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Neurology ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675105


BACKGROUND AND OBJECTIVES: Sport-related concussions affect millions of individuals across the United States each year and current techniques to diagnose and monitor them rely largely on subjective measures. Our goal was to discover and validate objective, quantifiable non-invasive biomarkers with the potential to be used in sport-related concussion diagnosis. METHODS: Urine samples from a convenience series of healthy control collegiate athletes who had not sustained a concussion and athletes who sustained a concussion as diagnosed by a sports medicine physician within seven days were collected prospectively and studied. Participants also completed an instrumented single-task gait analysis as a functional measure. Participants were recruited from a single collegiate athletic program, were ≥18 years old, and were excluded if they had a concomitant injury, active psychiatric conditions or pre-existing neurological disorders. Using Tandem Mass Tags (TMT) mass spectroscopy and enzyme-linked immunosorbent assays (ELISA), urinary biomarkers of concussion were identified and validated. RESULTS: Forty-eight control and 47 concussion age- and sex-matched athletes were included in the study (51.6%F, 48.4%M, average age 19.6y). Participants represented both contact and non-contact sports. All but one of the post-concussion participants reported experiencing symptoms at the time of data collection. Insulin-like growth factor 1 (IGF-1) and IGF binding protein 5 (IGFBP5) were downregulated in the urine of athletes with concussions compared to healthy controls. Multivariable risk algorithms developed to predict the probability of sport-related concussion showed that IGF-1 multiplexed with single-task gait velocity predicts concussion risk across a range of post-injury timepoints (AUC=0.786; 95% CI:0.690-0.884). When IGF-1 and IGFBP5 are multiplexed with single-task gait velocity, they accurately distinguish between healthy controls and concussion at acute timepoints (AUC=0.835, 95% CI:0.701-0·968, p<0.001). DISCUSSION: These noninvasive biomarkers, discovered in an objective and validated manner, may be useful in diagnosing and monitoring sport-related concussions in both acute phases of injury in addition to several days post-injury. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that urinary IGF-1 and IGFBP5 multiplexed with single-task gait velocity may be useful in diagnosing sport-related concussion. TRIAL REGISTRATION INFORMATION: identifier NCT02354469, submitted February 2015, first patient enrolled August 2015 (

Int J Mol Sci ; 21(11)2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32481745


Breast cancer brain metastasis is a major clinical challenge and is associated with a dismal prognosis. Understanding the mechanisms underlying the early stages of brain metastasis can provide opportunities to develop efficient diagnostics and therapeutics for this significant clinical challenge. We have previously reported that breast cancer-derived extracellular vesicles (EVs) breach the blood-brain barrier (BBB) via transcytosis and can promote brain metastasis. Here, we elucidate the functional consequences of EV transport across the BBB. We demonstrate that brain metastasis-promoting EVs can be internalized by astrocytes and modulate the behavior of these cells to promote extracellular matrix remodeling in vivo. We have identified protein and miRNA signatures in these EVs that can lead to the interaction of EVs with astrocytes and, as such, have the potential to serve as targets for development of diagnostics and therapeutics for early detection and therapeutic intervention in breast cancer brain metastasis.

Astrócitos/metabolismo , Barreira Hematoencefálica , Neoplasias da Mama/metabolismo , Vesículas Extracelulares/metabolismo , MicroRNAs/genética , Proteína cdc42 de Ligação ao GTP/metabolismo , Animais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Meios de Cultivo Condicionados/metabolismo , Endocitose , Matriz Extracelular/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Metástase Neoplásica , Prognóstico , Proteômica , Inibidor Tecidual de Metaloproteinase-2/metabolismo
ACS Nano ; 13(12): 13853-13865, 2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31479239


The restrictive nature of the blood-brain barrier (BBB) creates a major challenge for brain drug delivery with current nanomedicines lacking the ability to cross the BBB. Extracellular vesicles (EVs) have been shown to contribute to the progression of a variety of brain diseases including metastatic brain cancer and have been suggested as promising therapeutics and drug delivery vehicles. However, the ability of native tumor-derived EVs to breach the BBB and the mechanism(s) involved in this process remain unknown. Here, we demonstrate that tumor-derived EVs can breach the intact BBB in vivo, and by using state-of-the-art in vitro and in vivo models of the BBB, we have identified transcytosis as the mechanism underlying this process. Moreover, high spatiotemporal resolution microscopy demonstrated that the endothelial recycling endocytic pathway is involved in this transcellular transport. We further identify and characterize the mechanism by which tumor-derived EVs circumvent the low physiologic rate of transcytosis in the BBB by decreasing the brain endothelial expression of rab7 and increasing the efficiency of their transport. These findings identify previously unknown mechanisms by which tumor-derived EVs breach an intact BBB during the course of brain metastasis and can be leveraged to guide and inform the development of drug delivery approaches to deliver therapeutic cargoes across the BBB for treatment of a variety of brain diseases including, but not limited to, brain malignancies.

Barreira Hematoencefálica/metabolismo , Neoplasias da Mama/metabolismo , Vesículas Extracelulares/metabolismo , Transcitose , Animais , Neoplasias Encefálicas/secundário , Caveolinas/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Endossomos/metabolismo , Endotélio/metabolismo , Vesículas Extracelulares/ultraestrutura , Feminino , Humanos , Camundongos Nus , Transporte Proteico , Proteínas SNARE/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo