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  • 1
    Online Resource
    Online Resource
    Coronal Heating as Determined by the Solar Flare Frequency Distribution Obtained by Aggregating Case Studies
    American Astronomical Society ; 2023
    In:  The Astrophysical Journal Vol. 948, No. 2 ( 2023-05-01), p. 71-
    Details
    In: The Astrophysical Journal, American Astronomical Society, Vol. 948, No. 2 ( 2023-05-01), p. 71-
    Abstract: Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counterintuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfvén waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, α = 2 as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed 〉 600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: preflare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that α = 1.63 ± 0.03. This is below the critical threshold, suggesting that Alfvén waves are an important driver of coronal heating.
    Type of Medium: Online Resource
    ISSN: 0004-637X , 1538-4357
    URL: Article
    DOI: 10.3847/1538-4357/accc89
    RVK:
    UA 1000
    Language: Unknown
    Publisher: American Astronomical Society
    Publication Date: 2023
    detail.hit.zdb_id: 2207648-7
    detail.hit.zdb_id: 1473835-1
    SSG: 16,12
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  • 2
    Online Resource
    Online Resource
    A new calibration method for charm jet identification validated with proton-proton collision events at √s = 13 TeV
    IOP Publishing ; 2022
    In:  Journal of Instrumentation Vol. 17, No. 03 ( 2022-03-01), p. P03014-
    Details
    In: Journal of Instrumentation, IOP Publishing, Vol. 17, No. 03 ( 2022-03-01), p. P03014-
    Abstract: Many measurements at the LHC require efficient identification of heavy-flavour jets, i.e. jets originating from bottom (b) or charm (c) quarks. An overview of the algorithms used to identify c jets is described and a novel method to calibrate them is presented. This new method adjusts the entire distributions of the outputs obtained when the algorithms are applied to jets of different flavours. It is based on an iterative approach exploiting three distinct control regions that are enriched with either b jets, c jets, or light-flavour and gluon jets. Results are presented in the form of correction factors evaluated using proton-proton collision data with an integrated luminosity of 41.5 fb -1 at  √s = 13 TeV, collected by the CMS experiment in 2017. The closure of the method is tested by applying the measured correction factors on simulated data sets and checking the agreement between the adjusted simulation and collision data. Furthermore, a validation is performed by testing the method on pseudodata, which emulate various mismodelling conditions. The calibrated results enable the use of the full distributions of heavy-flavour identification algorithm outputs, e.g. as inputs to machine-learning models. Thus, they are expected to increase the sensitivity of future physics analyses.
    Type of Medium: Online Resource
    ISSN: 1748-0221
    URL: Article
    DOI: 10.1088/1748-0221/17/03/P03014
    Language: Unknown
    Publisher: IOP Publishing
    Publication Date: 2022
    detail.hit.zdb_id: 2235672-1
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  • 3
    Online Resource
    Online Resource
    Elective surgery system strengthening: development, measurement, and validation of the surgical preparedness index across 1632 hospitals in 119 countries
    Elsevier BV ; 2022
    In:  The Lancet Vol. 400, No. 10363 ( 2022-11), p. 1607-1617
    Details
    In: The Lancet, Elsevier BV, Vol. 400, No. 10363 ( 2022-11), p. 1607-1617
    Type of Medium: Online Resource
    ISSN: 0140-6736
    URL: Article
    DOI: 10.1016/S0140-6736(22)01846-3
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2067452-1
    detail.hit.zdb_id: 3306-6
    detail.hit.zdb_id: 1476593-7
    SSG: 5,21
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  • 4
    Online Resource
    Online Resource
    EPEN-08. THE TREM1 POSITIVE HYPOXIC MYELOID SUBPOPULATION IN POSTERIOR FOSSA EPENDYMOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_1 ( 2021-06-01), p. i15-i15
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_1 ( 2021-06-01), p. i15-i15
    Abstract: We have previously shown the importance of immune factors in posterior fossa ependymoma (PF EPN). Recently, we found eight transcriptionally unique subpopulations of myeloid cells infiltrating PF EPN with one population particularly enriched in PFA1 tumors. This subpopulation, denoted as hypoxia myeloid subpopulation, is defined by genes associated with angiogenesis, hypoxia response, wound healing, cell migration, neutrophil activation, and response to oxygen levels. TREM1 (Triggering receptor expressed on myeloid cells 1) was found to be expressed almost exclusively within this hypoxia myeloid subpopulation. TREM1 encodes for a receptor belonging to the immunoglobulin superfamily that is expressed on myeloid cells, and stimulates neutrophil and monocyte inflammatory responses. However, single-cell RNAseq give little data suggesting location of cells within the tumor microenvironment. We performed immunohistochemistry (IHC) on our bank of ~90 FFPE PFA EPN samples using TREM1 to characterize and identify the location of the hypoxia myeloid cells. The TREM1 positive cells have an ambiguous cytomorphology reminiscent of a monocyte with modest cytoplasm and a mono-lobated nucleus. IHC also showed that TREM1+ myeloid cells are largely localized to the interface of necrosis and viable tissue, most frequently in a perivascular and intravascular distribution. The latter finding suggests that the TREM1+ cells are derived from the bone marrow and that they may be associated with the mesenchymal tumor population (MEC), which we have previously described as being enriched in PFA1 tumors and localizing to perinecrotic zones. This is supported by parallel IHC analysis of subpopulation-specific markers in the same cohort of PFA EPN which showed the highest TREM1 correlation was with CAIX, a marker of MEC. In PFA matched primary/recurrent pairs, the proportion of TREM1+ cells were increased at recurrence in the majority of cases, suggesting an evolving interaction between this TREM1+ hypoxia myeloid subpopulation and neoplastic cells over the disease course.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab090.058
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 5
    Online Resource
    Online Resource
    EPEN-11. TUMOR DIFFERENTIATION IMPACTS THE BIOLOGY OF RECURRENCE IN CHILDHOOD POSTERIOR FOSSA EPENDYMOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_1 ( 2021-06-01), p. i15-i16
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_1 ( 2021-06-01), p. i15-i16
    Abstract: Ependymoma (EPN) of childhood is curable in only 50% of cases, with recurrences in the remainder that are refractory to treatment. In recent years significant advances have been made in understanding the molecular and cellular biology of EPN. Recent studies show that PFA subgroup EPN are comprised of multiple neoplastic subpopulations that show undifferentiated, differentiated and mesenchymal characteristics. These studies focused on tumor at presentation, with recurrent EPN being less well understood. In the present longitudinal study we examine changes in neoplastic cell heterogeneity in serial presentations of PFA EPN using deconvolution (Cibersort) of bulk RNAseq data. Analysis of a cohort of 48 PFA EPN presenting at Children’s Colorado showed survival and PFA1/PFA2 subtype assignment was associated with the proportion of individual neoplastic subpopulations as determined by deconvolution. Tumors that subsequently regrew had a significantly higher estimated proportion of undifferentiated EPN cells (UEC) at presentation, than those that were non-recurrent after 5 years follow-up. This outcome association potentially age related, as UEC proportions are significantly higher in PFA arising in children & lt; 1 year old who have a particularly poor prognosis. Changes in PFA neoplastic subpopulations at recurrence was performed in two cohorts of patients from Children’s Colorado (n=23) and Nottingham, UK (n=15). As a whole, no subpopulation proportion was significantly changed at recurrence. However, separation of PFA into subtypes PFA1 and PFA2 revealed an increase in the proportion of the cilia-differentiated EPN cell subpopulation is more frequent event in PFA1 (15/24), and rare in PFA2 (2/11). Changes in other neoplastic subpopulations at recurrence were smaller and only seen in PFA1, both UEC and mesenchymal subpopulations being lower at recurrence. In summary, only PFA1 showed dynamic changes in neoplastic subpopulation proportions at recurrence, with potential impacts on transcriptomic based-subgroup assignment, whereas PFA2 proportions remained largely stable.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab090.061
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 6
    Online Resource
    Online Resource
    EPEN-07. SINGLE-CELL RNA SEQUENCING IDENTIFIES A UNIQUE MYELOID SUBPOPULATION ASSOCIATED WITH MESENCHYMAL TUMOR SUBPOPULATION IN POOR OUTCOME PEDIATRIC EPENDYMOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_1 ( 2021-06-01), p. i14-i15
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_1 ( 2021-06-01), p. i14-i15
    Abstract: We have previously shown immune gene phenotype variations between posterior fossa ependymoma subgroups. PFA1 tumors chronically secrete IL-6, which induces secretion of myeloid cell IL-8 and pushes the infiltrating myeloid cells to an immune suppressive function. In contrast, PFA2 tumors have a more immune activated phenotype associated with a better prognosis. The objective of this study was to use single-cell(sc) RNAseq to descriptively characterize the infiltrating myeloid cells. We analyzed approximately 8500 cells from 21 PFA patient samples. Using advanced machine learning, we identified eight myeloid cell subpopulations with unique gene expression profiles. Interestingly, only one subpopulation was significantly enriched in PFA1 tumors. This subpopulation, denoted as the hypoxia myeloid subpopulation, was defined by genes associated with angiogenesis, response to hypoxia, wound healing, cell migration, neutrophil activation and response to oxygen levels. These myeloid cells also share similar gene expression profile to a mesenchymal tumor subpopulation (MEC) enriched in PFA1 and associated with poor outcome in EPN patients. This tumor subpopulation was the only population expressing IL-6. Using immunohistochemistry, we found the hypoxia myeloid located in regions of tumor necrosis and perivascular niches. The MEC cells were also more abundant in these regions. In an independent single-cell cytokine release assay, we identified eight subpopulations of functional myeloid cells. One subpopulation significantly secreted IL-8, which represented the hypoxia subpopulation based on IL-8 gene expression in the scRNAseq dataset. This data suggests the tumor necrosis resulting in the development of MEC tumor subpopulation is driving the immune suppressive myeloid phenotype in PFA1 tumors through polarization of myeloid cells to the hypoxia subpopulation. Further studies are needed to determine how these myeloid cells interact with the lymphocyte subpopulations and whether they contribute to the progression of PFA1 EPN.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab090.057
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 7
    Online Resource
    Online Resource
    MEDB-44. Transcriptomic resolution of subgroup-specific medulloblastoma architecture
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i115-i116
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i115-i116
    Abstract: Despite a growing understanding and stratification of medulloblastoma, it remains an aggressive childhood brain tumor with high morbidity and mortality. Multimodal genomic and epigenomic analysis has permitted the classification of medulloblastoma into four subgroups with varying biology and clinical behavior: WNT, Sonic-Hedgehog (SHH), Group 3, and Group 4. In our previously published work, Single-cell RNA sequencing (scRNAseq) identified distinct tumor cell subpopulations in specific medulloblastoma groups. However, this technology is limited by its lack of architectural information. Spatial transcriptomics is a relatively new technology that permits the analysis of gene expression as it occurs within organized tissue. In our ongoing study, we utilized Visium spatial transcriptomics, integrated with scRNAseq data and immunohistochemistry, to analyze frozen samples of medulloblastomas (SHH, Group 4, and Group 3 with and without MYC amplification). In SHH in particular, we were able to identify scRNAseq populations within the geographically constricted Visium data, including SHH-C2, a population located in histologic nodules, the predominant neuronal-differentiated population SHH-C1, and progenitor populations (SHH-B1 and B2). In addition, we were able to visualize clusters not detectable by scRNAseq – a cluster lining nodules with expression of vascular endothelium marker, reticulin and M2-macrophage genes, and a novel DNA-repair cluster. In addition, Visium data permits the spatial constraint of proliferating cells, which is frequently problematic in scRNAseq, as dividing cells cluster independently. The proliferation is highest in the SHH-B2 minor progenitor population, absent in the SHH-C1 major differentiated population, and is moderate in other population including the SHH-C2 nodules. Group 3 and 4 medulloblastoma are more complex but show preliminary corroboration with scRNAseq data. In summary, Visium allows us to map subpopulations identified by scRNAseq to tumor architecture more definitively and rapidly than IHC. These novel insights advance our understanding of medulloblastoma, a critical step in improving treatment options for children with this disease.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.418
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 8
    Online Resource
    Online Resource
    HGG-17. Novel Fusion in Congenital Brainstem Diffuse High-Grade Glioma
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i64-i64
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i64-i64
    Abstract: BACKGROUND: Infant-type hemispheric glioma, previously termed infantile glioblastoma multiforme, is a rare infantile neoplasm with improved survival and distinct molecular features when compared to other pediatric and adult-type high-grade glioma. Infant-type high-grade gliomas are typically located in the cerebral hemispheres and are characterized by ALK, ROS1, MET, and NTRK fusions. Typical brainstem gliomas (diffuse midline glioma, H3 K27-altered or diffuse intrinsic pontine glioma) are comparatively rare in this age group. As a result, the biology of brainstem congenital high-grade gliomas is poorly described. RESULTS: A 3 month old female who initially presented with failure to thrive had an apneic event and was found to have an infiltrative mass in the medulla with expansion into the pons and cervical spine on magnetic resonance imaging. She underwent surgical biopsy with pathology revealing diffuse high-grade glioma, WHO grade 4. Next generation sequencing showed no alterations to H3F3A, IDH, or fusions involving BRAF, ALK, ROS1, MET, or NTRK. Whole-transcriptome sequencing revealed a novel fusion of PDGFRB:APOBEC3C. She received chemotherapy with 2 cycles of carboplatin/etoposide and 2 cycles of carboplatin/etoposide/imatinib before having disease progression. She then underwent palliative radiation (35 Gy in 10 fractions) with near complete regression of her disease. Surprisingly, our patient has not had any progression of disease or new lesions now two years from her last therapy. CONCLUSION: Congenital high-grade glioma is a rare, unique entity that greatly differs from its adult and childhood counterparts. Here, we discuss a previously-unreported fusion of PDGFB:APOBEC3C in a patient with congenital brainstem diffuse high-grade glioma with a favorable clinical course. This highlights the importance of routine molecular characterization, both to better understand the complex biology of this rare disease and to guide prognosis and clinical decision making for individual patients and families.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.232
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 9
    Online Resource
    Online Resource
    EMBR-27. NEOPLASTIC AND IMMUNE SINGLE CELL TRANSCRIPTOMICS DEFINE SUBGROUP-SPECIFIC INTRA-TUMORAL HETEROGENEITY OF CHILDHOOD MEDULLOBLASTOMA
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Vol. 23, No. Supplement_1 ( 2021-06-01), p. i11-i12
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 23, No. Supplement_1 ( 2021-06-01), p. i11-i12
    Abstract: Medulloblastoma (MB) is a heterogeneous disease in which neoplastic cells and associated immune cells contribute to disease progression. To better understand cellular heterogeneity in MB we used single-cell RNA sequencing, immunohistochemistry and deconvolution of transcriptomic data to profile neoplastic and immune populations in childhood MB samples and MB genetically engineered mouse models (GEMM). Neoplastic cells clustered primarily according to individual sample of origin which is in part due to the effect of chromosomal copy number gains and losses. Harmony alignment of single cell transcriptomic data revealed novel MB subgroup/subtype-associated subpopulations that recapitulate neurodevelopmental processes and are associated with clinical outcomes. This includes photoreceptor-like cells and glutamatergic lineage unipolar brush cells in both GP3 and GP4 subgroups of MB, and a SHH subgroup nodule-associated neuronally-differentiated cell subpopulation. We definitively chart the spectrum of MB immune cell infiltrates, which reveals unexpected degree of myeloid cell diversity. Myeloid subpopulations include subgroup/subtype-associated developmentally-related neuron-pruning as well as antigen presenting myeloid cells. Human MB cellular diversity is recapitulated in subgroup-specific MB GEMM, supporting the fidelity of these models. These findings provide a clearer understanding of both the neoplastic and immune cell heterogeneity in MB and how these impact subgroup/subtype classification and clinical outcome.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noab090.044
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2094060-9
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  • 10
    Online Resource
    Online Resource
    EPEN-16. Epithelial Progenitor Cell Abundance and Copy Number Variant Gains and Losses Impact the Biology of Recurrent Ependymoma
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_1 ( 2022-06-03), p. i41-i42
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_1 ( 2022-06-03), p. i41-i42
    Abstract: Ependymoma (EPN) is a common pediatric brain tumor that is fatal in approximately 50% of cases. Posterior fossa A (PFA) EPN has the highest rate of recurrence and the worst prognosis of all EPN subtypes. At relapse, it is typically incurable even with re-resection and re-irradiation. The biology of recurrent ependymoma remains largely unknown, which hinders clinical advances. In this study, we use paired samples of primary and recurrent disease from the same patient to investigate the drivers of recurrence. DNA methylation studies reveal frequent copy number variants at recurrence that were not present at primary presentation. We report a frequent gain of chromosome 1q and loss of 6p at recurrence, which has not been previously reported and may be a driver of recurrent disease. We have previously shown that PFA EPN is comprised of 4 main neoplastic cell populations, two well-differentiated populations termed ciliated and transportive ependymal cells, a mesenchymal cell population, and an undifferentiated population. Using spatial transcriptomics (Visium) integrated with single-nuclei RNA-seq (Chromium), we discovered that a highly proliferative EPN progenitor population of epithelial lineage is significantly upregulated at recurrence which we hypothesize drives refractory disease. Accordingly, we found higher expression of EPN progenitor gene signatures in bulk RNA transcriptomes of primary tumors that later recurred compared to tumors that never recurred. Together, these findings highlight the biologic differences between primary and recurrent disease and add to our understanding of treatment resistance in childhood ependymoma.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac079.153
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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