SERPINB3 delays glomerulonephritis and attenuates the lupus-like disease in lupus murine models by inducing a more tolerogenic immune phenotype

Objective: To explore the effects of SERPINB3 administration in murine lupus models with a focus on lupus-like nephritis. Methods: 40 NZB/W F1 mice were subdivided into 4 groups and intraperitoneally injected with recombinant SERPINB3 (7.5 \u3bcg/0.1 mL or 15 \u3bcg/0.1 mL) or PBS (0.1 mL) before (group 1 and 2) or after (group 3 and 4) the development of proteinuria ( 65100 mg/dl). Two additional mice groups were provided by including 20 MRL/lpr mice which were prophylactically injected with SERPINB3 (10 mice, group 5) or PBS (10 mice, group 6). Time of occurrence and levels of anti-dsDNA and anti-C1q antibodies, proteinuria and serum creatinine, overall- and proteinuria-free survival were assessed in mice followed up to natural death. Histological analysis was performed in kidneys of both lupus models. The Th17:Treg cell ratio was assessed by flow-cytometry in splenocytes of treated and untreated MRL/lpr mice. Statistical analysis was performed using non parametric tests and Kaplan-Meier curves, when indicated. Results: Autoantibody levels and proteinuria were significantly decreased and time of occurrence significantly delayed in SERPINB3-treated mice vs. controls. In agreement with these findings, proteinuria-free and overall survival were significantly improved in SERPINB3-treated groups vs. controls. Histological analysis demonstrated a lower prevalence of severe tubular lesions in kidneys of group 5 vs. group 6. SERPINB3-treated mice showed an overall trend toward a reduced prevalence of severe lesions in both strains. Th17:Treg ratio was significantly decreased in splenocytes of MRL/lpr mice treated with SERPINB3, compared to untreated control mice. Conclusions: SERPINB3 significantly improves disease course and delays the onset of severe glomerulonephritis in lupus-prone mice, possibly inducing a more tolerogenic immune phenotype

Au(III)-Proline derivatives exhibiting selective antiproliferative activity against HepG2/SB3 apoptosis-resistant cancer cells

This paper deals with the combination of a proline-based moiety with biologically active gold centers in the oxidation states +1 and +3. In particular, six Au(i)/(iii)-proline dithiocarbamato (DTC) complexes with general formulae [AuI2(DTC)(2)] and [(AuX2)-X-III(DTC)] (X = Cl, Br) are reported here. After the synthesis of the ligand and the complexes, all derivatives were characterized via several techniques and tested for their stability in DMSO/water media. This study was focused on the demonstration of a peculiar behavior of Au(iii)-DTC species in solution. Finally, the complexes were screened for their antiproliferative activity against 2 human cancer cell lines, namely HepG2 and HepG2/SB3, taken as models of hepatocellular carcinoma. The latter, chosen for its aggressiveness due to the upregulation of the anti-apoptotic protein SerpinB3, was selectively inhibited in terms of growth by some Au(iii)-DTC complexes

GPU-based Real-time Triggering in the NA62 Experiment

Over the last few years the GPGPU (General-Purpose computing on Graphics Processing Units) paradigm represented a remarkable development in the world of computing. Computing for High-Energy Physics is no exception: several works have demonstrated the effectiveness of the integration of GPU-based systems in high level trigger of different experiments. On the other hand the use of GPUs in the low level trigger systems, characterized by stringent real-time constraints, such as tight time budget and high throughput, poses several challenges. In this paper we focus on the low level trigger in the CERN NA62 experiment, investigating the use of real-time computing on GPUs in this synchronous system. Our approach aimed at harvesting the GPU computing power to build in real-time refined physics-related trigger primitives for the RICH detector, as the the knowledge of Cerenkov rings parameters allows to build stringent conditions for data selection at trigger level. Latencies of all components of the trigger chain have been analyzed, pointing out that networking is the most critical one. To keep the latency of data transfer task under control, we devised NaNet, an FPGA-based PCIe Network Interface Card (NIC) with GPUDirect capabilities. For the processing task, we developed specific multiple ring trigger algorithms to leverage the parallel architecture of GPUs and increase the processing throughput to keep up with the high event rate. Results obtained during the first months of 2016 NA62 run are presented and discussed

Mutant p53 improves cancer cells\u2019 resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6

Missense mutations in the TP53 gene are frequent in human cancers, giving rise to mutant p53 proteins that can acquire oncogenic properties. Gain of function mutant p53 proteins can enhance tumour aggressiveness by promoting cell invasion, metastasis and chemoresistance. Accumulating evidences indicate that mutant p53 proteins can also modulate cell homeostatic processes, suggesting that missense p53 mutation may increase resistance of tumour cells to intrinsic and extrinsic cancer-related stress conditions, thus offering a selective advantage. Here we provide evidence that mutant p53 proteins can modulate the Unfolded Protein Response (UPR) to increase cell survival upon Endoplasmic Reticulum (ER) stress, a condition to which cancer cells are exposed during tumour formation and progression, as well as during therapy. Mechanistically, this action of mutant p53 is due to enhanced activation of the pro-survival UPR effector ATF6, coordinated with inhibition of the pro-apoptotic UPR effectors JNK and CHOP. In a triple-negative breast cancer cell model with missense TP53 mutation, we found that ATF6 activity is necessary for viability and invasion phenotypes. Together, these findings suggest that ATF6 inhibitors might be combined with mutant p53-targeting drugs to specifically sensitise cancer cells to endogenous or chemotherapy-induced ER stress

Detection of high levels of Survivin-immunoglobulin M immune complex in sera from hepatitis C virus infected patients with cirrhosis

The identification and surveillance of patients with liver dysfunctions and the discovering of new disease biomarkers are needed in the clinical practice. The aim of this study was to investigate on Survivin-immunoglobulin (Ig)M immune complex (IC) as a potential biomarker of chronic liver diseases.Serum levels of Survivin-IgM were measured using an enzyme-linked immunoassay that had been standardized and validated in our laboratory in 262 individuals, including healthy subjects and patients with chronic viral hepatitis, cirrhosis and hepatocellular carcinoma (HCC).Survivin-IgM IC was lower in healthy subjects (median, 99.39 AU/mL) than in patients with chronic viral hepatitis (median, 148.03 AU/mL; P = 0.002) or with cirrhosis (median, 371.00 AU/mL; P  0.001). Among patients with cirrhosis, those with hepatitis C virus (HCV) infection showed the highest level of Survivin-IgM IC (median, 633.71 AU/mL; P  0.001). The receiver-operator curve analysis revealed that Survivin-IgM accurately distinguishes HCV correlated cirrhosis from chronic viral hepatitis (area under the curve [AUC], 0.738; sensitivity, 74.5%; specificity, 70.7%). A multivariate logistic regression model, including Survivin-IgM IC, aspartate aminotransferase (AST) and AST/alanine aminotransferase (ALT) ratio increased the prediction accuracy for the identification of the cirrhotic HCV patients (AUC, 0.818; sensitivity, 87.2%; specificity, 65.9%). Conversely, Survivin-IgM IC significantly decreased in HCC patients (median, 165.72 AU/mL; P = 0.022).Our results suggest that Survivin-IgM immune complex may be used as a potential biomarker for liver damage, particularly for the identification of the HCV-related cirrhotic population

S7A:7 Administration of serpinb3 delays glomerulonephritis and attenuates the lupus-like disease in lupus murine models by an immunomodulatory effect

Background Abnormal apoptosis and clearance of cellular debris concur to development of systemic lupus erythematosus (SLE). SERPINS (serin-protease inhibitors) are ancient molecules regulating immune homeostasis. SERPINB3 modulates apoptosis and is hypoexpressed on SLE B cells. Aim To explore the effects of SERPINB3 administration in murine lupus models, focusing on glomerulonephritis. Methods NZB/W F1 and MRL/lpr mice were used. 40 NZB/W F1 mice were divided into 4 groups of 10 mice each and intraperitoneally injected twice a week starting before occurrence of proteinuria traces (group 1 and 2, prophylactic approach) or after development of proteinuria 30 mg/dl (group 3 and 4, therapeutic approach) with hrSERPINB3 (7.5 µg/0.1 mL prophylactic approach, or 15 µg/0.1 mL therapeutic approach) or PBS (0.1 mL). 20 MRL/lpr mice were injected with hrSERPINB3 (group 5, n=10) or PBS (group 6, n=10) with a prophylactic approach. We assessed time of occurrence and titers of anti-dsDNA and anti-C1q antibodies by ELISA; proteinuria and serum creatinine; overall- and proteinuria-free survival. Six NZB/W F1 mice were sacrificed at week 27, while 10 MRL/lpr mice at week 13 and another 10 at 16/18 weeks for histological kidneys comparison. Flow-cytometry was performed on MRL/lpr splenocytes. Non parametric tests were performed for statistics; proteinuria-free ( Results Levels of autoantibodies were significantly decreased and delayed in group 1 vs group 2, group 3 vs group 4, and group 5 vs group 6 (p Conclusions Administration of SERPINB3 significantly improves disease and delays the onset of severe glomerulonephritis in lupus-prone mice. SERPINB3 may influence immune-cell function through immunoregulatory effects involving promotion of Treg

Fast algorithm for real-time rings reconstruction

The GAP project is dedicated to study the application of GPU in several contexts in which real-time response is important to take decisions. The definition of real-time depends on the application under study, ranging from answer time of μs up to several hours in case of very computing intensive task. During this conference we presented our work in low level triggers [1] [2] and high level triggers [3] in high energy physics experiments, and specific application for nuclear magnetic resonance (NMR) [4] [5] and cone-beam CT [6]. Apart from the study of dedicated solution to decrease the latency due to data transport and preparation, the computing algorithms play an essential role in any GPU application. In this contribution, we show an original algorithm developed for triggers application, to accelerate the ring reconstruction in RICH detector when it is not possible to have seeds for reconstruction from external trackers

Search for π⁰ decays to invisible particles

The NA62 experiment at the CERN SPS reports a study of a sample of 4 × 109 tagged π0 mesons from K+ → π+π0(γ), searching for the decay of the π0 to invisible particles. No signal is observed in excess of the expected background fluctuations. An upper limit of 4.4 × 10−9 is set on the branching ratio at 90% confidence level, improving on previous results by a factor of 60. This result can also be interpreted as a model- independent upper limit on the branching ratio for the decay K+ → π+X, where X is a particle escaping detection with mass in the range 0.110–0.155 GeV/c2 and rest lifetime greater than 100 ps. Model-dependent upper limits are obtained assuming X to be an axion-like particle with dominant fermion couplings or a dark scalar mixing with the Standard Model Higgs boson