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

Benchmarking the SPARC software program for estimating solubilities of naphthalene and anthracene in organic solvents

The SPARC software program was benchmarked for calculating the solubilities of two representative polyaromatic hydrocarbons (PAHs), naphthalene and anthracene, in a range of organic solvents at various temperatures. Although SPARC was able to reasonably approximate the solubilities of naphthalene in some organic solvents, gross errors were obtained for other solvents. For anthracene, poor prediction performance was observed in all solvents considered. Overall, the results suggest that SPARC is currently not suitable for accurately predicting the solubilities of representative PAHs relevant for the petroleum sector in various organic solvents

A Denotational Semantics for SPARC TSO

The SPARC TSO weak memory model is defined axiomatically, with a non-compositional formulation that makes modular reasoning about programs difficult. Our denotational approach uses pomsets to provide a compositional semantics capturing exactly the behaviours permitted by SPARC TSO. It uses buffered states and an inductive definition of execution to assign an input-output meaning to pomsets. We show that our denotational account is sound and complete relative to the axiomatic account, that is, that it captures exactly the behaviours permitted by the axiomatic account. Our compositional approach facilitates the study of SPARC TSO and supports modular analysis of program behaviour

Overexpression of SPARC obliterates the in vivo tumorigenicity of human hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide. Current treatments are extremely disappointing. SPARC (Secreted protein, acidic and rich in cysteine) is a matricellular glycoprotein with differential expression in several tumors, including HCC, which significance remains unclear. We infected HCC cells (HepG2, Hep3B and Huh7) with an adenovirus expressing SPARC (AdsSPARC) to examine the role of SPARC expression on HCC cells and its effect on tumor aggressiveness. The in vitro HCC cells substrate-dependent proliferation and cell cycle profile were unaffected; however, SPARC overexpression reduced HCC proliferation when cells were grown in spheroids. A mild induction of cellular apoptosis was observed upon SPARC overexpression. SPARC overexpression resulted in spheroid growth inhibition in vitro while no effects were found when recombinant SPARC was exogenously applied. Moreover, the clonogenic and migratory capabilities were largely decreased in SPARC-overexpressing HCC cells, altogether suggesting a less aggressive HCC cell phenotype. Consistently, AdsSPARC-transduced cells showed increased E-cadherin expression and a concomitant decrease in N-cadherin expression. Furthermore, SPARC overexpression was found to reduce HCC cell viability in response to 5-FU-based chemotherapy in vitro, partially through induction of apoptosis. In vivo experiments revealed that SPARC overexpression in HCC cells inhibited their tumorigenic capacity and increased animal survival through a mechanism that partially involves host macrophages. Our data suggest that SPARC overexpression in HCC cells results in a reduced tumorigenicity partially through the induction of mesenchymal-to-epithelial transition (MET). These evidences point to SPARC as a novel target for HCC treatment.Fil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bolontrade, Marcela Fabiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Rizzo, Manglio Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Operative complications and results of the "SPARC" procedure for stress urinary incontinence [Operativne komplikacije i ishod metode SPARC u liječenju statičke inkontinencije mokraće]

The aim of this study was to determine the efficacy and operative complications of the suprapubic arc (SPARC) procedure in stress incontinent women with and without previous anti-incontinence surgery. One-hundred and twenty-one patients with stress urinary incontinence (SUI) were treated with SPARC for correction of urethral hypermobility (N = 65) and intrinsic sphincter deficiency (N = 56) between August 2002 and February 2007. The long-term surgical results, operative complications (bladder injury, retropubic hematoma, de novo urgency and urinary infection) and patients' satisfaction were assessed. The overall complication rate was 9.9% (12/121). The perioperative complication rate was 1.7% including 2 urinary bladder injuries. Significant difference in the overall complications rate was detected between women with and without previous surgery (23/45, 51.1% vs. 6/108, 5.5%, chi2 = 49.89, P < 0.001). The overall postoperative complication rate was 8.3% (10/121) including 4 de novo urgencies, 4 urinary infections and 2 retropubic hematomas. There were 3 patients with postoperative urinary retention managed conservatively, without voiding difficulties on control visits. The objective cure rate after the follow-up was 86.8% (105/121). In patients with SUI and without preceding vaginal operations SPARC is a good method with low incidence of perioperative complications, promising long-term results and high patient satisfaction

Sparse Regression Codes for Multi-terminal Source and Channel Coding

We study a new class of codes for Gaussian multi-terminal source and channel coding. These codes are designed using the statistical framework of high-dimensional linear regression and are called Sparse Superposition or Sparse Regression codes. Codewords are linear combinations of subsets of columns of a design matrix. These codes were recently introduced by Barron and Joseph and shown to achieve the channel capacity of AWGN channels with computationally feasible decoding. They have also recently been shown to achieve the optimal rate-distortion function for Gaussian sources. In this paper, we demonstrate how to implement random binning and superposition coding using sparse regression codes. In particular, with minimum-distance encoding/decoding it is shown that sparse regression codes attain the optimal information-theoretic limits for a variety of multi-terminal source and channel coding problems.Comment: 9 pages, appeared in the Proceedings of the 50th Annual Allerton Conference on Communication, Control, and Computing - 201

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