SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities

Myeloid-derived suppressor cells (MDSC) are well-known key negative regulators of the immune response during tumor growth, however scattered is the knowledge of their capacity to influence and adapt to the different tumor microenvironments and of the markers that identify those capacities. Here we show that the secreted protein acidic and rich in cysteine (SPARC) identifies in both human and mouse MDSC with immune suppressive capacity and pro-tumoral activities including the induction of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In mice the genetic deletion of SPARC reduced MDSC immune suppression and reverted EMT. Sparc−/− MDSC were less suppressive overall and the granulocytic fraction was more prone to extrude neutrophil extracellular traps (NET). Surprisingly, arginase-I and NOS2, whose expression can be controlled by STAT3, were not down-regulated in Sparc−/− MDSC, although less suppressive than wild type (WT) counterpart. Flow cytometry analysis showed equal phosphorylation of STAT3 but reduced ROS production that was associated with reduced nuclear translocation of the NF-kB p50 subunit in Sparc−/− than WT MDSC. The limited p50 in nuclei reduce the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers. Supporting this hypothesis, the production of TNF by Sparc−/− MDSC was significantly higher than by WT MDSC. Although associated with tumor-induced chronic inflammation, TNF, if produced at high doses, becomes a key factor in mediating tumor rejection. Therefore, it is foreseeable that an unbalance in TNF production could skew MDSC toward an inflammatory, anti-tumor phenotype. Notably, TNF is also required for inflammation-driven NETosis. The high level of TNF in Sparc−/− MDSC might explain their increased spontaneous NET formation as that we detected both in vitro and in vivo, in association with signs of endothelial damage. We propose SPARC as a new potential marker of MDSC, in both human and mouse, with the additional feature of controlling MDSC suppressive activity while preventing an excessive inflammatory state through the control of NF-kB signaling pathway

Full Speed String Test On LM6000PF Gas Turbine Driven Refrigeration Compressors

LectureChevron Australia, as part of the Wheatstone Project, constructed a two train liquefied natural gas (LNG) facility and domestic gas plant at the Ashburton North Strategic Industrial Area, 12 kilometers west of Onslow on the Pilbara coast of Western Australia. A driver selection study was performed based on the ConocoPhillips Optimized Cascade® natural gas liquefaction process. Details of this driver selection study are covered by Shah et al [1]. This driver study evaluated a variety of project-specific parameters and resulted in the selection of a General Electric LM6000 PF aeroderivative gas turbine. The final decision to use the LM6000 engine was based on a detailed technology qualification program. Following the completion of the technology qualification, a detailed risk mitigation plan was developed. The plan was incorporated into the purchase order of the equipment and, subsequently, incorporated into the equipment manufacturer’s Failure Mode Effects Analysis (FMEA) process. The risk mitigation plan highlighted extensive testing requirements during the full-load, full-speed (FLFS) string test. This paper covers the details of the FLFS testing that was performed in the fourth quarter of 2013

SPARC is a new myeloid-derived suppressor cell marker licensing suppressive activities

Myeloid-derived suppressor cells (MDSC) are well-known key negative regulators of the immune response during tumor growth, however scattered is the knowledge of their capacity to influence and adapt to the different tumor microenvironments and of the markers that identify those capacities. Here we show that the secreted protein acidic and rich in cysteine (SPARC) identifies in both human and mouse MDSC with immune suppressive capacity and pro-tumoral activities including the induction of epithelial-to-mesenchymal transition (EMT) and angiogenesis. In mice the genetic deletion of SPARC reduced MDSC immune suppression and reverted EMT. Sparc-/- MDSC were less suppressive overall and the granulocytic fraction was more prone to extrude neutrophil extracellular traps (NET). Surprisingly, arginase-I and NOS2, whose expression can be controlled by STAT3, were not down-regulated in Sparc-/- MDSC, although less suppressive than wild type (WT) counterpart. Flow cytometry analysis showed equal phosphorylation of STAT3 but reduced ROS production that was associated with reduced nuclear translocation of the NF-kB p50 subunit in Sparc-/- than WT MDSC. The limited p50 in nuclei reduce the formation of the immunosuppressive p50:p50 homodimers in favor of the p65:p50 inflammatory heterodimers. Supporting this hypothesis, the production of TNF by Sparc-/- MDSC was significantly higher than by WT MDSC. Although associated with tumor-induced chronic inflammation, TNF, if produced at high doses, becomes a key factor in mediating tumor rejection. Therefore, it is foreseeable that an unbalance in TNF production could skew MDSC toward an inflammatory, anti-tumor phenotype. Notably, TNF is also required for inflammation-driven NETosis. The high level of TNF in Sparc-/- MDSC might explain their increased spontaneous NET formation as that we detected both in vitro and in vivo, in association with signs of endothelial damage. We propose SPARC as a new potential marker of MDSC, in both human and mouse, with the additional feature of controlling MDSC suppressive activity while preventing an excessive inflammatory state through the control of NF-kB signaling pathway

Ultraviolet-Optical observations of the Seyfert 2 Galaxies NGC 7130, NGC 5135 and IC 3639: Implications for the Starburst-AGN Connection

We present and discuss HST (WFPC2 and FOC) images and UV GHRS spectra plus ground-based near UV through to near IR spectra of three Seyfert 2 nuclei (NGC 7130, NGC 5135 and IC 3639). These galaxies, together to Mrk 477, were selected from a bigger sample that comprises the 20 brightest Seyfert 2 nuclei, with the goal to study the origin of the UV-optical-near IR featureless continuum in Seyfert 2 nuclei. These four galaxies have bolometric luminosities, as computed with the four IRAS bands, of 10^11 Lsol. They are close enough to be resolved with HST the nuclear zone. This makes these Seyfert 2 galaxies benchmarks to study the Starburst-AGN connection in more distant galaxies. The data provide direct evidence of the existence of a central nuclear starburst that dominates the UV light, and that seem to be responsible for the origin of the so called featureless continuum. These starbursts are dusty and compact. They have sizes (from less than 100 pc to a few hundred pc) much smaller and closer to the nucleus than that seen in the prototype Seyfert 2 galaxy NGC 1068. The bolometric luminosity of these starbursts is similar to the estimated bolometric luminosities of their obscured Seyfert 1 nuclei, and thus they contribute in the same amount to the overall energetics of these galaxies.Comment: to be published in ApJ 505, September issue. The figures are in a tar files at: http://www.iaa.es/~rosa/Seyfert

CD40 provides immune privilege to the bone marrow hematopoietic niche

Allogeneic bone marrow transplantation remains the only therapeutic option for a wide range of hematological malignancies despite the risk of possible adverse, immune-related events, such as infection and acute graft-versus-host disease (aGVHD). aGVHD is characterized by T-cell activation, defective B-cell development and osteoblastic niche destruction in bone marrow (BM) among other issues. Transplant conditioning regimens cause excessive inflammatory cytokines production and impaired regulatory T-cell control of aberrant T-cell activation. Here, we show that mesenchymal cells (MSCs) upregulated CD40 upon irradiation at the expense of mesenchymal markers, and that CD40 endows MSC of regulatory function on Treg homeostasis and fitness. Transplantation of wild type hematopoietic cells into a CD40-null recipient reduces Treg numbers allowing persistent T-cell activation and pro-inflammatory cytokines production causing, impaired B-lymphopoiesis. These evidences find correlation in aGVHD patients showing the loss of CD40+ BM-MSCs along with reduction in cells of the B-lineage. Modeling aGVHD in mice we show that the elimination of CD40+ BM-MSCs relies on their higher expression of MHC-I molecules. Indeed, aGVHD mice compared to MHC-matched controls showed the loss of MHC-I + radio-resistant host BM-MSCs. Our data point to CD40+ MHC-I+BM-MSCs as a key regulator of BM tolerogenic niches

How do cardiologists select patients for dual antiplatelet therapy continuation beyond 1 year after a myocardial infarction? Insights from the EYESHOT Post-MI Study

Background: Current guidelines suggest to consider dual antiplatelet therapy (DAPT) continuation for longer than 12 months in selected patients with myocardial infarction (MI). Hypothesis: We sought to assess the criteria used by cardiologists in daily practice to select patients with a history of MI eligible for DAPT continuation beyond 1 year. Methods: We analyzed data from the EYESHOT Post-MI, a prospective, observational, nationwide study aimed to evaluate the management of patients presenting to cardiologists 1 to 3 years from the last MI event. Results: Out of the 1633 post-MI patients enrolled in the study between March and December 2017, 557 (34.1%) were on DAPT at the time of enrolment, and 450 (27.6%) were prescribed DAPT after cardiologist assessment. At multivariate analyses, a percutaneous coronary intervention (PCI) with multiple stents and the presence of peripheral artery disease (PAD) resulted as independent predictors of DAPT continuation, while atrial fibrillation was the only independent predictor of DAPT interruption for patients both at the second and the third year from MI at enrolment and the time of discharge/end of the visit. Conclusions: Risk scores recommended by current guidelines for guiding decisions on DAPT duration are underused and misused in clinical practice. A PCI with multiple stents and a history of PAD resulted as the clinical variables more frequently associated with DAPT continuation beyond 1 year from the index MI

Methodologies for assessing the quality of 3D models obtained using close-range photogrammetry

Although reality-based models are widely used to describe the geometric surfaces of an entity in a digital space, a systematic and universally recognised treatment of issues such as accuracy is lacking. The topic is certainly complex as this analysis should involve not only shape approximation but also other attributes (e.g., colour). Wanting to limit ourselves to geometry alone, this work proposes solutions for assessing the quality of photogrammetric models, differentiating them according to possible scenarios: sometimes, homologous models obtained using different techniques and technologies are available. In these cases, a comparison between digital reconstructions can serve to effectively quantify accuracy; more often, no terms of comparison are available, and one is forced to derive indicators from the same photogrammetric process to describe quality. We propose for this scenario a statistical analysis on the covariance matrix of the estimated coordinates for the tie points. The main goal is to provide a range of possible approaches to the conscious management of survey data

A Methodological Proposal for the Comparison of 3D Photogrammetric Models

The field of simplification of geometric surfaces still lacks a formal and universally recognized definition of the error, which should involve both the approximation of the shape and the conservation of the other attributes of the mesh (starting from the colour). In order to solve this problem, we propose a hypothesis of methodological comparison that allow the evaluation of differences between two homologous surfaces, quantified employing the Hausdorff distance. The main advantage of this method is the independence from sampling techniques used to produce the mesh, without losing its characteristics of objectivity and generality. The Hausdorff distance geometrically represents the distance between two sets A and B in a suitable metric space, and it is defined as the maximum between the excess of A over B and the excess of B over A. This value is then compared with the average length of the diagonals of the “bounding boxes” of the homologous models, i.e. the parallelepipeds corresponding to the minimum volume that completely envelops each set; this results in an effective representation of error in relative terms