Applied immuno-epidemiological research: an approach for integrating existing knowledge into the statistical analysis of multiple immune markers.

BACKGROUND: Immunologists often measure several correlated immunological markers, such as concentrations of different cytokines produced by different immune cells and/or measured under different conditions, to draw insights from complex immunological mechanisms. Although there have been recent methodological efforts to improve the statistical analysis of immunological data, a framework is still needed for the simultaneous analysis of multiple, often correlated, immune markers. This framework would allow the immunologists' hypotheses about the underlying biological mechanisms to be integrated. RESULTS: We present an analytical approach for statistical analysis of correlated immune markers, such as those commonly collected in modern immuno-epidemiological studies. We demonstrate i) how to deal with interdependencies among multiple measurements of the same immune marker, ii) how to analyse association patterns among different markers, iii) how to aggregate different measures and/or markers to immunological summary scores, iv) how to model the inter-relationships among these scores, and v) how to use these scores in epidemiological association analyses. We illustrate the application of our approach to multiple cytokine measurements from 818 children enrolled in a large immuno-epidemiological study (SCAALA Salvador), which aimed to quantify the major immunological mechanisms underlying atopic diseases or asthma. We demonstrate how to aggregate systematically the information captured in multiple cytokine measurements to immunological summary scores aimed at reflecting the presumed underlying immunological mechanisms (Th1/Th2 balance and immune regulatory network). We show how these aggregated immune scores can be used as predictors in regression models with outcomes of immunological studies (e.g. specific IgE) and compare the results to those obtained by a traditional multivariate regression approach. CONCLUSION: The proposed analytical approach may be especially useful to quantify complex immune responses in immuno-epidemiological studies, where investigators examine the relationship among epidemiological patterns, immune response, and disease outcomes

Investigation of the key chemical structures involved in the anticancer activity of disulfiram in A549 non-small cell lung cancer cell line

© 2018 The Author(s). Background: Disulfiram (DS), an antialcoholism medicine, demonstrated strong anticancer activity in the laboratory but did not show promising results in clinical trials. The anticancer activity of DS is copper dependent. The reaction of DS and copper generates reactive oxygen species (ROS). After oral administration in the clinic, DS is enriched and quickly metabolised in the liver. The associated change of chemical structure may make the metabolites of DS lose its copper-chelating ability and disable their anticancer activity. The anticancer chemical structure of DS is still largely unknown. Elucidation of the relationship between the key chemical structure of DS and its anticancer activity will enable us to modify DS and speed its translation into cancer therapeutics. Methods: The cytotoxicity, extracellular ROS activity, apoptotic effect of DS, DDC and their analogues on cancer cells and cancer stem cells were examined in vitro by MTT assay, western blot, extracellular ROS assay and sphere-reforming assay. Results: Intact thiol groups are essential for the in vitro cytotoxicity of DS. S-methylated diethyldithiocarbamate (S-Me-DDC), one of the major metabolites of DS in liver, completely lost its in vitro anticancer activity. In vitro cytotoxicity of DS was also abolished when its thiuram structure was destroyed. In contrast, modification of the ethyl groups in DS had no significant influence on its anticancer activity. Conclusions: The thiol groups and thiuram structure are indispensable for the anticancer activity of DS. The liver enrichment and metabolism may be the major obstruction for application of DS in cancer treatment. A delivery system to protect the thiol groups and development of novel soluble copper-DDC compound may pave the path for translation of DS into cancer therapeutics.This work was supported by grant from British Lung Foundation (RG14–8) and Innovate UK (104022).Published versio

Endothelial Cells Obtained from Patients Affected by Chronic Venous Disease Exhibit a Pro-Inflammatory Phenotype

The inflammatory properties of vein endothelium in relation to chronic venous disease (CVD) have been poorly investigated. Therefore, new insights on the characteristics of large vein endothelium would increase our knowledge of large vessel physiopathology. METHODOLOGY/PRINCIPAL FINDINGS: Surgical specimens of veins were obtained from the tertiary venous network (R3) and/or saphenous vein (SF) of patients affected by CVD and from control individuals. Highly purified venous endothelial cell (VEC) cultures obtained from CVD patients were characterized for morphological, phenotypic and functional properties compared to control VEC. An increase of CD31/PECAM-1, CD146 and ICAM-1 surface levels was documented at flow cytometry in pathological VEC with respect to normal controls. Of note, the strongest expression of these pro-inflammatory markers was observed in VEC obtained from patients with more advanced disease. Similarly, spontaneous cell proliferation and resistance to starvation was higher in pathological than in normal VEC, while the migratory response of VEC showed an opposite trend, being significantly lower in VEC obtained from pathological specimens. In addition, in keeping with a higher baseline transcriptional activity of NF-kB, the release of the pro-inflammatory cytokines osteoprotegerin (OPG) and vascular endothelial growth factor (VEGF) was higher in pathological VEC cultures with respect to control VEC. Interestingly, there was a systemic correlation to these in vitro data, as demonstrated by higher serum OPG and VEGF levels in CVD patients with respect to normal healthy controls. CONCLUSION/SIGNIFICANCE: Taken together, these data indicate that large vein endothelial cells obtained from CVD patients exhibit a pro-inflammatory phenotype, which might significantly contribute to systemic inflammation in CVD patients

Thermal weakening friction during seismic slip experiments and models with heat sources and sinks

Experiments that systematically explore rock friction under crustal earthquake conditions reveal that faults undergo abrupt dynamic weakening. Processes related to heating and weakening of fault surfaces have been invoked to explain pronounced velocity weakening. Both contact asperity temperature Ta and background temperature T of the slip zone evolve significantly during high-velocity slip due to heat sources (frictional work), heat sinks (e.g., latent heat of decomposition processes), and diffusion. Using carefully calibrated High-Velocity Rotary Friction experiments, we test the compatibility of thermal weakening models: (1) a model of friction based only on T in an extremely simplified, Arrhenius-like thermal dependence; (2) a flash heating model which accounts for the evolution of both V and T; (3) same but including heat sinks in the thermal balance; and (4) same but including the thermal dependence of diffusivity and heat capacity. All models reflect the experimental results but model (1) results in unrealistically low temperatures and model (2) reproduces the restrengthening phase only by modifying the parameters for each experimental condition. The presence of dissipative heat sinks in stage (3) significantly affects T and reflects on the friction, allowing a better joint fit of the initial weakening and final strength recovery across a range of experiments. Temperature is significantly altered by thermal dependence of (4). However, similar results can be obtained by (3) and (4) by adjusting the energy sinks. To compute temperature in this type of problem, we compare the efficiency of three different numerical approximations (finite difference, wavenumber summation, and discrete integral)

reference architecture and framework

M. Adorni, F. Arcelli, S. Bandini, L. Baresi, C. Batini, A. Bianchi, D. Bianchini, M. Brioschi, A. Caforio, A. Cali, P. Cappellari, C. Cappiello, T. Catarci, A. Corallo, V. De Antonellis, C. Franza, G. Giunta, A. Limonta, G. Lorenzo, P. Losi, A. Maurino, M. Melideo, D. Micucci, S. Modafferi, E. Mussi, L. Negri, C. Pandolfo, B. Pernici, P. Plebani, D. Ragazzi, C. Raibulet, M. Riva, N. Simeoni, C. Simone, G. Solazzo, F. Tisato, R. Torlone, G. Vizzari, and A. Zill

Workflow to numerically reproduce laboratory ultrasonic datasets

The risks and uncertainties related to the storage of high-level radioactive waste (HLRW) can be reduced thanks to focused studies and investigations. HLRWs are going to be placed in deep geological repositories, enveloped in an engineered bentonite barrier, whose physical conditions are subjected to change throughout the lifespan of the infrastructure. Seismic tomography can be employed to monitor its physical state and integrity. The design of the seismic monitoring system can be optimized via conducting and analyzing numerical simulations of wave propagation in representative repository geometry. However, the quality of the numerical results relies on their initial calibration. The main aim of this paper is to provide a workflow to calibrate numerical tools employing laboratory ultrasonic datasets. The finite difference code SOFI2D was employed to model ultrasonic waves propagating through a laboratory sample. Specifically, the input velocity model was calibrated to achieve a best match between experimental and numerical ultrasonic traces. Likely due to the imperfections of the contact surfaces, the resultant velocities of P- and S-wave propagation tend to be noticeably lower than those a priori assigned. Then, the calibrated model was employed to estimate the attenuation in a montmorillonite sample. The obtained low quality factors (Q) suggest that pronounced inelastic behavior of the clay has to be taken into account in geophysical modeling and analysis. Consequently, this contribution should be considered as a first step towards the creation of a numerical tool to evaluate wave propagation in nuclear waste repositories