Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization

Background : Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-κB. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. Methods : Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor-transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-β) and low (TNF-α) expression in M2 macrophages, and molecules in NF-κB pathway (IKKα and Iκ-B) were evaluated by RT-qPCR or western blot. Results : EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-β and increased TNF-α. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKKα suppression and concomitant I-κB accumulation; increase of IL-6 and TGF-β; and, decrease of TNF-α. EGCG up-regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-κB pathway elicited by EGCG-treated exosomes. Conclusions : Our data demonstrate that EGCG up-regulates miR-16 in tumor cells, which can be transferred to TAM via exosomes and inhibits TAM infiltration and M2 polarization. We suggest a novel mechanism by which EGCG exerts anti-tumor activity via regulation of TAM in tumor microenvironment.This work was supported by the Global Core Research Center (GCRC) grant (No. 2012–0001190) from the National Research Foundation (NRF), Ministry of Education, Science and Technology (MEST) (Republic of Korea).Peer Reviewe

Intra-arterial delivery of triolein emulsion increases vascular permeability in skeletal muscles of rabbits

<p>Abstract</p> <p>Background</p> <p>To test the hypothesis that triolein emulsion will increase vascular permeability of skeletal muscle.</p> <p>Methods</p> <p>Triolein emulsion was infused into the superficial femoral artery in rabbits (triolein group, n = 12). As a control, saline was infused (saline group, n = 18). Pre- and post-contrast T1-weighted MR images were obtained two hours after infusion. The MR images were qualitatively and quantitatively evaluated by assessing the contrast enhancement of the ipsilateral muscles. Histologic examination was performed in all rabbits.</p> <p>Results</p> <p>The ipsilateral muscles of the rabbits in the triolein group showed contrast enhancement, as opposed to in the ipsilateral muscles of the rabbits in the saline group. The contrast enhancement of the lesions was statistically significant (p < 0.001). Histologic findings showed that most examination areas of the triolein and saline groups had a normal appearance.</p> <p>Conclusion</p> <p>Rabbit thigh muscle revealed significantly increased vascular permeability with triolein emulsion; this was clearly demonstrated on the postcontrast MR images.</p

Advanced Robotic Therapy Integrated Centers (ARTIC): an international collaboration facilitating the application of rehabilitation technologies

Background: The application of rehabilitation robots has grown during the last decade. While meta-analyses have shown beneficial effects of robotic interventions for some patient groups, the evidence is less in others. We established the Advanced Robotic Therapy Integrated Centers (ARTIC) network with the goal of advancing the science and clinical practice of rehabilitation robotics. The investigators hope to exploit variations in practice to learn about current clinical application and outcomes. The aim of this paper is to introduce the ARTIC network to the clinical and research community, present the initial data set and its characteristics and compare the outcome data collected so far with data from prior studies. Methods: ARTIC is a pragmatic observational study of clinical care. The database includes patients with various neurological and gait deficits who used the driven gait orthosis Lokomat® as part of their treatment. Patient characteristics, diagnosis-specific information, and indicators of impairment severity are collected. Core clinical assessments include the 10-Meter Walk Test and the Goal Attainment Scaling. Data from each Lokomat® training session are automatically collected. Results: At time of analysis, the database contained data collected from 595 patients (cerebral palsy: n = 208; stroke: n = 129; spinal cord injury: n = 93; traumatic brain injury: n = 39; and various other diagnoses: n = 126). At onset, average walking speeds were slow. The training intensity increased from the first to the final therapy session and most patients achieved their goals. Conclusions: The characteristics of the patients matched epidemiological data for the target populations. When patient characteristics differed from epidemiological data, this was mainly due to the selection criteria used to assess eligibility for Lokomat® training. While patients included in randomized controlled interventional trials have to fulfill many inclusion and exclusion criteria, the only selection criteria applying to patients in the ARTIC database are those required for use of the Lokomat®. We suggest that the ARTIC network offers an opportunity to investigate the clinical application and effectiveness of rehabilitation technologies for various diagnoses. Due to the standardization of assessments and the use of a common technology, this network could serve as a basis for researchers interested in specific interventional studies expanding beyond the Lokomat®

BIFEST: A Built-in Intermediate Fault Effect Sensing and Test Generation System for Cmos Bridging Faults

[[abstract]]This paper presents BIFEST, an ATPG system that employs the built-in intermediate voltage test technique in an efficient ATPG process to deal with CMOS bridging faults. Fast and accurate calculations of the intermediate bridging voltages and the variant threshold tolerance margins on a resistive bridging fault model are presented. A PODEM-like, PPSFP-based ATPG process is developed to generate test patterns for faults that are conventionally logic-testable. The remaining faults are then dealt with by special circuits, called built-in intermediate voltage sensors (BIVSs). By this methodology, almost the same fault coverage as that employing IDOQ testing can be achieved with only logic monitoring required

An Interleaving Technique for Reducing Peak Power in Multiple-Chain Scan Circuits During Test Application

[[abstract]]This paper proposes a novel method to reduce the peak power of multiple scan chain based circuits during testing. The peak periodicity and the peak width of the power waveforms for scan-based circuits are analyzed. An interleaving scan architecture based on adding delay buffers among the scan chains is developed which can significantly reduce the peak power. This method can be efficiently integrated with a recently proposed broadcast multiple scan architecture due to the sharing of scan patterns. The effects of the interleaving scan technique applied to the conventional multiple scan and the broadcast multiple scan with 10 scan chains are investigated. Up to 51% peak power reduction can be achieved when the data output of a scan cell is affected by the scan path during scan. When the data output is disabled during scan, up to 76% of peak-power reduction is observed

Combination of Automatic Test Pattern Generation and Built-in Intermediate Voltage Sensing for Detecting CMOS Bridging Faults

[[abstract]]This paper presents the BIFEST, an ATPG system that combines the conventional ATPG process and the built-in intemediate voltage test technique to deal with CMOS bridging faults. A PODEM-like, PPSFP-based ATPG process that can effectively and efficiently model the bridging fault effects is developed to process those faults that are conventionally logic-testable. The remaining faults are then dealt with by special circuits called built-in intermediate voltage sensors. By this methodology almost the same fault coverage as that employing IDDQ testing can be achieved with only logic monitoring required

Peak-power Reduction for Multiple-scan Circuits During Test Application

[[abstract]]This paper proposes a novel method to reduce the peak power of multiple scan chain based circuits during testing. The peak periodicity and the peak width of the power waveforms for scan-based circuits are analyzed. An interleaving scan architecture based on adding delay buffers among the scan chains is proposed which can significantly reduce the peak power. This method can be efficiently employed in a recently proposed broadcast multiple scan architecture due to the sharing of scan patterns. The effects of the interleaving scan technique applied to the conventional multiple scan and the broadcast multiple scan with 10 scan chains are investigated. The improvement percentage can be up to 50% when the data output of a scan cell is affected by the scan path during scan. When the data output is disabled during scan, 76% of peak-power reduction can be achieved