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

NaNet: a Low-Latency, Real-Time, Multi-Standard Network Interface Card with GPUDirect Features

While the GPGPU paradigm is widely recognized as an effective approach to high performance computing, its adoption in low-latency, real-time systems is still in its early stages. Although GPUs typically show deterministic behaviour in terms of latency in executing computational kernels as soon as data is available in their internal memories, assessment of real-time features of a standard GPGPU system needs careful characterization of all subsystems along data stream path. The networking subsystem results in being the most critical one in terms of absolute value and fluctuations of its response latency. Our envisioned solution to this issue is NaNet, a FPGA-based PCIe Network Interface Card (NIC) design featuring a configurable and extensible set of network channels with direct access through GPUDirect to NVIDIA Fermi/Kepler GPU memories. NaNet design currently supports both standard - GbE (1000BASE-T) and 10GbE (10Base-R) - and custom - 34~Gbps APElink and 2.5~Gbps deterministic latency KM3link - channels, but its modularity allows for a straightforward inclusion of other link technologies. To avoid host OS intervention on data stream and remove a possible source of jitter, the design includes a network/transport layer offload module with cycle-accurate, upper-bound latency, supporting UDP, KM3link Time Division Multiplexing and APElink protocols. After NaNet architecture description and its latency/bandwidth characterization for all supported links, two real world use cases will be presented: the GPU-based low level trigger for the RICH detector in the NA62 experiment at CERN and the on-/off-shore data link for KM3 underwater neutrino telescope

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

Progress report on the online processing upgrade at the NA62 experiment

A new FPGA-based low-level trigger processor has been installed at the NA62 experiment. It is intended to extend the features of its predecessor due to a faster interconnection technology and additional logic resources available on the new platform. With the aim of improving trigger selectivity and exploring new architectures for complex trigger computation, a GPU system has been developed and a neural network on FPGA is in progress. They both process data streams from the ring imaging Cherenkov detector of the experiment to extract in real time high level features for the trigger logic. Description of the systems, latest developments and design flows are reported in this paper

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

Genetic and epigenetic characteristics of human multiple hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Multiple carcinogenesis is one of the major characteristics of human hepatocellular carcinoma (HCC). The history of multiple tumors, that is, whether they derive from a common precancerous or cancerous ancestor or individually from hepatocytes, is a major clinical issue. Multiple HCC is clinically classified as either intratumor metastasis (IM) or multicentric carcinogenesis (MC). Molecular markers that differentiate IM and MC are of interest to clinical practitioners because the clinical diagnoses of IM and MC often lead to different therapies.</p> <p>Methods</p> <p>We analyzed 30 multiple tumors from 15 patients for somatic mutations of cancer-related genes, chromosomal aberrations, and promoter methylation of tumor suppressor genes using techniques such as high-resolution melting, array-comparative genomic hybridization (CGH), and quantitative methylation-specific PCR.</p> <p>Results</p> <p>Somatic mutations were found in <it>TP53 </it>and <it>CTNNB1 </it>but not in <it>CDKN2A </it>or <it>KRAS</it>. Tumors from the same patient did not share the same mutations. Array-CGH analysis revealed variations in the number of chromosomal aberrations, and the detection of common aberrations in tumors from the same patient was found to depend on the total number of chromosomal aberrations. A promoter methylation analysis of genes revealed dense methylation in HCC but not in the adjacent non-tumor tissue. The correlation coefficients (<it>r</it>) of methylation patterns between tumors from the same patient were more similar than those between tumors from different patients. In total, 47% of tumor samples from the same patients had an <it>r </it>≥ 0.8, whereas, in contrast, only 18% of tumor samples from different patients had an <it>r </it>≥ 0.8 (p = 0.01). All IM cases were highly similar; that is, <it>r </it>≥ 0.8 (<it>p </it>= 0.025).</p> <p>Conclusions</p> <p>The overall scarcity of common somatic mutations and chromosomal aberrations suggests that biological IM is likely to be rare. Tumors from the same patient had a methylation pattern that was more similar than those from different patients. As all clinical IM cases exhibited high similarity, the methylation pattern may be applicable to support the clinical diagnosis of IM and MC.</p