Combining synchrotron radiation techniques for the analysis of gold coins from the Roman Empire.

Four gold coins minted in the V century have been studied with non-destructive synchrotron radiation techniques, namely X-Ray Fluorescence (XRF) and X-ray Absorption Near Edge Spectroscopy (XANES). XRF data analyzed coupling standard and statistical methods were used to distinguish the composition of the alloy constituting the coins from that of successive deposits processes. Our analysis presents a quantification of the trace elements present in the metallic alloy providing interesting details for historical insight. Furthermore, on the basis of the XRF maps, some regions of interest were selected for XANES at the K-edge of Fe. Our analysis of the Fe spectra points out two main phases which can be related to Fe oxides naturally present in soil. From the relative abundance of these oxides, information on the site where the coins were found can be obtained, providing additional information on their fate across the centuries.

Coexisting multi-states in catalytic hydrogen oxidation on rhodium.

Catalytic hydrogen oxidation on a polycrystalline rhodium foil used as a surface structure library is studied by scanning photoelectron microscopy (SPEM) in the 10-6 mbar pressure range, yielding spatially resolved X-ray photoemission spectroscopy (XPS) measurements. Here we report an observation of a previously unknown coexistence of four different states on adjacent differently oriented domains of the same Rh sample at the exactly same conditions. A catalytically active steady state, a catalytically inactive steady state and multifrequential oscillating states are simultaneously observed. Our results thus demonstrate the general possibility of multi-states in a catalytic reaction. This highly unusual behaviour is explained on the basis of peculiarities of the formation and depletion of subsurface oxygen on differently structured Rh surfaces. The experimental findings are supported by mean-field micro-kinetic modelling. The present observations raise the interdisciplinary question of how self-organising dynamic processes in a heterogeneous system are influenced by the permeability of the borders confining the adjacent regions.

How the anisotropy of surface oxide formation influences the transient activity of a surface reaction.

Scanning photoelectron microscopy (SPEM) and photoemission electron microscopy (PEEM) allow local surface analysis and visualising ongoing reactions on a µm-scale. These two spatio-temporal imaging methods are applied to polycrystalline Rh, representing a library of well-defined high-Miller-index surface structures. The combination of these techniques enables revealing the anisotropy of surface oxidation, as well as its effect on catalytic hydrogen oxidation. In the present work we observe, using locally-resolved SPEM, structure-sensitive surface oxide formation, which is summarised in an oxidation map and quantitatively explained by the novel step density (SDP) and step edge (SEP) parameters. In situ PEEM imaging of ongoing H2 oxidation allows a direct comparison of the local reactivity of metallic and oxidised Rh surfaces for the very same different stepped surface structures, demonstrating the effect of Rh surface oxides. Employing the velocity of propagating reaction fronts as indicator of surface reactivity, we observe a high transient activity of Rh surface oxide in H2 oxidation. The corresponding velocity map reveals the structure-dependence of such activity, representing a direct imaging of a structure-activity relation for plenty of well-defined surface structures within one sample.

The Electron Affinity as the Highest Occupied Anion Orbital Energy with a Sufficiently Accurate Approximation of the Exact Kohn-Sham Potential.

Negative ions are not accurately represented in density functional approximations (DFAs) such as (semi)local density functionals (LDA or GGA or meta-GGA). This is caused by the much too high orbital energies (not negative enough) with these DFAs compared to the exact Kohn-Sham values. Negative ions very often have positive DFA HOMO energies, hence they are unstable. These problems do not occur with the exact Kohn-Sham potential, the anion HOMO energy then being equal to minus the electron affinity. It is therefore desirable to develop sufficiently accurate approximations to the exact Kohn-Sham potential. There are further beneficial effects on the orbital shapes and the density of using a good approximation to the exact KS potential. Notably the unoccupied orbitals are not unduly diffuse, as they are in the Hartree-Fock model, with hybrid functionals, and even with (semi)local density functional approximations (LDFAs). We show that the recently developed B-GLLB-VWN approximation [Gritsenko et al. J. Chem. Phys. 2016, 144, 204114] to the exact KS potential affords stable negative ions with HOMO orbital energy close to minus the electron affinity.

Turning down the heat: An enhanced understanding of the relationship between urban vegetation and surface temperature at the city scale.

Guiding urban planners on the cooling returns of different configurations of urban vegetation is important to protect urban dwellers from adverse heat impacts. To this end, we estimated statistical models that fused multi-temporal very fine spatial (20 cm) and vertical (1 mm) resolution imagery, that captures the complexity of urban vegetation, with remotely sensed temperature data to assess how urban vegetation configuration influences urban temperatures. Perth, Western Australia, was used as a case-study for this analysis. Panel regression models showed that within a location an increase in tree and shrub cover has a larger cooling effect than grass coverage. On average, holding all else equal, an approximate 1 km2 increase in shrub (tree) cover within a location reduces surface temperatures by 12 °C (5 °C). We included a range of robustness checks for the observed relationships between urban vegetation type and temperature. Geographically weighted regression models showed spatial variation in the cooling effect of different vegetation types; this indicates that i) unobserved factors moderate temperature-vegetation relationships across urban landscapes, and ii) that urban vegetation type and temperature relationships are complex. Machine learning models (Random Forests) were used to further explore complex and non-linear relationships between different urban vegetation configurations and temperature. The Random Forests showed that vegetation type explained 31.84% of the out-of-bag variance in summer surface temperatures, that increased cover of large vegetation within a location increases cooling, and that different configurations of urban vegetation structure can lead to cooling gains. The models in this study were trained with vegetation data capturing local detail, multiple time-periods, and entire city coverage. Thus, these models illustrate the potential to develop locally-detailed and spatially explicit tools to guide planning of vegetation configuration to optimise cooling at local- and city-scales.

Features and prognostic impact of distant metastases in 45 dogs with de novo stage IV cutaneous mast cell tumours: A prospective study.

BACKGROUND: Distant metastases in dogs with cutaneous mast cell tumors (cMCT) are rare and incurable. The aims of this prospective study were to clarify the clinico-pathological features of stage IV cMCTs and to identify possible prognostic factors for progression-free interval (PFI) and survival time (ST). MATERIAL AND METHODS: Dogs were eligible for recruitment if they had a previously untreated, histologically confirmed cMCT and if they underwent complete staging demonstrating stage IV disease. Dogs were uniformly followed-up, whereas treatment was not standardized and included no therapy, surgery, radiation therapy, chemotherapy, tyrosine-kinase inhibitors or a combination of these. RESULTS: 45 dogs with stage IV cMCT were enrolled. All dogs had distant metastatic disease, and 41 (91.1%) dogs had also metastasis in the regional lymph node. Histopathological grade and mutational status greatly varied among dogs. Median ST was 110 days. Notably, PFI and ST were independent of well-known prognostic factors, including anatomic site, histological grade, and mutational status. Conversely, tumor diameter >3 cm, more than 2 metastatic sites, bone marrow infiltration, and lack of tumor control at the primary site were confirmed to be negative prognostic factors by multivariate analysis. CONCLUSION: Currently, there is no satisfactory treatment for stage IV cMCT. Asymptomatic dogs with tumor diameter <3 cm and a low tumor burden, without bone marrow infiltration may be candidates for multimodal treatment. Stage IV dogs without lymph node metastasis may enjoy a surprisingly prolonged survival. The achievement of local tumor control seems to predict a better outcome in dogs with stage IV cMCT.

Probing plasma fluorinated graphene via spectromicroscopy.

Plasma fluorination of graphene is studied using a combination of spectroscopy and microscopy techniques, giving insight into the yield and fluorination mechanism for functionalization of supported graphene with both CF4 and SF6 gas precursors. Ion acceleration during fluorination is used to probe the effect on grafting functionalities. Adatom clustering, which occurs with CF4 plasma treatment, is suppressed when higher kinetic energy is supplied to the ions. During SF6 plasma functionalization, the sulfur atoms tend to bond to bare copper areas instead of affecting the graphene chemistry, except when the kinetic energy of the ions is restricted. Using scanning photoelectron microscopy, with a 100 nm spatial resolution, the chemical bonding environment is evaluated in the fluorinated carbon network at selected regions and the functionalization homogeneity is controlled in individual graphene flakes.

Surface Effects on the Mott-Hubbard Transition in Archetypal V{2}O{3}.

We present an experimental and theoretical study exploring surface effects on the evolution of the metal-insulator transition in the model Mott-Hubbard compound Cr-doped V{2}O{3}. We find a microscopic domain formation that is clearly affected by the surface crystallographic orientation. Using scanning photoelectron microscopy and x-ray diffraction, we find that surface defects act as nucleation centers for the formation of domains at the temperature-induced isostructural transition and favor the formation of microscopic metallic regions. A density-functional theory plus dynamical mean-field theory study of different surface terminations shows that the surface reconstruction with excess vanadyl cations leads to doped, and hence more metallic, surface states, which explains our experimental observations.

Pharmacogenomic information in drug labels: European Medicines Agency perspective.

Pharmacogenomics (PGx) has a growing impact on healthcare and constitutes one of the major pillars of personalised medicine. For the purpose of improved individualised drug treatment, there is an increasing effort to develop drugs suitable for specific subpopulations and to incorporate pharmacogenomic drug labels in existing and novel medicines. Here, we review the pharmacogenomic drug labels of all 517 medicinal products centrally approved in the European Union (EU) since the establishment of the European Medicines Agency in 1995. We identified all pharmacogenomic-related information mentioned in the product labels and classified it according to its main effect and function on drug treatment, that is, metabolism, transport and pharmacodynamics, and according to the place of the respective section of the Summary of Product Characteristics (SmPC). The labels are preferentially present in drugs having antineoplastic properties. We find that the number of drugs with pharmacogenomic labels in EU increases now steadily and that it will be an important task for the future to refine the legislation on how this information should be utilised for improvement of drug therapy.

Gatekeepers and enablers: how drug regulators respond to a challenging and changing environment by moving toward a proactive attitude.

This article analyzes the role of regulatory authorities in facilitating innovation in the pharmaceutical sector. We describe how regulators are expanding their role to be not only gatekeepers but also enablers of development. They have already responded to the challenging and changing environment by moving toward a proactive attitude beyond evaluation of products, thereby more actively contributing to their development. Regulators have to continuously evolve their knowledge and standards alongside evolution in science. Creation of supportive regulatory frameworks and multistakeholder interaction will help address unmet regulatory needs.

Carcinocythaemia (carcinoma cell leukaemia) in a dog: an acute leukaemia-like picture due to metastatic carcinoma.

An eight-year-old entire female boxer was presented with a two-week history of anorexia and lethargy and two-day history of unilateral left epistaxis. Clinical findings and laboratory test results suggested disseminated intravascular coagulation. On blood smear evaluation, occasional large epithelioid-like unclassified cells were detected. Occasionally these cells were organised in small clusters. Bone marrow examination revealed a marked infiltration by a malignant population of the same epithelioid-like cells. The dog was euthanased because of the guarded prognosis. Following histology and immunohistochemistry, a widespread undifferentiated carcinoma of unknown primary origin was diagnosed. To the authors' knowledge, this is the first case of carcinoma cell leukaemia reported in a dog. Carcinoma cell leukaemia is a rare oncological condition previously described in humans, characterised by non-haematopoietic neoplastic cells in peripheral blood.

The advanced therapy classification procedure. Overview of experience gained so far.

The classification procedure, introduced by the European Regulation on advanced therapy medicinal products (ATMPs), has received a tremendous interest from companies, academic and public sponsors developing ATMPs. This procedure gives companies the opportunity to verify whether or not the product they are developing can be considered an ATMP and can therefore benefit from the new regulatory pathway introduced in the European Union for these types of medicinal products. This procedure is optional, free of charge and may take place at any stage of the development of an ATMP in advance of applying for a marketing authorisation. In case of doubt, briefing meetings organised by the European Medicines Agency Innovation Task Force may help preparing for an ATMP classification and are a starting point for the interactions between the Agency and the developers of ATMPs. This article reviews the advantages of the classification procedure for both the developers of ATMPs and the European regulatory network. Since the introduction of this procedure and up to 10 November 2010, the Committee for Advanced Therapies (CAT) has finalised 38 applications for classification.

Phenotype standardization for immune-mediated drug-induced skin injury.

Advances in genetic research and molecular biology techniques have made it possible to begin to characterize the underlying genetic factors that predispose patients to serious forms of drug-induced skin injury (DISI). To facilitate research in this area, we have set out standardized phenotypic definitions for (i) Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), (ii) acute generalized exanthematous pustulosis (AGEP), and (iii) hypersensitivity syndrome (HSS; also known as drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced hypersensitivity syndrome (DIHS)). A DISI Expert Working Group comprising participants with varied expertise reviewed and debated current terminology and diagnostic criteria for DISI and agreed on the minimum phenotypic criteria for selected forms of DISI (SJS/TEN, AGEP, and HSS). In addition, an algorithm has been developed to aid appropriate clinical categorization of patients with DISI. These standardized criteria will be important in facilitating adequate and accurate patient recruitment in order to advance research in pharmacogenomic, immunological, mechanistic, and epidemiological studies.

[Expression of thrombomodulin in malignant pleural mesothelioma]. / Espressione della trombomodulina nel mesotelioma maligno della pleura.

The malignant mesothelioma (MM) is often complicated by thromboembolic episodes, with thrombomodulin (TM) playing a role in the anti-coagulant process. We analyzed TM expression in biopsies of MM patients and in normal mesothelial tissue. The role of DNA methylation-associated gene silencing in TM expression was investigated. A correlation between low TM expression and high level of TM promoter methylation was found in MM biopsies. Low expression of TM was restored in MM cells by their treatment with 5-aza-2'-deoxycytidine while the epigenetic agent did not affect TM expression in Met-5A cells. Methylation of the TM promoter is responsible for silencing of TM expression in MM tissue.

Pharmacogenomics: role in medicines approval and clinical use.

Pharmacogenomics (PGx) and pharmacogenetics (PGt) are emerging interdisciplinary areas recently defined by the regulatory authorities at an international level as 'the investigation of variations of DNA and RNA characteristics as related to drug response' (PGx), and the study of 'the influence of variations in DNA sequence on drug efficacy and toxicity' (PGt). In recent years a number of studies have in fact produced growing evidence that, besides the effects of age, sex, diseases, and different drugs interactions, genetic factors play a role in the inter-individual variability of drugs response. The increasing genomic knowledge has also raised the profile and role of the so called 'genomic biomarkers' (GBs) in drug development, approval, and clinical use. The aims of this review are to (a) revisit the general understanding of the role of genomics and genetics in drug response, (b) provide an update on the definition and classification criteria of GBs as recently defined at a global level by regulatory agencies such as the European Medicines Agency and the Food and Drug Administration, and (c) illustrate with some examples current and potential applications of biomarkers in clinical practice and in drug development.

Electronic structure of cluster assembled nanostructured TiO(2) by resonant photoemission at the Ti L(2,3) edge.

The electronic structure of cluster assembled nanostructured TiO(2) thin films has been investigated by resonant photoemission experiments with photon energies across the Ti L(2,3) edge. The samples were produced by supersonic cluster beam deposition with a pulsed microplasma cluster source. The valence band shows resonance enhancements in the binding energy region between 4 and 8 eV, populated by O 2p and hybridized Ti 3d states, and in the region about 1 eV below the Fermi level associated with defects related Ti 3d states. The data show that in as-deposited films Ti atoms are mainly fully (sixfolds) coordinated to oxygen atoms in octahedral symmetry and only a small fraction is in a broken symmetry environment. Since resonant photoemission is closely linked to the local electronic and structural configurations around the Ti atom, it is possible to correlate the resonant photoemission intensity and lineshape with the presence of defects of the films and with the degree of hybridization between the titanium and oxygen atoms.

[Biomarkers for prevention and early diagnosis of malignant pleural mesothelioma]. / Utilizzo di biomarkers nella prevenzione e diagnosi precoce del Mesotelioma Maligno della pleura.

Improved detection methods for diagnosis of asymptomatic malignant pleural mesothelioma (MPM) are essential for an early and reliable detection and treatment of this disease. Thus, focus has been on finding tumour markers in the blood. 94 asbestos-exposed subjects, 22 patients with MM, and 54 healthy subjects were recruited for evaluation of the significance of 8-hydroxy-2'-deoxy-guanosine (80HdG) in white blood cells and plasma concentrations of soluble mesothelin-related peptides (SMRPs), angiogenic factors (PDGFbeta, HGF, bFGF, VEGFbeta), and matrix proteases (MMP2, MMP9, TIMP1, TIMP2) for potential early detection of MM. The area under ROC curves (AUC) indicates that 80HdG levels can discriminate asbestos-exposed subjects from controls but not from MPM patients. Significant AUC values were found for SMRP discriminating asbestos-exposed subjects from MPM patients but not from controls. VEGFbeta can significantly differentiate asbestos-exposed subjects from control and cancer groups. No diagnostic value was observed for MMP2, MMP9, TIMP1, TIMP2. The sensitivity and specificity results of markers were calculated at defined cut-offs. The combination of 80HdG, VEGFbeta and SMRPs best distinguished the individual groups, suggesting a potential indicator of early and advanced MPM cancers. The combination of blood biomarkers and radiographic findings could be used to stratify the risk of mesothelioma in asbestos-exposed populations.

[Study of a population exposed to occupational stress: correlation among psychometrics tests and biochemical-immunological parameters]. / Studio di una popolazione esposta a stress occupazionale: correlazione tra tests psicometrici e parametri biochimico-immunologici.

A longitudinal study was carried out to evaluate the effect of psycho-physical and occupational stress on some biochemical and immunological parameters. The study was aimed to the identification of new and reliable method for the identification of subjects at high risk of occupational stress. 101 nurses which were working at several departments were enrolled. A blood sample was collected from all subjects after have filled the questionnaires at the time T0 and at the followed time points of 4 months (T1), 8 months (T2) and 12 months (T3). The self-reported questionnaires were: Rating Scale for Rapid Stress Assessment (VRS), General Health Questionnaire to 12 items (GHQ-12) Multidimensional Scale of Perceived Social Support (MSPSS) and a questionnaire on the occupational satisfaction (SOD). Haemachrome glycaemia, homocysteine, cortisol, lymphocyte numbers and their subtypes (CD4, CD8, CD19, NK CD56, NK CD57), NK activity and inflammatory cytokines were evaluated. A high reliability has been found between the psychometric tests. Correlations between biochemical and immunological variables were performed by Pearson coefficients and multiple regression analysis. Subjects with elevated value of stress evaluated as VRS and GHQ-12 score showed an altered immune response. A reduction of NK CD57 and IL-6 content better characterize the occupational satisfaction.

[Preventing measures facilitate the preservation of the levels of employment]. / Interventi prevenzionistici possono consentire di conservare i livelli occupazionali.

The implementation of the European Directive No 391/89, among the other news, introduced the obligation for the occupational physician to actively participate to the assessment of risks. The reduction of the incidence of "historical" professional pathologies and the arising of work-related disease is making the role of the occupational physician, in the survey and risk assessment, ever more important, especially in consideration of the physiological and biomechanical peculiar competences required. In addition, a correct risk assessment allows to optimise the valorisation of human resources. The occupational physician, in other terms, can not only protect the health of workers, but "save" jobs too. The survey carried out in a logistic unit of a large-scale distributors group, documented herein, can give evidence of that.

[Low back pain in VDT operators: importance of sports activities]. / Disturbi muscoloscheletrici lombari in addetti al VDT: influenza dell'attività sportiva svolta nel tempo libero.

Video display terminal (VDT) operators are required to maintain a sitting position for extended periods of time. This transverse study assessed the prevalence of lumbar musculoskeletal disorders (low back pain, LBP) in a population of VDT operators and related results to occupational factors and other interfering variables. Data were collected using questionnaires administered to 210 public employees. LBP was defined and evaluated using the Standardized Nordic Questionnaire. The prevalence of LBP was 58.4%; it correlated significantly with the female sex, spinal disorders, sleep disturbances and stress levels. There was a significant negative correlation with exercise and sports activities and with leisure time computer use. Multiple logistic regression adjusted for age and body mass index yielded an LBP odds ratio of 0.19 (C.I.95% 0.07-0.51) for sport-practicing subjects. At least one hour of exercise weekly was the cut-off for a significant reduction in LBP prevalence. The proportion of lumbar musculoskeletal symptoms was not significantly different in VDT operators and the general population. None of the occupational variables considered correlated with development of LBP. The occupational physician should recommend VDT operators to devote some leisure time to exercise.