Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy.

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.

Exosome platform for diagnosis and monitoring of traumatic brain injury.

We have previously demonstrated the release of membranous structures by cells into their extracellular environment, which are termed exosomes, microvesicles or extracellular vesicles depending on specific characteristics, including size, composition and biogenesis pathway. With activation, injury, stress, transformation or infection, cells express proteins and RNAs associated with the cellular responses to these events. The exosomes released by these cells can exhibit an array of proteins, lipids and nucleic acids linked to these physiologic events.

The origin, function, and diagnostic potential of RNA within extracellular vesicles present in human biological fluids.

We have previously demonstrated that tumor cells release membranous structures into their extracellular environment, which are termed exosomes, microvesicles or extracellular vesicles depending on specific characteristics, including size, composition and biogenesis pathway. These cell-derived vesicles can exhibit an array of proteins, lipids and nucleic acids derived from the originating tumor. This review focuses of the transcriptome (RNA) of these extracellular vesicles.

Alterations in antibody subclass immune reactivity to trophoblast-derived fetal fibronectin and α2-macroglobulin in women with recurrent pregnancy loss.

Problem: Increasing evidence supports the involvement of complex antibody-mediated immunologic events at the decidua-trophoblast interface. Our objective is to define the humoral immune responses of pregnant women with a history of recurrent pregnancy loss (RPL) compared with gestation-age-matched and non-pregnant controls in terms of trophoblast-derived antigenic targets and IgG subclasses.

Method Of Study: Immunoprecipitation and Western immunoblotting were performed to characterize IgG subclass reactivity to Sw.

Nanoparticle analysis of circulating cell-derived vesicles in ovarian cancer patients.

Cell-derived vesicles are recognized as essential components of intercellular communication, and many disease processes are associated with their aberrant composition and release. Circulating tumor-derived vesicles have major potential as biomarkers; however, the diagnostic use of exosomes is limited by the technology available for their objective characterization and measurement. In this study, we compare nanoparticle tracking analysis (NTA) with submicron particle analysis (SPA), dynamic light scattering (DLS), and electron microscopy (EM) to objectively define size distribution, number, and phenotype of circulating cell-derived vesicles from ovarian cancer patients.

Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments.

Cancer cells, both in vivo and in vitro, have been demonstrated to release membranous structures, defined as microvesicles or exosomes, consisting of an array of macromolecules derived from the originating cells, including proteins, lipids, and nucleic acids. While only recently have the roles of these vesicular components in intercellular communication become elucidated, significant evidence has demonstrated that tumor exosomes can exert a broad array of detrimental effects on the immune system-ranging from apoptosis of activated cytotoxic T cells to impairment of monocyte differentiation into dendritic cells, to induction of myeloid-suppressive cells and T regulatory cells. Immunosuppressive exosomes of tumor origin can be found within neoplastic lesions and in biologic fluids from cancer patients, implying a potential role of these pathways in in vivo tumor progression and systemic paraneoplastic syndromes.

Exosome isolation for proteomic analyses and RNA profiling.

While the existence of exosomes has been known for over three decades, they have garnered recent interest due to their potential diagnostic and therapeutic relevance. The expression and release of specific tumor-derived proteins into the peripheral circulation has served as the centerpiece of cancer screening and diagnosis. Recently, tissue-associated microRNA (miRNA) has been shown to be characteristic of tumor type and developmental origin, as well as exhibit diagnostic potential.

Human trophoblast-derived exosomal fibronectin induces pro-inflammatory IL-1β production by macrophages.

PROBLEM  Our previous studies demonstrated that trophoblast-derived exosomes induced synthesis and release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) by macrophages. The objective of this study was to characterize the mechanism and receptors associated with this induction. METHOD OF STUDY  Exosomes were isolated from Sw71 trophoblast-conditioned media by ultrafiltration and ultracentrifugation.

Morphologic and proteomic characterization of exosomes released by cultured extravillous trophoblast cells.

Exosomes represent an important intercellular communication vehicle, mediating events essential for the decidual microenvironment. While we have demonstrated exosome induction of pro-inflammatory cytokines, to date, no extensive characterization of trophoblast-derived exosomes has been provided. Our objective was to provide a morphologic and proteomic characterization of these exosomes.

Trophoblast-derived exosomes mediate monocyte recruitment and differentiation.

Introduction: trophoblast cells have been demonstrated to regulate monocyte migration and differentiation, leading to pro-inflammatory profiles. Because trophoblast cells release exosomes with immunoregulatory properties, trophoblast-derived exosomes are proposed to 'educate' monocytes, creating a pro-inflammatory environment.

Method Of Study: exosomes were isolated from conditioned media of Swan71 cells by ultrafiltration and ultracentrifugation.

Tumor-derived exosomes as mediators of disease and potential diagnostic biomarkers.

Tumor cells release membranous structures, defined as microvesicles or exosomes, consisting of an array of macromolecules derived from the originating cells, including proteins, lipids, and RNA. The expression of antigenic molecules recognizable by T cells originally suggested a role for these vesicles as a cell-free antigen source for anti-cancer vaccines; however, evidence demonstrates that tumor exosomes can exert a broad array of detrimental effects on the immune system - ranging from apoptosis of activated cytotoxic T cells to impairment of monocyte differentiation into dendritic cells, to induction of myeloid-suppressive cells. Immunosuppressive exosomes of tumor origin can be found in neoplastic lesions and biologic fluids from cancer patients, implying a potential role of these pathways in in vivo tumor progression and systemic paraneoplastic syndromes.

Characterization of humoral responses of ovarian cancer patients: antibody subclasses and antigenic components.

Objectives: Current antigen-based diagnostic assays for ovarian cancers rely on intravasation of specific aberrantly expressed proteins and their achieving detectable steady-state concentrations, resulting in their inability to truly detect small early lesions. In contrast, tumor antigen immunorecognition is observed following initial transformation events. Our objective was to characterize humoral antitumor responses in terms of IgG subclasses generated and tumor antigens recognized.

Patient-derived tumor-reactive antibodies as diagnostic markers for ovarian cancer.

Objective: Most ovarian cancers are diagnosed at advanced stage (67%) and prospects for significant improvement in survival reside in early diagnosis. Our objective was to validate our array assay for the identification of ovarian cancer based on quantitation of tumor-reactive IgG.

Methods: The diagnostic array utilizes specific exosome-derived antigens to detect reactive IgG in patients' sera.

Gene expression profiling in response to estradiol and genistein in ovarian cancer cells.

Background: Despite optimal primary treatment of ovarian cancer, overall prognosis is poor due to recurrences. While steroid hormone receptors are frequently expressed, the role of estrogen receptor (ER) in ovarian carcinogenesis, response to treatment or prognosis has not been established. We analyzed the gene-expression in response to estradiol (E2) and genistein (Gen) in ovarian cancer cells.

Exosomal microRNA: a diagnostic marker for lung cancer.

Purpose: To date, there is no screening test for lung cancer shown to affect overall mortality. MicroRNAs (miRNAs) are a class of small noncoding RNA genes found to be abnormally expressed in several types of cancer, suggesting a role in the pathogenesis of human cancer.

Patients And Methods: We evaluated the circulating levels of tumor exosomes, exosomal small RNA, and specific exosomal miRNAs in patients with and without lung adenocarcinoma, correlating the levels with the American Joint Committee on Cancer (AJCC) disease stage to validate it as an acceptable marker for diagnosis and prognosis in patients with adenocarcinoma of the lung.

Alterations of T cell activation signalling and cytokine production by postmenopausal estrogen levels.

Background: Immunosenescence is an age-associated disorder occurring primarily in T cell compartments, including altered subset composition, functions, and activation. In women, evidence implicates diminished estrogen in the postmenopausal period as a contributing factor to diminished T cell responsiveness. Since hypoestrogenism is present in postmenopausal women, our objective focused on whether T cell activation, defined as signalling molecule expressions and activation, and function, identified as IL-2 production, were affected by low estrogen.

Genistein reverses diminished T-cell signal transduction, induced by post-menopausal estrogen levels.

Problem: This study addressed the ability of genistein to reverse the loss of T-cell signaling components, induced by estrogen deficiency associated with aging.

Method Of Study: Using Jurkat 6.1 T cells, genistein regulation of CD3zeta, JAK3, and NFkappaB was analysed by Western immunoblotting at 4 or 40 pg/mL (post- and pre-menopausal levels, respectively) estradiol (E(2)).

MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer.

Objectives: Most ovarian cancer patients are diagnosed at an advanced stage (67%) and prospects for significant improvement in survival reside in early diagnosis. While expression patterns of a recently identified biomarker family, microRNA, appear to be characteristic of tumor type and developmental origin, microRNA profiling has been limited to tissue specimens. Tumors actively release exosomes into the peripheral circulation and we now demonstrate the association of microRNAs with circulating tumor-derived exosomes.

Endometriosis markers: immunologic alterations as diagnostic indicators for endometriosis.

Because endometriosis, a chronic disease affecting 7% to 10% of women, is associated with immunologic aberrations, the authors hypothesize that the presence of specific immune alterations may be diagnostic. Autoantibodies were assayed by Western immunoblotting using antigens derived from the plasma membrane, cytosol, and nucleus from endometrial and ovarian cells. Natural killer (NK) activity was defined by levels of signaling protein zeta and induction of interferon (IFN)-gamma following exposure to patients' sera.

Effects of the components of hormone therapy on matrix metalloproteinases in breast-cancer cells: an in vitro study.

A combination of E and progestogens significantly increased matrix metalloproteinase (MMP)-2 in both T47D cells (E(2)-medroxyprogesteroneacetate [MPA] and E(2)-P) and MCF-7 cells (E(2)-MPA, E(2)-P, and equilin-MPA). All combinations resulted in higher MMP-9 levels in MCF-7 cells, but higher MMP-9 levels resulted only with equilin-norethinderone in T47D cells.

Specific isolation of placenta-derived exosomes from the circulation of pregnant women and their immunoregulatory consequences.

Problem: One immunoregulatory pathway receiving little attention is placental exosome release. In normal pregnancy, as factors linked with early immunomodulation decline, placental exosomes become critical in modulating T-cell activation, suppressing effector T cells by enhancing lymphocyte apoptosis and CD3-zeta loss.

Method Of Study: Placental exosomes were specifically isolated from the maternal peripheral circulation by a chromatographic/immunosorbent procedure.