelves, and its CpG island in blood specimens collected from newborns and 9-year-old children participating (n = 449) in the CHAMACOS birth cohort study. The promoter polymorphism, PON1-108, was strongly associated with methylation, particularly for CpG sites located near the CpG island (P << 0.0005). Among newborns, these relationships were even more pronounced after adjusting for blood cell composition. We also observed significant decreases in arylesterase activity with increased methylation at the same nine CpG sites at both ages. Using causal mediation analysis, we found statistically significant indirect effects of methylation (β(95% confidence interval): 6.9(1.5, 12.4)) providing evidence that DNA methylation mediates the relationship between PON1-108 genotype and PON1 expression. Our findings show that integration of genetic, epigenetic, and expression data can shed light on the functional mechanisms involving genetic and epigenetic regulation of candidate susceptibility genes like PON1.