Efficient production and enhanced tumor delivery of engineered extracellular vesicles

Extracellular vesicles (EV), including exosomes and microvesicles, are nano-sized intercellular communication vehicles that participate in a multitude of physiological processes. Due to their biological properties, they are also promising candidates for the systemic delivery of therapeutic compounds, such as cytokines, chemotherapeutic drugs, siRNAs and viral vectors. However, low EV production yield and rapid clearance of administered EV by liver macrophages limit their potential use as therapeutic vehicles. We have used a hollow-fiber bioreactor for the efficient production of bioactive EV bearing the heterodimeric cytokine complex Interleukin-15:Interleukin-15 receptor alpha. Bioreactor culture yielded ∼40-fold more EV per mL conditioned medium, as compared to conventional cell culture. Biophysical analysis and comparative proteomics suggested a more diverse population of EV in the bioreactor preparations, while serum protein contaminants were detectable only in conventional culture EV preparations. We also identified the Scavenger Receptor Class A family (SR-A) as a novel monocyte/macrophage uptake receptor for EV. In vivo blockade of SR-A with dextran sulfate dramatically decreased EV liver clearance in mice, while enhancing tumor accumulation. These findings facilitate development of EV therapeutic methods. © 201

Expression and prognostic significance of cox-2 and p-53 in hodgkin lymphomas: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Cyclooxygenase (cox) is the rate-limiting enzyme, which catalyzes the conversion of arachidonic acid into prostaglandins and contributes to the inflammatory process. Cyclooxygenase-2 (cox-2), which is one of the two isoforms, plays a role in tumor progression and carcinogenesis. p53 contributes to apoptosis, DNA renewal and cell cycle. Studies concerning the relationship of cox-2 and p53 expressions and carcinogenesis are available, but the association between cox-2 and p53 in Hodgkin lymphoma (HL) is not exactly known.</p> <p>In our study, we examined the association of cox-2 and p53 expression, with age, stage, histopathological subtype, and survival in HL. We also examined correlation between cox-2 and p53 expression.</p> <p>Methods</p> <p>Cox-2 and p53 expressions in Hodgkin-Reed Sternberg cells (HRS) were examined in 54 patients with HL depending on cox-2 expression, stained cases were classified as positive, and unstained cases as negative. Nuclear staining of HRS cells with p53 was evaluated as positive. The classifications of positivity were as follows: negative if<10%; (1+) if 10-25%; (2+) if 25-50%; (3+) if 50-75%, (4+) if >75%.</p> <p>Results</p> <p>Cox-2 and p53 expressions were found in 49 (80%) and 29 (46%) patients, respectively. There were differences between histological subtypes according to cox-2 expression (p = 0.012). Mixed cellular (MC) and nodular sclerosing (NS) subtypes were seen most of the patients and cox-2 expression was evaluated mostly in the mixed cellular subtype.</p> <p>There were no statistically significant relationships between p53 and the histopathological subtypes; or between p53, cox-2 and the factors including stage, age and survival; or between p53 and cox-2 expression (p > 0.05).</p> <p>Conclusion</p> <p>Considering the significant relationship between the cox-2 expression and the subtypes of HL, cox-2 expression is higher in MC and NS subtypes. However the difference between these two subtypes was not significant. This submission must be advocated by studies with large series</p

ADAMDEC1 maintains a growth factor signaling loop in cancer stem cells

Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSCs), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by GSCs. ADAMDEC1 rapidly solubilizes fibroblast growth factor-2 (FGF2) to stimulate FGF receptor 1 (FGFR1) expressed on GSCs. FGFR1 signaling induces upregulation of Zinc-finger E-box-binding homeobox 1 (ZEB1) via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GB

SerpinB3 Drives Cancer Stem Cell Survival in Glioblastoma

Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a GBM CSC-specific survival mechanism involving a cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of GBM therapies against therapeutically resistant CSCs

Assessment of DEMs produced by medium resolution optical sensors considering land cover classes

ATHI TELECOM;e-geos;Thales Alenia Space;TELESPAZIO;SPACEALLIANCE33rd Asian Conference on Remote Sensing 2012, ACRS 2012 -- 26 November 2012 through 30 November 2012 -- Pattaya -- 97670A digital elevation model (DEM) presents immense data proving three dimensional terrain structure of any part of the Earth. DEMs are obtained by two main methods in space-borne remote sensing as stereoscopy using optical or radar imagery and interferometric synthetic aperture radar (InSAR) technology. In fact, the primary product of space-borne remote sensing techniques is a digital surface model (DSM) that contains points located on the top of ground objects. By removing these points that do not belong to the bare ground, the DEM is obtained. In optical imagery, DSMs are generated based on stereo matching using ground control points and co-located clear tie points at stereo image-pair with high correlation. In this case, correlation comes into prominence and affects the success of DSM acquired by stereoscopy. This investigation aims to assess the quality of DEMs produced by medium resolution spatial data derived from optical imagery depending upon the effect of correlation in stereoscopy correspondingly the land cover types. Towards this purpose, land cover classes have been generated such as open, forest, built-up, road network and rocky regions, DSM-DEM conversion was applied by optimal filtering methods and DEM accuracies have been achieved separately. The analyses were realized using actual ASTER GDEM Version 2 with 30m original grid spacing in Zonguldak, Turkey including rugged topography and suitable land cover classes. For the verification, a reference DEM derived from 1/1000 scaled aerial photos was employed

An assessment of urban area extraction using ALOS-2 data

Airbus;Aselsan;et al.;Roketsan;STM Engineering Technology Consultancy;Turkish Aerospace9th International Conference on Recent Advances in Space Technologies, RAST 2019 -- 11 June 2019 through 14 June 2019 -- -- 149874Urbanization has a dynamic structure especially in megacities and therefore rapid detection of the urban is vital for sustainable management of the city. In this work, we apply a multi-source feature data approach to investigate the urban area of Istanbul, Turkey which is a megacity with an approximate 15 million inhabitant, and under strong both anthropogenic and natural pressures. In order to analyse and compare the spatial pattern of the urban footprint, different techniques are applied. Speckle divergence, backscatter and repeat pass interferometric coherence values are considered for the analysis. To this aim, L-band HH and HV polarized ALOS-2 Synthetic Aperture Radar (SAR) data were acquired from Japan Space Exploration Agency's (JAXA). Pixel based Random Forest Classification method was used for the urban mapping. During the classification, different scenarios have been applied using speckle divergence, backscatter and coherence information. Overall, user and producer accuracies were calculated from the error matrix. While comparing HH and HV polarimetry, in each scenario HH provided much higher accuracies than HV results. Speckle divergence and backscatter values yielded similar accuracies which is around 88% for urban class. However, coherence gave approximately 69% while it is classified individually. The contribution of coherence was extracted while coherence was stacked with speckle divergence, and the result was improved to 91%. The urban areas was extracted with a maximum accuracy of maximum 93% while all information was combined. The preliminary results allow us to obtain a comprehensive image of urban structure, and indicate that the results may reference address for further analysis of multi-temporal SAR data over large and complicated mega cities. © 2019 IEEE

Factors Influencing the Differentiation of Human Monocytic Myeloid-Derived Suppressor Cells Into Inflammatory Macrophages

Monocytic myeloid-derived suppressor cells (mMDSC) accumulate within tumors where they create an immunosuppressive milieu that inhibits the activity of cytotoxic T and NK cells thereby allowing cancers to evade immune elimination. The toll-like receptors 7/8 agonist R848 induces human mMDSC to mature into inflammatory macrophage (MACinflam). This work demonstrates that TNFα, IL-6, and IL-10 produced by maturing mMDSC are critical to the generation of MACinflam. Neutralizing any one of these cytokines significantly inhibits R848-dependent mMDSC differentiation. mMDSC cultured in pro-inflammatory cytokine IFNγ or the combination of TNFα plus IL-6 differentiate into MACinflam more efficiently than those treated with R848. These mMDSC-derived macrophages exert anti-tumor activity by killing cancer cells. RNA-Seq analysis of the genes expressed when mMDSC differentiate into MACinflam indicates that TNFα and the transcription factors NF-κB and STAT4 are major hubs regulating this process. These findings support the clinical evaluation of R848, IFNγ, and/or TNFα plus IL-6 for intratumoral therapy of established cancers

UPDATING OBJECT FOR GIS DATABASE INFORMATION USING HIGH RESOLUTION SATELLITE IMAGES: A CASE STUDY ZONGULDAK

Nowadays Geographic Information Systems (GIS) uses Remote Sensing (RS) data for a lot of applications. One of the application areas is the updating of the GIS database using high resolution imagery. In this context high resolution satellite imagery data is very important for many applications areas today's and future. And also, high resolution satellite imagery data will be used in many applications for different purposes. Information systems needs to high resolution imagery data for updating. Updating is very important component for the any of the GIS systems. One of this area will be updated and kept alive GIS database information. High resolution satellite imagery is used with different data base which serve map information via internet and different aims of information systems applications in future topographic and cartographic information systems will very important in our country in this sense use of the satellite images will be unavoidable. In this study explain to how is acquired to satellite images and how is use this images in information systems for object and roads. Firstly, pan-sharpened two of the IKONOS's images have been produced by fusion of high resolution PAN and MS images using PCI Geomatica v9.1 software package. Automatic object extraction has been made using eCognition v4.0.6. On the other hand, these objects have been manually digitized from high resolution images using ArcGIS v9.3. software package. Application section of in this study, satellite images data will be compared each other and GIS objects and road database. It is also determined which data is useful in Geographic Information Systems. Finally, this article explains that integration of remote sensing technology and GIS applications.</i

UPDATING OBJECT FOR GIS DATABASE INFORMATION USING HIGH RESOLUTION SATELLITE IMAGES: A CASE STUDY ZONGULDAK

ISPRS Hannover Workshop on High-Resolution Earth Imaging for Geospatial Information -- JUN 14-17, 2011 -- Hannover, GERMANYWOS: 000358235900001Nowadays Geographic Information Systems (GIS) uses Remote Sensing (RS) data for a lot of applications. One of the application areas is the updating of the GIS database using high resolution imagery. In this context high resolution satellite imagery data is very important for many applications areas today's and future. And also, high resolution satellite imagery data will be used in many applications for different purposes. Information systems needs to high resolution imagery data for updating. Updating is very important component for the any of the GIS systems. One of this area will be updated and kept alive GIS database information. High resolution satellite imagery is used with different data base which serve map information via internet and different aims of information systems applications in future topographic and cartographic information systems will very important in our country in this sense use of the satellite images will be unavoidable. In this study explain to how is acquired to satellite images and how is use this images in information systems for object and roads. Firstly, pan-sharpened two of the IKONOS's images have been produced by fusion of high resolution PAN and MS images using PCI Geomatica v9.1 software package. Automatic object extraction has been made using eCognition v4.0.6. On the other hand, these objects have been manually digitized from high resolution images using ArcGIS v9.3. software package. Application section of in this study, satellite images data will be compared each other and GIS objects and road database. It is also determined which data is useful in Geographic Information Systems. Finally, this article explains that integration of remote sensing technology and GIS applications.Int Soc Photogrammetry & Remote Sensin