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"Nelson, Sarah J."
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Mutational Analysis Reveals the Origin and Therapy-Driven Evolution of Recurrent Glioma
Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exornes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations in TP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.
Journal Article
The new voices of science fiction
\"Your Future Is Bright! After all, your mother is a robot, your father has joined the alien hive mind, and your dinner will be counterfeit 3D-printed steak. Even though your worker bots have staged a mutiny, and your tour guide speaks only in memes, you can always sell your native language if you need some extra cash.\" -- From publisher's description.
Book
Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma
Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the
isocitrate dehydrogenase 1
and
2 (IDH1/2
) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study,
ex vivo
metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (
1
H HR-MAS). Distinct spectral profiles were observed for lesions with
IDH-
mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for
in vivo
characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy.
Journal Article
Defining frigid winter illuminates its loss across seasonally snow-covered areas of eastern North America
Winter is often understudied in ecosystem sciences and viewed as a burden for human systems and infrastructure. However, the importance of winter in regulating ecological processes and shaping human communities has emerged as a topic of great interest, particularly in areas that experience seasonal snow cover. Traditional seasonal definitions may not fully represent below freezing winters and snow accumulation that have historically characterized these areas. Here we: (1) propose the concept of 'frigid winter' to address longstanding problems with traditional delineations of winter; and (2) define frigid winter as a period of sustained temperatures below freezing and snow accumulation that together regulate ecological processes and their services. We explore this definition and the changes occurring within it using 100 years of meteorological data from northeastern North America. Trend analysis demonstrates that frigid winters have shortened by ∼3 weeks over the last century, that cold, snowy conditions have become more intermittent, and that the choice of winter delineation (astronomical, meteorological, hibernal, or frigid) influences the apparent rate at which winter conditions disappear.
Journal Article
Participatory science and education: bringing both views into focus
Aligning the goals of scientists and participants becomes more challenging when citizen science moves into middle- and high-school classrooms. Here, we describe a logic model developed in association with the Acadia Learning Project, a collaboration among scientists, teachers, and students that successfully meets both research and educational needs. The logic model is intended to assist other classroom-based citizen-science initiatives with project design and evaluation.
Journal Article
Effects of a Weekend‐Long Field Course on Undergraduates' Confidence, Identity, and Belonging
Field courses often serve as undergraduate students' first exposure to field‐based learning and are associated with a range of positive student outcomes including confidence in research skills, motivation to take more science classes, and learning gains. However, barriers such as family or work time commitments (i.e., most field courses are 7 weeks) can limit participation and inclusion, particularly for marginalized students. Much of the existing literature centers around traditional, multi‐week field experiences, creating a need to better understand outcomes related to shorter field courses. This study explored a weekend‐long field course designed to provide an early, low‐stakes research experience for undergraduate ecology and environmental science majors. Over 3 years and seven iterations of the course, we collected pre/post survey data (n = 104) in order to understand the efficacy of the short field course. After accounting for differences in student backgrounds, we found significant increases in research confidence, research identity, and sense of belonging. These findings suggested that even short field courses can have positive effects on students, similar to those resulting from multi‐week field experiences. This course can serve as a model for other universities and programs aiming to increase accessibility of field experiences and ecology as a career path. This study demonstrates that even a short, weekend‐long field course can significantly enhance undergraduate students' research identity, research confidence, and sense of belonging. By showing that short, low‐barrier experiences can produce meaningful outcomes, this work highlights an equitable model for expanding access to field experiences in ecology.
Journal Article
Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas
Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations.
Journal Article
Snow refugia: Managing temperate forest canopies to maintain winter conditions
Climate change is reducing snowpack across temperate regions with negative consequences for human and natural systems. Because forest canopies create microclimates that preserve snowpack, managing forests to support snow refugia—defined here as areas that remain relatively buffered from contemporary climate change over time that sustain snow quality, quantity, and/or timing appropriate to the landscape—could reduce climate change impacts on snow cover, sustaining the benefits of snow. We review the current understanding of how forest canopies affect snow, finding that while closed‐conifer forests and snow interactions have been extensively studied in western North America, there are knowledge gaps for deciduous and mixed forests with dormant season leaf loss. We propose that there is an optimal, intermediate zone along a gradient of dormant season canopy cover (DSCC; the proportion of the ground area covered by the canopy during the dormant season), where peak snowpack depth and the potential for snow refugia will be greatest because the canopy‐mediated effects of snowpack sheltering (which can preserve snowpack) outweigh those of snowfall interception (which can limit snowpack). As an initial test of our hypothesis, we leveraged snowpack measurements in the northeastern United States spanning the DSCC gradient (low, <25% DSCC; medium, 25%–50% DSCC; and high, >50% DSCC), including from 2 sites in Old Town, Maine; 12 sites in Acadia National Park, Maine; and 30 sites in the northern White Mountains of New Hampshire. Medium DSCC forests (typically mature mixed coniferous–deciduous forests) exhibited the deepest peak snowpacks, likely due to reduced snowfall interception compared to high DSCC forests and reduced snowpack loss compared to low DSCC forests. Many snow accumulation or snowpack studies focus on the contrast between coniferous and open sites, but our results indicate a need for enhanced focus on mixed canopy sites that could serve as snow refugia. Measurements of snowpack depth and timing across a wider range of forest canopies would advance understanding of canopy–snow interactions, expand the monitoring of changing winters, and support management of forests and snow‐dependent species in the face of climate change.
Journal Article
Refugia or at risk? Alpine snowbank communities in the face of climate change
High‐elevation alpine snowbank communities across the globe form where deep snow persists late into the growing season, creating unique environmental conditions. These plant communities support species assemblages not found elsewhere. Given the strong dependency of snowbank community composition on the persistence of snow, they may be particularly sensitive to climate change. However, alpine snowbanks may serve as climate refugia vis‐a‐vis buffering of environmental change by snow or soil moisture. Here, highlighting the Presidential Range of the White Mountains (New Hampshire, USA) as a focal system, we assess the risk posed by climate change to snowbank communities by analyzing the viability of possible refugia mechanisms. After conducting a literature review to summarize the current state of knowledge, we suggest these potential refugia may benefit some plant species but will not facilitate preservation of snowbank communities as historically composed. We identify management strategies for preserving critical ecosystem services under different climate scenarios. We then outline a monitoring strategy to detect threats to these systems in order to prioritize snowbank community biological resources and model their environmental tolerances. These strategies would create a framework that could help managers to support snowbank community stewardship in the face of climate change driven community restructuring. We used a literature review of the alpine snowbank communities of the Presidential Range of New Hampshire, USA as an model system for applying the climate change refugia conservation cycle framework to similar imperiled systems globally. We highlight threats posed to these systems, their ability to serve as future refugia, potential management interventions, and monitoring objectives to target these precious areas.
Journal Article