Extracellular Vesicles as Diagnostics and Therapeutics for Structural Epilepsies

Extracellular vesicles (EVs) are small vesicles involved in intercellular communication. Data is emerging that EVs and their cargo have potential as diagnostic biomarkers and treatments for brain diseases, including traumatic brain injury and epilepsy. Here, we summarize the current knowledge regarding changes in EV numbers and cargo in status epilepticus (SE) and traumatic brain injury (TBI), which are clinically significant etiologies for acquired epileptogenesis in animals and humans. We also review encouraging data, which suggests that EVs secreted by stem cells may serve as recovery-enhancing treatments for SE and TBI. Using Gene Set Enrichment Analysis, we show that brain EV-related transcripts are positively enriched in rodent models of epileptogenesis and epilepsy, and altered in response to anti-seizure drugs. These data suggest that EVs show promise as biomarkers, treatments and drug targets for epilepsy. In parallel to gathering conceptual knowledge, analytics platforms for the isolation and analysis of EV contents need to be further developed.

Download Full-text

What are the risk and protective factors for clinically significant suicide ideation or behavior in veterans with a history of traumatic brain injury?

PsycEXTRA Dataset ◽

10.1037/e522312010-004 ◽

2010 ◽

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Protective Factors ◽

Suicide Ideation ◽

Risk And Protective Factors ◽

History Of ◽

Clinically Significant

Download Full-text

Rapid Detection of Significant Traumatic Brain Injury Requiring Emergency Intervention

The American Surgeon ◽

10.1177/0003134820973355 ◽

2020 ◽

pp. 000313482097335

Author(s):

Isaac W. Howley ◽

Jonathan D. Bennett ◽

Deborah M. Stein

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Injuries ◽

Trauma Team ◽

Altered Mental Status ◽

Acute Care Surgery ◽

Ct Scanner ◽

Mickey Mouse ◽

Clinically Significant ◽

Care Surgery

Moderate and severe traumatic brain injuries (TBI) are a major cause of severe morbidity and mortality; rapid diagnosis and management allow secondary injury to be minimized. Traumatic brain injury is only one of many potential causes of altered mental status; head computed tomography (HCT) is used to definitively diagnose TBI. Despite its widespread use and obvious importance, interpretation of HCT images is rarely covered by formal didactics during general surgery or even acute care surgery training. The schema illustrated here may be applied in a rapid and reliable fashion to HCT images, expediting the diagnosis of clinically significant traumatic brain injury that warrants emergent medical and surgical therapies to reduce intracranial pressure. It consists of 7 normal anatomic structures (cerebrospinal fluid around the brain stem, open fourth ventricle, “baby’s butt,” “Mickey Mouse ears,” absence of midline shift, sulci and gyri, and gray-white differentiation). These 7 features can be seen even as the CT scanner obtains images, allowing the trauma team to expedite medical management of intracranial hypertension and pursue neurosurgical consultation prior to radiologic interpretation if the features are abnormal.

Download Full-text

Drug perturbation gene set enrichment analysis (dpGSEA): a new transcriptomic drug screening approach

BMC Bioinformatics ◽

10.1186/s12859-020-03929-0 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Mike Fang ◽

Brian Richardson ◽

Cheryl M. Cameron ◽

Jean-Eudes Dazard ◽

Mark J. Cameron

Keyword(s):

Drug Targets ◽

T Regulatory Cells ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Regulatory Cells ◽

Gene Set Enrichment ◽

Gene Set ◽

Gene Sets ◽

Gastroenteropancreatic Neuroendocrine Tumor ◽

Public Datasets

Abstract Background In this study, we demonstrate that our modified Gene Set Enrichment Analysis (GSEA) method, drug perturbation GSEA (dpGSEA), can detect phenotypically relevant drug targets through a unique transcriptomic enrichment that emphasizes biological directionality of drug-derived gene sets. Results We detail our dpGSEA method and show its effectiveness in detecting specific perturbation of drugs in independent public datasets by confirming fluvastatin, paclitaxel, and rosiglitazone perturbation in gastroenteropancreatic neuroendocrine tumor cells. In drug discovery experiments, we found that dpGSEA was able to detect phenotypically relevant drug targets in previously published differentially expressed genes of CD4+T regulatory cells from immune responders and non-responders to antiviral therapy in HIV-infected individuals, such as those involved with virion replication, cell cycle dysfunction, and mitochondrial dysfunction. dpGSEA is publicly available at https://github.com/sxf296/drug_targeting. Conclusions dpGSEA is an approach that uniquely enriches on drug-defined gene sets while considering directionality of gene modulation. We recommend dpGSEA as an exploratory tool to screen for possible drug targeting molecules.

Download Full-text

Social cognition and traumatic brain injury: current knowledge

Brain Injury ◽

10.1080/02699052.2018.1533143 ◽

2018 ◽

Vol 33 (1) ◽

pp. 1-3 ◽

Cited By ~ 2

Author(s):

Philippe Allain ◽

Leanne Togher ◽

Philippe Azouvi

Keyword(s):

Traumatic Brain Injury ◽

Social Cognition ◽

Brain Injury ◽

Current Knowledge

Download Full-text

Potential biomarkers to detect traumatic brain injury by the profiling of salivary extracellular vesicles

Journal of Cellular Physiology ◽

10.1002/jcp.28139 ◽

2019 ◽

Vol 234 (8) ◽

pp. 14377-14388 ◽

Cited By ~ 10

Author(s):

Yan Cheng ◽

Mandy Pereira ◽

Neha Raukar ◽

John L. Reagan ◽

Mathew Queseneberry ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Extracellular Vesicles ◽

Potential Biomarkers

Download Full-text

The Role of Free Radicals in Traumatic Brain Injury

Biological Research For Nursing ◽

10.1177/1099800411431823 ◽

2012 ◽

Vol 15 (3) ◽

pp. 253-263 ◽

Cited By ~ 24

Author(s):

Karen M. O’Connell ◽

Marguerite T. Littleton-Kearney

Keyword(s):

Traumatic Brain Injury ◽

Free Radicals ◽

Free Radical ◽

Brain Injury ◽

Current Knowledge ◽

Cellular Level ◽

Secondary Brain Injury ◽

Secondary Injury ◽

The Military

Traumatic brain injury (TBI) is a significant cause of death and disability in both the civilian and the military populations. The primary impact causes initial tissue damage, which initiates biochemical cascades, known as secondary injury, that expand the damage. Free radicals are implicated as major contributors to the secondary injury. Our review of recent rodent and human research reveals the prominent role of the free radicals superoxide anion, nitric oxide, and peroxynitrite in secondary brain injury. Much of our current knowledge is based on rodent studies, and the authors identified a gap in the translation of findings from rodent to human TBI. Rodent models are an effective method for elucidating specific mechanisms of free radical-induced injury at the cellular level in a well-controlled environment. However, human TBI does not occur in a vacuum, and variables controlled in the laboratory may affect the injury progression. Additionally, multiple experimental TBI models are accepted in rodent research, and no one model fully reproduces the heterogeneous injury seen in humans. Free radical levels are measured indirectly in human studies based on assumptions from the findings from rodent studies that use direct free radical measurements. Further study in humans should be directed toward large samples to validate the findings in rodent studies. Data obtained from these studies may lead to more targeted treatment to interrupt the secondary injury cascades.

Download Full-text

Compendium of skin molecular signatures identifies key pathological features associated with fibrosis in systemic sclerosis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-214778 ◽

2019 ◽

Vol 78 (6) ◽

pp. 817-825 ◽

Cited By ~ 7

Author(s):

Su-Jin Moon ◽

Jung Min Bae ◽

Kyung-Su Park ◽

Ilias Tagkopoulos ◽

Ki-Jo Kim

Keyword(s):

Systemic Sclerosis ◽

Drug Targets ◽

Leading Edge ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Skin Fibrosis ◽

Akt Pathway ◽

Data Sets ◽

Phosphoinositide 3 Kinase ◽

Genome Scale

ObjectivesTreatment of patients with systemic sclerosis (SSc) can be challenging because of clinical heterogeneity. Integration of genome-scale transcriptomic profiling for patients with SSc can provide insights on patient categorisation and novel drug targets.MethodsA normalised compendium was created from 344 skin samples of 173 patients with SSc, covering an intersection of 17 424 genes from eight data sets. Differentially expressed genes (DEGs) identified by three independent methods were subjected to functional network analysis, where samples were grouped using non-negative matrix factorisation. Finally, we investigated the pathways and biomarkers associated with skin fibrosis using gene-set enrichment analysis.ResultsWe identified 1089 upregulated DEGs, including 14 known genetic risk factors and five potential drug targets. Pathway-based subgrouping revealed four distinct clusters of patients with SSc with distinct activity signatures for SSc-relevant pathways. The inflammatory subtype was related to significant improvement in skin fibrosis at follow-up. The phosphoinositide-3-kinase-protein kinase B (PI3K-Akt) signalling pathway showed both the closest correlation and temporal pattern to skin fibrosis score. COMP, THBS1, THBS4, FN1, and TNC were leading-edge genes of the PI3K-Akt pathway in skin fibrogenesis.ConclusionsConstruction and analysis of normalised skin transcriptomic compendia can provide useful insights on pathway involvement by SSc subsets and discovering viable biomarkers for a skin fibrosis index. Particularly, the PI3K-Akt pathway and its leading players are promising therapeutic targets.

Download Full-text

Micro Ribonucleic Acid Profiles of Traumatic Brain Injury Isolated From Plasma Extracellular Vesicles

Neurosurgery ◽

10.1093/neuros/nyz310_831 ◽

2019 ◽

Vol 66 (Supplement_1) ◽

Author(s):

Ross Puffer ◽

Luz Cumba-Garcia ◽

Benjamin T Himes ◽

David O Okonkwo ◽

Ian F Parney

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Extracellular Vesicles ◽

Rna Isolation ◽

Extracellular Vesicle ◽

Micro Rna ◽

Altered Consciousness ◽

Rna Sequences ◽

Altered Level ◽

Level Of Consciousness

Abstract INTRODUCTION Extracellular vesicles (EVs) are membrane-bound particles released by the majority of human cells, including cells within the central nervous system. They may represent a diagnostic or prognostic target obtainable in peripheral blood of neurotrauma patients. We have isolated micro RNA sequences contained within EVs of 15 patients with traumatic brain injury (TBI) and compared them to miRNA sequences from 5 healthy controls. METHODS Extracellular vesicles were isolated from 15 TBI subjects, including 6 mild TBI (Glasgow Coma Scale (GCS) 13-15), 3 moderate TBI (GCS 9-12), and 6 severe TBI (GCS 3-8), as well as 5 healthy control. EVs were analyzed using nanoparticle tracking analysis. Samples underwent RNA isolation and extraction, followed by miRNA sequencing and analysis. RESULTS TBI patients presenting with an altered level of consciousness (GCS = 14) had a significantly higher mean extracellular vesicle size compared to subjects with normal GCS (mean + /− sem = 108.3 nm + /− 7.7 nm vs 89.2 nm + /− 6.7 nm; P < .04). GFAP ELISA of the samples demonstrated significantly higher GFAP concentration in subjects with altered level of consciousness (GCS = 14) as compared to those with normal GCS (mean + /− sem GFAP concentration 2204.2 pg/mL + /− 1067.2 pg/mL vs. 207.8 pg/mL + /− 270.8 pg/mL, P = .05). We identified 9 miRNA sequences that were found in a significantly higher proportion in patients with altered consciousness compared to controls, as well as 2 miRNA sequences that were significantly downregulated in subjects with altered consciousness as compared to controls. CONCLUSION EVs may contain brain specific biomarkers that are released in greater quantities after TBI. These molecules can be isolated from plasma and sequenced. Further analysis will better elucidate the final pathways affected by these up and downregulated miRNA sequences. Analysis of EVs in subjects with TBI may allow for the identification of novel diagnostic and potentially prognostic biomarkers.

Download Full-text

RNA profiling of neuroendocrine tumors (NETs) to define new targets and mechanisms of progression.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.302 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 302-302

Author(s):

Namrata Vijayvergia ◽

Suraj Peri ◽

Karthik Devarajan ◽

Jianming Pei ◽

Yulan Gong ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Drug Targets ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Enrichment Score ◽

Rna Profiling ◽

Histone Lysine Methyltransferase ◽

Canonical Pathways ◽

Lysine Methyltransferase

302 Background: NETs lack mutations in the “classical” signaling pathways but share mutations in regulators of gene expression (Jiao; 2011). We compared gene expression in PD & WD NETs to identify novel targets and biomarkers of differentiation. Methods: High quality RNA, extracted from paraffin blocks of deidentified NETs under an IRB-approved protocol, was profiled using a 770 gene panel (nCounter PanCancer pathway, Nanostring Technologies). The resulting data was used to identify the differentially expressed genes between PD and WD NETs using limma software (Ritchie; 2015). Gene Set Enrichment Analysis (Subramanian; 2005) identified differential pathway enrichment by calculating a Normalized Enrichment Score (NES). Results: Analysis of 16 PD and 23 WD NET samples identified 154 genes as extreme outliers ( > 2 fold up/downregulation between the subtypes). Compared to WD NETS, drug targets of interest overexpressed in PD NETs were histone lysine methyltransferase EZH2, and a cell cycle regulator CHEK1 (6.5x and 8.1x, respectively, p < 0.001). In contrast, serine/threonine protein kinase PAK 3 was upregulated in WD (10.6x, p < 0.001). These and other biomarkers will be further validated by immunolabeling of tissue sections. We also found differential enrichment of canonical pathways in PD versus WD NETs (table). Conclusions: Extreme outlier transcripts identified in PD & WD NETs support investigation of inhibitors of EZH2 (e.g. EPZ6438) and CHEK1 (e.g. LY2606368) in PD and PAK3(e.g. FRAX597) in WD NETs. Genes involved in cell cycle regulation and DNA repair in PD NETs and calcium / G protein coupled receptor signaling in WD NET account for biological differences between the 2 molecular subtypes and warrant future investigation as classifiers for NETs. Our findings provide mechanistic insights into the biology of NET and targets for therapy with direct clinical implications.[Table: see text]

Download Full-text