Limitations of the human iPSC-derived neuron model for early-onset Alzheimer's disease.

Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5-6% of all AD cases (Mendez et al. in Continuum 25:34-51, 2019). While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline (Sirkis et al.

Highly Sensitive EGFRvIII Detection in Circulating Extracellular Vesicle RNA of Glioma Patients.

Purpose: Liquid biopsy offers an attractive platform for noninvasive tumor diagnosis, prognostication, and prediction of glioblastoma clinical outcomes. Prior studies report that 30% to 50% of GBM lesions characterized by EGFR amplification also harbor the EGFRvIII mutation.

Experimental Design: A novel digital droplet PCR (ddPCR) assay for high GC content amplicons was developed and optimized for sensitive detection of EGFRvIII in tumor tissue and circulating extracellular vesicle RNA (EV RNA) isolated from the plasma of patients with glioma.

Blood-Based Detection of BRAF V600E in Gliomas and Brain Tumor Metastasis.

Liquid biopsy provides a minimally invasive platform for the detection of tumor-derived information, including hotspot mutations, such as BRAF V600E. In this study, we provide evidence of the technical development of a ddPCR assay for the detection of BRAF V600E mutations in the plasma of patients with glioma or brain metastasis. In a small patient cohort ( = 9, = 5 BRAF V600E, = 4 BRAF WT, = 4 healthy control), we were able to detect the BRAF V600E mutation in the plasma of 4/5 patients with BRAF V600E-tissue confirmed mutant tumors, and none of the BRAF WT tumors.

The role of extracellular vesicles in acquisition of resistance to therapy in glioblastomas.

Glioblastoma (GBM) is the most aggressive primary brain tumor with a median survival of 15 months despite standard care therapy consisting of maximal surgical debulking, followed by radiation therapy with concurrent and adjuvant temozolomide treatment. The natural history of GBM is characterized by inevitable recurrence with patients dying from increasingly resistant tumor regrowth after therapy. Several mechanisms including inter- and intratumoral heterogeneity, the evolution of therapy-resistant clonal subpopulations, reacquisition of stemness in glioblastoma stem cells, multiple drug efflux mechanisms, the tumor-promoting microenvironment, metabolic adaptations, and enhanced repair of drug-induced DNA damage have been implicated in therapy failure.

Promoter Mutation Analysis for Blood-Based Diagnosis and Monitoring of Gliomas.

Purpose: Liquid biopsy offers a minimally invasive tool to diagnose and monitor the heterogeneous molecular landscape of tumors over time and therapy. Detection of promoter mutations (, ) in cfDNA has been successful for some systemic cancers but has yet to be demonstrated in gliomas, despite the high prevalence of these mutations in glioma tissue (>60% of all tumors).

Experimental Design: Here, we developed a novel digital droplet PCR (ddPCR) assay that incorporates features to improve sensitivity and allows for the simultaneous detection and longitudinal monitoring of two promoter mutations ( and ) in cfDNA from the plasma of patients with glioma.

Liquid Biopsy Strategies to Distinguish Progression from Pseudoprogression and Radiation Necrosis in Glioblastomas.

Liquid biopsy for the detection and monitoring of central nervous system tumors is of significant clinical interest. At initial diagnosis, the majority of patients with central nervous system tumors undergo magnetic resonance imaging (MRI), followed by invasive brain biopsy to determine the molecular diagnosis of the WHO 2016 classification paradigm. Despite the importance of MRI for long-term treatment monitoring, in the majority of patients who receive chemoradiation therapy for glioblastoma, it can be challenging to distinguish between radiation treatment effects including pseudoprogression, radiation necrosis, and recurrent/progressive disease based on imaging alone.

Novel Gene Fusions in Glioblastoma Tumor Tissue and Matched Patient Plasma.

Sequencing studies have provided novel insights into the heterogeneous molecular landscape of glioblastoma (GBM), unveiling a subset of patients with gene fusions. Tissue biopsy is highly invasive, limited by sampling frequency and incompletely representative of intra-tumor heterogeneity. Extracellular vesicle-based liquid biopsy provides a minimally invasive alternative to diagnose and monitor tumor-specific molecular aberrations in patient biofluids.

From laboratory to clinic: Translation of extracellular vesicle based cancer biomarkers.

The past decade has witnessed a rapid growth in the field of extracellular vesicle (EV) based biomarkers for the diagnosis and monitoring of cancer. Several studies have reported novel EV based biomarkers, but the technical and clinical validation phase has been hampered by general challenges common to biomedical research field as well as specific challenges inherent to the nanoparticle field. This has led to more common failures than success stories in the biomarker discovery pipeline.

Extracellular Vesicles in Glioblastoma Tumor Microenvironment.

Glioblastomas (GBM) are highly aggressive primary brain tumors. Complex and dynamic tumor microenvironment (TME) plays a crucial role in the sustained growth, proliferation, and invasion of GBM. Several means of intercellular communication have been documented between glioma cells and the TME, including growth factors, cytokines, chemokines as well as extracellular vesicles (EVs).

Large and small extracellular vesicles released by glioma cells and .

Tumour cells release diverse populations of extracellular vesicles (EVs) ranging in size, molecular cargo, and function. We sought to characterize mRNA and protein content of EV subpopulations released by human glioblastoma (GBM) cells expressing a mutant form of epidermal growth factor receptor (U87) and with respect to size, morphology and the presence of tumour cargo. The two EV subpopulations purified from GBM U87 cancer cells, non-cancer human umbilical vein endothelial cells (HUVEC; control) and serum of U87 glioma-bearing mice using differential centrifugation (EVs that sediment at 10,000 × or 100,000 × are termed large EVs and small EVs, respectively) were characterized using transmission electron microscopy (TEM), confocal microscopy, nanoparticle tracking analysis (NTA), flow cytometry, immunofluorescence (IF), quantitative-polymerase chain reaction (qPCR), droplet digital polymerase chain reaction (ddPCR) and micro-nuclear magnetic resonance (μNMR).