scholarly journals Reconstruction of Ewing Sarcoma Developmental Context from Mass-Scale Transcriptomics Reveals Characteristics of EWSR1-FLI1 Permissibility

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 948 ◽  
Author(s):  
Henry E. Miller ◽  
Aparna Gorthi ◽  
Nicklas Bassani ◽  
Liesl A. Lawrence ◽  
Brian S. Iskra ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Fusion Gene ◽  
Developmental Trajectories ◽  
Mass Scale ◽  
Developmental Trajectory ◽  
Sequencing Data ◽  
Mesodermal Cell ◽  
Developmental Context ◽  
Translocation Event ◽  
Sarcoma Cells

Ewing sarcoma is an aggressive pediatric cancer of enigmatic cellular origins typically resulting from a single translocation event t (11; 22) (q24; q12). The resulting fusion gene, EWSR1-FLI1, is toxic or unstable in most primary tissues. Consequently, attempts to model Ewing sarcomagenesis have proven unsuccessful thus far, highlighting the need to identify the cellular features which permit stable EWSR1-FLI1 expression. By re-analyzing publicly available RNA-Sequencing data with manifold learning techniques, we uncovered a group of Ewing-like tissues belonging to a developmental trajectory between pluripotent, neuroectodermal, and mesodermal cell states. Furthermore, we demonstrated that EWSR1-FLI1 expression levels control the activation of these developmental trajectories within Ewing sarcoma cells. Subsequent analysis and experimental validation demonstrated that the capability to resolve R-loops and mitigate replication stress are probable prerequisites for stable EWSR1-FLI1 expression in primary tissues. Taken together, our results demonstrate how EWSR1-FLI1 hijacks developmental gene programs and advances our understanding of Ewing sarcomagenesis.

scholarly journals Germ-layer commitment and axis formation in sea anemone embryonic cell aggregates

2018 ◽  
Vol 115 (8) ◽  
pp. 1813-1818 ◽  
Author(s):  
Anastasia Kirillova ◽  
Grigory Genikhovich ◽  
Ekaterina Pukhlyakova ◽  
Adrien Demilly ◽  
Yulia Kraus ◽  
...  
Keyword(s):  
Normal Development ◽  
Developmental Trajectories ◽  
Embryonic Cell ◽  
Sea Anemone ◽  
Developmental Trajectory ◽  
Nematostella Vectensis ◽  
Axis Formation ◽  
Cell Aggregates ◽  
Embryonic Cells ◽  
Developmental Context

Robust morphogenetic events are pivotal for animal embryogenesis. However, comparison of the modes of development of different members of a phylum suggests that the spectrum of developmental trajectories accessible for a species might be far broader than can be concluded from the observation of normal development. Here, by using a combination of microsurgery and transgenic reporter gene expression, we show that, facing a new developmental context, the aggregates of dissociated embryonic cells of the sea anemone Nematostella vectensis take an alternative developmental trajectory. The self-organizing aggregates rely on Wnt signals produced by the cells of the original blastopore lip organizer to form body axes but employ morphogenetic events typical for normal development of distantly related cnidarians to re-establish the germ layers. The reaggregated cells show enormous plasticity including the capacity of the ectodermal cells to convert into endoderm. Our results suggest that new developmental trajectories may evolve relatively easily when highly plastic embryonic cells face new constraints.

From a molar to a molecular approach to the developmental trajectory of syntax comprehension by persons with intellectual disability

2020 ◽  
Author(s):  
Bruno Facon
Keyword(s):  
Developmental Trajectories ◽  
Developmental Trajectory ◽  
Typically Developing ◽  
Cognitive Level ◽  
Cross Sectional ◽  
Test Items ◽  
Complex Sentences ◽  
Regression Curves ◽  
Cognitive Measure ◽  
Syntactic Skills

The aim was to investigate whether a progressive dissociation between the cognitive level and syntax comprehension occurs during the development of persons with intellectual disabilities (ID). Two cross-sectional developmental trajectory analyses were successively conducted. Study 1 comprised 615 typically developing participants and 615 participants with ID. Their total scores on a syntax comprehension test were regressed on a nonverbal cognitive measure and the slopes of the two groups’ regression lines were compared. In Study 2, logistic regression curves of the two groups for each of the 92 test items were compared. Results showed only negligible between-groups differences of developmental trajectories, whatever the level of analysis. The idea of a progressive dissociation between cognitive level and receptive syntactic skills of people with ID is not confirmed. However, a syntax test evaluating more complex sentences than those used in this study might show such a dissociation.

Localization of genetic elements of intact and derivative chromosome 11 and 22 territories in nuclei of Ewing sarcoma cells

2006 ◽  
Vol 155 (3) ◽  
pp. 493-504 ◽  
Author(s):  
Renata Taslerová ◽  
Stanislav Kozubek ◽  
Eva Bártová ◽  
Pavla Gajdušková ◽  
Roman Kodet ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Derivative Chromosome ◽  
Chromosome 11 ◽  
Genetic Elements ◽  
Sarcoma Cells

scholarly journals Cognitive and School Functioning in Children and Adolescents with Chronic Pain: A Critical Review

2010 ◽  
Vol 15 (4) ◽  
pp. 238-244 ◽  
Author(s):  
Bruce D Dick ◽  
Rebecca Pillai Riddell
Keyword(s):  
Chronic Pain ◽  
Cognitive Function ◽  
Children And Adolescents ◽  
School Attendance ◽  
Developmental Trajectories ◽  
Critical Factor ◽  
Developmental Trajectory ◽  
Future Research ◽  
Research Directions ◽  
Future Research Directions

Cognitive function is a critical factor related to a child’s overall developmental trajectory. There is increasing evidence that chronic pain disrupts cognitive function in adults. Little is known about the nature or impact of cognitive disruption in children and adolescents with chronic pain. The present review examines the current literature related to cognitive function in children and adolescents with chronic pain, implications of these findings and future research directions. Nine studies on this topic were found, with a relatively recent increase in publications related to school attendance and subjective studies of school performance. The studies that were found on this topic suggested that chronic pain affects cognitive function in children but the scope of these effects on children’s function and developmental trajectories is not yet clear. While methodological issues surely make it difficult to study cognitive function in children with chronic pain, the potential gains from such research warrant a pursuit of such work. Much remains to be studied on this important topic.

Single-cell RNA profiling identifies diverse cellular responses to EWSR1/FLI1 downregulation in Ewing sarcoma cells

2022 ◽  
Author(s):  
Roxane Khoogar ◽  
Fuyang Li ◽  
Yidong Chen ◽  
Myron Ignatius ◽  
Elizabeth R. Lawlor ◽  
...  
Keyword(s):  
Single Cell ◽  
Ewing Sarcoma ◽  
Cellular Responses ◽  
Rna Profiling ◽  
Sarcoma Cells

scholarly journals Multidimensional brain-age prediction reveals altered brain developmental trajectory in psychiatric disorders

2020 ◽  
Author(s):  
Xin Niu ◽  
Alexei Taylor ◽  
Russell T. Shinohara ◽  
John Kounios ◽  
Fengqing Zhang
Keyword(s):  
Psychiatric Disorders ◽  
Robust Regression ◽  
Developmental Trajectories ◽  
Brain Structures ◽  
Brain Regions ◽  
Developmental Trajectory ◽  
Imaging Features ◽  
Neuroimaging Data ◽  
Brain Age ◽  
Age Prediction

AbstractBrain regions change in different ways and at different rates. This staggered developmental unfolding is determined by genetics and postnatal experience and is implicated in the progression of psychiatric and neurological disorders. Neuroimaging-based brain-age prediction has emerged as an important new approach for studying brain development. However, the unidimensional brain-age estimates provided by previous methods do not capture the divergent developmental trajectories of various brain structures. Here we propose and illustrate an analytic pipeline to compute an index of multidimensional brain-age that provides regional age predictions. First, using a database of 556 subjects that includes psychiatric and neurological patients as well as healthy controls we conducted robust regression to characterize the developmental trajectory of each MRI-based brain-imaging feature. We then utilized cluster analysis to identify subgroups of imaging features with a similar developmental trajectory. For each identified cluster, we obtained a brain-age prediction by applying machine-learning models with imaging features belonging to each cluster. Brain-age predictions from multiple clusters form a multidimensional brain-age index (MBAI). The MBAI is more sensitive to alterations in brain structures and captured distinct regional change patterns. In particular, the MBAI provided a more flexible analysis of brain age across brain regions that revealed changes in specific structures in psychiatric disorders that would otherwise have been combined in a unidimensional brain age prediction. More generally, brain-age prediction using a subset of homogeneous features circumvents the curse of dimensionality in neuroimaging data.

scholarly journals Identification of a Novel Oncogenic Fusion Gene SPON1-TRIM29 in Clinical Ovarian Cancer That Promotes Cell and Tumor Growth and Enhances Chemoresistance in A2780 Cells

2022 ◽  
Vol 23 (2) ◽  
pp. 689
Author(s):  
Saya Nagasawa ◽  
Kazuhiro Ikeda ◽  
Daisuke Shintani ◽  
Chiujung Yang ◽  
Satoru Takeda ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Rna Sequencing ◽  
Anticancer Drugs ◽  
Fusion Gene ◽  
Xenograft Model ◽  
Fusion Transcript ◽  
Serous Carcinoma ◽  
Fusion Genes ◽  
Sequencing Data ◽  
Chromosome 11

Gene structure alterations, such as chromosomal rearrangements that develop fusion genes, often contribute to tumorigenesis. It has been shown that the fusion genes identified in public RNA-sequencing datasets are mainly derived from intrachromosomal rearrangements. In this study, we explored fusion transcripts in clinical ovarian cancer specimens based on our RNA-sequencing data. We successfully identified an in-frame fusion transcript SPON1-TRIM29 in chromosome 11 from a recurrent tumor specimen of high-grade serous carcinoma (HGSC), which was not detected in the corresponding primary carcinoma, and validated the expression of the identical fusion transcript in another tumor from a distinct HGSC patient. Ovarian cancer A2780 cells stably expressing SPON1-TRIM29 exhibited an increase in cell growth, whereas a decrease in apoptosis was observed, even in the presence of anticancer drugs. The siRNA-mediated silencing of SPON1-TRIM29 fusion transcript substantially impaired the enhanced growth of A2780 cells expressing the chimeric gene treated with anticancer drugs. Moreover, a subcutaneous xenograft model using athymic mice indicated that SPON1-TRIM29-expressing A2780 cells rapidly generated tumors in vivo compared to control cells, whose growth was significantly repressed by the fusion-specific siRNA administration. Overall, the SPON1-TRIM29 fusion gene could be involved in carcinogenesis and chemotherapy resistance in ovarian cancer, and offers potential use as a diagnostic and therapeutic target for the disease with the fusion transcript.

The Cascading Effects of Gross Motor Development and the Impact of Intervention in Early Childhood

2021 ◽  
pp. 1-15
Author(s):  
Ali S. Brian
Keyword(s):  
Early Childhood ◽  
Physical Education ◽  
School Readiness ◽  
Motor Development ◽  
Developmental Trajectories ◽  
Developmental Trajectory ◽  
Gross Motor ◽  
Cascading Effects ◽  
Secular Decline ◽  
Developmental Domains

Today's preschoolers are facing a secular decline with their motor development. Intervention, via physical education in preschool, can be effective to remediate gross motor delays. Teachers need ongoing support in order to intervene. If teachers intervene, children may be placed onto a positive developmental trajectory towards lifespan health. Children's gains in gross motor can transcend into other domains of development. Thus, the author urges early childhood policymakers to strongly consider hiring a licensed physical educator to implement daily physical education to preschoolers to maximize positive developmental trajectories of health. If these policy changes do not occur, children may continue on their secular decline with deleterious consequences across multiple developmental domains and school readiness.

scholarly journals 3279 First in Man

2019 ◽  
Vol 3 (s1) ◽  
pp. 45-45
Author(s):  
Laura Adang ◽  
Francesco Gavazzi ◽  
Valentina De Giorgis ◽  
Micaela De Simone ◽  
Elisa Fazzi ◽  
...  
Keyword(s):  
Skill Acquisition ◽  
Classification System ◽  
Developmental Trajectories ◽  
Spastic Paraparesis ◽  
Altered Mental Status ◽  
Developmental Trajectory ◽  
Global Developmental Delay ◽  
P Value ◽  
Kaplan Meier ◽  
Neurologic Disability

OBJECTIVES/SPECIFIC AIMS: A mimic of congenital infections and a rare genetic cause of interferon overproduction, Aicardi Goutières Syndrome (AGS) results in significant neurologic disability. AGS is caused by pathogenic changes in the intracellular nucleic acid sensing machinery (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1). All affected individuals exhibit neurologic impairment: from mild spastic paraparesis to severe tetraparesis and global developmental delay. We hypothesize that genotype influences the heterogeneous developmental trajectory found in AGS. METHODS/STUDY POPULATION: To characterize this spectrum, age and symptoms at presentation and longitudinal developmental skill acquisition was collected from an international cohort of children (n=88) with genetically confirmed AGS. RESULTS/ANTICIPATED RESULTS: We found that individuals present at variable ages, with the largest range in SAMHD1, ADAR, and IFIH1. There are 3 clusters of symptoms at presentation: altered mental status (irritability or lethargy), systemic inflammatory symptoms, and acute neurologic symptoms, with variability across all genotypes. By creating Kaplan-Meier curves for developmental milestones, we were able to create genotype-based developmental trajectories for the children affected by the 5 most common genotypes: TREX1, IFIH1, SAMHD1, ADAR, and RNASEH2B. Individuals with AGS secondary to TREX1 were the most severely affected, significantly less likely to reach milestones compared to the other genotypes, including head control, sitting, and nonspecific mama/dada (p-value <0.005). Individuals affected by SAMHD1, IFIH1, and ADAR collectively attained the most advanced milestones, with 44% of the population achieving a minimum of a single word and 31% able to walk independently. Three retrospective scales were also applied: Gross Motor Function Classification System, Manual Ability Classification Scale, and Communication Function Classification System. Within each genotypic cohort, there was pronounced heterogeneity. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results demonstrate the influence of genotype on early development, but also suggest the importance of other unidentified variables. These results underscore the need for deep phenotyping to better characterize subcohorts within the AGS population.

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