Exosome secretion is a notable feature of malignancy owing to the roles of these nanoparticles in cancer growth, immune suppression, tumor angiogenesis and therapeutic resistance. Exosomes are 30–100 nm membrane vesicles released by many cells types during normal physiological processes. Tumors aberrantly secrete large quantities of exosomes that transport oncoproteins and immune suppressive molecules to support tumor growth and metastasis. The role of exosomes in intercellular signaling is exemplified by human epidermal growth factor receptor type 2 (HER2) over-expressing breast cancer, where exosomes with the HER2 oncoprotein stimulate tumor growth and interfere with the activity of the therapeutic antibody Herceptin®. Since numerous observations from experimental model systems point toward an important clinical impact of exosomes in cancer, several pharmacological strategies have been proposed for targeting their malignant activities. We also propose a novel device strategy involving extracorporeal hemofiltration of exosomes from the entire circulatory system using an affinity plasmapheresis platform known as the Aethlon ADAPT™ (adaptive dialysis-like affinity platform technology) system, which would overcome the risks of toxicity and drug interactions posed by pharmacological approaches. This technology allows affinity agents, including exosome-binding lectins and antibodies, to be immobilized in the outer-capillary space of plasma filtration membranes that integrate into existing kidney dialysis systems. Device therapies that evolve from this platform allow rapid extracorporeal capture and selective retention of target particles < 200 nm from the entire circulatory system. This strategy is supported by clinical experience in hepatitis C virus-infected patients using an ADAPT™ device, the Hemopurifier®, to reduce the systemic load of virions having similar sizes and glycosylated surfaces as cancer exosomes. This review discusses the possible therapeutic approaches for targeting immune suppressive exosomes in cancer patients, and the anticipated significance of these strategies for reversing immune dysfunction and improving responses to standard of care treatments.

Stress intensity factor Energy release rate CTOD CTOA J-integral J-R curve K-R curve ASTM standard a b s t r a c tThe present paper gives a technical review of fracture toughness testing, evaluation and standardization for metallic materials in terms of the linear elastic fracture mechanics as well as the elastic-plastic fracture mechanics. This includes the early investigations and recent advances of fracture toughness test methods and practices developed by American Society for Testing and Materials (ASTM). The review describes the most important fracture mechanics parameters: the elastic energy release rate G, the stress intensity factor K, the Jintegral, the crack-tip opening displacement (CTOD) and the crack-tip opening angle (CTOA) from the basic concept, definition, to experimental estimation, test methods and ASTM standardizing practices. Attention is paid to guidelines on how to choose an appropriate fracture parameter to characterize fracture toughness for the material of interest, and how to measure the fracture toughness value defined either at a critical point or in a resistance curve format using laboratory specimens. The relevant ASTM fracture toughness test standards considered in this paper are E399 for K Ic testing, E561 for K-R curve testing, E813 for J Ic testing, E1152 for J-R curve testing, E1737 for J Ic and J-R curve testing, E1290 for CTOD (d) testing, a combined common test standard E1820 for measuring the three parameters of K, J and d, E1921 for the transition reference temperature T 0 testing and the master curve of cleavage toughness K Jc testing, and E2472 for CTOA testing. The effects of loading rate, temperature and crack-tip constraint on fracture toughness as well as fracture instability analysis are also reviewed.

Background Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers. Objective The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. Methods Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. Results The NFL group had higher exosomal tau than the control group (p < .0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). Conclusion These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.

Advances in cancer therapy have been substantial in terms of molecular understanding of disease mechanisms, however these advances have not translated into increased survival in the majority of cancer types. One unsolved problem in current cancer therapeutics is the substantial immune suppression seen in patients. Conventionally, investigations in this area have focused on antigennonspecific immune suppressive molecules such as cytokines and T cell apoptosis inducing molecules such as Fas ligand. More recently, studies have demonstrated nanovesicle particles termed exosomes are involved not only in stimulation but also inhibition of immunity in physiological conditions. Interestingly, exosomes secreted by cancer cells have been demonstrated to express tumor antigens, as well as immune suppressive molecules such as PD-1L and FasL. Concentrations of exosomes from plasma of cancer patients have been associated with spontaneous T cell apoptosis, which is associated in some situations with shortened survival. In this paper we place the "exosome-immune suppression" concept in perspective of other tumor immune evasion mechanisms. We conclude by discussing a novel therapeutic approach to cancer immune suppression by extracorporeal removal of exosomes using hollow fiber filtration technology

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