Prostate hyperthermia and photodynamic therapy can be delivered by a variety of procedures which result in a wide range of temperatures and light energy and cause different kinds of cell death.
We ...have addressed the immunogenic effect of heating and UVC irradiation on the prostate cancer (PCa) cell line LNCaP, by studying the release of Danger Associated Molecule Pattern (DAMP) molecules HSP70 and HMGB1 and the dendritic cell (DC) antigen-presenting efficiency.
Intracellular upmodulation and extracellular release of HSP70 were inversely correlated. Mild temperatures (43-47 degrees C) induced an early increase of intracellular HSP70, whereas the highest temperature (56 degrees C) induced its extrusion from the cell. Likewise, UVC caused an immediate migration of HSP70 into the cell medium in the absence of any intracellular modulation. 56 degrees C and UVC also induced a robust release of HMGB1. The release of DAMP molecules was closely associated with post-apoptotic membrane damage, as shown by double Annexin V/propidium iodide staining, whereas beta-tubulin, a structural component of cell membranes, was specifically induced by 56 degrees C heating. Tumor uptake strongly impaired the cytokine-driven maturation of DCs and 56 degrees C heating led to a significant recovery of CD83 and CCR7 DC maturation markers, but did not influence the antigen cross-presentation activity. On the contrary, UVC-treated LNCaP had negligible effects on DC maturation, but increased the cross-priming of tumor specific CTL.
These data may be of use in the design of effective non-surgical PCa ablations that combine tumor destruction with long lasting immunity.
Dendritic cells (DC) operate through an immature (iDC) step (where tumor antigens are internalized) and a mature step (mDC) (where tumor antigens (TA) are cross-presented to naive TA-specific ...cytotoxic T lymphocyte (CTL) progenitors). Receptors by which cellbound antigens can access the DC cross-presentation pathway include the Fcgamma receptors (FcgammaR). This route has been exploited to deliver opsonized tumors to DC and promising results have been obtained with mAbs raised against overexpressed or specific tumor antigens. In order to extend this strategy to tumor for which no antigens have been described, we have exploited the ubiquitous molecule MHC Class I as target antigen. The low membrane expression of tumor antigens on KATO cells, a previously studied human gastric carcinoma cell line, suggested its use here as a model. The IgG1 TP25.99 and the IgG2a W6/32 anti-MHC Class I mAbs, which strongly reacted with KATO cells, where employed as tumor coating mAbs. Since these mAbs recognize the FcgammaRI (CD64) and FcgammaRIII (CD16), respectively on DCs, the frequencies of the two classes of FcgammaRI on DCs was evaluated. CD64 was expressed on 35% of iDCs compared to 11% expression of CD16, the two molecules being co-expressed. IgG1 mAb-opsonized KATO (KATO(TP25)) cells were taken up by iDCs with the same efficiency as KATO cells opsonized with IgG2a mAb (KATO(W6/32)), but induced a higher expression of the maturation marker CD83. CTL cross-priming by KATO(TP25) (but not KATO(W6/32))-loaded and cytokine-matured DCs was also higher than cross-priming induced by uncoated- or FcgammaRI-targeted KATO(W6/32)-DC. Together the present results indicate that: (i) MHC Class I antigens are advantageous antigens for targeting tumor cells to the FcgammaR-mediated cross-presentation pathway and (ii) immunogenic signals seem to be prevalently conveyed by FcgammaRIII.
Managing the lifecycle of the elements of a complex and safety-critical system, from conceptual design to support in operation, is still a relevant challenge in the industrial domain. Starting from ...research and engineering activities, up to production and delivery, the need of maintaining the trace of dependence, changes, and possible updates regarding the final product is a crucial aspect for success. Particularly, conceptual and preliminary design activities are affected by a high level of uncertainty and a certain degree of project instability, usually caused by the need to explore alternative solutions and variants. Different tasks are performed concerning the identification of system requirements, functional and physical behavior using model-based design (MBD), and model-based systems engineering, which, generally, are subjected to extensive trade studies aimed at identifying the best solution. In this context, this paper presents how model-based digital twin and threads concepts will likely change the way in which the MBD process is managed, overcoming the issues associated with federated IT infrastructures and with tools integration. Notably, lifecycle and nonlifecycle related interoperability aspects are described, with particular focus on the exploitation of standards for lifecycle collaboration and heterogeneous simulation. The design of an ice protection system for a regional aircraft is selected as case study, starting from the work performed by the authors within the EC-funded research project CRYSTAL.
In this study, we present a novel and environmentally sustainable protocol for the γ-hydrofunctionalization of N-allenyl compounds using various heteronucleophiles catalyzed solely by simple Brønsted ...acids. The method displays remarkable attributes, highlighting its sustainability, efficiency, regio- and stereoselectivity, as well as its versatile applicability to diverse heteroatom-containing enamides. Notably, our approach eliminates the need for metal catalysts and toxic solvents, representing a significant advancement in greener chemistry practices. We demonstrate the broad scope of our protocol by successfully scaling up reactions to gram-scale syntheses, underscoring its robustness for potential industrial implementation. The resulting γ-heterosubstituted enamides offer new possibilities for further synthetic transformations, yielding highly functionalized compounds with diverse applications. Mechanistic investigations reveal the pivotal role of CSA as a catalyst, enabling alcohol addition via a covalent activation mode.
Sustainability issues are becoming increasingly prominent in applications requiring the use of heavy-duty engines. Therefore, it is important to cut the emissions and costs of such engines to reduce ...the carbon footprint and keep the operating expenses under control. Even if for some applications a battery electric equipment is introduced, the diesel-equipped machinery is still popular thanks to the longer operating range. In this field, the open pit mines are a good example. In fact, the Total Cost of Ownership (TCO) of the mining equipment is highly impacted by fuel consumption (engine efficiency) and reliability (service interval and engine life). The present work is focused on efficiency enhancements achievable through the application of a combustion control strategy based on the in-cylinder pressure information. The benefits are mainly due to two factors. First, the negative effects of injectors aging can be compensated. Second, cylindrical online calibration of the control parameters enables the combustion system optimization. The article is divided into two parts. The first part describes the toolchain that is designed for the real-time application of the combustion control system, while the second part concerns the algorithm that would be implemented on the Engine Control Unit (ECU) to leverage the in-cylinder pressure information. The assessment of the potential benefits and feasibility of the combustion control algorithm is carried out in a Software in the Loop (SiL) environment, simulating both the developed control strategy and the engine behavior (Liebherr D98). Our goal is to validate the control algorithm through SiL simulations. The results of the validation process demonstrate the effectiveness of the control strategy: firstly, cylinder disparity on IMEP (+/−2.5% in reference conditions) is virtually canceled. Secondly, MFB50 is individually optimized, equalizing Pmax among the cylinders (+/−4% for the standard calibration) without exceeding the reliability threshold. In addition to this, BSFC is reduced by 1% thanks to the accurate cylinder-by-cylinder calibration. Finally, aging effects or fuel variations can be implicitly compensated, keeping optimal performance thorough the engine life.
This work focuses on the implementation of innovative adaptive strategies and a closed-loop chain in a piston-damage-based combustion controller. In the previous paper (Part 1), implemented models ...and the open loop algorithm are described and validated by reproducing some vehicle maneuvers at the engine test cell. Such controller is further improved by implementing self-learning algorithms based on the analytical formulations of knock and the combustion model, to update the fuel Research Octane Number (RON) and the relationship between the combustion phase and the spark timing in real-time. These strategies are based on the availability of an on-board indicating system for the estimation of both the knock intensity and the combustion phase index. The equations used to develop the adaptive strategies are described in detail. A closed-loop chain is then added, and the complete controller is finally implemented in a Rapid Control Prototyping (RCP) device. The controller is validated with specific tests defined to verify the robustness and the accuracy of the adaptive strategies. Results of the online validation process are presented in the last part of the paper and the accuracy of the complete controller is finally demonstrated. Indeed, error between the cyclic and the target combustion phase index is within the range ±0.5 Crank Angle degrees (°CA), while the error between the measured and the calculated maximum in-cylinder pressure is included in the range ±5 bar, even when fuel RON or spark advance map is changing.
The sustainability of mines is becoming ever more important to reduce the
greenhouse gas footprint and keep the resources extraction economically
sustainable. Despite the electrification and ...hybridization trend of mining
equipment, diesel engines are still expected to maintain their importance as a
primary source of power especially for open pit equipment, thanks to their
longer operating range. However, in order to keep high efficiency and minimize
fuel consumption for the entire operating life it is crucial to understand and
tackle the aging effect on the engine performance. In this research a 500-h
durability test was performed on a Liebherr mining engine, with the aim of
better understanding how aging affects the combustion process and engine
performance (power and fuel consumption), and how this effect can be
compensated. Experimental results show a 1% specific fuel consumption increase,
ascribable to injector aging. Moreover, with the objective of emphasizing other
possible opportunities to further reduce fuel consumption, the possibility of
cancelling cylinder-to-cylinder disparities (maximum IMEP variations of 7%
compared to the average value of 12 cylinders) and optimizing the calibration
setting near the reliability limits (BSFC decrease by 0.7%, compared to the base
calibration) were investigated in the article. The role of cylinder
pressure-based closed-loop control systems as enabling technology to seize these
potential benefits is discussed in this article.
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