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  • 1
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    A standardized method to determine the concentration of extracellular vesicles using tunable resistive pulse sensing
    Wiley ; 2016
    In:  Journal of Extracellular Vesicles Vol. 5, No. 1 ( 2016-01)
    Details
    In: Journal of Extracellular Vesicles, Wiley, Vol. 5, No. 1 ( 2016-01)
    Abstract: Understanding the pathogenic role of extracellular vesicles (EVs) in disease and their potential diagnostic and therapeutic utility is extremely reliant on in‐depth quantification, measurement and identification of EV sub‐populations. Quantification of EVs has presented several challenges, predominantly due to the small size of vesicles such as exosomes and the availability of various technologies to measure nanosized particles, each technology having its own limitations. Materials and Methods A standardized methodology to measure the concentration of extracellular vesicles (EVs) has been developed and tested. The method is based on measuring the EV concentration as a function of a defined size range. Blood plasma EVs are isolated and purified using size exclusion columns (qEV) and consecutively measured with tunable resistive pulse sensing (TRPS). Six independent research groups measured liposome and EV samples with the aim to evaluate the developed methodology. Each group measured identical samples using up to 5 nanopores with 3 repeat measurements per pore. Descriptive statistics and unsupervised multivariate data analysis with principal component analysis (PCA) were used to evaluate reproducibility across the groups and to explore and visualise possible patterns and outliers in EV and liposome data sets. Results PCA revealed good reproducibility within and between laboratories, with few minor outlying samples. Measured mean liposome (not filtered with qEV) and EV (filtered with qEV) concentrations had coefficients of variance of 23.9% and 52.5%, respectively. The increased variance of the EV concentration measurements could be attributed to the use of qEVs and the polydisperse nature of EVs. Conclusion The results of this study demonstrate the feasibility of this standardized methodology to facilitate comparable and reproducible EV concentration measurements.
    Type of Medium: Online Resource
    ISSN: 2001-3078 , 2001-3078
    URL: Article
    DOI: 10.3402/jev.v5.31242
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2683797-3
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  • 2
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    Orally Administered 5-aminolevulinic Acid for Isolation and Characterization of Circulating Tumor-Derived Extracellular Vesicles in Glioblastoma Patients
    MDPI AG ; 2020
    In:  Cancers Vol. 12, No. 11 ( 2020-11-07), p. 3297-
    Details
    In: Cancers, MDPI AG, Vol. 12, No. 11 ( 2020-11-07), p. 3297-
    Abstract: Background: In glioblastoma (GB), tissue is required for accurate diagnosis and subtyping. Tissue can be obtained through resection or (stereotactic) biopsy, but these invasive procedures provide risks for patients. Extracellular vesicles (EVs) are small, cell-derived vesicles that contain miRNAs, proteins, and lipids, and possible candidates for liquid biopsies. GB-derived EVs can be found in the blood of patients, but it is difficult to distinguish them from circulating non-tumor EVs. 5-aminolevulinic acid (5-ALA) is orally administered to GB patients to facilitate tumor visualization and maximal resection, as it is metabolized to fluorescent protoporphyrin IX (PpIX) that accumulates in glioma cells. In this study, we assessed whether PpIX accumulates in GB-derived EVs and whether these EVs could be isolated and characterized to enable a liquid biopsy in GB. Methods: EVs were isolated from the conditioned media of U87 cells treated with 5-ALA by differential ultracentrifugation. Blood samples were collected and processed from healthy controls and patients undergoing 5-ALA guided surgery for GB. High-resolution flow cytometry (hFC) enabled detection and sorting of PpIX-positive EVs, which were subsequently analyzed by digital droplet PCR (ddPCR). Results: PpIX-positive EVs could be detected in conditioned cell culture media as well as in patient samples after administration of 5-ALA. By using hFC, we could sort the PpIX-positive EVs for further analysis with ddPCR, which indicated the presence of EVs and GB-associated miRNAs. Conclusion: GB-derived EVs can be isolated from the plasma of GB patients by using 5-ALA induced fluorescence. Although many challenges remain, our findings show new possibilities for the development of blood-based liquid biopsies in GB patients.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers12113297
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2527080-1
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  • 3
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    Obstacles and opportunities in the functional analysis of extracellular vesicle RNA – an ISEV position paper
    Wiley ; 2017
    In:  Journal of Extracellular Vesicles Vol. 6, No. 1 ( 2017-12)
    Details
    In: Journal of Extracellular Vesicles, Wiley, Vol. 6, No. 1 ( 2017-12)
    Abstract: The release of RNA‐containing extracellular vesicles (EV) into the extracellular milieu has been demonstrated in a multitude of different in vitro cell systems and in a variety of body fluids. RNA‐containing EV are in the limelight for their capacity to communicate genetically encoded messages to other cells, their suitability as candidate biomarkers for diseases, and their use as therapeutic agents. Although EV‐RNA has attracted enormous interest from basic researchers, clinicians, and industry, we currently have limited knowledge on which mechanisms drive and regulate RNA incorporation into EV and on how RNA‐encoded messages affect signalling processes in EV‐targeted cells. Moreover, EV‐RNA research faces various technical challenges, such as standardisation of EV isolation methods, optimisation of methodologies to isolate and characterise minute quantities of RNA found in EV, and development of approaches to demonstrate functional transfer of EV‐RNA in vivo . These topics were discussed at the 2015 EV‐RNA workshop of the International Society for Extracellular Vesicles. This position paper was written by the participants of the workshop not only to give an overview of the current state of knowledge in the field, but also to clarify that our incomplete knowledge – of the nature of EV(‐RNA)s and of how to effectively and reliably study them – currently prohibits the implementation of gold standards in EV‐RNA research. In addition, this paper creates awareness of possibilities and limitations of currently used strategies to investigate EV‐RNA and calls for caution in interpretation of the obtained data.
    Type of Medium: Online Resource
    ISSN: 2001-3078 , 2001-3078
    URL: Article
    DOI: 10.1080/20013078.2017.1286095
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 2683797-3
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  • 4
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    Glioblastoma hijacks microglial gene expression to support tumor growth
    Springer Science and Business Media LLC ; 2020
    In:  Journal of Neuroinflammation Vol. 17, No. 1 ( 2020-12)
    Details
    In: Journal of Neuroinflammation, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2020-12)
    Abstract: Glioblastomas are the most common and lethal primary brain tumors. Microglia, the resident immune cells of the brain, survey their environment and respond to pathogens, toxins, and tumors. Glioblastoma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Despite the presence of large numbers of microglia in glioblastoma, the tumors continue to grow, and these neuroimmune cells appear incapable of keeping the tumor in check. To understand this process, we analyzed gene expression in microglia interacting with glioblastoma cells . Methods We used RNASeq of isolated microglia to analyze the expression patterns of genes involved in key microglial functions in mice with glioblastoma. We focused on microglia that had taken up tumor-derived EVs and therefore were within and immediately adjacent to the tumor. Results We show that these microglia have downregulated expression of genes involved in sensing tumor cells and tumor-derived danger signals, as well as genes used for tumor killing. In contrast, expression of genes involved in facilitating tumor spread was upregulated. These changes appear to be in part EV-mediated, since intracranial injection of EVs in normal mice led to similar transcriptional changes in microglia. We observed a similar microglial transcriptomic signature when we analyzed datasets from human patients with glioblastoma. Conclusion Our data define a microglia Glioblastoma specific phenotype, whereby glioblastomas have hijacked gene expression in the neuroimmune system to favor avoiding tumor sensing, suppressing the immune response, clearing a path for invasion, and enhancing tumor propagation. For further exploration, we developed an interactive online tool at http://www.glioma-microglia.com with all expression data and additional functional and pathway information for each gene.
    Type of Medium: Online Resource
    ISSN: 1742-2094
    URL: Article
    DOI: 10.1186/s12974-020-01797-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2156455-3
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  • 5
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    Image_1.PDF
    Frontiers Media SA ; 2020
    In:  Frontiers in Molecular Biosciences Vol. 7 ( 2020-11-12)
    Details
    In: Frontiers in Molecular Biosciences, Frontiers Media SA, Vol. 7 ( 2020-11-12)
    Type of Medium: Online Resource
    ISSN: 2296-889X
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fmolb.2020.554649
    DOI: 10.3389/fmolb.2020.554649.s001
    DOI: 10.3389/fmolb.2020.554649.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2020
    detail.hit.zdb_id: 2814330-9
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  • 6
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    Study protocol of the GLOW study: maximising treatment options for recurrent glioblastoma patients by whole genome sequencing-based diagnostics—a prospective multicenter cohort study
    Springer Science and Business Media LLC ; 2022
    In:  BMC Medical Genomics Vol. 15, No. 1 ( 2022-11-04)
    Details
    In: BMC Medical Genomics, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2022-11-04)
    Abstract: Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The Netherlands. Despite neurosurgery, chemo -and radiation therapy, these tumours inevitably recur. Currently, there is no gold standard at time of recurrence and treatment options are limited. Unfortunately, the results of dedicated trials with new drugs have been very disappointing. The goal of the project is to obtain the evidence for changing standard of care (SOC) procedures to include whole genome sequencing (WGS) and consequently adapt care guidelines for this specific patient group with very poor prognosis by offering optimal and timely benefit from novel therapies, even in the absence of traditional registration trials for this small volume cancer indication. Methods The GLOW study is a prospective diagnostic cohort study executed through collaboration of the Hartwig Medical Foundation (Hartwig, a non-profit organisation) and twelve Dutch centers that perform neurosurgery and/or treat GBM patients. A total of 200 patients with a first recurrence of a glioblastoma will be included. Dual primary endpoint is the percentage of patients who receive targeted therapy based on the WGS report and overall survival. Secondary endpoints include WGS report success rate and number of targeted treatments available based on WGS reports and number of patients starting a treatment in presence of an actionable variant. At recurrence, study participants will undergo SOC neurosurgical resection. Tumour material will then, together with a blood sample, be sent to Hartwig where it will be analysed by WGS. A diagnostic report with therapy guidance, including potential matching off-label drugs and available clinical trials will then be sent back to the treating physician for discussing of the results in molecular tumour boards and targeted treatment decision making. Discussion The GLOW study aims to provide the scientific evidence for changing the SOC diagnostics for patients with a recurrent glioblastoma by investigating complete genome diagnostics to maximize treatment options for this patient group. Trial registration: ClinicalTrials.gov Identifier: NCT05186064.
    Type of Medium: Online Resource
    ISSN: 1755-8794
    URL: Article
    DOI: 10.1186/s12920-022-01343-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2411865-5
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  • 7
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    International practice variation in perioperative laboratory testing in glioblastoma patients—a retrospective cohort study
    Springer Science and Business Media LLC ; 2022
    In:  Acta Neurochirurgica Vol. 164, No. 2 ( 2022-02), p. 385-392
    Details
    In: Acta Neurochirurgica, Springer Science and Business Media LLC, Vol. 164, No. 2 ( 2022-02), p. 385-392
    Abstract: Although standard-of-care has been defined for the treatment of glioblastoma patients, substantial practice variation exists in the day-to-day clinical management. This study aims to compare the use of laboratory tests in the perioperative care of glioblastoma patients between two tertiary academic centers—Brigham and Women’s Hospital (BWH), Boston, USA, and University Medical Center Utrecht (UMCU), Utrecht, the Netherlands. Methods All glioblastoma patients treated according to standard-of-care between 2005 and 2013 were included. We compared the number of blood drawings and laboratory tests performed during the 70-day perioperative period using a Poisson regression model, as well as the estimated laboratory costs per patient. Additionally, we compared the likelihood of an abnormal test result using a generalized linear mixed effects model. Results After correction for age, sex, IDH1 status, postoperative KPS score, length of stay, and survival status, the number of blood drawings and laboratory tests during the perioperative period were 3.7-fold ( p   〈  0.001) and 4.7-fold ( p   〈  0.001) higher, respectively, in BWH compared to UMCU patients. The estimated median laboratory costs per patient were 82 euros in UMCU and 256 euros in BWH. Furthermore, the likelihood of an abnormal test result was lower in BWH (odds ratio [OR] 0.75, p   〈  0.001), except when the prior test result was abnormal as well (OR 2.09, p   〈  0.001). Conclusions Our results suggest a substantially lower clinical threshold for ordering laboratory tests in BWH compared to UMCU. Further investigating the clinical consequences of laboratory testing could identify over and underuse, decrease healthcare costs, and reduce unnecessary discomfort that patients are exposed to.
    Type of Medium: Online Resource
    ISSN: 0001-6268 , 0942-0940
    URL: Article
    DOI: 10.1007/s00701-021-05090-w
    RVK:
    XA 10000
    RVK:
    XA 12300
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1464215-3
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  • 8
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    Comparative Analysis Identifies Similarities between the Human and Murine Microglial Sensomes
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 3 ( 2021-02-02), p. 1495-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 3 ( 2021-02-02), p. 1495-
    Abstract: One of the essential functions of microglia is to continuously sense changes in their environment and adapt to those changes. For this purpose, they use a set of genes termed the sensome. This sensome is comprised of the most abundantly expressed receptors on the surface of microglia. In this study, we updated previously identified mouse microglial sensome by incorporating an additional published RNAseq dataset into the data-analysis pipeline. We also identified members of the human microglial sensome using two independent human microglia RNAseq data sources. Using both the mouse and human microglia sensomes, we identified a key set of genes conserved between the mouse and human microglial sensomes as well as some differences between the species. We found a key set of 57 genes to be conserved in both mouse and human microglial sensomes. We define these genes as the “microglia core sensome”. We then analyzed expression of genes in this core sensome in five different datasets from two neurodegenerative disease models at various stages of the diseases and found that, overall, changes in the level of expression of microglial sensome genes are specific to the disease or condition studied. Our results highlight the relevance of data generated in mice for understanding the biology of human microglia, but also stress the importance of species-specific gene sets for the investigation of diseases involving microglia. Defining this microglial specific core sensome may help identify pathological changes in microglia in humans and mouse models of human disease.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22031495
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 9
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    GlioM&M: Web-based tool for studying circulating and infiltrating monocytes and macrophages in glioma
    Springer Science and Business Media LLC ; 2020
    In:  Scientific Reports Vol. 10, No. 1 ( 2020-06-18)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-06-18)
    Abstract: Monocytes, macrophages and microglia make up a large part of the glioma environment and have an important role in maintaining and propagating glioma progression. Targeting these cells to inhibit their tumor-promoting effect and reprogramming them into an anti-tumor phenotype is a potential therapeutic approach for glioma. In this study we analyzed the transcriptomes of eight different monocyte subgroups derived from the brain and the blood of glioma-bearing mice. We compared the expression profile of blood-derived monocytes versus tumor-infiltrating monocytes and found increased expression of both pro- and anti-inflammatory pathways in tumor infiltrating monocytes. To help disseminate these datasets, we created a user-friendly web-based tool accessible at www.glioma-monocytes.com . This tool can be used for validation purposes and to elucidate gene expression profiles of tumor-interacting monocytes and macrophages as well as blood-derived circulating monocytes. This tool can also be used to identify new markers and targets for therapy in these different cell populations.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-020-66728-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2615211-3
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  • 10
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    Glioblastomas with primitive neuronal component harbor a distinct methylation and copy-number profile with inactivation of TP53, PTEN, and RB1
    Springer Science and Business Media LLC ; 2021
    In:  Acta Neuropathologica Vol. 142, No. 1 ( 2021-07), p. 179-189
    Details
    In: Acta Neuropathologica, Springer Science and Business Media LLC, Vol. 142, No. 1 ( 2021-07), p. 179-189
    Abstract: Glioblastoma IDH-wildtype presents with a wide histological spectrum. Some features are so distinctive that they are considered as separate histological variants or patterns for the purpose of classification. However, these usually lack defined (epi-)genetic alterations or profiles correlating with this histology. Here, we describe a molecular subtype with overlap to the unique histological pattern of glioblastoma with primitive neuronal component. Our cohort consists of 63 IDH-wildtype glioblastomas that harbor a characteristic DNA methylation profile. Median age at diagnosis was 59.5 years. Copy-number variations and genetic sequencing revealed frequent alterations in TP53 , RB1 and PTEN, with fewer gains of chromosome 7 and homozygous CDKN2A/B deletions than usually described for IDH-wildtype glioblastoma. Gains of chromosome 1 were detected in more than half of the cases. A poorly differentiated phenotype with frequent absence of GFAP expression, high proliferation index and strong staining for p53 and TTF1 often caused misleading histological classification as carcinoma metastasis or primitive neuroectodermal tumor. Clinically, many patients presented with leptomeningeal dissemination and spinal metastasis. Outcome was poor with a median overall survival of only 12 months. Overall, we describe a new molecular subtype of IDH-wildtype glioblastoma with a distinct histological appearance and genetic signature.
    Type of Medium: Online Resource
    ISSN: 0001-6322 , 1432-0533
    URL: Article
    DOI: 10.1007/s00401-021-02302-6
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    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1458410-4
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