Extracellular Vesicles from a Novel Chordoma Cell Line, ARF-8, Promote Tumorigenic Microenvironmental Changes When Incubated with the Parental Cells and with Human Osteoblasts.

Chordomas are rare, generally slow-growing spinal tumors that nonetheless exhibit progressive characteristics over time, leading to malignant phenotypes and high recurrence rates, despite maximal therapeutic interventions. The tumors are notoriously resistant to therapies and are often located in regions that complicate achieving gross total resections. Cell lines from these tumors are rare as well.

Differential Effects of Extracellular Vesicles from Two Different Glioblastomas on Normal Human Brain Cells.

Glioblastomas (GBMs) are dreadful brain tumors with abysmal survival outcomes. GBM extracellular vesicles (EVs) dramatically affect normal brain cells (largely astrocytes) constituting the tumor microenvironment (TME). We asked if EVs from different GBM patient-derived spheroid lines would differentially alter recipient brain cell phenotypes.

Possible regulation of the immune modulator tetraspanin CD81 by alpha-synuclein in melanoma.

We probed the mechanism by which the Parkinson's disease-associated protein α-synuclein (α-syn)/SNCA promotes the pathogenesis and progression of melanoma. We found that the human melanoma cell line SK-MEL-28 in which SNCA is knocked out (SNCA-KO) has low levels of tetraspanin CD81, which is a cell-surface protein that promotes invasion, migration, and immune suppression. Analyzing data from the Cancer Genome Atlas, we show that SNCA and CD81 mRNA levels are positively correlated in melanoma; melanoma survival is inversely related to the levels of SNCA and CD81; and SNCA/CD81 are inversely related to the expression of key cytokine genes (IL12A, IL12B, IFN, IFNG, PRF1 and GZMB) for immune activation and immune cell-mediated killing of melanoma cells.

A tale of two tumors: differential, but detrimental, effects of glioblastoma extracellular vesicles (EVs) on normal human brain cells.

Glioblastomas (GBMs) are dreadful brain tumors with abysmal survival outcomes. GBM EVs dramatically affect normal brain cells (largely astrocytes) constituting the tumor microenvironment (TME). EVs from different patient-derived GBM spheroids induced differential transcriptomic, secretomic, and proteomic effects on cultured astrocytes/brain tissue slices as GBM EV recipients.

Specific Binding of Alzheimer's Aβ Peptides to Extracellular Vesicles.

Alzheimer's disease (AD) is the fifth leading cause of death among adults aged 65 and older, yet the onset and progression of the disease is poorly understood. What is known is that the presence of amyloid, particularly polymerized Aβ42, defines when people are on the AD continuum. Interestingly, as AD progresses, less Aβ42 is detectable in the plasma, a phenomenon thought to result from Aβ becoming more aggregated in the brain and less Aβ42 and Aβ40 being transported from the brain to the plasma via the CSF.

High-Throughput Screening of Epigenetic Inhibitors in Meningiomas Identifies HDAC, G9a, and Jumonji-Domain Inhibition as Potential Therapies.

 Epigenetics may predict treatment sensitivity and clinical course for patients with meningiomas more accurately than histopathology. Nonetheless, targeting epigenetic mechanisms is understudied for pharmacotherapeutic development for these tumors. The bio-molecular insights and potential therapeutic development of meningioma epigenetics led us to investigate epigenetic inhibition in meningiomas.

Rapid Activation of Neuroinflammation in Stroke: Plasma and Extracellular Vesicles Obtained on a Mobile Stroke Unit.

Background: Neuroinflammation is ubiquitous in acute stroke and worsens outcome. However, the precise timing of the inflammatory response is unknown, hindering the design of acute anti-inflammatory therapeutic interventions. We sought to identify the onset of the neuroinflammatory cascade using a mobile stroke unit.

Glioblastoma Extracellular Vesicle-Specific Peptides Inhibit EV-Induced Neuronal Cytotoxicity.

WHO Grade 4 IDH-wild type astrocytoma (GBM) is the deadliest brain tumor with a poor prognosis. Meningioma (MMA) is a more common "benign" central nervous system tumor but with significant recurrence rates. There is an urgent need for brain tumor biomarkers for early diagnosis and effective treatment options.

Targeting DNA Methyl Transferases with Decitabine in Cultured Meningiomas.

Objective: Meningiomas are a common primary central nervous system tumor that lack a U.S. Food and Drug Administration-approved pharmacotherapy.

Higher Levels of IgG3 Antibodies in Serum, But Not in CSF, Distinguish Multiple Sclerosis From Other Neurological Disorders.

Increased intrathecal IgG and oligoclonal bands (OCB) are seminal features of multiple sclerosis (MS). Although no such differences in MS blood total IgG antibodies have been reported, serum OCB are a common and persistent finding in MS and have a systemic source. Recent studies showed that IgG3 B cells and higher levels of serum IgG3 are linked to the development of MS.

Cytokine-Laden Extracellular Vesicles Predict Patient Prognosis after Cerebrovascular Accident.

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines-many associated with worse outcomes-occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood-brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling.

High-Throughput Mechanistic Screening of Epigenetic Compounds for the Potential Treatment of Meningiomas.

Background: Meningiomas are the most common primary central nervous system tumors. 20-30% of these tumors are considered high-grade and associated with poor prognosis and high recurrence rates. Despite the high occurrence of meningiomas, there are no FDA-approved compounds for the treatment of these tumors.

Making HSP90 Inhibitors Great Again? Unite for Better Cancer Immunotherapy.

HSP90 inhibitors are in numerous cancer clinical trials, but treatments often induce toxicity at effective dosages. In this issue of Cell Chemical Biology, Zavareh et al. (2020) serendipitously found that HSP90 inhibitors, at manageable doses, can reduce target cell expression of immune checkpoint molecules, potentially enabling improved anti-cancer immunotherapy.

Antibodies from Multiple Sclerosis Brain Identified Epstein-Barr Virus Nuclear Antigen 1 & 2 Epitopes which Are Recognized by Oligoclonal Bands.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), the etiology of which is poorly understood. The most common laboratory abnormality associated with MS is increased intrathecal immunoglobulin G (IgG) synthesis and the presence of oligoclonal bands (OCBs) in the brain and cerebrospinal fluid (CSF). However, the major antigenic targets of these antibody responses are unknown.

Recombinant antibodies derived from laser captured single plasma cells of multiple sclerosis brain identified phage peptides which may be used as tools for characterizing intrathecal IgG response.

Oligoclonal bands and increased IgG antibody levels can be detected in the cerebrospinal fluid in vast majority of patients with Multiple Sclerosis (MS). However, the antigenic specificity of oligoclonal IgG has yet to be determined. Using laser capture microdissection, we isolated single CD38+ plasma cells from lesion areas in two autopsy MS brains, and generated three recombinant antibodies (rAbs) from clonally expanded plasma cells.

Varicella-Zoster Virus infected human neurons are resistant to apoptosis.

Varicella-zoster virus (VZV) is a pathogenic human herpesvirus that causes varicella (chickenpox) as a primary infection following which it becomes latent in ganglionic neurons. Following viral reactivation many years later VZV causes herpes zoster (shingles) as well as a variety of other neurological syndromes. The molecular mechanisms of the conversion of the virus from a lytic to a latent state in ganglia are not well understood.

Roles of Extracellular Vesicles in High-Grade Gliomas: Tiny Particles with Outsized Influence.

High-grade gliomas, particularly glioblastomas (grade IV), are devastating diseases with dismal prognoses; afflicted patients seldom live longer than 15 months, and their quality of life suffers immensely. Our current standard-of-care therapy has remained essentially unchanged for almost 15 years, with little new therapeutic progress. We desperately need a better biologic understanding of these complicated tumors in a complicated organ.

The Potential of Exosomes From Cow Milk for Oral Delivery.

Many pharmaceuticals must be administered intravenously due to their poor oral bioavailability. In addition to issues associated with sterility and inconvenience, the cost of repeated infusion over a 6-week course of therapy costs the health care system tens of billions of dollars per year. Attempts to improve oral bioavailability have traditionally focused on enhancing drug solubility and membrane permeability, and the use of synthetic nanoparticles has also been investigated.

Extracellular vesicles in cancer immune responses: roles of purinergic receptors.

Extracellular vesicles (EVs) are nano- to micro-scale membrane-enclosed vesicles that are released from presumably all cell types. Tumor cells and immune cells are prodigious generators of EVs often with competing phenotypes in terms of immune suppression versus immune stimulation. Purinergic receptors, proteins that bind diverse purine nucleotides and nucleosides (ATP, ADP, AMP, adenosine), are widely expressed across tissues and cell types, and are prominent players in immune and tumor cell nucleotide metabolism.