Exposure data and risk indicators for safety performance assessment in Europe

The objective of this paper is the analysis of the state-of-the-art in risk indicators and exposure data for safety performance assessment in Europe, in terms of data availability, collection methodologies and use. More specifically, the concepts of exposure and risk are explored, as well as the theoretical properties of various exposure measures used in road safety research (e.g. vehicle- and person-kilometres of travel, vehicle fleet, road length, driver population, time spent in traffic, etc.). Moreover, the existing methods for collecting disaggregate exposure data for risk estimates at national level are presented and assessed, including survey methods (e.g. travel surveys, traffic counts) and databases (e.g. national registers). A detailed analysis of the availability and quality of existing risk exposure data is also carried out. More specifically, the results of a questionnaire survey in the European countries are presented, with detailed information on exposure measures available, their possible disaggregations (i.e. variables and values), their conformity to standard definitions and the characteristics of their national collection methods. Finally, the potential of international risk comparisons is investigated, mainly through the International Data Files with exposure data (e.g. Eurostat, IRTAD, ECMT, UNECE, IRF, etc.). The results of this review confirm that comparing risk rates at international level may be a complex task, as the availability and quality of exposure estimates in European countries varies significantly. The lack of a common framework for the collection and exploitation of exposure data limits significantly the comparability of the national data. On the other hand, the International Data Files containing exposure data provide useful statistics and estimates in a systematic way and are currently the only sources allowing international comparisons of road safety performance under certain conditions.     

Neutrophils Mediate Pulmonary Artery Thrombosis In Situ

Pulmonary embolism is a life-threatening condition, which can result in respiratory insufficiency and death. Blood clots occluding branches of the pulmonary artery (PA) are traditionally considered to originate from thrombi in deep veins (usually in legs). However, growing evidence suggests that occlusion of the vessels in the lungs can develop without preceding deep vein thrombosis (DVT). In this work, we used an inferior vena cava (IVC) complete ligation model of DVT in Wistar rats to explore the possibility and mechanisms of PA thrombosis under the conditions where all routes of thrombotic mass migration from peripheral veins are blocked. We demonstrate that rats both with normal and reduced neutrophil counts developed thrombi in the IVC, although, neutropenia caused a substantial decrease in thrombus size and a shift from fresh fibrin toward mature fibrin and connective tissue inside the thrombus. Massive fibrin deposition was found in the PA branches in the majority of DVT rats with normal neutrophil counts, but in none of the neutropenic animals. Neutrophil ablation also abolished macroscopic signs of lung damage. Altogether, the results demonstrate that thrombi in the lung vasculature can form in situ by mechanisms that require local neutrophil recruitment taking place in the DVT setting.     

The [1,2,4]Triazolo[4,3-a]pyridine as a New Player in the Field of IDO1 Catalytic Holo-Inhibitors

Inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) are considered a promising strategy in cancer immunotherapy as they are able to boost the immune response and to work in synergy with other immunotherapeutic agents. Despite the fact that no IDO1 inhibitor has been approved so far, recent studies have shed light on the additional roles that IDO1 mediates beyond its catalytic activity, conferring new life to the field. Here we present a novel class of compounds originated from a structure-based virtual screening made on IDO1 active site. The starting hit compound is a novel chemotype based on a [1,2,4]triazolo[4,3-a]pyridine scaffold, so far underexploited among the heme binding moieties. Thanks to the rational and in silico-guided design of analogues, an improvement of the potency to sub-micromolar levels has been achieved, with excellent in vitro metabolic stability and exquisite selectivity with respect to other heme-containing enzymes.     

Recent advances in mycotoxin determination in food and feed by hyphenated chromatographic techniques/mass spectrometry

Mycotoxins are fungal toxins produced by molds, which occur universally in food and feed derivatives, and are produced under certain environmental conditions in the field before harvest, post-harvest, during storage, processing, and feeding. Mycotoxin contamination is one of the most relevant and worrisome problem concerning food and feed safety because it can cause a variety of toxic acute and chronic effects in human and animals. In this review we report the use of mass spectrometry in connection with chromatographic techniques for mycotoxin determination by considering separately the most diffuse class of mycotoxins: patulin, aflatoxins, ochratoxin A, zearalenone, trichothecenes, and fumonisins. Although the selectivity of mass spectrometry is unchallenged if compared to common GC and LC detection methods, accuracy, precision, and sensitivity may be extremely variable concerning the different mycotoxins, matrices, and instruments. The sensitivity issue may be a real problem in the case of LC/MS, where the response can be very different for the different ionization techniques (ESI, APCI, APPI). Therefore, when other detection methods (such as fluorescence or UV absorbance) can be used for the quantitative determination, LC/MS appears to be only an outstanding confirmatory technique. In contrast, when the toxins are not volatile and do not bear suitable chromophores or fluorophores, LC/MS appears to be the unique method to perform quantitative and qualitative analyses without requiring any derivatization procedure. The problem of exact quantitative determination in GC/MS and LC/MS methods is particularly important for mycotoxin determination in food, given the high variability of the matrices, and can be solved only by the use of isotopically labeled internal standards or by the use of ionization interfaces able to lower matrix effects and ion suppressions. When the problems linked to inconstant ionization and matrix effects will be solved, only MS detectors will allow to simplify more and more the sample preparation procedures and to avoid clean-up procedures, making feasible low-cost, high-throughput determination of mycotoxins in many different food matrices.     

Constrained two‐dimensional guillotine cutting problem: upper‐bound review and categorization

In the two‐dimensional (2D) cutting (2DC) problem, a large rectangular sheet has to be dissected into smaller rectangular pieces with the aim of maximizing the total profit associated with the extracted pieces. When the number of copies of each piece to be extracted is bounded, it is referred to as constrained 2DC (C2DC) problem. The C2DC has been widely studied by the operations research community for its applications and theoretical issues. In this work, we recall the best exact and heuristic solving approaches for the C2DC and we provide a review and a categorization of the available upper bounds. We also discuss improvements and combinations of these upper bounds and give directions for their effective exploitation. Finally, we demonstrate the loss of accuracy of several exact methods present in literature because of the effect of the used antiredundancy strategies on the implemented bounding criteria. This work, based on more than 90 contributions, has a twofold target. For researchers working in C2DC, it provides a useful insight on the topic. For expert practitioners, it represents a systematic collection of the main findings and achievements, posing also the basis for future research.     

Photosensitizedcis-trans isomerization of jojoba wax

Jojoba wax solutions were irradiated at wavelengths longer than 366 nm, in the presence of sensitizers, at room temperature.Cis-trans isomerization took place only with sensitizers with triplet energy greater than 68 kcal/mol. Quantum yields were low and a conversion of up to 25% of thetrans isomer was achieved at the photostationary state.     

EN AW-4032 T6 Piston Alloy After High-Temperature Exposure: Residual Strength and Microstructural Features

This study aims to evaluate the effects of prolonged thermal exposure on both microstructural evolution and mechanical properties of the EN AW-4032 T6 piston alloy. For the purpose, the experimental activities have been carried out on samples machined from forged and heat-treated automotive pistons. The effects of overaging have been investigated in the temperature range of 140-290 °C, firstly by evaluating the time-temperature-hardness curves and then by carrying out room-temperature tensile tests on overaged samples. The material softening was substantial and extremely rapid when the soaking temperature exceeded 250 °C. During overaging, both the tensile strength and the residual hardness considerably decreased, and a relationship between these parameters has been established. The alloy behavior in the plastic field has been modeled according to the Hollomon’s equation, showing that both the strain hardening exponent and the strength coefficient are a function of the residual hardness. The results were finally related to the corresponding microstructural changes: OM and FEG-SEM metallographic and fractographic analyses on overaged samples gave evidence of coarsened precipitates along the grain boundaries.     

Mass spectrometry‐based proteomics: The road to lung cancer biomarker discovery

Lung cancer is the leading cause of cancer death in men and women in Western nations, and is among the deadliest cancers with a 5‐year survival rate of 15%. The high mortality caused by lung cancer is attributable to a late‐stage diagnosis and the lack of effective treatments. So, it is crucial to identify new biomarkers that could function not only to detect lung cancer at an early stage but also to shed light on the molecular mechanisms that underlie cancer development and serve as the basis for the development of novel therapeutic strategies. Considering that DNA‐based biomarkers for lung cancer showed inadequate sensitivity, specificity, and reproducibility, proteomics could represent a better tool for the identification of useful biomarkers and therapeutic targets for this cancer type. Among the proteomics technologies, the most powerful tool is mass spectrometry. In this review, we describe studies that use mass spectrometry‐based proteomics technologies to analyze tumor proteins and peptides, which might represent new diagnostic, prognostic, and predictive markers for lung cancer. We focus in particular on those findings that hold promise to impact significantly on the clinical management of this disease. © 2012 Wiley Periodicals, Inc., Mass Spec Rev 32:129–142, 2013     

In vitro lipolysis tests on lipid nanoparticles: comparison between lipase/co-lipase and pancreatic extract

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLC) are lipid nanocarriers aimed to the delivery of drugs characterized by a low bioavailability, such as poorly water-soluble drugs and peptides or proteins. The oral administration of these lipid nanocarriers implies the study of their lipolysis in presence of enzymes that are commonly involved in dietary lipid digestion in the gastrointestinal tract. In this study, a comparison between two methods was performed: on one hand, the lipase/co-lipase assay, commonly described in the literature to study the digestion of lipid nanocarriers, and on the other hand, the lipolysis test using porcine pancreatic extract and the pH-stat apparatus. This pancreatic extract contains both the pancreatic lipase and carboxyl ester hydrolase (CEH) that permit to mimic in a biorelevant manner the duodenal digestive lipolysis. The test was performed by means of a pH-stat apparatus to work at constant pH, 5.5 or 6.25, representing respectively the fasted or fed state pH conditions. The evolution of all acylglycerol entities was monitored during the digestion by sampling the reaction vessel at different time points, until 60?min, and the lipid composition of the digest was analyzed by gas chromatography. SLN and NLC systems obtained with long-chain saturated acylglycerols were rapidly and completely digested by pancreatic enzymes. The pH-stat titration method appears to be a powerful technique to follow the digestibility of these solid lipid-based nanoparticles.     

Dysregulation of Muscle-Specific MicroRNAs as Common Pathogenic Feature Associated with Muscle Atrophy in ALS,SMA and SBMA: Evidence from Animal Models and Human Patients

Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients’ sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.