Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.     

Direct-Ink-Writing of Electroactive Polymers for Sensing and Energy Storage Applications

Considering the high levels of materials used in the fields of electronics and energy storage systems, it is increasingly necessary to take into consideration environmental impact. Thus, it is important to develop devices based on environmentally friendlier materials and/or processes, such as additive manufacturing techniques. In this work, poly(vinylidene fluoride) (PVDF) and poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) are prepared by direct-ink-writing (DIW) by varying solvent evaporation temperature and fill density percentage. Different morphologies for both polymers are obtained, including dense films and porous membranes, as well as different electroactive β-phase content, thermal and mechanical properties. The dielectric constant and piezoelectric d₃₃ coefficient for dense films reaches up to 16 at 1 kHz and 4 pC N⁻¹, respectively for PVDF-HFP with a fill density of 80 and a solvent evaporation temperature of 50 °C. Porous structures are developed for battery separator membranes in lithium-ion batteries, with a highest ionic conductivity value of 3.8 mS cm⁻¹ for the PVDF-HFP sample prepared with a fill density of 100 and a solvent evaporation temperature of 25 °C, the sample showing an excellent cycling performance. It is demonstrated that electroactive films and membranes can be prepared by direct-ink writing suitable for sensors/actuators and energy storage systems.     

A Methionine Chemical Shift Based Order Parameter Characterizing Global Protein Dynamics

Coupling of side chain dynamics over long distances is an important component of allostery. Methionine side chains show the largest intrinsic flexibility among methyl-containing residues but the actual degree of conformational averaging depends on the proximity and mobility of neighboring residues. The ¹³C NMR chemical shifts of the methyl groups of methionine residues located at long distances in the same protein show a similar scaling with respect to the values predicted from the static X-ray structure by quantum methods. This results in a good linear correlation between calculated and observed chemical shifts. The slope is protein dependent and ranges from zero for the highly flexible calmodulin to 0.7 for the much more rigid calcineurin catalytic domain. The linear correlation is indicative of a similar level of side-chain conformational averaging over long distances, and the slope of the correlation line can be interpreted as an order parameter of the global side-chain flexibility.     

Nitrogen dynamics during till and no-till pasture restoration sequences in Rondônia,Brazil

The clearing of tropical rain forest in the Amazon basin has created large areas of cattle pasture that are now declining in productivity. Practices adopted by ranchers to restore productivity to degraded pastures have the potential to alter soil N availability and gaseous N losses from soils. We examined how soil inorganic N pools, net N mineralization and net nitrification rates, nitrification potential and NO and N₂O emissions from soils of a degraded pasture responded to the following restoration treatments: (1) soil tillage followed by replanting of grass and fertilization, (2) no-till application of non-selective herbicide, planting of rice, harvest followed by no-till replanting of grass and fertilization, and (3) the same no-till sequence with soybeans instead of rice. Tillage increased soil NH₄⁺ and NO₃^? pools but NH₄⁺ and NO₃^? pools remained relatively constant in the control and no-till treatments. Cumulative rates of net N mineralization and net nitrification during the first 6 months after treatment varied widely but were hightest in the tilled treatment. Emissions of NO and N₂O fluxes increased with tillage and with N fertilization. There were no clear relationships among rates of N fertilizer application, net N mineralization, net nitrification, NO, N₂O and total N oxide emissions. Our results indicate that pasture restoration sequences involving tilling and fertilizing will increase emissions of N oxides, but the magnitude of the increase is likely to differ based on timing of fertilizer application relative to the presence of plants and the magnitude of plant N demand. Emissions of N oxides appear to be decreased by the use of restoration sequences that minimize reductions in pasture grass cover.     

Tetragonal structure, anionic vacancies and catalytic activity of SO4-ZrO2 catalysts for n-butane isomerization

An assessment of the influence of the crystal structure, surface hydroxylation state and previous oxidation/reduction pretreatments on the activity of sulfate-zirconia catalysts for isomerization of n-butane was performed using crystalline and amorphous zirconia supports. Different sulfation methods were used for the preparation of bulk and supported SO₄²⁻-ZrO₂ with monoclinic, tetragonal and tetragonal+monoclinic structures. Activity was important only for the samples that contained tetragonal crystals. The catalysts prepared from pure monoclinic zirconia showed negligible activity. SO₄²⁻-ZrO₂ catalysts prepared by sulfation of crystalline zirconia displayed sites with lower acidity and cracking activity than those sulfated in the amorphous state. Prereduction of the zirconia samples with H₂ was found to greatly increase the catalytic activity, and a maximum rate was found at a reduction temperature of 550–600 °C, coinciding with a TPR peak supposedly associated with the removal of lattice oxygen and the creation of lattice defects. A weaker dependence of catalytic activity on the density or type of surface OH groups on zirconia (before sulfation) was found in this work.

A model of active site generation was constructed in order to stress the dependence on the crystal structure and crystal defects. Current and previous results suggest that tetragonal structure in active SO₄²⁻-ZrO₂ is a consequence of the stabilization of anionic vacancies in zirconia. Anionic vacancies are in turn supposed to be related to the catalytic activity for n-butane isomerization through the stabilization of electrons from ionized intermediates.     

On reactive routing protocols in ZigBee wireless sensor networks

ZigBee is the primary standard solution for wireless sensor networks, implementing the Ad hoc On‐Demand Distance Vector (AODV) protocol in the network layer and supported by the standard IEEE 802.15.4. This study is focused on mesh topologies and the critical problems encountered when AODV is executed in conjunction with the Carrier Sense Multiple Access with Collision Avoidance protocol. These problems are mainly related to the packet overhead required to carry out route creation. To perform preliminary experiments to be able to implement AODV in a real network, a new metric is proposed herein. This metric uses fuzzy logic to help in the decision‐making process. The objective of the fuzzy routine is to determine, during the route‐discovery process, the best node to forward request/reply packets, with the aim of reducing packet overhead and energy consumption. Moreover, minor changes are also added to the discovery procedure of AODV to improve the performance of the route‐creation process. This intelligent version of AODV has provided promising experimental results, greatly reducing the number of packets required, with the consequent energy saving while selecting the best nodes to be part of the routes.     

An Algorithm Template for Domain-Based Parallel Irregular Algorithms

The parallelization of irregular algorithms has not been as widely studied as the one of regular codes. In particular, while there are many proposals of parallel skeletons and libraries very well suited to regular algorithms, this is not the case for irregular ones. This is probably due to the complexity of finding common patterns, behaviors and semantics in these algorithms. This is unfortunate, as the parallelization of irregular algorithms would benefit even more than that of regular codes from the higher degree of abstraction provided by skeletons. This work proposes to exploit the concept of domain defined on some property of the elements to process in order to enable the simple and effective parallelization of irregular applications. Namely, we propose to use such domains both to decompose the computations in parallel tasks and to detect and avoid conflicts between these tasks. A generic C++ library providing a skeleton for multicore systems built on this idea is described and evaluated. Our experimental results show that this library is a very practical tool for the parallelization of irregular algorithms with little programming effort.     

A complete and efficient CUDA-sharing solution for HPC clusters

In this paper we detail the key features, architectural design, and implementation of rCUDA, an advanced framework to enable remote and transparent GPGPU acceleration in HPC clusters. rCUDA allows decoupling GPUs from nodes, forming pools of shared accelerators, which brings enhanced flexibility to cluster configurations. This opens the door to configurations with fewer accelerators than nodes, as well as permits a single node to exploit the whole set of GPUs installed in the cluster. In our proposal, CUDA applications can seamlessly interact with any GPU in the cluster, independently of its physical location. Thus, GPUs can be either distributed among compute nodes or concentrated in dedicated GPGPU servers, depending on the cluster administrator’s policy. This proposal leads to savings not only in space but also in energy, acquisition, and maintenance costs. The performance evaluation in this paper with a series of benchmarks and a production application clearly demonstrates the viability of this proposal. Concretely, experiments with the matrix–matrix product reveal excellent performance compared with regular executions on the local GPU; on a much more complex application, the GPU-accelerated LAMMPS, we attain up to 11x speedup employing 8 remote accelerators from a single node with respect to a 12-core CPU-only execution. GPGPU service interaction in compute nodes, remote acceleration in dedicated GPGPU servers, and data transfer performance of similar GPU virtualization frameworks are also evaluated.     

Holistic schedulability analysis for multipacket messages in AFDX networks

The ARINC-664, Part 7 (AFDX) standard defines a communication network based on Ethernet and the UDP/IP protocols. Contrary to general-purpose Ethernet, the timing behavior in AFDX is deterministic due to the use of special network switches and end systems with static routing tables and traffic policing at the sending end through mechanisms called virtual links. Even though the latencies in this network are bounded, there are scheduling and contention effects that need to be analyzed. In this paper we develop a response-time analysis for multipacket messages transmitted through an AFDX network including the scheduling of the virtual links and sub-virtual links, and also the contention in the end systems and in the switches. This analysis allows us to obtain worst-case latencies and output jitter for the network messages with a precise modeling of the sending and receiving ends. These results can be integrated in a holistic approach with the response time analysis of the threads in the processing nodes to obtain end-to-end response times in heterogeneous distributed systems.