Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy

Shao, Huilin; Chung, Jaehoon; Balaj, Leonora; Charest, Alain; Bigner, Darell D.; Carter, Bob S.; Hochberg, Fred H.; Breakefield, Xandra O.; Weissleder, Ralph; Lee, Hakho

doi:10.1038/nm.2994

Cited by 658 publications

(722 citation statements)

References 37 publications

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“…Alternatively, to overcome these issues, beads can be used to specifically capture MVs. For example, micro-NMR technology using tetrazine-labelled magnetic nanoparticle-captured EVs has also been successfully used to detect tumoural EGFRv3+ EVs in glioblastoma patients [37]. In agreement with these results, the present study demonstrates the ability of antibody-coated magnetic beads to specifically isolate MVs of a definite cellular origin independently of the coating process.…”

Section: Discussionsupporting

confidence: 80%

“…Interestingly, in our series of septic patients, we found that survivors had significantly higher MV-PGC values both at inclusion and 24 h later than healthy controls (Figure 5(a)) and nonsurvivors (3.1 [1.7–18] vs 1.4 [0.8–3.0] A 405nm × 10 −3 /min, p = 0.02, H0; 5.2 [2.2–16] vs 1.4 [1–1.6] A 405nm × 10 −3 /min, p = 0.004, H24). As expected, PAI-1 activity was significantly lower at admission in the patients who survived (S) compared with those who died (NS) (median [interquartile range]; 3 [2–37] vs 43 [34–55] a.u. (arbitrary units)/mL, p = 0.008, Figure 5(b)).…”

Section: Resultssupporting

confidence: 60%

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A new assay to evaluate microvesicle plasmin generation capacity: validation in disease with fibrinolysis imbalance

Cointe

Souab

Bouriche³

et al. 2018

J of Extracellular Vesicle

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Among extracellular vesicles, leukocyte-derived microvesicles (LMVs) have emerged as complex vesicular structures. Primarily identified as procoagulant entities, they were more recently ascribed to plasmin generation capacity (MV-PGC). The objectives of this work were (1) to develop a new hybrid bio-assay combining the specific isolation of LMVs and measurement of their PGC, and compare its performance to the original method based on centrifugation, (2) to validate MV-PGC in septic shock, combining increased levels of LMVs and fibrinolytic imbalance. Using plasma sample spiked with LMVs featuring different levels of PGC, we demonstrated that CD15-beads specifically extracted LMVs. The MV dependency of the test was demonstrated using electron microscopy, high speed centrifugation, nanofiltration and detergent-mediated solubilization and the MV-PGC specificity using plasmin-specific inhibitors, or antibodies blocking elastase or uPA. Thanks to a reaction booster (ε-ACA), we showed that the assay was more sensitive and reproducible than the original method. Moreover, it exhibited a good repeatability, inter-operator and inter-experiment reproducibility. The new immunomagnetic bio-assay was further validated in patients with septic shock. As a result, we showed that MV-PGC values were significantly lower in septic shock patients who died compared to patients who survived, both at inclusion and 24 h later (1.4 [0.8–3.0] vs 3.1 [1.7–18] A405 × 10−3/min, p = 0.02; 1.4 [1–1.6] vs 5.2 [2.2–16] A405 × 10−3/min, p = 0.004). Interestingly, combining both MV-PGC and PAI-1 in a ratio significantly improved the predictive value of PAI-1. This strategy, a hybrid capture bioassay to specifically measure LMV-PGC using for the first time, opens new perspectives for measuring subcellular fibrinolytic potential in clinical settings with fibrinolytic imbalance.

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Section: Discussionsupporting

confidence: 80%

Section: Resultssupporting

confidence: 60%

A new assay to evaluate microvesicle plasmin generation capacity: validation in disease with fibrinolysis imbalance

Cointe

Souab

Bouriche³

et al. 2018

J of Extracellular Vesicle

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“…Interestingly, one other type of microfluidic chip was recently reported for MV characterization in biological fluids based on labelling with magnetic nanoparticles and miniaturized nuclear magnetic resonance detection 7 . Although it was shown to be capable of discriminating different types of MVs with high sensitivity, it does not feature independent size and concentration measurements.…”

Section: Resultsmentioning

confidence: 99%

“…tumour growth and metastasis, is a topic that receives a lot of attention nowadays [1][2][3][4][5][6] . The size, origin and concentration of cell-derived MVs could entail clinically relevant signatures with diagnostic and prognostic value 2,5,7 . Thus, substantial efforts have gone into evaluating and developing techniques suitable for submicron MV characterization in terms of specificity, size and concentration 8 .…”

Section: Introductionmentioning

confidence: 99%

On-chip light sheet illumination enables diagnostic size and concentration measurements of membrane vesicles in biofluids

et al. 2014

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Cell-derived membrane vesicles that are released in biofluids, like blood or saliva, are emerging as potential non-invasive biomarkers for diseases, such as cancer. Techniques capable of measuring the size and concentration of membrane vesicles directly in biofluids are urgently needed. Fluorescence Single Particle Tracking microscopy has the potential of doing exactly that, by labelling the membrane vesicles with a fluorescent label and analysing their Brownian motion in the biofluid. However, unbound dye in the biofluid can cause high background intensity that strongly biases the fluorescence Single Particle Tracking size and concentration measurements. While such background can be avoided with light sheet illumination, current set-ups require specialty sample holders that are not compatible with high-throughput diagnostics. Here, a microfluidic chip with integrated light sheet illumination is reported, and accurate fluorescence Single Particle Tracking size and concentration measurements of membrane vesicles in cell culture medium and in interstitial fluid collected from primary human breast tumours are demonstrated.3

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“…Shao et al used μ NMR to detect target-specific magnetic nanoparticles after on-chip isolation [106]. …”

Section: Microfluidics-based Detection and Analysis Systemsmentioning

confidence: 99%

Microfluidics‐based on‐a‐chip systems for isolating and analysing extracellular vesicles

Guo

Tao

Dawn

2018

J of Extracellular Vesicle

142

111

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Extracellular vesicles (EVs), which can be found in almost all body fluids, consist of a lipid bilayer enclosing proteins and nucleic acids from their cells of origin. EVs can transport their cargo to target cells and have therefore emerged as key players in intercellular communication. Their potential as either diagnostic and prognostic biomarkers or therapeutic drug delivery systems (DDSs) has generated considerable interest in recent years. However, conventional methods used to study EVs still have significant limitations including the time-consuming and low throughput techniques required, while at the same time the demand for better research tools is getting stronger and stronger. In the past few years, microfluidics-based technologies have gradually emerged and have come to play an essential role in the isolation, detection and analysis of EVs. Such technologies have several advantages, including low cost, low sample volumes, high throughput and precision. This review summarizes recent advances in microfluidics-based technologies, compares conventional and microfluidics-based technologies, and includes a brief survey of recent progress towards integrated “on-a-chip” systems. In addition, this review also discusses the potential clinical applications of “on-a-chip” systems, including both “liquid biopsies” for personalized medicine and DDS devices for precision medicine, and then anticipates the possible future participation of cloud-based portable disease diagnosis and monitoring systems, possibly with the participation of artificial intelligence (AI).

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Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy

Cited by 658 publications

References 37 publications

A new assay to evaluate microvesicle plasmin generation capacity: validation in disease with fibrinolysis imbalance

A new assay to evaluate microvesicle plasmin generation capacity: validation in disease with fibrinolysis imbalance

On-chip light sheet illumination enables diagnostic size and concentration measurements of membrane vesicles in biofluids

Microfluidics‐based on‐a‐chip systems for isolating and analysing extracellular vesicles

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