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.     

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.     

Ethylene-propylene copolymers by a supported Ziegler-Natta catalyst based on TiCl4/MgCl2

Ethylene-propylene copolymers have been prepared by using Ziegler-Natta catalysts based on TiCl₄, MgCl₂, PCl₃ and (n-Bu)₃PO₄. The catalysts TiCl₄/MgCl₂/PCl₃ and TiCl₄/MgCl₂/(n-Bu)₃PO₄ were prepared by reacting TiCl₄ with pretreated MgCl₂. The support was prepared by ball milling of MgCl₂ with varied amounts of PCl₃ or (n-Bu)₃PO₄. The addition of PCl₃ has remarkably increased the MgCl₂ surface area in comparison with (n-Bu)₃PO₄. The effects of PCl₃ and (n-Bu)₃PO₄ on ethylene homopolymerization, ethylene-propylene copolymerization and on copolymer properties were evaluated. The catalyst system containing PCl₃ permitted to synthesize propylene-ethylene copolymers with up to 75% (w/w) of propylene and provided control of copolymer crystallinity. The reduction of the copolymer molecular weight distribution suggested that PCl₃ acted as an internal donor, poisoning some active catalytic sites. Received: 2 April 1997/Revised: 6 June 1997/Accepted: 18 June 1997     

Gaussian,Lobatto and Radau positive quadrature rules with a prescribed abscissa

For a given $\theta \in (a,b)$ , we investigate the question whether there exists a positive quadrature formula with maximal degree of precision which has the prescribed abscissa $\theta $ plus possibly $a$ and/or $b$ , the endpoints of the interval of integration. This study relies on recent results on the location of roots of quasi-orthogonal polynomials. The above positive quadrature formulae are useful in studying problems in one-sided polynomial $L_1$ approximation.     

(CO2 + 2‐propanol) mixture as a foaming agent for polystyrene: A simple thermodynamic model for the high pressure VLE‐phase diagrams taking into account the foam vitrification

The equation of state model developed by Lacombe and Sanchez (J Phys Chem 1976, 80, 2352) is used in the form proposed later by Sanchez and Stone (Polymer Blends, Vol. 1: Formulation, 2000; Chapter 2) to correlate experimental vapor‐liquid equilibrium (VLE) data for the three binaries and the ternary systems. Experimental data from the binary systems carbon dioxide‐isopropyl alcohol (CO₂‐IPrOH), isopropyl alcohol‐polystyrene (IPrOH‐PS), and carbon dioxide‐polystyrene (CO₂‐PS) are used to calculate VLE properties for the ternary system CO₂‐IPrOH‐PS. Two‐dimensional VLE‐phase diagrams were calculated and used to describe from a thermodynamic point of view the pressure, volume, and temperature values that characterize a thermoplastic foam evolution process, from the extruder to the foaming die. For different initial mixture CO₂ + IPrOH concentrations, pressure reduction produces liquid foaming until the vitrification curve arrests the final foam volume expansion. The dependence of the vitreous transition with the system CO₂ + IPrOH concentration while foaming is represented by the Chow (Macromolecules 1980, 13, 362) equation. The calculation procedure is proposed as a design tool to reduce the amount of experimental data usually needed as a requirement previous to the design stage. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 104: 2663–2671, 2007     

The effect of pre-warming on performance during simulated firefighting exercise

This study examined the effect of active pre-warming on speed and quality of performance during simulated firefighting exercise. Twelve male firefighters performed two trials in counterbalanced order. They were either pre-warmed by 20-min cycling at 1.5 Watt kg⁻¹ body mass (WARM) or remained thermoneutral (CON) prior to a simulated firefighting activity. After the pre-warming, gastrointestinal temperature (P < 0.001), skin temperature (P = 0.002), and heart rate (P < 0.001) were higher in WARM than in CON. During the firefighting activity, rating of perceived exertion, thermal sensation and discomfort were higher for WARM than for CON. Finish time of the firefighting activity was similar, but the last task of the activity was completed slower in WARM than in CON (P = 0.04). In WARM, self-reported performance quality was lower than in CON (P = 0.04). It is concluded that pre-warming reduces the speed during the last part of simulated firefighting activity and reduces self-reported quality of performance.     

Pervaporation of 50 wt % ethanol–water mixtures with poly(1‐trimethylsilyl‐1‐propyne) membranes at high temperatures

Poly(1‐trimethylsilyl‐1‐propyne) (PTMSP) membranes have been used to separate ethanol–water mixtures by pervaporation. This polyacetylene is known to present high affinity toward ethanol, showing high selectivity and ethanol permeation flux. The performance of this polymer in the separation of alcohol–water solutions has been evaluated over long periods (572 h) at a high temperature (75°C) to examine the deterioration of the transport properties in the separation of 50 wt % ethanol–water solutions. Although PTMSP membranes present good characteristics for the separation of gases and liquid mixtures, their organic selectivity decrease with the operating time because of the relaxation processes of the polymeric chains, which affect the free volume of the polymer, the deterioration being more evident for concentrated solutions. The effects of the operation temperature on the characteristic parameters of pervaporation have also been studied to establish how this variable affects the performance of PTMSP membranes. The selectivity increases slightly with the operation temperature, but the effect of the temperature on the separation factor decreases as membranes are degraded with the operation time. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 2843–2848, 2007     

Development and implementation of clinical guidelines: An artificial intelligence perspective

Clinical practice guidelines in paper format are still the preferred form of delivery of medical knowledge and recommendations to healthcare professionals. Their current support and development process have well identified limitations to which the healthcare community has been continuously searching solutions. Artificial intelligence may create the conditions and provide the tools to address many, if not all, of these limitations.. This paper presents a comprehensive and up to date review of computer-interpretable guideline approaches, namely Arden Syntax, GLIF, PROforma, Asbru, GLARE and SAGE. It also provides an assessment of how well these approaches respond to the challenges posed by paper-based guidelines and addresses topics of Artificial intelligence that could provide a solution to the shortcomings of clinical guidelines. Among the topics addressed by this paper are expert systems, case-based reasoning, medical ontologies and reasoning under uncertainty, with a special focus on methodologies for assessing quality of information when managing incomplete information. Finally, an analysis is made of the fundamental requirements of a guideline model and the importance that standard terminologies and models for clinical data have in the semantic and syntactic interoperability between a guideline execution engine and the software tools used in clinical settings. It is also proposed a line of research that includes the development of an ontology for clinical practice guidelines and a decision model for a guideline-based expert system that manages non-compliance with clinical guidelines and uncertainty.     

Carbohydrate type and amount alter intravascular processing and catabolism of plasma lipoproteins in guinea pigs

To test the effects of exchanging dietary complex and simple carbohydrate for fat calories on lipoprotein metabolism, guinea pigs were fed two different fat/carbohydrate ratios: 2.5∶58% (w/w) or 25∶29% (w/w) with either sucrose or starch as the carbohydrate source. Animals fed high-fat had higher plasma low-density lipoprotein (LDL) and hepatic cholesterol concentrations than animals fed low-fat diets (P<0.01). The cholesteryl ester content per particle was higher, and the number of triacylglycerol (TAG) molecules was lower in very low density lipoprotein (VLDL) and LDL from animals fed high-fat diets. Intake of high-fat/sucrose resulted in higher plasma LDL concentrations than intake of high-fat/starch, and animals fed low-fat/starch had the highest plasma TAG concentrations associated with VLDL particles containing more TAG molecules, as well as a TAG-enriched LDL. The activity of plasma lecithin cholesteryl:acyl transferase (LCAT) was highest in animals fed high-fat/sucrose, and heart lipoprotein lipase (LPL) activity was higher in animals fed high-fat diets. Hepatic apoprotein B/E (apo B/E) receptor number (B_max) was increased 21% with low-fat diets (P<0.01). These results suggest that the hypercholesterolemia induced by high-fat and by sucrose intake are associated with a higher plasma LCAT activity which results in a cholesteryl ester-enriched VLDL which, by the action of LPL, might be more readily converted to LDL through the delipidation cascade leading to downregulation of hepatic apo B/E receptors. The hypertriglyceridemia associated with low-fat intake may result from increased production of VLDL TAG, which would explain the increased TAG content and the higher TAG/CE ratio of VLDL from animals fed the low-fat/starch diet.