EPCO-07. HYBRID NEURO-GLIAL CELLULAR ARCHITECTURE IN HIGH-GRADE GLIOMA DRIVEN BY H3-G34R MUTATION

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi2-vi2
Author(s):  
Julie Laffy ◽  
Masashi Nomura ◽  
Chen He ◽  
Lillian Bussema ◽  
Michal Slyper ◽  
...  
Keyword(s):  
Young Adults ◽  
Rna Sequencing ◽  
Developmental Trajectories ◽  
High Grade Glioma ◽  
Cerebral Hemispheres ◽  
High Grade ◽  
Malignant Cells ◽  
Aberrant Expression ◽  
Cellular Architecture ◽  
Single Nucleus

Abstract High-grade gliomas (HGG) with histone H3.3 G34R mutation are rare intractable tumours in the cerebral hemispheres that preferentially affect adolescents and young adults, but have unknown mechanisms of neuroanatomical specificity and tumourigenesis. Here, we performed single-nucleus RNA-sequencing of twenty patient samples, encompassing twelve tumours with G34R mutation and eight H3.3 wildtype HGGs, age- and location-matched. Both classes of HGG were heterogeneous, with malignant cells in multiple states, recapitulating neural and glial developmental trajectories. G34R HGG is distinguished by lack of malignant cells in the oligodendroglial lineage, and aberrant expression of neuronal programs superimposed over cellular states, resulting in hybrid glio-neuronal malignant programs. Singe-cell barcoding supports plasticity between cellular states in HGG with multiple possible transitions. CRISPR-correction of G34R in HGG models followed by scRNA-seq supports that the G34R mutation directly drives these aberrant programs. Our study provides a framework for studying the origin and tumourigenesis of paediatric gliomas.

scholarly journals CTIM-06. DENDRITIC CELL VACCINE STUDY FOR RECURRENT, HIGH-GRADE GLIOMA: TISSUE-BASED RNA SEQUENCING AND SERUM CYTOKINE LEVELS AS POTENTIAL BIOMARKERS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii33-ii34
Author(s):  
Macarena De La Fuente ◽  
Tulay Koru-Sengul ◽  
Deborah Heros ◽  
Feng Miao ◽  
Alain Fernandez Marrero ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Rna Sequencing ◽  
Tumor Antigens ◽  
High Grade Glioma ◽  
Treatment Discontinuation ◽  
Sequencing Analysis ◽  
High Grade ◽  
Who Grade ◽  
Cytokine Levels ◽  
Grade 3

Abstract BACKGROUND Glioblastoma is the most common primary malignant brain tumor. Despite multimodality treatment approach, median progression-free survival (PFS) is only 8 months, median overall-survival (OS) 14 months and 5-year survival rate of under 10%. Dendritic cells (DCs) are the professional antigen presenting cells of the immune system. The rationale for sensitizing dendritic cells to a pool of non-selected tumor antigens is based on the marked heterogeneity present within glioblastoma tumor cells. METHODS Phase 1/feasibility study of DC vaccine for recurrent high-grade glioma was conducted. Pooled, non-selected tumor antigens collected via tumor cell lysate were used for DC sensitization. RNA sequencing analysis was performed on all tumor samples. Cytokine levels in serum were detected using a Luminex cytokine panel. RESULTS A total of 20 patients were enrolled onto this study (median age 58yrs, range: 39–74, 65% male). Pathology showed WHO grade IV glioblastoma in 14 (70%) and grade III anaplastic astrocytoma in 6 (30%) patients. IDH wild type in 19 (95%) patients. Treatment emergent adverse events (all grades, regardless of attribution) occurred in more than 15% of the patients (20% fatigue, 15% dizziness, 15% headache, none leading to treatment discontinuation). There were five grade 3–4 and none grade 5 events. One grade 4 event (seizure) probable related to investigational treatment leading to treatment discontinuation. Four grade 3 events (dysphasia, possible related; intracranial hemorrhage unrelated; muscle weakness, unlikely related and hematoma, unrelated). Median PFS was 3.8 months. Median OS was 11 months. RNA sequencing in tumor samples and correlation with cytokine levels in serum is currently been analyzed. CONCLUSION Tumor lysate pulsed DC vaccination demonstrates acceptable safety and tolerability in high-grade glioma patients. Evaluations of integrating molecular profiling RNA sequencing information and cytokine levels to identify potential subset of patients with significant clinical benefit will be provided.

scholarly journals Prospective evaluation of local control and late effects of conformal radiation therapy in children, adolescents, and young adults with high-grade glioma

2014 ◽  
Vol 16 (12) ◽  
pp. 1652-1660 ◽  
Author(s):  
Tamara Z. Vern-Gross ◽  
Jane E. Schreiber ◽  
Alberto Broniscer ◽  
Shengjie Wu ◽  
Xiaoping Xiong ◽  
...  
Keyword(s):  
Young Adults ◽  
Radiation Therapy ◽  
Local Control ◽  
Late Effects ◽  
High Grade Glioma ◽  
Adolescents And Young Adults ◽  
High Grade ◽  
Prospective Evaluation ◽  
Conformal Radiation Therapy

Pseudoprogression in children, adolescents and young adults with non-brainstem high grade glioma and diffuse intrinsic pontine glioma

2016 ◽  
Vol 129 (1) ◽  
pp. 109-121 ◽  
Author(s):  
Fernando Carceller ◽  
Lucy A. Fowkes ◽  
Komel Khabra ◽  
Lucas Moreno ◽  
Frank Saran ◽  
...  
Keyword(s):  
Young Adults ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Adolescents And Young Adults ◽  
High Grade ◽  
Pontine Glioma

scholarly journals Conserved cell types with divergent features between human and mouse cortex

2018 ◽  
Author(s):  
Rebecca D Hodge ◽  
Trygve E Bakken ◽  
Jeremy A Miller ◽  
Kimberly A Smith ◽  
Eliza R Barkan ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Cognitive Abilities ◽  
Cell Types ◽  
Mouse Cell ◽  
Middle Temporal Gyrus ◽  
Cellular Architecture ◽  
Mouse Cortex ◽  
Single Nucleus ◽  
Species Specific ◽  
Human And Mouse

AbstractElucidating the cellular architecture of the human neocortex is central to understanding our cognitive abilities and susceptibility to disease. Here we applied single nucleus RNA-sequencing to perform a comprehensive analysis of cell types in the middle temporal gyrus of human cerebral cortex. We identify a highly diverse set of excitatory and inhibitory neuronal types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to a similar mouse cortex single cell RNA-sequencing dataset revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of human cell type properties. Despite this general conservation, we also find extensive differences between homologous human and mouse cell types, including dramatic alterations in proportions, laminar distributions, gene expression, and morphology. These species-specific features emphasize the importance of directly studying human brain.

scholarly journals 18F-FAZA PET imaging in tumor hypoxia: A focus on high-grade glioma

2020 ◽  
Vol 35 (1_suppl) ◽  
pp. 42-46 ◽  
Author(s):  
Paola Mapelli ◽  
Maria Picchio
Keyword(s):  
Tumor Hypoxia ◽  
High Grade Glioma ◽  
Short Review ◽  
Typical Feature ◽  
Emission Tomography ◽  
High Grade ◽  
Malignant Cells ◽  
Hostile Environment ◽  
Non Invasive ◽  
Positron Emission

The presence of hypoxia is a typical feature of solid tumors and has been identified in many neoplasms, favouring the survival of malignant cells in a hostile environment and the expression of an aggressive phenotype. Malignant brain tumors have large proportions of hypoxic tissue, thus contributing to resistance to radiation and chemotherapy. Positron emission tomography (PET) is an attractive technique to gain a non-invasive assessment of tumor hypoxia within the whole tumor, with 18F-fluoromisonidazole (18F-FMISO) and 18F-flouroazomycin arabinoside (18F-FAZA) being the most promising radiotracers. In this short review, we aim to discuss the available clinical studies focused on the use of 18F-FAZA PET/computed tomography in patients affected by high-grade glioma.

scholarly journals DIPG-66. FEASIBILITY AND APPLICABILITY OF MOLECULAR GUIDED THERAPY IN HIGH GRADE GLIOMA/DIFFUSE MIDLINE GLIOMA: RESULTS FROM BEAT CHILDHOOD CANCER NMTRC-009 MOLECULAR GUIDED THERAPY STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii300-iii300
Author(s):  
Virginia Harrod ◽  
Abhinav Nagulapally ◽  
Elizabeth Lewis ◽  
Giselle Sholler
Keyword(s):  
Rna Sequencing ◽  
Individualized Medicine ◽  
Treatment Options ◽  
Treatment Protocol ◽  
High Grade Glioma ◽  
Tumor Board ◽  
Tumor Type ◽  
High Grade ◽  
Dna And Rna ◽  
Guided Therapy

Abstract High grade gliomas/diffuse midline gliomas (HGG/DMG) historically have a poor prognosis with an overall survival of less than 20% at 5 years. The pathophysiology is under close investigation across the world in efforts to understand this tumor type with aims of increasing effective treatment options. We present our results on the feasibility and outcomes of patients treated on our Molecular Guided Therapy study. Tumor samples were analyzed with whole exome (DNA) and RNA sequencing. Three drug matching algorithms were utilized to generate a report that was reviewed at a multi-institutional tumor board meeting, culminating in a proposed treatment protocol. Eleven patients enrolled, but one did not complete cycle 1 of therapy due to progression of disease, thus ten patients (6-HGG, 4-DMG) were evaluable and received at least 2 cycles of therapy. Time to reports generated and tumor board assembly was (median) 18 and 24 days, respectively. Secondary goals included evaluation of efficacy. Responses showed 50% of patients with stable disease or better at 2 cycles of therapy, but these were temporary with median time to progression of 81 days. In conclusion, we determined that it is feasible to collect individual biological DNA and RNA sequencing information to offer patients individualized treatment plans for this devastating group of diseases. Though data is not statistically significant, we show that there is a suggestion of efficacy in this approach to treatment for patients, indicating a need to expand on this treatment approach with individualized medicine.

scholarly journals High Frequency of PDGFRA and MUC Family Gene Mutations in Diffuse Hemispheric Glioma, H3 G34-mutant: A Glimmer of Hope?

2021 ◽  
Author(s):  
Wanming Hu ◽  
Hao Duan ◽  
Sheng Zhong ◽  
Jing Zeng ◽  
Yonggao Mou
Keyword(s):  
Targeted Therapy ◽  
Rna Sequencing ◽  
High Frequency ◽  
High Grade Glioma ◽  
Chinese Patients ◽  
Molecular Characteristics ◽  
High Grade ◽  
Rna Seq ◽  
Immune Infiltration ◽  
Genome Atlas

Abstract BackgroundDiffuse hemispheric glioma H3 G34-mutant (G34-DHG) is a new type of pediatric-type diffuse high-grade glioma in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. The current treatment for G34-DHG involves a combination of surgery and conventional radiotherapy or chemotherapy; however, the therapeutic efficacy of this approach is not satisfactory. In recent years, molecular targeted therapy and immunotherapy have achieved significant benefits in a variety of tumors. In-depth understanding of molecular changes and immune infiltration in G34-DHGs will help to establish personalized tumor treatment strategies. Here, we report the clinicopathological, molecular and immune infiltration characteristics of G34-DHG cases from our center along with cases from the HERBY Trial and the Chinese Glioma Genome Atlas database (CGGA). MethodsHematoxylin-eosin (HE) and immunohistochemistry (IHC) staining were used to present the clinicopathological characteristics of 10 Chinese G34-DHG patients treated at our institution. To address the molecular characteristics of G34-DHG, we performed whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analyses of 5 patients from our center and 3 Chinese patients from the Chinese Glioma Genome Atlas (CGGA) database. Additionally, 7 European G34-DHG patients from the HERBY Trail were also subjected to analyses, with 7 cases of WES data and 2 cases of RNA-seq data.ResultsWES showed a high frequency of PDGFRA mutation in G34-DHGs (12/15). We further identified frequent mutations in MUC family genes in G34-DHGs, including MUC16 (8/15) and MUC17 (8/15). Although no statistical difference was found, PDGFRA mutation tended to be an indicator for worse prognosis whereas MUC16/MUC17 mutation indicated a favorable prognosis in G34-DHGs. RNA sequencing results revealed that most G34-DHG are considered to be immune cold tumors. However, one patient in our cohort with MUC16 mutation showed significant immune infiltration, and the total overall survival of this patient reached 75 months. ConclusionsOur results demonstrate that G34-DHG is a new high-grade glioma with high frequency of PDGFRA and MUC gene family mutations. PDGFRA may serve as an indicator of poor prognosis and an effective therapeutic target. Moreover, MUC16 tends to be a favorable prognostic factor and indicates high immune infiltration in certain patients, and these findings may provide a new direction for targeted therapy and immunotherapy of patients with G34-DHGs.

scholarly journals Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

2020 ◽  
Vol 21 (24) ◽  
pp. 9654
Author(s):  
Santiago Haase ◽  
Fernando M. Nuñez ◽  
Jessica C. Gauss ◽  
Sarah Thompson ◽  
Emily Brumley ◽  
...  
Keyword(s):  
Cell Biology ◽  
High Grade Glioma ◽  
Cerebral Hemispheres ◽  
Clinical State ◽  
Molecular Characteristics ◽  
High Grade ◽  
Molecular Alterations ◽  
Current Therapies ◽  
Pediatric High Grade Glioma

In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies.

scholarly journals Single-nucleus RNA-seq resolves spatiotemporal developmental trajectories in the tomato shoot apex

2020 ◽  
Author(s):  
Caihuan Tian ◽  
Qingwei Du ◽  
Mengxue Xu ◽  
Fei Du ◽  
Yuling Jiao
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Rna Sequencing ◽  
Shoot Apex ◽  
Developmental Trajectories ◽  
Gene Expression Pattern ◽  
Cell Types ◽  
Plant Research ◽  
Expression Atlas ◽  
Single Nucleus

Single cell transcriptomics is revolutionizing our understanding of development and response to environmental cues1–3. Recent advances in single cell RNA sequencing (scRNA-seq) technology have enabled profiling gene expression pattern of heterogenous tissues and organs at single cellular level and have been widely applied in human and animal research4,5. Nevertheless, the existence of cell walls significantly encumbered its application in plant research. Protoplasts have been applied for scRNA-seq analysis, but mostly restricted to tissues amenable for wall digestion, such as root tips6–10. However, many cell types are resistant to protoplasting, and protoplasting may yield ectopic gene expression and bias proportions of cell types. Here we demonstrate a method with minimal artifacts for high-throughput single-nucleus RNA sequencing (snRNA-Seq) that we use to profile tomato shoot apex cells. The obtained high-resolution expression atlas identifies numerous distinct cell types covering major shoot tissues and developmental stages, delineates developmental trajectories of mesophyll cells, vasculature cells, epidermal cells, and trichome cells. In addition, we identify key developmental regulators and reveal their hierarchy. Collectively, this study demonstrates the power of snRNA-seq to plant research and provides an unprecedented spatiotemporal gene expression atlas of heterogeneous shoot cells.

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