Xandra O. Breakefield's research while affiliated with Harvard Medical School and other places
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Publications (688)
The interaction between gliomas and the immune system is poorly understood and thus hindering development of effective immunotherapies for glioma patients. The immune response is highly variable during tumor development, and affected by therapies such as surgery, radiation, and chemotherapy. Currently, analysis of these local changes is difficult d...
Glioblastoma (GB) tumors are one of the most insidious cancers which take over the brain and defy therapy. Over time and in response to treatment the tumor and the brain cells in the tumor microenvironment (TME) undergo many genetic/epigenetic driven changes in their phenotypes and this is reflected in the cellular contents within the extracellular...
Glioma, the most aggressive tumor of the CNS has poor patient outcome with limited effective treatments. CRISPR-CAS technology recently opened a new avenue for gene therapy and has been previously used to target non-coding RNAs, including microRNA-21, an oncogene associated with glioma progression. Here we show that an all-in-one construct containi...
Background
Glioblastoma (GBM) is a highly aggressive and invasive brain tumor associated with high patient mortality. A large fraction of GBM tumors have been identified as epidermal growth factor receptor (EGFR) amplified and ~50% also are EGFRvIII mutant positive. In a previously reported multicenter phase II study, we have described the response...
In glioblastoma, a malignant primary brain tumor, liposomes have shown promise in pre-clinical and early phase clinical trials as delivery vehicles for therapeutics. However, external factors influencing cellular uptake of liposomes in glioma cells are poorly understood. Heparin and heparin analogues are commonly used in glioma patients to decrease...
X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a retrotransposon insertion in intron 32 of the TAF1 gene. This insertion causes mis-splicing of intron 32 (TAF1-32i) and reduced TAF1 levels. TAF1-32i transcript is unique to XDP patient cells and can be detected in their extracellular vesicles (EVs). We engrafted patien...
In the central nervous system (CNS), the crosstalk between neural cells is mediated by extracellular mechanisms, including brain-derived extracellular vesicles (bdEVs). To study endogenous communication across the brain and periphery, we explored Cre-mediated DNA recombination to permanently record the functional uptake of bdEVs cargo overtime. To...
Diseases of the central nervous system (CNS) are challenging to treat, mainly due to the blood-brain barrier (BBB), which restricts drugs in circulation from entering target regions in the brain. To address this issue extracellular vesicles (EVs) have gained increasing scientific interest as carriers able to cross the BBB with multiplex cargos. EVs...
Tools to effectively demonstrate and quantify functional delivery in cellular communication have been lacking. This study reports the use of a fluorescently labeled split Nanoluc reporter system to demonstrate and quantify functional transfer between cells in vitro and in a subcutaneous tumor mouse model. Our construct allows monitoring of direct,...
In the central nervous system (CNS), the crosstalk between neural cells is mediated by extracellular mechanisms, including brain-derived extracellular vesicles (bdEVs).
To study endogenous communication across the brain and periphery, we explored Cre-mediated DNA recombination to permanently record the functional uptake of bdEVs cargo overtime. To...
Dystonia is a common movement disorder involving abnormal, often twisting postures and is a challenging condition to diagnose as we present here in a comprehensive overview. The pathophysiology of dystonia involves abnormalities in brain motor networks, sensorimotor integration, and maladaptive cortical plasticity in the context of genetic factors....
Myeloid cells are abundant, create a highly immunosuppressive environment in glioblastoma and thus contribute to poor immunotherapy responses. Based on the hypothesis that small molecules can be used to stimulate myeloid cells to elicit anti‐tumor effector functions, we developed a synthetic nanoparticle approach to deliver dual NF‐kB pathway‐induc...
Brain metastases are a significant therapeutic challenge and are associated with high morbidity and mortality. Recent evidence suggests that brain metastases have increased fatty acid synthesis compared to extracranial tumors. The enzyme stearoyl-CoA desaturase (SCD), which converts saturated long-chain fatty acids into monounsaturated fatty acids,...
Loss of function of the neurofibromatosis type 2 tumor suppressor gene leads to the formation of schwannomas, meningiomas and ependymomas, comprising ∼50% of all sporadic cases of primary nervous system tumors. NF2 syndrome is an autosomal dominant condition, with bi-allelic inactivation of germline and somatic alleles resulting in loss of function...
Cell membrane-based biovesicles (BVs) are important candidate drug delivery vehicles and comprise extracellular vesicles, virus-like particles, and lentiviral vectors. Here, we introduce a non-enzymatic assembly of purified BVs, supercharged proteins, and plasmid DNA called pDNA-scBVs. This multicomponent vehicle results from the interaction of neg...
Extracellular vesicles (EVs) are membrane-encapsulated particles that carry genetically active and protein/lipid cargo that can affect the function of the recipient cell. A number of studies have described the effect of these vesicles on recipient cells and demonstrated their promise as therapeutic delivery vectors. Here we demonstrate functional d...
Non-coding RNAs, including microRNAs, support the progression of glioma. miR-21 is a small, non-coding transcript, involved in regulating gene expression in multiple cellular pathways, including the regulation of proliferation. High expression of miR-21 has been shown to be a major driver of glioma growth. Manipulating the expression of microRNAs i...
The lack of techniques to trace brain cell behavior in vivo hampers the ability to monitor status of cells in a living brain. Extracellular vesicles (EVs), nanosized membrane-surrounded vesicles, released by virtually all brain cells might be able to report their status in easily accessible biofluids, such as blood. EVs communicate among tissues us...
The central nervous system (CNS) consists of a heterogeneous population of cells with highly specialized functions. For optimal functioning of the CNS, in disease and in health, intricate communication between these cells is vital. One important mechanism of cellular communication is the release and uptake of extracellular vesicles (EVs). EVs are m...
Introduction
Liquid biopsy for the detection and monitoring of brain tumors is of significant clinical interest. The ability to non-invasively profile tumors can avoid a risky biopsy and opens avenues for testing novel therapies by accurately stratifying patients to receive the right therapy. Here, we provide evidence of EV RNA-based diagnosis, pat...
Adeno-associated virus (AAV)-based gene therapy is gaining popularity owing to its excellent safety profile and effective therapeutic outcomes in a number of diseases. Intravenous (IV) injection of AAV into the tail vein, facial vein and retro-orbital (RO) venous sinus have all been useful strategies to infuse the viral vector systemically. However...
Liquid biopsy in cancer has gained momentum in clinical research and is experiencing a boom for a variety of applications. There are significant efforts to utilize liquid biopsies in cancer for early detection and treatment stratification, as well as residual disease and recurrence monitoring. Although most efforts have used circulating tumor cells...
Tuberous sclerosis complex (TSC) results from loss of a tumor suppressor gene - TSC 1 or TSC 2, encoding hamartin and tuberin, respectively. These proteins formed a complex to inhibit mTORC1-mediated cell growth and proliferation. Loss of either protein leads to overgrowth lesions in many vital organs. Gene therapy was evaluated in a mouse model of...
Introduction: Glioma cells exert influence over the tumor-microenvironment in part through the release of extracellular vesicles (EVs), membrane-enclosed structures containing proteins, lipids, and RNAs. In this study, we evaluated the function of Ras-associated protein 27a (Rab27a) in glioma and evaluated the feasibility of assessing its role in E...
Glioblastoma the most aggressive form of brain cancer, comprises a complex mixture of tumor cells and nonmalignant stromal cells, including neurons, astrocytes, microglia, infiltrating monocytes/macrophages, lymphocytes, and other cell types. All nonmalignant cells within and surrounding the tumor are affected by the presence of glioblastoma. Astro...
Background:
X-linked dystonia-parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a redu...
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...
PURPOSE
Despite the high frequency of EGFR genetic alterations in glioblastoma (GBM), EGFR-targeted therapies have not had success in this disease. To improve the likelihood of efficacy, we targeted adult patients with recurrent GBM enriched for EGFR gene amplification, which occurs in approximately half of GBM, with dacomitinib, a second-generatio...
The term ‘extracellular vesicles’ refers to a heterogeneous population of vesicular bodies of cellular origin that derive either from the endosomal compartment (exosomes) or as a result of shedding from the plasma membrane (microvesicles, oncosomes and apoptotic bodies). Extracellular vesicles carry a variety of cargo, including RNAs, proteins, lip...
Most individuals affected with DYT1 dystonia have a heterozygous three base-pair deletion in the TOR1A gene (c.907_909delGAG). The mutation appears to act through a dominant negative mechanism compromising normal torsinA function, and it is proposed that reducing mutant torsinA may normalize torsinA activity. Here we used an engineered Cas9 variant...
Development of effective prevention and treatment strategies for pre-eclampsia is limited by the lack of accurate methods for identification of at-risk pregnancies. We performed small RNA sequencing (RNA-seq) of maternal serum extracellular RNAs (exRNAs) to discover and verify microRNAs (miRNAs) differentially expressed in patients who later develo...
The cover image is based on the Original Article Exosome/Microvesicle Content is Altered in LRRK2 Mutant iPSCderived Neural Cells by Dennis A. Steindler, Kate M. Candelario, Johan Skog et al., https://doi.org/10.1002/cne.24819.
Background:
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...
Glioblastoma is the most aggressive brain malignancy, for which immunotherapy has failed to prolong survival. Glioblastoma-associated immune infiltrates are dominated by tumor-associated macrophages and microglia (TAMs), which are key mediators of immune suppression and resistance to immunotherapy. We and others demonstrated aberrant expression of...
Glioblastoma (GBM) is characterized by aberrant vascularization and a complex tumor microenvironment. The failure of anti-angiogenic therapies suggests pathways of GBM neovascularization, possibly attributable to glioblastoma stem cells (GSCs) and their interplay with the tumor microenvironment. It has been established that GSC-derived extracellula...
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 (U87EGFRvIII) in vitro and in vivo with respect to si...
Extracellular vesicles (EVs) released by cells play a role in intercellular communication. Reporter and targeting proteins can be modified and exposed on the surface of EVs to investigate their half-life and biodistribution. A characterization of membrane-bound Gaussia luciferase (mbGluc) revealed that its signal was detected also in a form smaller...
Extracellular vesicles, including exosomes and other microvesicles (EMVs), have been described as sensitive biomarkers that represent disease states and response to therapies. In light of recent reports of disease-mirroring EMV molecular signatures, the present study profiled 2 EMVs from different Parkinson's disease (PD) tissue sources: 1. neural...
Adeno-associated virus (AAV) vectors have shown promising results in preclinical models, but the genomic consequences of transduction with AAV vectors encoding CRISPR-Cas nucleases is still being examined. In this study, we observe high levels of AAV integration (up to 47%) into Cas9-induced double-strand breaks (DSBs) in therapeutically relevant g...
Gliomas are primary, diffusely infiltrating brain tumors. Microglia are innate immune cells in the CNS and make up a substantial portion of the tumor mass. Glioma cells shape their microenvironment, communicating with and reprogramming surrounding cells, resulting in enhanced angiogenesis, immune suppression, and remodeling of the extracellular mat...
Tuberous sclerosis complex (TSC) is a tumor suppressor syndrome caused by mutations in TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins act as a complex that inhibits mammalian target of rapamycin (mTOR)-mediated cell growth and proliferation. Loss of either protein leads to overgrowth in many organs, including subependymal...
Glioblastoma cells release extracellular vesicles (EVs), sometimes referred to as microvesicles and exosomes, to transfer immune modulating molecules to immune cells, resulting in an immune privileged microenvironment. Here we discuss the potential EV-mediated mechanisms underlying glioma immune modulation, as well as the technical difficulties in...
Extracellular vesicles (EVs) are nanometer-sized, lipid membrane–enclosed vesicles secreted by most, if not all, cells and contain lipids, proteins, and various nucleic acid species of the source cell. EVs act as important mediators of intercellular communication that influence both physiological and pathological conditions. Given their ability to...
Background:
Extracellular vesicles (EV) are shed by tumor cells but little is known about their individual molecular phenotypes and heterogeneity. While exosomes have received considerable attention, much less is known about larger microvesicles. Here we profile single microvesicles (MV) and exosomes from glioblastoma (GB) cells and MV from the pl...
The Extracellular RNA Communication Consortium (ERCC) was launched to accelerate progress in the new field of extracellular RNA (exRNA) biology and to establish whether exRNAs and their carriers, including extracellular vesicles (EVs), can mediate intercellular communication and be utilized for clinical applications. Phase 1 of the ERCC focused on...
Poor reproducibility within and across studies arising from lack of knowledge regarding the performance of extracellular RNA (exRNA) isolation methods has hindered progress in the exRNA field. A systematic comparison of 10 exRNA isolation methods across 5 biofluids revealed marked differences in the complexity and reproducibility of the resulting s...
Analysis of cancer-derived extracellular vesicles (EVs) in biofluids potentially provides a source of disease biomarkers. At present there is no procedure to systematically identify which antigens should be targeted to differentiate cancer-derived from normal host cell-derived EVs. Here, we propose a computational framework that integrates informat...
Cells release heterogeneous nano-sized vesicles either as exosomes, being derived from endosomal compartments, or through budding from the plasma membrane as so-called microvesicles, commonly referred to as extracellular vesicles (EVs). EVs are known for their important roles in mammalian physiology and disease pathogenesis and provide a potential...
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many...
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many...
Glioblastoma is the most aggressive brain malignancy, for which conventional therapy has failed to achieve major improvements in survival since 2005. Glioblastoma-associated immune infiltrates are dominated by tumour-associated macrophages (TAM), which could be the key mediators of immune suppression. Recently we proposed the tumour “glyco-code” as...
In Parkinson’s disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular α-synuclein (α-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of α-syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether...
Urine contains extracellular RNA (exRNA) markers of urogenital cancers. However, the capacity of genetic material in urine to identify systemic diseases is unknown. Here we describe exRNA splice products in human urine as a source of biomarkers for the two most common forms of muscular dystrophies, myotonic dystrophy (DM) and Duchenne muscular dyst...
Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid de...
Glioblastomas are heterogeneous and invariably lethal tumours. They are characterized by genetic and epigenetic variations among tumour cells, which makes the development of therapies that eradicate all tumour cells challenging and currently impossible. An important component of glioblastoma growth is communication with and manipulation of other ce...
Binding of programmed death ligand-1 (PD-L1) to programmed cell death protein-1 (PD1) leads to cancer immune evasion via inhibition of T cell function. One of the defining characteristics of glioblastoma, a universally fatal brain cancer, is its profound local and systemic immunosuppression. Glioblastoma has also been shown to generate extracellula...
The APPswe (Swedish) mutation in the amyloid precursor protein (APP) gene causes dominantly inherited Alzheimer’s disease (AD) as a result of increased β-secretase cleavage of the amyloid-β (Aβ) precursor protein. This leads to abnormally high Aβ levels, not only in brain but also in peripheral tissues of mutation carriers. Here, we selectively dis...
Most cases of early onset torsion dystonia (DYT1) are caused by a 3-base pair deletion in one allele of the TOR1A gene causing loss of a glutamate in torsinA, a luminal protein in the nuclear envelope. This dominantly inherited neurologic disease has reduced penetrance and no other medical manifestations. It has been challenging to understand the n...
X-linked Dystonia-Parkinsonism (XDP) is a Mendelian neurodegenerative disease that is endemic to the Philippines and is associated with a founder haplotype. We integrated multiple genome and transcriptome assembly technologies to narrow the causal mutation to the TAF1 locus, which included a SINE-VNTR-Alu (SVA) retrotransposition into intron 32 of...
Extracellular vesicles (EVs) are diverse, nanoscale membrane vesicles actively released by cells. Similar-sized vesicles can be further classified (e.g., exosomes, microvesicles) based on their biogenesis, size, and biophysical properties. Although initially thought to be cellular debris, and thus under-appreciated, EVs are now increasingly recogni...
Extracellular vesicles (EVs) carry RNA, DNA, proteins, and lipids. Specifically, tumor-derived EVs have the potential to be utilized as disease-specific biomarkers. However, a lack of methods to isolate tumor-specific EVs has limited their use in clinical settings. Here we report a sensitive analytical microfluidic platform (EVHB-Chip) that enables...
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many...
Extracellular vesicles (EV) are a family of cell-originating, membrane-containing nanoparticles with diverse biological function, diagnostic potential and therapeutic applications. While EV can be abundant in circulation, their small size (~4 order of magnitude smaller than cells) has necessitated bulk analyses, making many more nuanced biological...
Significance
The genetic basis of X-Linked dystonia-parkinsonism (XDP) has been difficult to unravel, in part because all patients inherit the same haplotype of seven sequence variants, none of which has ever been identified in control individuals. This study revealed that one of the haplotype markers, a retrotransposon insertion within an intron o...
Tumor-released RNA may mediate intercellular communication and serve as biomarkers. Here we develop a protocol enabling quantitative, minimally biased analysis of extracellular RNAs (exRNAs) associated with microvesicles, exosomes (collectively called EVs), and ribonucleoproteins (RNPs). The exRNA complexes isolated from patient-derived glioma stem...
Background:
Combined immunotherapy approaches are promising cancer treatments. We evaluated anti-PD-1 treatment combined with Gene-mediated cytotoxic immunotherapy (GMCI) performed by intratumoral injection of a prodrug metabolizing non-replicating adenovirus (AdV-tk), providing insitu chemotherapy and immune stimulation.
Methods:
The effects of...
Citations
... This transportation could be a way to increase tumorigenicity, although there is also information that indicates that Hsp70-enriched EVs possess negative immunomodulatory activities on tumor growth [52][53][54]. Notably, EVs act not only at short distances between neighboring cells within the tumor mass, but exert long-distance effects eliciting potentially higher pathogenicity [12,55,56]. ...
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... The abovementioned oligonucleotides, ncRNA-targeted small molecules [111], and adenoassociated virus vectors carrying connexin genes are desirable cargos for these EVs. These EV drug carriers can enhance the uptake efficiency and infiltration of oligonucleotides into the blood-brain barrier, providing a promising approach for treating cancers and CNS diseases [97,112,113]. ...
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... More recently, a lentivirus vector expressing Cre was injected at a focal point in the brain of a Cre reporter mouse. The transfer of brain-derived EVs carrying Cre mRNA showed spread overtime throughout the CNS and release into biofluids, thus providing an innovative method to track EV communication in the normal brain [104]. ...
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... Typical nucleic acid conjugates for such purposes include polyinosinic:polycytidylic acid (poly I:C, a TLR3 agonist) and cyclic dinucleotides (CDN; STING agonist), whereas small-molecule therapeutics include toll like receptor (TLR) 7/8 and cellular inhibitor of apoptosis protein (cIAP) inhibitors. There is emerging evidence that combination treatments [30] result in synergistic immunostimulation with higher immune responses at reduced drug concentration, reducing potential therapy side effects. While lipid nanoparticles have been used to deliver poly I:C and NFkB pathway modulators [31], we reasoned that more stable, polymeric constructs would have practical, pharmacological, and biological advantages. ...
... This activation leads to the conversion of palmitic acid (PA) into OA through elongation and desaturation reactions. BC cells utilize this OA for proliferation and migration [33,34]. However, whether free fatty acids are involved in FAHFA synthesis remains unclear. ...
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... Several preclinical studies have indicated promising results with gene therapy in treating NF2. Merlin re-expression via gene replacement in NF2-null schwannomas led to increased apoptosis and tumor regression [237]. In a mouse model of schwannoma, direct injection of an AAV1 vector expressing caspase-1, under the control of Schwann-cell specific promoter, resulted in tumor regression [238]. ...
... In addition, Qin Zhou and colleagues demonstrated the therapeutic efficacy of MSC-derived exosomes in improving survival rates in septic animal models while highlighting their role in alleviating sepsis-related damage to cardiac tissue [17]. Considering the limitations inherent in traditional MSC therapy and the unique attributes of EV-MSCs, their application in the treatment of sepsis presents promising solution to common challenges associated with live-cell therapies [18,19]. Moreover, several additional advantages associated with EV-MSCs are noteworthy. ...
... Surprisingly, we found that this trans-synaptic transfer is not required for several physiological functions of EV cargoes Evi and Syt4. Further, neuronally derived Syt4 is taken up by phagocytosis and could not be detected in the muscle cytoplasm, consistent with findings from HeLa cells that the majority of EV cargoes remain in the endosomal system of the recipient cell (O'Brien et al., 2022). Our results suggest that neuronal EV release for these cargoes at this developmental stage serves primarily proteostatic and not signaling functions. ...
... Although multiple algorithms exist to predict microRNA targets, it is very common to find that many predicted targets are not deregulated in the absence of a specific microRNA. [47][48][49][50] Of the 1520 predicted miR-26 direct target genes (formed from the intersection of two different prediction algorithms), 26 were upregulated in all miR-26 TKO lens samples as examined analyzed by RNA-seq. These included several immune response genes, including Lyz2, encoding a lysozyme; Lyve1, encoding a hyaluronan receptor; and Csf1r, encoding a receptor that binds both CSF-1 and IL-34. ...
... Subsequent efforts further strengthened the use of this methodology, including studies validating both the BBB permeability to brain EVs (Dickens et al., 2017;Rufino-Ramos et al., 2022) and the enrichment of EV and neuronal markers in protein lysates of L1CAM IP eluates from human blood (Blommer et al., 2023;Fu et al., 2020;Jiang et al., 2020;Mustapic et al., 2017;Niu et al., 2020;Nogueras-Ortiz et al., 2020;Pulliam et al., 2019;Pulliam et al., 2020;Vreones et al., 2023). Additional observations supporting the suitability of the L1CAM IP for the isolation of brain NDEVs from blood include: 1) the recovery of GFP-positive EVs from the plasma of Nestin-GFP mice selectively expressing GFP in neurons ; 2) positive correlations between brain and NDEV levels of pathological proteins in multiple AD mouse models ; and 3) proteomic analyses detecting L1CAM in EVs isolated from human brains (Vella et al., 2017;You et al., 2022) and showing that a high percentage of proteins carried by EVs isolated from human blood via L1CAM IP are highly expressed in the human brain and shared with EVs isolated from the conditioned media of human neurons in culture (Anastasi et al., 2021;Pulliam et al., 2019). ...
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