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The landscape and function of the immune infiltrate of intrahepatic cholangiocarcinoma (iCCA), a rare, yet aggressive tumor of the biliary tract, remains poorly characterized, limiting development of successful immunotherapies. Herein, we aimed to define the molecular characteristics of tumor-infiltrating leukocytes with a special focus on CD4+ regulatory T cells (Tregs).We used high-dimensional single-cell technologies to characterize the T-cell and myeloid compartments of iCCA tissues, comparing these with their tumor-free peritumoral and circulating counterparts. We further used genomics and cellular assays to define the iCCA-specific role of a novel transcription factor, mesenchyme homeobox 1 (MEOX1), in Treg biology.We found poor infiltration of putative tumor-specific CD39+ CD8+ T cells accompanied by abundant infiltration of hyperactivated CD4+ Tregs. Single-cell RNA-sequencing identified an altered network of transcription factors in iCCA-infiltrating compared to peritumoral T cells, suggesting reduced effector functions by tumor-infiltrating CD8+ T cells and enhanced immunosuppression by CD4+ Tregs. Specifically, we found that expression of MEOX1 was highly enriched in tumor-infiltrating Tregs, and demonstrated that MEOX1 overexpression is sufficient to reprogram circulating Tregs to acquire the transcriptional and epigenetic landscape of tumor-infiltrating Tregs. Accordingly, enrichment of the MEOX1-dependent gene program in Tregs was strongly associated with poor prognosis in a large cohort of patients with iCCA.We observed abundant infiltration of hyperactivated CD4+ Tregs in iCCA tumors along with reduced CD8+ T-cell effector functions. Interfering with hyperactivated Tregs should be explored as an approach to enhance antitumor immunity in iCCA.Immune cells have the potential to slow or halt the progression of tumors. However, some tumors, such as intrahepatic cholangiocarcinoma, are associated with very limited immune responses (and infiltration of cancer-targeting immune cells). Herein, we show that a specific population of regulatory T cells (a type of immune cell that actually suppresses the immune response) are hyperactivated in intrahepatic cholangiocarcinoma. Targeting these cells could enable cancer-targeting immune cells to act more effectively and should be looked at as a potential therapeutic approach to this aggressive cancer type.

After a short introduction of cultural models underlying the prevention policies of business risks, the manuscript explains, through an unconventional reading filtered by the systemic, socio-technical theoretical approach, how the competencies, as well as the role, of Italy’s HSE professionals evolved over years and what were the challenges that were faced and the opportunities caught. Starting from the description of the different cultural backgrounds owned by Italy’s Health, Safety, and Environment professionals, the paper explains how the HSE profiles evolved according to both the legislative and the societal evolution. Further, it explains how the HSE professionals, thanks to the contribution of the unions, the (industrials and practitioners) associations and the national (as well as regional) policies, evolved from the simple role of technicians to that of professionals and, finally, will (hopefully) evolve into that of HSE managers.

Sustainable development has become the cornerstone of environmental policy worldwide and a leading principle for innovative industrial processes. The philosophy lies in the progress in balance with nature that ensures the existing productive systems' survival through a new design paradigm shift. Even in the industrial framework, the sustainability concept should always drive technological innovation. The blended Life Cycle (LCA) and Risk assessment (RA) can accomplish this demanding goal to highlight the process's potential health and environmental impacts. LCA is the process that analyses and assesses the environmental impact of a material, product, or service throughout its entire life cycle. RA instead assesses imposed risks by inherent hazards of systems and substances both qualitatively or quantitatively. Different approaches typically drive LCA and RA, respectively a deterministic and a stochastic approach. This feature usually causes an unconnected use of LCA and RA quantifying the potential impact of products and processes and thus determines controversial decisions concerning a balance between environmental impacts and operational risks. The new paradigm suggests a unified blended LCA - RA approach with preliminary hazard identification, initially applied to an innovative Acid Gas to Syngas (AG2S™) process for carbon dioxide emission reduction and on-site reuse, avoiding costly and hazardous waste transportation steps.

This paper deals with a first-principle mathematical model that describes the electrostatic coalescer units devoted to the separation of water from oil in water-in-oil emulsions, which are typical of the upstream operations in oil fields. The main phenomena governing the behavior of the electrostatic coalescer are described, starting from fundamental laws. In addition, the gradual coalescence of the emulsion droplets is considered in the mathematical modeling in a dynamic fashion, as the phenomenon is identified as a key step in the overall yield of the unit operation. The resulting differential system with boundary conditions is then integrated via performing numerical libraries, and the simulation results confirm the available literature and the industrial data. A sensitivity analysis is provided with respect to the main parameters. The mathematical model results in a flexible tool that is useful for the purposes of design, unit behavior prediction, performance monitoring, and optimization.

Vanadium-based Redox Flow Batteries (VRFBs) seem to be a promising solution for medium and large storage systems required to smooth the fluctuating provision of solar and wind energy. Beside technological considerations, the challenge for VRFBs is the availability of vanadium, influenced by the high demand by the steel and chemical sectors and the small number of mines operating worldwide. Given vanadium's toxicity, the health, safety, and environmental (HSE) implications might, too, affect vanadium's availability. This study assesses the risks of supply disruptions associated with vanadium for VRFBs for the German market through the Holistic Risk Analysis and Modelling (HoRAM) method. The analysis includes not only technological parameters but also HSE and societal ones. In total, 242 variables were selected to characterize vanadium's supply chain. Considering a successful energy transformation in 2050, four logic-stochastic models were created to assess the supply risks associated with four different market shares of VRFBs at the storage market, i.e. 10%, 25%, 50%, and 100%. The most crucial factor influencing the overall risk of supply turned out to be mining activities. These are driven by a lack of qualified personnel, but the HSE and societal aspects can also hamper the supply chain. Therefore, both the Government and companies should consider these aspects to better orientate their future strategies. Of the four analysed market shares, surprisingly the 50% one has shown the lowest risk. Further, the mitigation strategy of opening the domestic market could reduce the risk of vanadium supply disruption, i.e. high impacts for VRFBs.

Oxidative stress and glucolipotoxicity have been associated with endothelial dysfunction, underlying the development of cardiovascular diseases (CVD), atherosclerosis and diabetes. Lipids are involved in cell signaling, proliferation, apoptosis and inflammation. Thus, analysis of lipid profiles in endothelial cells (EC) can reflect the molecular alterations occurring in endothelial dysfunction. In this study, we used hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) for the analysis of the phospholipids (PL) from bovine aortic EC exposed to oxidative (H2O2), glycative (glucose), or lipoxidative (4-hydroxynonenal, HNE) stress. We observed a sharper adaptation of the PL profile after treatment with H2O2, compared with the shifts due to treatment with glucose or HNE. Unsaturated PL species were up-regulated by H2O2, while an opposite trend was observed after treatment with glucose or HNE. Overall, distinct phospholipid signatures characterize EC in response to specific types of stress. Further studies are needed to validate the biological significance of these results.

Phosphatidylethanolamines (PEs) are a major class of phospholipids in cellular membranes and lipoproteins. Oxidation of PEs generates products exerting a vast number of biological functions, not totally unveiled yet. In vitro biomimetic models have been used to identify oxidized PEs and to develop analytical strategies for their targeted in vivo detection. Most models are based on radical oxidation, but the oxidative metabolism of PE also relies on controlled reactions catalyzed by enzymes as lipoxygenase (LOX), which can be mimicked by electrochemical (EC) oxidation. In this study, three PE standards were oxidized using an EC flow-through cell as a biomimetic model of oxidative injury. The oxidation products were identified by on-line EC-electrospray ionization mass spectrometry (ESI-MS and MS/MS). Long chain and short chain oxidation products were identified as modifications in the sn-2 acyl chain, whereas the oxidation pattern was dependent on the unsaturation level. Some of these oxidized species have already been observed during the modification of PEs driven by radical oxygen species (ROS), and among these products it was possible to characterize the oxidized isomers synthesized by 15-LOX in human immune cells. This EC-MS platform was, therefore, able to mimic the oxidative metabolism of PEs mediated by both ROS and enzymes.

Left atrial appendage occlusion (LAAO) is a non-pharmacological alternative for stroke prevention in high-risk patients with non-valvular atrial fibrillation. The aim of this real world retrospective registry was to obtain clinical data about procedural success, complications and mid-term outcomes