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.     

Protein design to understand peptide ligand recognition by tetratricopeptide repeat proteins

Protein design aims to understand the fundamentals of protein structure by creating novel proteins with pre-specified folds. An equally important goal is to understand protein function by creating novel proteins with pre-specified activities. Here we describe the design and characterization of a tetratricopeptide (TPR) protein, which binds to the C-terminal peptide of the eukaryotic chaperone Hsp90. The design emphasizes the importance of both direct, short-range protein-peptide interactions and of long-range electrostatic optimization. We demonstrate that the designed protein binds specifically to the desired peptide and discriminates between it and the similar C-terminal peptide of Hsp70.     

Role of cognitive and functional performance in the interactions between elderly people with cognitive decline and an avatar on TV

The complexity of new information technologies (IT) may limit the access of elderly people to the information society, exacerbating what is known as “the digital divide,” as they appear to be too challenging for elderly citizens regardless of the integrity of their cognitive status. This study is an attempt to clarify how some cognitive functions (such as attention or verbal memory) may determine the interaction of cognitively impaired elderly people with technology. Twenty participants ranging from mild cognitive impairment to moderate Alzheimer’s disease were assessed by means of a neuropsychological and functional battery and were asked to follow simple commands from an avatar appearing on a TV by means of a remote control, such as asking the participant to confirm their presence or to respond Yes/No to a proposal to see a TV program. The number of correct answers and command repetitions required for the user to respond were registered. The results show that participants with a better cognitive and functional state in specific tests show a significantly better performance in the TV task. The derived conclusion is that neuropsychological assessment may be used as a useful complementary tool for assistive technology developers in the adaptation of IT to the elderly with different cognitive and functional profiles. Further studies with larger samples are required to determine to what extent cognitive functions can actually predict older users’ interaction with technology.     

A novel scheme inspired by the compute-and-forward relaying strategy for the multiple access relay channel

Wireless Networks - This paper proposes a novel scheme for the slow block fading Gaussian multiple access relay channel inspired by the compute-and-forward (CoF) relaying strategy. The CoF relaying...     

Design and performance of a combined secondary ion mass spectrometry-scanning probe microscopy instrument for high sensitivity and high-resolution elemental three-dimensional analysis

State-of-the-art secondary ion mass spectrometry (SIMS) instruments allow producing 3D chemical mappings with excellent sensitivity and spatial resolution. Several important artifacts however arise from the fact that SIMS 3D mapping does not take into account the surface topography of the sample. In order to correct these artifacts, we have integrated a specially developed scanning probe microscopy (SPM) system into a commercial Cameca NanoSIMS 50 instrument. This new SPM module, which was designed as a DN200CF flange-mounted bolt-on accessory, includes a new high-precision sample stage, a scanner with a range of 100 μm in x and y direction, and a dedicated SPM head which can be operated in the atomic force microscopy (AFM) and Kelvin probe force microscopy modes. Topographical information gained from AFM measurements taken before, during, and after SIMS analysis as well as the SIMS data are automatically compiled into an accurate 3D reconstruction using the software program "SARINA," which was developed for this first combined SIMS-SPM instrument. The achievable lateral resolutions are 6 nm in the SPM mode and 45 nm in the SIMS mode. Elemental 3D images obtained with our integrated SIMS-SPM instrument on Al/Cu and polystyrene/poly(methyl methacrylate) samples demonstrate the advantages of the combined SIMS-SPM approach.     

The determination of nitrate in cured meat products. A comparison of the HPLC UV/VIS and Cd/spectrophotometric methods.

A comparison of the traditional spectrophotometric method, with prior application of a reducing Cd column, and a high performance liquid chromatography method with an anion exchanging column for the determination of nitrate in spiced Spanish sausage, was carried out. Both methods demonstrated a high correlation. The chromatographic method proved more precise, reproducible and appropriate for routine work.     

Scenario Cluster Decomposition of the Lagrangian dual in two-stage stochastic mixed 0–1 optimization

In this paper we introduce four scenario Cluster based Lagrangian Decomposition procedures for obtaining strong lower bounds to the (optimal) solution value of two-stage stochastic mixed 0–1 problems. At each iteration of the Lagrangian based procedures, the traditional aim consists of obtaining the solution value of the corresponding Lagrangian dual via solving scenario submodels once the nonanticipativity constraints have been dualized. Instead of considering a splitting variable representation over the set of scenarios, we propose to decompose the model into a set of scenario clusters. We compare the computational performance of the four Lagrange multiplier updating procedures, namely the Subgradient Method, the Volume Algorithm, the Progressive Hedging Algorithm and the Dynamic Constrained Cutting Plane scheme for different numbers of scenario clusters and different dimensions of the original problem. Our computational experience shows that the Cluster based Lagrangian Decomposition bound and its computational effort depend on the number of scenario clusters to consider. In any case, our results show that the Cluster based Lagrangian Decomposition procedures outperform the traditional Lagrangian Decomposition scheme for single scenarios both in the quality of the bounds and computational effort. All the procedures have been implemented in a C++ experimental code. A broad computational experience is reported on a test of randomly generated instances by using the MIP solvers COIN-OR (2010, [18]) and CPLEX (2009, [17]) for the auxiliary mixed 0–1 cluster submodels, this last solver within the open source engine COIN-OR. We also give computational evidence of the model tightening effect that the preprocessing techniques, cut generation and appending and parallel computing tools have in stochastic integer optimization. Finally, we have observed that the plain use of both solvers does not provide the optimal solution of the instances included in the testbed with which we have experimented but for two toy instances in affordable elapsed time. On the other hand the proposed procedures provide strong lower bounds (or the same solution value) in a considerably shorter elapsed time for the quasi-optimal solution obtained by other means for the original stochastic problem.     

Experimental and analytical studies on the rotational stiffness of joints for single-layer structures

In the design of single-layer structures, the hypothesis of pinned joints leads to structures with low capacity in terms of stability and resistance. Therefore, one of the main concerns of structural designers in recent years has been to find an appropriate joint design which would endow the joint with sufficient stiffness. In this paper, the results of experimental tests conducted with the aim of establishing geometrical parameters for a semi-rigid joint that may be used in single-layer structures are presented. They showed how the combination of different parameters can improve the stiffness of the joint and its rotational capacity. At the same time, the experimental tests provided the initial rotational stiffness of the tested joints which is to be introduced into the analysis of the structure. The paper presents an analytical method for the determination of the initial rotational stiffness of the joint. The method follows a technique similar to the component method of Eurocode 3 part 1.8, although it has been adapted to the geometry of this particular joint.     

Regionalization of housing policies? An exploratory study of Andalusia,Catalonia and the Basque Country

The Spanish home ownership sector has been hit hard by the economic crisis. Repossessions stand at around half a million in the period from 2008 to 2014. This article investigates how the authorities, both at the level of the Spanish state and of the autonomous communities (regions), have responded to this problem. We investigated whether they assist troubled home owners and aim to design a less risky housing system, with more (social) rental housing. Our research in Catalonia, the Basque Country and Andalusia shows that Autonomous Communities are playing an increasingly important role in this matter. This finding fits well with theories on the formation of regional varieties of welfare, which indicate that flaws of the central governments in providing social welfare, are increasingly addressed by regions. The Basque Country seems to be on the way of designing the most comprehensive system of housing policies of the three regions, including a strong Right to Housing. All three regions regard the mobilisation of the large vacant dwelling stock as an important means to provide more affordable rental housing. However, the owners are often unwilling and the three regions have proposed drastic measures, such as fines and even temporary expropriations. The central government resists such measures, because they might interfere with the proper working of the country’s financial system. It shows that certain policy competences can never be totally isolated from other policy fields and multi-level distribution of competences makes it all the more complex.     

High‐Shear‐Strength Waterborne Polyurethane/Acrylic Soft Adhesives

Urethane/acrylic hybrid latex particles are prepared by miniemulsion polymerization for an application as soft adhesives. The polymerization of the acrylic monomers and grafting of an isocyanate functionalized PU on a hydroxyl functionalized monomer (HEMA) take place simultaneously, resulting in a complex PU/acrylic network while avoiding any macroscopic phase separation. Its structure can be tuned by changing the extent of grafting and a specific model is applied to analyze the final polymer microstructure. The resulting materials have a low level of adhesion but display an exceptionally high resistance to shear. Two parameters are varied: the fraction of HEMA in the monomer composition and the diol concentration.