Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas

Background: Recent developments in genomic sequencing have advanced our understanding of the mutations underlying human malignancy. Melanoma is a prototype of an aggressive, genetically heterogeneous cancer notorious for its biologic plasticity and predilection towards developing resistance to targeted therapies. Evidence is rapidly accumulating that dysregulated epigenetic mechanisms (DNA methylation/demethylation, histone modification, non-coding RNAs) may play a central role in the pathogenesis of melanoma. Therefore, we sought to characterize the frequency and nature of mutations in epigenetic regulators in clinical, treatment-naïve, patient melanoma specimens obtained from one academic institution. Results: Targeted next-generation sequencing for 275 known and investigative cancer genes (of which 41 genes, or 14.9 %, encoded an epigenetic regulator) of 38 treatment-naïve patient melanoma samples revealed that 22.3 % (165 of 740) of all non-silent mutations affected an epigenetic regulator. The most frequently mutated genes were BRAF, MECOM, NRAS, TP53, MLL2, and CDKN2A. Of the 40 most commonly mutated genes, 12 (30.0 %) encoded epigenetic regulators, including genes encoding enzymes involved in histone modification (MECOM, MLL2, SETD2), chromatin remodeling (ARID1B, ARID2), and DNA methylation and demethylation (TET2, IDH1). Among the 38 patient melanoma samples, 35 (92.1 %) harbored at least one mutation in an epigenetic regulator. The genes with the highest number of total UVB-signature mutations encoded epigenetic regulators, including MLL2 (100 %, 16 of 16) and MECOM (82.6 %, 19 of 23). Moreover, on average, epigenetic genes harbored a significantly greater number of UVB-signature mutations per gene than non-epigenetic genes (3.7 versus 2.4, respectively; p = 0.01). Bioinformatics analysis of The Cancer Genome Atlas (TCGA) melanoma mutation dataset also revealed a frequency of mutations in the 41 epigenetic genes comparable to that found within our cohort of patient melanoma samples. Conclusions: Our study identified a high prevalence of somatic mutations in genes encoding epigenetic regulators, including those involved in DNA demethylation, histone modification, chromatin remodeling, and microRNA processing. Moreover, UVB-signature mutations were found more commonly among epigenetic genes than in non-epigenetic genes. Taken together, these findings further implicate epigenetic mechanisms, particularly those involving the chromatin-remodeling enzyme MECOM/EVI1 and histone-modifying enzyme MLL2, in the pathobiology of melanoma. Electronic supplementary material The online version of this article (doi:10.1186/s13148-015-0091-3) contains supplementary material, which is available to authorized users

Orbital wall thickness and the spread of infection from the paranasal sinuses

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72646/1/j.1365-2273.1985.tb00243.x.pd

Determinants of Manganese in Prenatal Dentin of Shed Teeth from CHAMACOS Children Living in an Agricultural Community

Manganese (Mn) is an essential nutrient, but overexposure can be neurotoxic. Over 800 000 kg of Mn-containing fungicides are applied each year in California. Manganese levels in teeth are a promising biomarker of perinatal exposure. Participants in our analysis included 207 children enrolled in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a longitudinal birth cohort study in an agricultural area of California. Mn was measured in teeth using laser-ablation-inductively coupled plasma-mass spectrometry. Our purpose was to determine environmental and lifestyle factors related to prenatal Mn levels in shed teeth. We found that storage of farmworkers’ shoes in the home, maternal farm work, agricultural use of Mn-containing fungicides within 3 km of the residence, residence built on Antioch Loam soil and Mn dust loading (μg/m(2) of floor area) during pregnancy were associated with higher Mn levels in prenatal dentin (p < 0.05). Maternal smoking during pregnancy was inversely related to Mn levels in prenatal dentin (p < 0.01). Multivariable regression models explained 22–29% of the variability of Mn in prenatal dentin. Our results suggest that Mn measured in prenatal dentin provides retrospective and time specific levels of fetal exposure resulting from environmental and occupational sources. [Image: see text

Potential for large-scale CO₂ removal via enhanced rock weathering with croplands

Enhanced silicate rock weathering (ERW), deployable with croplands, has potential use for atmospheric carbon dioxide (CO2) removal (CDR), which is now necessary to mitigate anthropogenic climate change. ERW also has possible co-benefits for improved food and soil security, and reduced ocean acidification. Here we use an integrated performance modelling approach to make an initial techno-economic assessment for 2050, quantifying how CDR potential and costs vary among nations in relation to business-as-usual energy policies and policies consistent with limiting future warming to 2 degrees Celsius. China, India, the USA and Brazil have great potential to help achieve average global CDR goals of 0.5 to 2 gigatonnes of carbon dioxide (CO2) per year with extraction costs of approximately US$80–180 per tonne of CO2. These goals and costs are robust, regardless of future energy policies. Deployment within existing croplands offers opportunities to align agriculture and climate policy. However, success will depend upon overcoming political and social inertia to develop regulatory and incentive frameworks. We discuss the challenges and opportunities of ERW deployment, including the potential for excess industrial silicate materials (basalt mine overburden, concrete, and iron and steel slag) to obviate the need for new mining, as well as uncertainties in soil weathering rates and land–ocean transfer of weathered products

Toward the Theory of Enterprise: Dialogue Between Business and Economics Women Scholars

Studies on gender accounting are quite recent. Drawing upon criticism of dominant economic theories as developed within Feminist Economics, this paper aims to provide an original contribution to studies on gender accounting by establishing whether the (male) assumptions of the theory of the enterprise can be submitted to critical revision. As a foray into a field of research that we intend to further explore in the future, this paper focuses on the work of Italian women scholars Isa Marchini and Rosella Ferraris Franceschi. More specifically, it ponders the contribution they gave to the discipline in order to identify innovative insights that could enable original and enriching criticism to mainstream theories