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Search terms: exosomes OR "extracellular vesicles" OR microvesicles OR microparticles. Direct link to the PubMed search here.

Exosomal DNA Aptamer Targeting α-Synuclein Aggregates Reduced Neuropathological Deficits in a Mouse Parkinson's Disease Model.

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Exosomal DNA Aptamer Targeting α-Synuclein Aggregates Reduced Neuropathological Deficits in a Mouse Parkinson's Disease Model.

Mol Ther Nucleic Acids. 2019 Jul 23;17:726-740

Authors: Ren X, Zhao Y, Xue F, Zheng Y, Huang H, Wang W, Chang Y, Yang H, Zhang J

Abstract
The α-synuclein aggregates are the main component of Lewy bodies in Parkinson's disease (PD) brain, and they showed immunotherapy could be employed to alleviate α-synuclein aggregate pathology in PD. Recently we have generated DNA aptamers that specifically recognize α-synuclein. In this study, we further investigated the in vivo effect of these aptamers on the neuropathological deficits associated with PD. For efficient delivery of the aptamers into the mouse brain, we employed modified exosomes with the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface. We demonstrated that the aptamers were efficiently packaged into the RVG-exosomes and delivered into neurons in vitro and in vivo. Functionally, the aptamer-loaded RVG-exosomes significantly reduced the α-synuclein preformed fibril (PFF)-induced pathological aggregates, and rescued synaptic protein loss and neuronal death. Moreover, intraperitoneal administration of these exosomes into the mice with intra-striatally injected α-synuclein PFF reduced the pathological α-synuclein aggregates and improved motor impairments. In conclusion, we demonstrated that the aptamers targeting α-synuclein aggregates could be effectively delivered into the mouse brain by the RVG-exosomes and reduce the neuropathological and behavioral deficits in the mouse PD model. This study highlights the therapeutic potential of the RVG-exosome delivery of aptamer to alleviate the brain α-synuclein pathology.

PMID: 31437653 [PubMed - as supplied by publisher]

Differential tetraspanin genes expression and subcellular localization during mutualistic interactions in Phaseolus vulgaris.

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Differential tetraspanin genes expression and subcellular localization during mutualistic interactions in Phaseolus vulgaris.

PLoS One. 2019;14(8):e0219765

Authors: Jimenez-Jimenez S, Santana O, Lara-Rojas F, Arthikala MK, Armada E, Hashimoto K, Kuchitsu K, Salgado S, Aguirre J, Quinto C, Cárdenas L

Abstract
Arbuscular mycorrhizal fungi and rhizobia association with plants are two of the most successful plant-microbe associations that allow the assimilation of P and N by plants, respectively. These mutualistic interactions require a molecular dialogue, i.e., legume roots exude flavonoids or strigolactones which induce the Nod factors or Myc factors synthesis and secretion from the rhizobia or fungi, respectively. These Nod or Myc factors trigger several responses in the plant root, including calcium oscillations, and reactive oxygen species (ROS). Furthermore, superoxide and H2O2 have emerged as key components that regulate the transitions from proliferation to differentiation in the plant meristems. Similar to the root meristem, the nodule meristem accumulates superoxide and H2O2. Tetraspanins are transmembrane proteins that organize into tetraspanin web regions, where they recruit specific proteins into platforms required for signal transduction, membrane fusion, cell trafficking and ROS generation. Plant tetraspanins are scaffolding proteins associated with root radial patterning, biotic and abiotic stress responses, cell fate determination, and hormonal regulation and recently have been reported as a specific marker of exosomes in animal and plant cells and key players at the site of plant fungal infection. In this study, we conducted transcriptional profiling of the tetraspanin family in common bean (Phaseolus vulgaris L. var. Negro Jamapa) to determine the specific expression patterns and subcellular localization of tetraspanins during nodulation or under mycorrhizal association. Our results demonstrate that the tetraspanins are transcriptionally modulated during the mycorrhizal association, but are also expressed in the infection thread and nodule meristem development. Subcellular localization indicates that tetraspanins have a key role in vesicular trafficking, cell division, and root hair polar growth.

PMID: 31437164 [PubMed - in process]

In situ Composite Ion-Triggered Gellan Gum Gel Incorporating Amino Methacrylate Copolymer Microparticles: A Therapeutic Modality for Buccal Applicability.

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In situ Composite Ion-Triggered Gellan Gum Gel Incorporating Amino Methacrylate Copolymer Microparticles: A Therapeutic Modality for Buccal Applicability.

Pharm Dev Technol. 2019 Aug 22;:1-50

Authors: Elmowafy E, Cespi M, Bonacucina G, Soliman ME

Abstract
The aim of the current investigation is to delineate the buccal applicability of an in situ composite gel containing aceclofenac (AC) amino methacrylate copolymer microparticles (MPs), surmounting limitations of oral existing conventional therapy. AC Eudragit RL100 MPs were fabricated and statistically optimized using 2241 factorial design. Better buccal applicability and enhanced localization were achieved by combining the optimum MPs with in situ ion-activated gellan gum gel. The crosslinking and gelation of in situ gel were investigated by morphological and solid state characterizations. Suitability for buccal delivery and in vivo therapeutic efficacy in inflammation model of rats were also assessed. Results showed that the best performing formula displayed particle size (PS) of 51.00 µm and high entrapment efficiency (EE%) of 94.73%. MPs were successfully entrapped inside the gel network of the composite system. Gelation tendency, pH, shear-thinning properties and mucoadhesivity of the prepared in situ composite gel guaranteed its buccal suitability. Sustained AC release features and promising in vitro anti-arthritic response were also demonstrated. Moreover, consistent and prolonged in vivo anti-inflammatory effect was achieved, relative to standard AC. Taken together; this study proves the potential of in situ composite gel as an appropriate therapeutic proposal for AC buccal delivery.

PMID: 31437077 [PubMed - as supplied by publisher]

Rapid On-Demand Extracellular Vesicle Augmentation with Versatile Oligonucleotide Tethers.

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Rapid On-Demand Extracellular Vesicle Augmentation with Versatile Oligonucleotide Tethers.

ACS Nano. 2019 Aug 22;:

Authors: Yerneni SS, Lathwal S, Shrestha P, Shirwan H, Matyjaszewski K, Weiss L, Yolcu ES, Campbell PG, Das SR

Abstract
Exosomes show potential as ideal vehicles for drug delivery because of their natural role in transferring biological cargo between cells. However, current methods to engineer exosomes without negatively impacting their function remain challenging. Manipulating exosome-secreting cells is complex and time-consuming, while direct functionalization of exosome surface proteins suffers from low specificity and low efficiency. We demonstrate a rapid, versatile and scalable method with oligonucleotide tethers to enable diverse surface functionalization on both human and murine exosomes. These exosome surface modifiers that range from reactive functional groups and small molecules to aptamers and large proteins, can readily and efficiently enhance native exosome properties. We show that cellular uptake of exosomes can be specifically altered with a tethered AS1411 aptamer and targeting specificity can be altered with a tethered protein. We functionalize exosomes with an im-munomodulatory protein, FasL, and demonstrate their biological activity both in vitro and in vivo. FasL-functionalized exosomes, when bioprinted on collagen matrix allows spatial induction of apoptosis in tumor cells, and when injected in mice, suppresses proliferation of alloreactive T-cells. This oligonucleotide tethering strategy is independent of the exosome source and further circumvents the need to genetically modify exosome-secreting cells.

PMID: 31436946 [PubMed - as supplied by publisher]

Circulating extracellular vesicle-associated TGFβ3 modulates response to cytotoxic therapy in head and neck squamous cell carcinoma.

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Circulating extracellular vesicle-associated TGFβ3 modulates response to cytotoxic therapy in head and neck squamous cell carcinoma.

Carcinogenesis. 2019 Aug 22;:

Authors: Rodrigues-Junior DM, Tan SS, Lim SK, Leong HS, Melendez ME, Ramos CRN, Viana LS, Tan DSW, Carvalho AL, Iyer NG, Vettore AL

Abstract
Management of locally-advanced head and neck squamous cell carcinoma (HNSCC) requires a multi-prong approach comprising surgery, radiation- and/or chemo-therapy, yet outcomes are limited. This is largely due to a paucity of biomarkers that can predict response to specific treatment modalities. Here, we evaluated TGFβ3 protein levels in extracellular vesicles (EV) released by HNSCC cells as a predictor for response to chemoradiation therapy (CRT). To this end, specific EV-fractions were isolated from cell lines or HNSCC patient plasma, and TGFβ3 protein was quantified. In patients treated with CRT, TGFβ3 levels were found to be significantly higher in plasma EV-fractions or non-responders compared to responders. High levels of TGFβ3 levels in Annexin V-EVs were associated with the worst progression-free survival. In vitro experiments demonstrated that TGFβ3-silencing sensitized HNSCC cells to cytotoxic therapies, and this phenotyped could be rescued by treatment with exogenous. In addition, specific EV-fractions shed by cisplatin-resistant cells were sufficient to transfer the resistant phenotype to sensitive cells through activation of TGFβ-signaling pathway. Therefore, our data show that TGFβ3 transmitted through EV plays a significant role in response to cytotoxic therapy, which can be exploited as a potential biomarker for CRT response in HNSCC-patients treated with curative intent.

PMID: 31436806 [PubMed - as supplied by publisher]

Distinct mechanisms of microRNA sorting into cancer cell-derived extracellular vesicle subtypes.

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Distinct mechanisms of microRNA sorting into cancer cell-derived extracellular vesicle subtypes.

Elife. 2019 Aug 22;8:

Authors: Temoche-Diaz MM, Shurtleff MJ, Nottingham RM, Yao J, Fadadu RP, Lambowitz AM, Schekman R

Abstract
Extracellular vesicles (EVs) encompass a variety of vesicles secreted into the extracellular space. EVs have been implicated in promoting tumor metastasis, but the molecular composition of tumor-derived EV sub-types and the mechanisms by which molecules are sorted into EVs remain mostly unknown. We report the separation of two small EV sub-populations from a metastatic breast cancer cell line, with biochemical features consistent with different sub-cellular origins. These EV sub-types use different mechanisms of miRNA sorting (selective and non-selective), suggesting that sorting occurs via fundamentally distinct processes, possibly dependent on EV origin. Using biochemical and genetic tools, we identified the Lupus La protein as mediating sorting of selectively packaged miRNAs. We found that two motifs embedded in miR-122 are responsible for high-affinity binding to Lupus La and sorting into vesicles formed in a cell-free reaction. Thus, tumor cells can simultaneously deploy multiple EV species using distinct sorting mechanisms that may enable diverse functions in normal and cancer biology.

PMID: 31436530 [PubMed - as supplied by publisher]

LMP1-positive extracellular vesicles promote radioresistance in nasopharyngeal carcinoma cells through P38 MAPK signaling.

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LMP1-positive extracellular vesicles promote radioresistance in nasopharyngeal carcinoma cells through P38 MAPK signaling.

Cancer Med. 2019 Aug 22;:

Authors: Zhang Z, Yu X, Zhou Z, Li B, Peng J, Wu X, Luo X, Yang L

Abstract
Radioresistance has been one of the impediments to effective nasopharyngeal carcinoma (NPC) therapy in clinical settings. Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is expressed in NPC and has potent effects on radioresistance. It has been detected in extracellular vesicles (EVs) or exosomes and shown to promote tumor proliferation and invasive potential. However, whether LMP1-positive EVs can confer radioresistance to cancer cells and the mechanism used to promote radioresistance need to be elucidated. In this study, the data showed that EVs derived from LMP1-positive NPC cells could induce recipient NPC cell proliferation and invasion and suppress apoptosis, especially promoting radioresistance. In addition, LMP1 could increase the secretion of LMP1-positive EVs. Furthermore, transmitted LMP1 subsequently performed its oncogenic functions through activating P38 MAPK signaling in recipient cells, and inhibiting P38 activity could efficaciously restore the sensitivity of NPC cells to ionizing radiation (IR). Finally, we found that LMP1-positive EVs could promote tumor growth and P38 inhibition eliminates this promoting effect in vivo, and EV formation is associated with a poor prognosis in NPC patients. These results showed that a few cells expressing LMP1 could enhance the radioresistance of NPC cells through potentially impacting the infected host and also modulating the tumor microenvironment.

PMID: 31436393 [PubMed - as supplied by publisher]

Controlling the bioreceptor spatial distribution at the nanoscale for single molecule counting in microwell arrays.

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Controlling the bioreceptor spatial distribution at the nanoscale for single molecule counting in microwell arrays.

ACS Sens. 2019 Aug 22;:

Authors: Daems D, Rutten I, Bath J, Decrop D, van Gorp H, Pérez Ruiz E, De Feyter S, Turberfield AJ, Lammertyn J

Abstract
The ability to detect low concentrations of protein biomarkers is crucial for the early-stage detection of many diseases, and therefore indispensable for improving diagnostic devices for healthcare. Here, we demonstrate that by integrating DNA nanotechnologies like DNA origami and aptamers we can design innovative biosensing concepts for reproducible and sensitive detection of specific targets. DNA origami structures decorated with aptamers were studied as a novel tool to structure the biosensor surface with nanoscale precision in a digital detection bioassay, enabling control of the density, orientation and accessibility of the bioreceptor to optimize the interaction between target and aptamer. DNA origami was used to control the spatial distribution of an in-house generated aptamer on superparamagnetic microparticles, resulting in an origami-linked digital aptamer bioassay to detect the main peanut antigen Ara h1 with 2-fold improved signal to noise ratio and 15-fold improved limit of detection compared to a digital bioassay without DNA origami. Moreover, the sensitivity achieved was 4 orders of magnitude higher than commercially available and literature-reported ELISA techniques. In conclusion, this novel and innovative approach to engineer biosensing interfaces will be of major interest to scientists and clinicians looking for new molecular insights and ultrasensitive detection of a broad range of targets, and, for the next generation of diagnostics.

PMID: 31436077 [PubMed - as supplied by publisher]

Inhibiting exosomal MIC-A and MIC-B shedding of cancer cells to overcome immune escape: new insight of approved drugs.

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Inhibiting exosomal MIC-A and MIC-B shedding of cancer cells to overcome immune escape: new insight of approved drugs.

Daru. 2019 Aug 21;:

Authors: Moloudizargari M, Asghari MH, Mortaz E

Abstract
Our knowledge of the role of innate immunity in protecting against cancers has expanded greatly in recent years. An early focus was on the adoptive transfer of natural killer (NK) cells and, although this approach has demonstrated promising results in many patients, a few limitations including immune escape of tumors from cytotoxic killing by NK cells have caused treatment failures. Downregulation of the expression of activating ligands on the surface of cancer cells and prevention of the activity of soluble factors are among the mechanisms employed by cancer cells to overcome NK-mediated immunity. It has become evident that a class of small membranous structures of endosomal origin known as exosomes play a key role in regulating the local tumor microenvironment. Here we hypothesize that exosome secretion by cancer cells, which is greater than that of normal cells, is an important escape mechanism employed by cancer cells. Interruption of exosome release by various inhibitory agents in combination with the adoptive transfer of NK cells may overcome, at least in part, the treatment failures that occur with adoptive NK cell transfer. In this regard, repositioning of approved drugs with previously shown effects on exosome release may be a good strategy to bypass the safety issues of newly identified agents and will also dramatically reduce the huge costs of drug approval process.

PMID: 31435903 [PubMed - as supplied by publisher]

Exosome-mediated transfer of miR-1290 promotes cell proliferation and invasion in gastric cancer via NKD1.

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Exosome-mediated transfer of miR-1290 promotes cell proliferation and invasion in gastric cancer via NKD1.

Acta Biochim Biophys Sin (Shanghai). 2019 Aug 21;:

Authors: Huang J, Shen M, Yan M, Cui Y, Gao Z, Meng X

Abstract
Currently, exosomes rich in RNAs and proteins are regarded as vital mediators of intercellular communication. Here, we aimed to explore the effects of exosomal miR-1290 in gastric cancer (GC) and understand its mechanism of action on GC progression. We first isolated exosomes from serum samples of GC patients and healthy people and characterized them by transmission electron microscopy. Then, we examined the expression level of miR-1290 contained in the exosomes by quantitative reverse-transcription polymerase chain reaction and found that exosomal miR-1290 was overexpressed in GC patients and cell lines. Promotion of proliferation, migration, and invasiveness of GC cells was noted after they were incubated with the isolated miR-1290-rich exosomes compared with incubation with a negative control. Furthermore, we predicted that naked cuticle homolog 1 (NKD1) mRNA is a direct target of miR-1290 and confirmed their interaction by a dual luciferase reporter assay. NKD1 overexpression attenuated the stimulatory effects of miR-1290 on GC cells. Collectively, our results suggest that exosomal miR-1290 enhances GC cell proliferation and invasion by targeting NKD1 mRNA and downregulating NKD1 expression. A better understanding of this process may facilitate the development of novel therapeutic agents for GC.

PMID: 31435644 [PubMed - as supplied by publisher]

Multiple "Omics" data-based biomarker screening for hepatocellular carcinoma diagnosis.

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Multiple "Omics" data-based biomarker screening for hepatocellular carcinoma diagnosis.

World J Gastroenterol. 2019 Aug 14;25(30):4199-4212

Authors: Liu XN, Cui DN, Li YF, Liu YH, Liu G, Liu L

Abstract
The huge prognostic difference between early and late stage hepatocellular carcinoma (HCC) is a challenging diagnostic problem. Alpha-fetoprotein is the mostly widely used biomarker for HCC used in the clinic, however it's sensitivity and specificity of is not optimal. The development and application of multiple biotechnologies, including next generation sequencing, multiple "omics" data, that include genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics has been used for HCC diagnostic biomarker screening. Effective biomarkers/panels/models have been identified and validated at different clinical levels. A large proportion of these have a good diagnostic performance for HCC, especially for early HCC. In this article, we reviewed the various HCC biomarkers derived from "omics" data and discussed the advantages and disadvantages for diagnosis HCC.

PMID: 31435173 [PubMed - in process]

Exosomal microRNA-122 mediates obesity-related cardiomyopathy through suppressing mitochondrial ADP-ribosylation factor-like 2.

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Exosomal microRNA-122 mediates obesity-related cardiomyopathy through suppressing mitochondrial ADP-ribosylation factor-like 2.

Clin Sci (Lond). 2019 Aug 21;:

Authors: Wang Y, Jin P, Liu J, Xie X

Abstract
Emerging studies have demonstrated that microRNAs (miRs) participate in the development of multiple metabolic complications including cardiovascular diseases. Among them, circulating level of liver-secreted miR-122 was closely correlated with several consequences of heart diseases in clinical studies, and overexpression of miR-122 impaired cardiomyocyte function. However, it was unknown whether miR-122 could regulate cardiac biology in obesity. Therefore, present study was to disclose the role of miR-122 in cardiac metabolic disorders and potential molecular mechanisms. Through utilizing clinical samples and high fat diet-fed mice, we investigated the physiological roles of miR-122 in obesity-related cardiomyopathy. Besides, present study explored the mitochondrial function under exosomal miR-122 stimulation in mouse primary cardiomyocytes. In clinical samples and obese mice, the circulating level of exosomal miR-122 was positively correlated with cardiac dysfunctional parameters, including reduction of ejection fraction (EF) and increased levels of NT-proBNP. Human plasma exosomes transported miR-122 into mouse primary cardiomyocytes, and impaired mitochondrial ATP production and oxygen consumption, whereas miR-122 sponge improved these inhibitory effects. In dietary-induced mice, increased hepatic and circulating exosomal miR-122 deteriorated cardiac structure and functional index, and inhibited mitochondrial function. Liver-specific blockage of miR-122 attenuated abnormal cardiac remodelling. Mechanistically, miR-122 directly bound and suppressed mitochondrial protein ADP-ribosylation factor-like 2 (Arl-2) in vitro and in vivo Knockdown of Arl-2 abolished the mitochondrial benefits of miR-122 sponge in exosome-treated mouse primary cardiomyocytes. In conclusions, our present study firstly showed that liver-secreted exosomal miR-122 played a critical role in the development of metabolic cardiomyopathy, and miR-122/mitochondrial Arl-2 signaling affected cardiac energy homeostasis.

PMID: 31434696 [PubMed - as supplied by publisher]

Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction.

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Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction.

Arterioscler Thromb Vasc Biol. 2019 Aug 22;:ATVBAHA119312826

Authors: Haynes BA, Yang LF, Huyck RW, Lehrer EJ, Turner JM, Barabutis N, Correll VL, Mathiesen A, McPheat W, Semmes OJ, Dobrian AD

Abstract
OBJECTIVE: Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV). Approach and Results: We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA. We showed that AT EC exposed in vitro to TGF-β (tumor growth factor-β), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) undergo EndoMT with progressive loss of endothelial markers. The phenotypic change results in failure to maintain a tight barrier in culture, increased migration, and reduced angiogenesis. EndoMT also reduced mitochondrial oxidative phosphorylation and glycolytic capacity of EC. EVs produced by EC that underwent EndoMT dramatically reduced angiogenic capacity of the recipient naïve ECs without affecting their migration or proliferation. Proteomic analysis of EV produced by EC in the proinflammatory conditions showed presence of several pro-inflammatory and immune proteins along with an enrichment in angiogenic receptors.
CONCLUSIONS: We demonstrated the presence of EndoMT in human AT in obesity. EndoMT in vitro resulted in production of EV that transferred some of the functional and metabolic features to recipient naïve EC. This result suggests that functional and molecular features of EC that underwent EndoMT in vivo can be disseminated in a paracrine or endocrine fashion and may induce endothelial dysfunction in distant vascular beds.

PMID: 31434495 [PubMed - as supplied by publisher]

Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles.

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Mechanism of Enhanced MerTK-Dependent Macrophage Efferocytosis by Extracellular Vesicles.

Arterioscler Thromb Vasc Biol. 2019 Aug 22;:ATVBAHA119313115

Authors: de Couto G, Jaghatspanyan E, DeBerge M, Liu W, Luther K, Wang Y, Tang J, Thorp EB, Marbán E

Abstract
OBJECTIVE: Extracellular vesicles secreted by cardiosphere-derived cells (CDCev) polarize macrophages toward a distinctive phenotype with enhanced phagocytic capacity (MCDCev). These changes underlie cardioprotection by CDCev and by the parent CDCs, notably attenuating the no-reflow phenomenon following myocardial infarction, but the mechanisms are unclear. Here, we tested the hypothesis that MCDCev are especially effective at scavenging debris from dying cells (ie, efferocytosis) to attenuate irreversible damage post-myocardial infarction. Approach and Results: In vitro efferocytosis assays with bone marrow-derived macrophage, and in vivo transgenic rodent models of myocardial infarction, demonstrate enhanced apoptotic cell clearance with MCDCev. CDCev exposure induces sustained MerTK expression in MCDCev through extracellular vesicle transfer of microRNA-26a (via suppression of Adam17); the cardioprotective response is lost in animals deficient in MerTK. Single-cell RNA-sequencing revealed phagocytic pathway activation in MCDCev, with increased expression of complement factor C1qa, a phagocytosis facilitator.
CONCLUSIONS: Together, these data demonstrate that extracellular vesicle modulation of MerTK and C1qa expression leads to enhanced macrophage efferocytosis and cardioprotection.

PMID: 31434491 [PubMed - as supplied by publisher]

Leukocyte-Derived Extracellular Vesicles in Blood with and without EpCAM Enrichment.

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Leukocyte-Derived Extracellular Vesicles in Blood with and without EpCAM Enrichment.

Cells. 2019 Aug 20;8(8):

Authors: Nanou A, Zeune LL, Terstappen LWMM

Abstract
Large tumor-derived Extracellular Vesicles (tdEVs) detected in blood of metastatic prostate, breast, colorectal, and non-small cell lung cancer patients after enrichment for Epithelial Cell Adhesion Molecule (EpCAM) expression and labeling with 4',6-diamidino-2-phenylindole (DAPI), phycoerythrin-conjugated antibodies against Cytokeratins (CK-PE), and allophycocyanin-conjugated antibody against the cluster of differentiation 45 (CD45-APC), are negatively associated with the overall survival of patients. Here, we investigated whether, similarly to tdEVs, leukocyte-derived EVs (ldEVs) could also be detected in EpCAM-enriched blood. Presence of ldEVs and leukocytes in image data sets of EpCAM-enriched samples of 25 healthy individuals and 75 metastatic cancer patients was evaluated using the ACCEPT software. Large ldEVs could indeed be detected, but in contrast to the 20-fold higher frequency of tdEVs as compared to Circulating Tumor Cells (CTCs), ldEVs were present in a 5-fold lower frequency as compared to leukocytes. To evaluate whether these ldEVs pre-exist in the blood or are formed during the CellSearch procedure, the blood of healthy individuals without EpCAM enrichment was labelled with the nuclear dye Hoechst and fluorescently tagged monoclonal antibodies recognizing the leukocyte-specific CD45, platelet-specific CD61, and red blood cell-specific CD235a. Fluorescence microscopy imaging using a similar setup as the CellSearch was performed and demonstrated the presence of a similar population of ldEVs present at a 3-fold lower frequency as compared to leukocytes.

PMID: 31434250 [PubMed - in process]

Syncope as Initial Presentation in an Undifferentiated Type Acute Myeloid Leukemia Patient with Acute Intracranial Hemorrhage.

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Syncope as Initial Presentation in an Undifferentiated Type Acute Myeloid Leukemia Patient with Acute Intracranial Hemorrhage.

Brain Sci. 2019 Aug 20;9(8):

Authors: Wu MY, Lin CH, Hou YT, Lin PC, Yiang GT, Tien YC, Yeh HC

Abstract
Intracranial hemorrhage (ICH) is a catastrophic complication in patients with acute myeloid leukemia (AML). AML cells, especially in the acute promyelocytic leukemia subtype, may release microparticles (MPs), tissue factor (TF), and cancer procoagulant (CP) to promote coagulopathy. Hyperfibrinolysis is also triggered via release of annexin II, t-PA, u-PA, and u-PAR. Various inflammatory cytokines from cancer cells, such as IL-1β and TNF-α, activate endothelial cells and promote leukostasis. This condition may increase the ICH risk and lead to poor clinical outcomes. Here, we present a case under a unique situation with acute ICH detected prior to the diagnosis of AML. The patient initially presented with two episodes of syncope. Rapidly progressive ICH was noted in follow-up computed tomography (CT) scans. Therefore, we highlight that AML should be among the differential diagnoses of the etiologies of ICH. Early diagnosis and timely intervention are very important for AML patients.

PMID: 31434194 [PubMed]

Renal Injury During Preclampsia: Role of Extracellular Vesicles.

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Renal Injury During Preclampsia: Role of Extracellular Vesicles.

Nephron. 2019 Aug 21;:1-5

Authors: Pagani F, Cantaluppi V

Abstract
Preeclampsia (PE) represents an important cause of acute kidney injury during pregnancy with a high rate of both maternal and fetal morbidity and mortality. The presence of endothelial dysfunction is the main cause of PE development; however, the pathogenic mechanisms are not still fully elucidated. A plethora of harmful mediators are released in response to endothelial damage: these circulating molecules (soluble fms-like tyrosine kinase 1, endothelin-1) can exert antiangiogenic and vasoconstrictive effects on distant organs including the kidney. In this scenario, extracellular vesicles (EVs), microparticles released by different types of activated cells and involved in intercellular communication, are produced both in normal pregnancy and PE. The aim of this review is to summarize the modern concepts of PE-associated kidney damage and the potential role of EV in these detrimental mechanisms.

PMID: 31434070 [PubMed - as supplied by publisher]

Proteomic and structural characterization of self-assembled vesicles from excretion/secretion products of Toxoplasma gondii.

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Proteomic and structural characterization of self-assembled vesicles from excretion/secretion products of Toxoplasma gondii.

J Proteomics. 2019 Aug 18;:103490

Authors: Ramírez-Flores CJ, Cruz-Mirón R, Mondragón-Castelán ME, González-Pozos S, Ríos-Castro E, Mondragón-Flores R

Abstract
After the cell invasion, the parasite Toxoplasma gondii locates within a parasitophorous vacuole to proliferate. It continuously modifies the composition of the parasitophorous vacuole by the secretion of GRA and ROP proteins, some of which become inserted into the vacuole membrane, remain as soluble proteins or involved in the intravacuolar network. In this report, we analyze the excretion/secretion products and the vesicles released by extracellular tachyzoites, this structures were morphologically analyzed by electron microscopy and characterized by mass spectrometry. The structural analysis showed parasites secreting in vitro individual vesicles with similarities to ectosomes and exosomes and which characterized to self-assembly in vitro forming vesicle-tubular structures morphologically similar to the intravacuolar network from infected cells. The vesicle-tubular structures were recognized with antibodies against ROP2 and GRA2. In addition, analysis by Western blot evidenced proteins from the secretory organelles. A detailed proteomic analysis of exosomes, ectosomes and soluble proteins released in vitro is here reported. Presence of GRA proteins in secretions from resting extracellular parasites indicates that these molecules are not exclusively secreted within the parasitophorous vacuole of the infected cell as reported but they are constitutively excreted/secreted even in an extracellular condition. Data are available via ProteomeXchange with identifier PXD013767. SIGNIFICANCE: Extracellular tachyzoites constitutively secrete components that previously were considered be secreted only within the parasitophorous vacuole, suggesting that in the infected host these molecules are in direct interaction with cells and molecules of the host cell including those of the immune response.

PMID: 31434009 [PubMed - as supplied by publisher]

Exosomal miR-1246 derived from human umbilical cord blood mesenchymal stem cells attenuates hepatic ischemia reperfusion injury by modulating T helper 17/regulatory T balance.

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Exosomal miR-1246 derived from human umbilical cord blood mesenchymal stem cells attenuates hepatic ischemia reperfusion injury by modulating T helper 17/regulatory T balance.

IUBMB Life. 2019 Aug 21;:

Authors: Xie K, Liu L, Chen J, Liu F

Abstract
The purpose of this study was to explore the mechanism by which human umbilical cord blood mesenchymal stem cells (hUCB-MSCs)-derived exosomes exerted protective effect in hepatic ischemia/reperfusion injury (IRI). hUCB-MSCs-derived exosomes were administrated into hepatic IRI mice or cocultured with naïve CD4+ T cells exposed to hepatic hypoxia/reoxygenation microenvironment. Hepatic function was assessed by determining serum transaminases. Histological changes were observed using hematoxylin and eosin staining. The proportion of T helper 17 (Th17) and regulatory T (Treg) cells were analyzed by flow cytometry. The concentration of inflammatory cytokines was determined by enzyme-linked immunosorbent assay. The interaction between miR-1246 and interleukin 6 (IL-6) signal transducer (also known as gp130) was verified by luciferase activity assay. The miR-1246 expression, Th17/Treg-related genes, and gp130-signal transducer and activator of transcription 3 (STAT3) pathway were detected by quantitative real-time polymerase chain reaction and western blotting. hUCB-MSCs-derived exosomes ameliorated IRI-induced hepatic dysfunction and decreased Th17/Treg ratio in CD4+ T cells in vitro, whereas treatment of hUCB-MSCs with miR-1246 inhibitor showed opposite effects, which was mediated via the IL-6-gp130-STAT3 pathway. hUCB-MSCs-derived exosomes could alleviate hepatic IRI through modulating the balance between Tregs and Th17 cells via miR-1246-mediated IL-6-gp130-STAT3 axis.

PMID: 31433911 [PubMed - as supplied by publisher]

Circulating exosomes and their role in stroke.

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Circulating exosomes and their role in stroke.

Curr Drug Targets. 2019 Aug 21;:

Authors: Jafarzadeh-Esfehani R, Soudyab M, Parizadeh SM, Jaripoor ME, Nejad PS, Shariati M, Nabavi AS

Abstract
Stroke is an acute neurologic disorder which can be life threatening if left untreated or diagnosed lately. Various detecting techniques including neurologic imaging of brain by computed tomography or magnetic resonance imaging can facilitate diagnosis of stroke. However, according to the recent advances in molecular detection techniques new diagnostic and prognostic has been emerged. Exosomes as an extra cellar particle are one of these markers which can have useful diagnostic, prognostic and even therapeutic impact after stroke. We have previously discussed the role of exosomes in cardiovascular disease and in the present review we focus on the most common cerebrovascular disease. The aim of present review is summarizing the recent diagnostic role of exosomes which are specifically secreted during stroke and can guide clinicians to better diagnosis of stroke.

PMID: 31433753 [PubMed - as supplied by publisher]

Senescent Kidney Cells in Hypertensive Patients Release Urinary Extracellular Vesicles.

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Senescent Kidney Cells in Hypertensive Patients Release Urinary Extracellular Vesicles.

J Am Heart Assoc. 2019 Jun 04;8(11):e012584

Authors: Santelli A, Sun IO, Eirin A, Abumoawad AM, Woollard JR, Lerman A, Textor SC, Puranik AS, Lerman LO

Abstract
Background Hypertension may be associated with renal cellular injury. Cells in distress release extracellular vesicles (EVs), and their numbers in urine may reflect renal injury. Cellular senescence, an irreversible growth arrest in response to a noxious milieu, is characterized by release of proinflammatory cytokines. We hypothesized that EVs released by senescent nephron cells can be identified in urine of patients with hypertension. Methods and Results We recruited patients with essential hypertension (EH) or renovascular hypertension and healthy volunteers (n=14 each). Renal oxygenation was assessed using magnetic resonance imaging and blood samples collected from both renal veins for cytokine-level measurements. EVs isolated from urine samples were characterized by imaging flow cytometry based on specific markers, including p16 (senescence marker), calyxin (podocytes), urate transporter 1 (proximal tubules), uromodulin (ascending limb of Henle's loop), and prominin-2 (distal tubules). Overall percentage of urinary p16+ EVs was elevated in EH and renovascular hypertension patients compared with healthy volunteers and correlated inversely with renal function and directly with renal vein cytokine levels. Urinary levels of p16+/urate transporter 1+ were elevated in all hypertensive subjects compared with healthy volunteers, whereas p16+/prominin-2+ levels were elevated only in EH versus healthy volunteers and p16+/uromodulin+ in renovascular hypertension versus EH. Conclusions Levels of p16+ EVs are elevated in urine of hypertensive patients and may reflect increased proximal tubular cellular senescence. In EH, EVs originate also from distal tubules and in renovascular hypertension from Henle's loop. Hence, urinary EVs levels may be useful to identify intrarenal sites of cellular senescence.

PMID: 31433703 [PubMed - in process]

Integrin β1-enriched Extracellular Vesicles Mediate Monocyte Adhesion and Promote Liver Inflammation in Murine NASH.

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Integrin β1-enriched Extracellular Vesicles Mediate Monocyte Adhesion and Promote Liver Inflammation in Murine NASH.

J Hepatol. 2019 Aug 06;:

Authors: Guo Q, Furuta K, Lucien F, Sanchez LHG, Hirsova P, Krishnan A, Kabashima A, Pavelko KD, Madden B, Alhuwaish H, Gao Y, Revzin A, Ibrahim SH

Abstract
BACKGROUND AND AIMS: Hepatic recruitment of monocyte-derived macrophages (MoMF) contributes to the inflammatory response in nonalcoholic steatohepatitis (NASH). However, how hepatocyte lipotoxicity promotes MoMF inflammation is unclear. Here we demonstrate that lipotoxic hepatocyte-derived extracellular vesicles (EVs) are enriched with active integrin β1 (ITGβ1), which promotes monocyte adhesion and liver inflammation in murine NASH.
METHODS: Hepatocytes were treated with either vehicle or the toxic lipid mediator lysophosphatidylcholine (LPC); EVs were isolated from the conditioned media and subjected to proteomic analysis. C57BL/6J mice were fed a diet rich in fat, fructose, and cholesterol (FFC) to induce NASH. Mice were treated with anti-ITGβ1 neutralizing antibody (ITGβ1Ab) or control IgG isotype.
RESULTS: Ingenuity Pathway Analysis of the lipotoxic hepatocyte-derived EV (LPC-EVs) proteome indicated that integrin signaling is an overrepresented canonical pathway. Immunogold electron microscopy and nanoscale flow cytometry confirmed enrichment of LPC-EVs with active ITGβ1. Furthermore, we showed that LPC treatment in hepatocytes activates ITGβ1 and mediates its endocytic trafficking and sorting into EVs. LPC-EVs-enhanced monocytes adhesion to liver sinusoidal endothelial cells (LSECs) was observed by shear stress adhesion assay, and was attenuated in the presence of ITGβ1Ab. FFC-fed, ITGβ1Ab-treated mice displayed reduced inflammation defined by decreased proinflammatory MoMF hepatic infiltration and activation as assessed by immunohistochemistry, mRNA expression, and flow cytometry. Likewise, mass cytometry by time-of-flight (CyTOF) on intrahepatic leukocytes (IHL) displayed reduced infiltrating proinflammatory monocytes. Furthermore, ITGβ1Ab treatment significantly ameliorated liver injury and fibrosis.
CONCLUSIONS: Lipotoxic EVs mediate monocyte adhesion to LSECs mainly by an ITGβ1-dependent mechanism. ITGβ1Ab ameliorates diet-induced NASH in mice by reducing MoMF-driven inflammation, suggesting that blocking ITGβ1 is a potential anti-inflammatory therapeutic strategy in human NASH.
LAY SUMMARY: Herein, we report that a cell adhesion molecule termed integrin β1 (ITGβ1) plays a key role in the progression of nonalcoholic steatohepatitis (NASH). ITGβ1 is released from hepatocytes under lipotoxic stress as a cargo of extracellular vesicles, and mediates monocyte adhesion to liver sinusoidal endothelial cells, which is an essential step in hepatic inflammation. In a mouse model of NASH, blocking ITGβ1 reduces liver inflammation, injury and fibrosis. Hence, ITGβ1 inhibition may serve as a new therapeutic strategy for NASH.

PMID: 31433301 [PubMed - as supplied by publisher]

A review on protein markers of exosome from different bio-resources and the antibodies used for characterization.

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A review on protein markers of exosome from different bio-resources and the antibodies used for characterization.

J Histotechnol. 2019 Aug 21;:1-14

Authors: Deng F, Miller J

Abstract
Exosomes are small membrane vesicles (ranging from 30 nm to 150 nm), secreted by different cell types upon fusion of multivesicular bodies (MVB) to the cell plasma membrane under a variety of normal and pathological conditions. Through transferring their cargos such as proteins, lipids and nucleic acids from donor cells to recipient cells, exosomes play a crucial role in cell-to-cell communication. Due to their presence in most body fluids (such as blood, breast milk, saliva, urine, bile, pancreatic juice, cerebrospinal and peritoneal fluids), and their role in carrying bioactive molecules from the cells of origin, exosomes have attracted great interest in their diagnostic and prognostic value for various diseases and therapeutic approaches. Although a large body of literature has documented the importance of exosomes over the past decade, there is no article systematically summarizing protein markers of exosome from different resources and the antibodies that are suited to characterize exosomes. In this review, we briefly summarize the exosome marker proteins, exosomal biomarkers for different diseases, and the antibodies suitable for different bio-resources exosomes characterization.

PMID: 31432761 [PubMed - as supplied by publisher]

Characterization of Alzheimer's Disease Micro-RNA Profile in Exosome-Enriched CSF Samples.

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Characterization of Alzheimer's Disease Micro-RNA Profile in Exosome-Enriched CSF Samples.

Methods Mol Biol. 2019;2044:343-352

Authors: Riancho J, Santurtun A, Sánchez-Juan P

Abstract
Micro-RNAs (miRNAs) are small endogenous noncoding ribonucleic acids that modulate gene expression at a post-transcriptional level. miRNAs have been postulated as potential biomarkers and therapeutic targets in a wide list of human diseases including cancer, autoimmune, cardiovascular, and neurodegenerative diseases. miRNAs are secreted by the cells into exosomes. These are small cell-derived membrane vesicles that can be isolated from many body fluids including urine, saliva, blood, and cerebrospinal fluid (CSF). Exosomes contain a variety of proteins and noncoding RNAs and seem to play an important role in cell-cell communication and the regulation of immune response and other body functions. In this chapter, we will discuss the sequential procedure to characterize the miRNA profile in exosome-enriched CSF samples.

PMID: 31432424 [PubMed - in process]

Hsa_circ_0065149 is an Indicator for Early Gastric Cancer Screening and Prognosis Prediction.

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Hsa_circ_0065149 is an Indicator for Early Gastric Cancer Screening and Prognosis Prediction.

Pathol Oncol Res. 2019 Aug 20;:

Authors: Shao Y, Tao X, Lu R, Zhang H, Ge J, Xiao B, Ye G, Guo J

Abstract
Circular RNAs (circRNAs) are an endogenous RNAs with a covalently closed cyclic structure. They have emerged recently as key regulators in the development and progression of human cancers. However, the clinical values of most circRNAs in gastric cancer (GC) are unknown. Hsa_circ_0065149, one of the dysregulated circRNAs in gastric carcinogenesis detected by circRNA microarray, was chose as a targeted circRNA in this study. We firstly enlarged sample size and identified the level changes of hsa_circ_0065149 among four stages of gastric tumorigenesis from healthy gastric mucosa, gastritis, intestinal metaplasia to GC. Then, the potential relationship between hsa_circ_0065149 expression levels and GC patients' clinicopathological factors was investigated. Moreover, the clinical significance of hsa_circ_0065149 in plasma exosomes and gastric juice were explored. Receiver operating characteristic (ROC) curve and Kaplan-Meier survival curve were constructed to evaluate diagnostic and prognostic values. Finally, bioinformatics analysis was performed to excavate the potential functions of hsa_circ_0065149. Hsa_circ_0065149 expression was only significantly down-regulated in gastric cancer, not changed among healthy gastric mucosa and gastritis intestinal metaplasia. Low hsa_circ_0065149 expression levels in GC tissues were significantly associated with tumor diameter (P = 0.034) and perineural invasion (P = 0.037). GC patients with low hsa_circ_0065149 levels had a much longer overall survival than those in high group (P = 0.020). More important, hsa_circ_0065149 levels were significantly decreased in plasma exosomes of early GC patients. As a screening biomarker for early GC, hsa_circ_0065149 in plasma exosomes has higher sensitivity and specificity than traditional clinical biomarkers. Bioinformatics analysis suggest that the abnormal expression of hsa_circ_0065149 may play an important role during gastric carcinogenesis. Those results indicate that hsa_circ_0065149 in exosmoes is an indicator for early GC screening and prognosis prediction.

PMID: 31432324 [PubMed - as supplied by publisher]

The identification of CRNDE, H19, UCA1 and HOTAIR as the key lncRNAs involved in oxaliplatin or irinotecan resistance in the chemotherapy of colorectal cancer based on integrative bioinformatics analysis.

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The identification of CRNDE, H19, UCA1 and HOTAIR as the key lncRNAs involved in oxaliplatin or irinotecan resistance in the chemotherapy of colorectal cancer based on integrative bioinformatics analysis.

Mol Med Rep. 2019 Aug 14;:

Authors: Sun F, Liang W, Qian J

Abstract
With the increasing rate of chemoresistance in colorectal cancer (CRC) patients with advanced tumor stages, it is a matter of urgent importance to delineate the factors involved in the drug resistance process. In this study, gene expression profiles were downloaded from the Gene Expression Omnibus database and an integrated analysis with the aim of detecting hub long non‑coding RNAs (lncRNAs) and their regulated, differentially expressed genes (DEGs) during treatment with oxaliplatin (OxPt) or irinotecan was conducted. A total of seven differentially expressed lncRNAs were correlated with OxPt resistance and 21 were correlated with resistance to SN‑38, the active metabolite of irinotecan. Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis confirmed that drug resistance was strongly associated with an imbalance between cell proliferation and apoptosis, cell energetic metabolism under hypoxic conditions, and angiogenesis. Moreover, a large number of lncRNA‑targeted DEGs were located in extracellular exosomes. Further analyses identified four hub lncRNAs involved in the process of drug resistance, including CRNDE, H19, UCA1 and HOTAIR, which are predictive factors for treatment sensitivity. Among them, HOTAIR stands out as a strong factor, the elevated expression of which is also associated with advanced tumor node and metastasis stage and poor CRC disease prognosis.

PMID: 31432188 [PubMed - as supplied by publisher]

TGFBR2‑dependent alterations of microRNA profiles in extracellular vesicles and parental colorectal cancer cells.

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TGFBR2‑dependent alterations of microRNA profiles in extracellular vesicles and parental colorectal cancer cells.

Int J Oncol. 2019 Aug 19;:

Authors: Fricke F, Mussack V, Buschmann D, Hausser I, Pfaffl MW, Kopitz J, Gebert J

Abstract
In colorectal cancer (CRC) with microsatellite instability (MSI), >90% of cases are affected by inactivating frameshift mutations of transforming growth factor β receptor type 2 (TGFBR2). TGFBR2 deficiency is considered to drive MSI tumor progression by abrogating downstream TGF‑β signaling. This pathway can alter the expression of coding and non‑coding RNAs, including microRNAs (miRNAs), which are also present in extracellular vesicles (EVs) as post‑transcriptional modulators of gene expression. In our previous study, it was shown that TGFBR2 deficiency alters the protein composition and function of EVs in MSI tumors. To investigate whether mutant TGFBR2 may also affect the miRNA cargo of EVs, the present study characterized miRNAs in EVs and their parental MSI tumor cells that differed only in TGFBR2 expression status. The HCT116‑TGFBR2 MSI cell line model enables the doxycycline (dox)‑inducible reconstituted expression of TGFBR2 in an isogenic background (‑dox, TGFBR2 deficient; +dox, TGFBR2 proficient). Small RNA sequencing of cellular and EV miRNAs showed that the majority of the miRNAs (263/471; 56%) were shared between MSI tumor cells and their EVs. Exploratory data analysis revealed the TGBFR2‑dependent cluster separation of miRNA profiles in EVs and MSI tumor cells. This segregation appeared to result from two subsets of miRNAs, the expression of which were regulated in a TGFBR2‑dependent manner (EVs: n=10; MSI cells: n=15). In the EV subset, 7/10 miRNAs were downregulated and 3/10 were upregulated by TGFBR2 deficiency. In the cellular subset, 13/15 miRNAs were downregulated and 2/15 miRNAs were upregulated in the TGFBR2‑deficient cells. The present study emphasizes the general overlap of miRNA profiles in MSI tumor cells and their EVs, but also highlights the impact of a single tumor driver mutation on the expression of individual miRNAs, as exemplified by the downregulation of miR‑381‑3p in TGFBR2‑deficient MSI tumor cells and their secreted EVs.

PMID: 31432155 [PubMed - as supplied by publisher]

Recent advances in microfluidic methods in cancer liquid biopsy.

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Recent advances in microfluidic methods in cancer liquid biopsy.

Biomicrofluidics. 2019 Jul;13(4):041503

Authors: Iliescu FS, Poenar DP, Yu F, Ni M, Chan KH, Cima I, Taylor HK, Cima I, Iliescu C

Abstract
Early cancer detection, its monitoring, and therapeutical prediction are highly valuable, though extremely challenging targets in oncology. Significant progress has been made recently, resulting in a group of devices and techniques that are now capable of successfully detecting, interpreting, and monitoring cancer biomarkers in body fluids. Precise information about malignancies can be obtained from liquid biopsies by isolating and analyzing circulating tumor cells (CTCs) or nucleic acids, tumor-derived vesicles or proteins, and metabolites. The current work provides a general overview of the latest on-chip technological developments for cancer liquid biopsy. Current challenges for their translation and their application in various clinical settings are discussed. Microfluidic solutions for each set of biomarkers are compared, and a global overview of the major trends and ongoing research challenges is given. A detailed analysis of the microfluidic isolation of CTCs with recent efforts that aimed at increasing purity and capture efficiency is provided as well. Although CTCs have been the focus of a vast microfluidic research effort as the key element for obtaining relevant information, important clinical insights can also be achieved from alternative biomarkers, such as classical protein biomarkers, exosomes, or circulating-free nucleic acids. Finally, while most work has been devoted to the analysis of blood-based biomarkers, we highlight the less explored potential of urine as an ideal source of molecular cancer biomarkers for point-of-care lab-on-chip devices.

PMID: 31431816 [PubMed]

New insights into the physics of inertial microfluidics in curved microchannels. II. Adding an additive rule to understand complex cross-sections.

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New insights into the physics of inertial microfluidics in curved microchannels. II. Adding an additive rule to understand complex cross-sections.

Biomicrofluidics. 2019 May;13(3):034118

Authors: Rafeie M, Hosseinzadeh S, Huang J, Mihandoust A, Warkiani ME, Taylor RA

Abstract
Curved microchannels allow controllable microparticle focusing, but a full understanding of particle behavior has been limited-even for simple rectangular and trapezoidal shapes. At present, most microfluidic particle separation literature is dedicated to adding "internal" complexity (via sheath flow or obstructions) to relatively simple cross-sectional channel shapes. We propose that, with sufficient understanding of particle behavior, an equally viable pathway for microparticle focusing could utilize complex "external" cross-sectional shapes. By investigating three novel, complex spiral microchannels, we have found that it is possible to passively focus (6, 10, and 13 μm) microparticles in the middle of a convex channel. Also, we found that in concave and jagged channel designs, it is possible to create multiple, tight focusing bands. In addition to these performance benefits, we report an "additive rule" herein, which states that complex channels can be considered as multiple, independent, simple cross-sectional shapes. We show with experimental and numerical analysis that this new additive rule can accurately predict particle behavior in complex cross-sectional shaped channels and that it can help to extract general inertial focusing tendencies for suspended particles in curved channels. Overall, this work provides simple, yet reliable, guidelines for the design of advanced curved microchannel cross sections.

PMID: 31431814 [PubMed]

New insights into the physics of inertial microfluidics in curved microchannels. I. Relaxing the fixed inflection point assumption.

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New insights into the physics of inertial microfluidics in curved microchannels. I. Relaxing the fixed inflection point assumption.

Biomicrofluidics. 2019 May;13(3):034117

Authors: Rafeie M, Hosseinzadeh S, Taylor RA, Warkiani ME

Abstract
Inertial microfluidics represents a powerful new tool for accurately positioning cells and microparticles within fluids for a variety of biomedical, clinical, and industrial applications. In spite of enormous advancements in the science and design of these devices, particularly in curved microfluidic channels, contradictory experimental results have confounded researchers and limited progress. Thus, at present, a complete theory which describes the underlying physics is lacking. We propose that this bottleneck is due to one simple mistaken assumption-the locations of inflection points of the Dean velocity profile in curved microchannels are not fixed, but can actually shift with the flow rate. Herein, we propose that the dynamic distance (δ) between the real equilibrium positions and their nearest inflection points can clearly explain several (previously) unexplained phenomena in inertial microfluidic systems. More interestingly, we found that this parameter, δ, is a function of several geometric and operational parameters, all of which are investigated (in detail) here with a series of experiments and simulations of different spiral microchannels. This key piece of understanding is expected to open the door for researchers to develop new and more effective inertial microfluidic designs.

PMID: 31431813 [PubMed]

Mesenchymal stem cell-derived exosomes for clinical use.

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Mesenchymal stem cell-derived exosomes for clinical use.

Bone Marrow Transplant. 2019 Aug;54(Suppl 2):789-792

Authors: Mendt M, Rezvani K, Shpall E

Abstract
Mesenchymal stem/stromal cells (MSCs) are commonly used as a source of cellular therapy due to their strong immunosuppressive and regenerative effects. One of the key mechanisms of MSC efficacy appears to derive from their paracrine activity. Recently, it has been shown that the secretion of different factors through extracellular vesicles known as exosomes, orchestrate the principle mechanisms of action of MSCs after infusion. The use of MSC-derived exosomes may provide considerable advantages over their counterpart live cells, potentially reducing undesirable side effects including infusional toxicities. In this review, we examine clinical trials of MSC-derived exosomes currently in progress for gene delivery, regenerative medicine, and immunomodulation. In addition, we summarize the limitations and clinical potential of this cell-free therapeutic strategy.

PMID: 31431712 [PubMed - in process]

Perspective on Adenoviruses: Epidemiology, Pathogenicity, and Gene Therapy.

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Perspective on Adenoviruses: Epidemiology, Pathogenicity, and Gene Therapy.

Biomedicines. 2019 Aug 19;7(3):

Authors: Crenshaw BJ, Jones LB, Bell CR, Kumar S, Matthews QL

Abstract
Human adenoviruses are large (150 MDa) doubled-stranded DNA viruses that cause respiratory infections. These viruses are particularly pathogenic in healthy and immune-compromised individuals, and currently, no adenovirus vaccine is available for the general public. The purpose of this review is to describe (i) the epidemiology and pathogenicity of human adenoviruses, (ii) the biological role of adenovirus vectors in gene therapy applications, and (iii) the potential role of exosomes in adenoviral infections.

PMID: 31430920 [PubMed]

Extracellular Vesicles in the Blood of Dogs with Cancer-A Preliminary Study.

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Extracellular Vesicles in the Blood of Dogs with Cancer-A Preliminary Study.

Animals (Basel). 2019 Aug 19;9(8):

Authors: Żmigrodzka M, Witkowska-Piłaszewicz O, Rzepecka A, Cywińska A, Jagielski D, Winnicka A

Abstract
Extracellular vesicles (EVs) are a heterogeneous population of submicron-sized structures released during the activation, proliferation, or apoptosis of various types of cells. Due to their size, their role in cell-to-cell communication in cancer is currently being discussed. In blood, the most abundant population of EVs is platelet-derived EVs (PEVs). The aim of this study was to estimate the absolute number and the origin of EVs in the blood of healthy dogs and of dogs with various types of cancer. The EV absolute number and cellular origin were examined by flow cytometry technique. EVs were classified on the basis of surface annexin V expression (phosphatidylserine PS+) and co-expression of specific cellular markers (CD61, CD45, CD3, CD21). The number of PEVs was significantly higher in dogs with cancer (median: 409/µL, range: 42-2748/µL vs. median: 170/µL, range: 101-449/µL in controls). The numbers of EVs derived from leukocytes (control median: 86/µL, range: 40-240/µL; cancer median: 443/µL, range: 44-3 352/µL) and T cells (control median: 5/µL, range: 2-66/µL; cancer median: 108/µL, range: 3-1735/µL) were higher in dogs with neoplasia compared to healthy controls. The estimation of PEV and leukocyte-derived EV counts may provide a useful biological marker in dogs with cancer.

PMID: 31430895 [PubMed]

 

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