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A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins was formulated by recapitulating key biological mechanisms, including antigen presentation, activation, proliferation, and differentiation of immune cells, secretion of antidrug antibodies (ADA), as well as in vivo disposition of ADA and therapeutic proteins. This system‐level model contains three scales: a subcellular level representing antigen presentation processes by dendritic cells; a cellular level accounting for cell kinetics during humoral immune response; and a whole‐body level accounting for therapeutic protein in vivo disposition. The model simulations for in vivo responses against antigenic protein challenge are consistent with many known immunological observations. By simulating immune responses under various initial parameter conditions, the model suggests hypotheses for future experimental investigation and contributes to the mechanistic understanding of immunogenicity. With future experimental validation, this model may potentially provide a platform to generate and test hypotheses about immunogenicity risk assessment and ultimately aid in immunogenicity prediction. CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e133; doi:10.1038/psp.2014.30; published online 03 September 2014

Erectile dysfunction (ED), the second most common male sexual disorder, has an important impact on man sexuality and quality of life affecting also female partner’s sexual life. ED is usually related to cardiovascular disease or is an iatrogenic cause of pelvic surgery. Many non-surgical treatments have been developed with results that are controversial, while surgical treatment has reached high levels of satisfaction. The aim is to evaluate outcomes and complications related to prosthesis implant in patients suffering from ED not responding to conventional medical therapy or reporting side effects with such a therapy. One hundred eighty Caucasian male suffering from ED were selected. The patient population were divided into two groups: 84 patients with diabetes and metabolic syndrome (group A) and 96 patients with dysfunction following laparoscopic radical prostatectomy for prostate cancer (group B). All subjects underwent primary inflatable penile prosthesis implant with an infrapubic minimally invasive approach. During 12 months of follow-up, we reported 3 (1.67%) explants for infection, 1 (0.56%) urethral erosion, 1 (0.56%) prosthesis extrusion while no intraoperative complications were reported. Mean International Index of Erectile Function-5 (IIEF-5) was 8.2±4.0 and after the surgery (12 months later) was 20.6±2.7. The improvement after the implant is significant in both groups without a statistically significant difference between the two groups ( P -value 0.65). Mean Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) score 1 year after the implant is 72.2±20.7, and there was no statistically significant difference between groups A and B ( P -value 0.55). Implantation of an inflatable prosthesis, for treatment of ED, is a safe and efficacious approach; and the patient and partner satisfaction is very high. Surgical technique should be minimally invasive and latest technology equipment should be implanted in order to decrease after surgery common complications (infection and mechanical failure).

A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins was built by recapitulating key underlying known biological processes for immunogenicity. The model is able to simulate immune responses based on protein‐specific antigenic properties (e.g., number of T‐epitopes and their major histocompatibility complex (MHC)‐II binding affinities) and host‐specific immunological/physiological characteristics (e.g., MHC‐II allele genotype, drug clearance rate). Preliminary validation was performed using mouse studies with antigens such as ovalbumin (OVA) or OVA‐derived peptide. Further, using adalimumab as an example therapeutic protein, the model is able to simulate immune responses against adalimumab in individual subjects and in a population, and also provides estimations of immunogenicity incidence and drug exposure reduction that can be validated experimentally. This is a first attempt at modeling immunogenicity of biologics, so the model simulations should be used to help understand the immunogenicity mechanisms and impacting factors, rather than making direct predictions. This prototype model needs to be subjected to extensive experimental validation and refinement before fulfilling its ultimate mission of predicting immunogenicity. Nevertheless, the current model could potentially set up the starting framework to integrate various in silico, in vitro, in vivo, and clinical immunogenicity assessment results to help meet the challenge of immunogenicity prediction. CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e134; doi:10.1038/psp.2014.31; published online 03 September 2014

We present the use of a modified corporoplasty, based on geometrical principles, to determine the exact site for the incision in the tunica or plaque and the exact amount of albuginea for overlaying to correct with extreme precision the different types of congenital or acquired penile curvature due to Peyronie’s disease. To describe our experience with a new surgical procedure for the enhancement of penile curvature avoiding any overcorrection or undercorrection. Between March 2004 and April 2013, a total of 74 patients underwent the geometrical modified corporoplasty. All patients had congenital curvature until 90° or acquired stable penile curvature ‘less’ than 60°, that made sexual intercourse very difficult or impossible, normal erectile function, absence of hourglass or hinge effect. Preoperative testing included a physical examination, 3 photographs (frontal, dorsal and lateral) of penis during erection, a 10 mcg PGE1-induced erection and Doppler ultrasound, administration of the International Index of Erectile Function (IIEF-15) questionnaire. A follow-up with postoperative evaluation at 12 weeks, 12 and 24 months, included the same preoperative testing. Satisfaction rates were better assessed with the use of validated questionnaire such as the International Erectile Dysfunction Inventory of the Treatment Satisfaction (EDITS). Statistical analysis with Student’s t -test was performed using commercially available, personal computer software. A total of 25 patients had congenital penile curvature with a mean deviation of 46.8° (range 40–90), another 49 patients had Peyronie’s disease with a mean deviation of 58.4 (range 45–60). No major complications were reported. Postoperative correction of the curvature was achieved in all patients (100%). Neither undercorrection nor overcorrection were recorded. No significant relapse (curvature>15°) occurred in our patients. Shortening of the penis was reported by 74% but did not influence the high overall satisfaction of 92% (patients completely satisfied with their sexual life). The erectile function was analyzed in both groups, Student’s t -test showed a significant improvement in erectile function, preoperative average IIEF-15 scores were 17.43±4.67, whereas postoperatively it was 22.57±4.83 ( P =0.001). This geometrical modified Nesbit corporoplasty is a valid therapy which allows penile straightening. The geometric principles make the technique reproducible in multicentre studies.

The use of GPUs to implement general purpose computational tasks, known as GPGPU since fifteen years ago, has reached maturity. Applications take advantage of the parallel architectures of these devices in many different domains. Over the last few years several works have demonstrated the effectiveness of the integration of GPU-based systems in the high level trigger of various HEP experiments. On the other hand, the use of GPUs in the DAQ and low level trigger systems, characterized by stringent real-time constraints, poses several challenges. In order to achieve such a goal we devised NaNet, a FPGA-based PCI-Express Network Interface Card design capable of direct (zero-copy) data transferring with CPU and GPU (GPUDirect) while online processing incoming and outgoing data streams. The board provides as well support for multiple link technologies (1/10/40GbE and custom ones). The validity of our approach has been tested in the context of the NA62 CERN experiment, harvesting the computing power of last generation NVIDIA Pascal GPUs and of the FPGA hosted by NaNet to build in real-time refined physics-related primitives for the RICH detector (i.e. the Cerenkov rings parameters) that enable the building of more stringent conditions for data selection in the low level trigger.

The NEMO Phase-2 tower is the first detector which was operated underwater for more than 1 year at the “record” depth of 3500 m. It was designed and built within the framework of the NEMO (NEutrino Mediterranean Observatory) project. The 380 m high tower was successfully installed in March 2013 80 km offshore Capo Passero (Italy). This is the first prototype operated on the site where the Italian node of the KM3NeT neutrino telescope will be built. The installation and operation of the NEMO Phase-2 tower has proven the functionality of the infrastructure and the operability at 3500 m depth. A more than 1 year long monitoring of the deep water characteristics of the site has been also provided. In this paper the infrastructure and the tower structure and instrumentation are described. The results of long term optical background measurements are presented. The rates show stable and low baseline values, compatible with the contribution of 40 K light emission, with a small percentage of light bursts due to bioluminescence. All these features confirm the stability and good optical properties of the site.

In the attempt to develop an interconnection architecture optimized for hybrid HPC systems dedicated to scientific computing, we designed APEnet+, a point-to-point, low-latency and high-performance network controller supporting 6 fully bidirectional off-board links over a 3D torus topology. The first release of APEnet+ (named V4) was a board based on a 40 nm Altera FPGA, integrating 6 channels at 34 Gbps of raw bandwidth per direction and a PCIe Gen2 x8 host interface. It has been the first-of-its-kind device to implement an RDMA protocol to directly read write data from to Fermi and Kepler NVIDIA GPUs using NVIDIA peer-to-peer and GPUDirect RDMA protocols, obtaining real zero-copy GPU-to-GPU transfers over the network. The latest generation of APEnet+ systems (now named V5) implements a PCIe Gen3 x8 host interface on a 28 nm Altera Stratix V FPGA, with multi-standard fast transceivers (up to 14.4 Gbps) and an increased amount of configurable internal resources and hardware IP cores to support main interconnection standard protocols. Herein we present the APEnet+ V5 architecture, the status of its hardware and its system software design. Both its Linux Device Driver and the low-level libraries have been redeveloped to support the PCIe Gen3 protocol, introducing optimizations and solutions based on hardware software co-design.

In the supercomputing arena, the strong rise of GPU-accelerated clusters is a matter of fact. Within INFN, we proposed an initiative — the QUonG project — whose aim is to deploy a high performance computing system dedicated to scientific computations leveraging on commodity multi-core processors coupled with latest generation GPUs. The inter-node interconnection system is based on a point-to-point, high performance, low latency 3D torus network which is built in the framework of the APEnet+ project. It takes the form of an FPGA-based PCIe network card exposing six full bidirectional links running at 34 Gbps each that implements the RDMA protocol. In order to enable significant access latency reduction for inter-node data transfer, a direct network-to-GPU interface was built. The specialized hardware blocks, integrated in the APEnet+ board, provide support for GPU-initiated communications using the so called PCIe peer-to-peer (P2P) transactions. This development is made in close collaboration with the GPU vendor NVIDIA. The final shape of a complete QUonG deployment is an assembly of standard 42U racks, each one capable of 80 TFLOPS/rack of peak performance, at a cost of 5 k€/T F LOPS and for an estimated power consumption of 25 kW/rack. In this paper we report on the status of final rack deployment and on the R&D activities for 2012 that will focus on performance enhancement of the APEnet+ hardware through the adoption of new generation 28 nm FPGAs allowing the implementation of PCIe Gen3 host interface and the addition of new fault tolerance-oriented capabilities.

With processor architecture evolution, the HPC market has undergone a paradigm shift. The adoption of low-cost, Linux-based clusters extended the reach of HPC from its roots in modelling and simulation of complex physical systems to a broader range of industries, from biotechnology, cloud computing, computer analytics and big data challenges to manufacturing sectors. In this perspective, the near future HPC systems can be envisioned as composed of millions of low-power computing cores, densely packed - meaning cooling by appropriate technology - with a tightly interconnected, low latency and high performance network and equipped with a distributed storage architecture. Each of these features - dense packing, distributed storage and high performance interconnect - represents a challenge, made all the harder by the need to solve them at the same time. These challenges lie as stumbling blocks along the road towards Exascale-class systems; the ExaNeSt project acknowledges them and tasks itself with investigating ways around them.

Mouse cancer models have provided critical insights into tumor biology; however, clinical translation of these findings has been challenging. This perspective posits that factors impacting on successful translation start with limitations in capturing human cancer pathophysiology and end with challenges in generating robust translatable preclinical end points. A comprehensive approach that considers clinically relevant mouse models with both an integrated biomarker strategy and a complementary modeling and simulation effort will strengthen the current oncology drug development paradigm. CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e128; doi:10.1038/psp.2014.28; published online 06 August 2014