Tim-3-galectin-9 immunosuppressive pathway in human acute myeloid leukaemia and solid tumour cells and biochemical functions of its crucial components

Cancer is one of the primary causes of human death worldwide. Acute myeloid leukaemia (AML), one of the most severe types of blood/bone marrow cancers, is derived from transformed human myeloid precursor cells which developed mechanisms allowing them to escape host immune surveillance by inactivating cytotoxic lymphoid cells. Further studies suggested that solid tumours operate similar immune escape strategies. Molecular mechanisms of the immune evasion by malignant cells are poorly understood, however a better comprehension of the biochemistry underlying these processes are vital for development of anti-cancer immunotherapy - a cure of new generation. Recent evidence suggested the crucial involvement of Tim-3 and galectin-9 proteins in the immunosuppression operated by malignant cells. Therefore, the aim of our work was to investigate the activity of Tim-3-galectin-9 immunosuppressive pathway in human malignant cells and biochemical functions of its crucial components. We discovered that triggering of the receptor called latrophilin (LPHN) 1, expressed in AML cells but absent in healthy leukocytes, induces biosynthesis and exocytosis of T-cell immunoglobulin and mucin domain 3 (Tim-3) and galectin-9. Galectin-9 suppresses anti-cancer immunity by impairing anti-cancer activities of cytotoxic lymphoid cells. Tim-3 is trafficking galectin-9 but also can act on its own and prevent generation of interleukin-2 (IL-2) required for activation of cytotoxic lymphoid cells. Furthermore, AML cells recruit crucial components of normal human metabolism to escape surveillance and progress the disease. In particular, human adrenal cortex hormone cortisol upregulates LPHN1 expression in AML cells; blood-available fibronectin leucine rich transmembrane protein 3 (FLRT3) interacts with LPHN1 leading to galetin-9/Tim-3 synthesis and exocytosis in AML cells. Crucial components of FLRT3/LPHN/Tim-3/galectin-9 pathway are expressed in the majority of cancer cell lines and thus may be common for a variety of malignant tumours. Tim-3-galectin-9 pathway is active in breast cancer and variety of other solid tumour cells and is used to protect malignant cells from host immune attack. However, unlike some other members of galectin family of proteins (for example, galectin-3), galectin-9 doesn't protect cancer cells against apoptosis via mitochondrial defunctionalisation. On the other hand, mitochondrial defunctionalisation reduces galectin-9 surface expression and leads to its accumulation in mitochondria in malignant cells but not in healthy ones. Therefore, targeted mitochondrial defunctionalisation may be a novel strategy for anti-cancer immunotherapy, since it would reduce galectin-9 surface expression allowing better elimination of cancer cells by immune system cells. Taken together our work demonstrates for the first time that Tim-3-galectin-9 immunosuppressive pathway plays a pivotal role in protection of AML and various solid tumour cells towards host immune surveillance - the machinery operated by cytotoxic lymphoid cells

Fractional Calculus Approach to Reproduce Material Viscoelastic Behavior, including the Time–Temperature Superposition Phenomenon

The design of modern products and processes cannot prescind from the usage of viscoelastic materials that provide extreme design freedoms at relatively low cost. Correct and reliable modeling of these materials allows effective use that involves the design, maintenance, and monitoring phase and the possibility of reuse and recycling. Fractional models are becoming more and more popular in the reproduction of viscoelastic phenomena because of their capability to describe the behavior of such materials using a limited number of parameters with an acceptable accuracy over a vast range of excitation frequencies. A particularly reliable model parametrization procedure, using the poles-zeros formulation, allows researchers to considerably reduce the computational cost of the calibration process and avoid convergence issues typically occurring for rheological models. The aim of the presented work is to demonstrate that the poles-zeros identification methodology can be employed not only to identify the viscoelastic master curves but also the material parameters characterizing the time-temperature superposition phenomenon. The proposed technique, starting from the data concerning the isothermal experimental curves, makes use of the fractional derivative generalized model to reconstruct the master curves in the frequency domain and correctly identify the coefficients of the WLF function. To validate the methodology, three different viscoelastic materials have been employed, highlighting the potential of the material parameters' global identification. Furthermore, the paper points out a further possibility to employ only a limited number of the experimental curves to feed the identification methodology and predict the complete viscoelastic material behavior

Review on friction and wear test rigs: An overview on the state of the art in tyre tread friction evaluation

The future evolution of autonomous mobility and road transportation will require substantial improvements in tyre adherence optimization. As new technologies being deployed in tyre manufacturing reduce total vehicle energy consumption, the contribution of tyre friction for safety and performance enhancement continues to increase. For this reason, the tyre’s grip is starting to drive the focus of many tyre developments nowadays. This is because the tread compound attitude to maximize the interaction forces with the ground is the result of a mix of effects, involving polymer viscoelastic characteristics, road roughness profiles and the conditions under which each tyre works during its lifespan. In such a context, mainly concerning the automotive market, the testing, analysis and objectivation of the friction arising at the tread interface is performed by means of specific test benches called friction testers. This paper reviews the state of the art in such devices’ development and use, with a global overview of the measurement methodologies and with a classification based on the working and specimen motion principle. Most tyre friction testers allow one to manage the relative sliding speed and the contact pressure between the specimen and the counter-surface, while just some of them are able to let the user vary the testing temperature. Few devices can really take into account the road real roughness, carrying out outdoor measurements, useful because they involve actual contact phenomena, but very complex to control outside the laboratory environment

Study on the generalized formulations with the aim to reproduce the viscoelastic dynamic behavior of polymers

Appropriate modelling of the real behavior of viscoelastic materials is of fundamental importance for correct studies and analyses of structures and components where such materials are employed. In this paper, the potential to employ a generalized Maxwell model and the relative fraction derivative model is studied with the aim to reproduce the experimental behavior of viscoelastic materials. For both models, the advantage of using the pole-zero formulation is demonstrated and a specifically constrained identification procedure to obtain the optimum parameters set is illustrated. Particular emphasis is given on the ability of the models to adequately fit the experimental data with a minimum number of parameters, addressing the possible computational issues. The question arises about the minimum number of experimental data necessary to estimate the material behavior in a wide frequency range, demonstrating that accurate results can be obtained by knowing only the data of the upper and low frequency plateaus plus the ones at the loss tangent peak

A benchmark study on the model-based estimation of the go-kart side-slip angle

Nowadays, the active safety systems that control the dynamics of passenger cars usually rely on real-time monitoring of vehicle side-slip angle (VSA). The VSA can’t be measured directly on the production vehicles since it requires the employment of high-end and expensive instrumentation. To realiably overcome the VSA estimation problem, different model-based techniques can be adopted. The aim of this work is to compare the performance of different model-based state estimators, evaluating both the estimation accuracy and the computational cost, required by each algorithm. To this purpose Extended Kalman Filters, Unscented Kalman Filters and Particle Filters have been implemented for the vehicle system under analysis. The physical representation of the process is represented by a single-track vehicle model adopting a simplified Pacejka tyre model. The results numerical results are then compared to the experimental data acquired within a specifically designed testing campaign, able to explore the entire vehicle dynamic range. To this aim an electric go-kart has been employed as a vehicle, equipped with steering wheel encoder, wheels angular speed encoder and IMU, while an S-motion has been adopted for the measurement of the experimental VSA quantity

Cross-combined UKF for vehicle sideslip angle estimation with a modified Dugoff tire model: design and experimental results

Abstract: The knowledge of key vehicle states is crucial to guarantee adequate safety levels for modern passenger cars, for which active safety control systems are lifesavers. In this regard, vehicle sideslip angle is a pivotal state for the characterization of lateral vehicle behavior. However, measuring sideslip angle is expensive and unpractical, which has led to many years of research on techniques to estimate it instead. This paper presents a novel method to estimate vehicle sideslip angle, with an innovative combination of a kinematic-based approach and a dynamic-based approach: part of the output of the kinematic-based approach is fed as input to the dynamic-based approach, and vice-versa. The dynamic-based approach exploits an Unscented Kalman Filter (UKF) with a double-track vehicle model and a modified Dugoff tire model, that is simple yet ensures accuracy similar to the well-known Magic Formula. The proposed method is successfully assessed on a large amount of experimental data obtained on different race tracks, and compared with a traditional approach presented in the literature. Results show that the sideslip angle is estimated with an average error of 0.5 deg, and that the implemented cross-combination allows to further improve the estimation of the vehicle longitudinal velocity compared to current state-of-the-art techniques, with interesting perspectives for future onboard implementation

A New Approach for Estimating Tire-Road Longitudinal Forces for a Race Car

© 2019, Springer Nature Switzerland AG. In vehicle dynamics, the determination of the tire-road interaction forces plays a fundamental role in the analysis of vehicle behavior. This paper proposes a simple yet effective approach to estimate longitudinal forces. The proposed approach: i) is based on equilibrium equations; ii) analyses the peculiarities of driving and braking phases; iii) takes into account the interactions between vehicle sprung mass and unsprung mass. The unsprung mass is often neglected but that might lead to significant approximations, which are deemed unacceptable in performance or motorsport environments. The effectiveness of the proposed approach is assessed using experimental data obtained from a high performance racing car. Results show that the proposed approach estimates tire longitudinal forces with differences up to 10% when compared against a simpler formulation which uses only the overall mass of the vehicle. Therefore the distinction among vehicle sprung and unsprung masses, which is likely to be an easily obtainable piece of information in motorsport environments, is exploited in this approach to provide significant benefits in terms of longitudinal force estimation, ultimately aimed at maximizing vehicle performance

A real-time thermal model for the analysis of tire/road interaction in motorcycle applications

While in the automotive field the relationship between road adherence and tire temperature is mainly investigated with the aim to enhance the vehicle performance in motorsport, the motorcycle sector is highly sensitive to such theme also from less extreme applications. The small extension of the footprint, along with the need to guarantee driver stability and safety in the widest possible range of riding conditions, require that tires work as most as possible at a temperature able to let the viscoelastic compounds - constituting the tread and the composite materials of the whole carcass structure - provide the highest interaction force with soil. Moreover, both for tire manufacturing companies and for single track vehicles designers and racing teams, a deep knowledge of the thermodynamic phenomena involved at the ground level is a key factor for the development of optimal solutions and setup. This paper proposes a physical model based on the application of the Fourier thermodynamic equations to a three-dimensional domain, accounting for all the sources of heating like friction power at the road interface and the cyclic generation of heat due to rolling and to asphalt indentation, and for the cooling effects due to air forced convection, to road conduction and to turbulences in the inflation chamber. The complex heat exchanges in the system are fully described and modelled, with particular reference to the management of contact patch position, correlated to camber angle and requiring the adoption of an innovative multi-ribbed and multilayered tire structure. The completely physical approach induces the need of a proper parameterization of the model, whose main stages are described, both from the experimental and identification points of view, with particular reference to non-destructive procedures for thermal parameters definition

Mitochondrial Defunctionalization Supresses Tim-3-Galectin-9 Secretory Pathway in Human Colorectal Cancer Cells and Thus Can Possibly Affect Tumor Immune Escape

The Tim-3-galectin-9 secretory pathway is known to protect various types of cancer cells against host immune surveillance. We found that pharmacologically induced mitochondrial dysfunction leads to a reduced galectin-9 expression/exocytosis in human colorectal cancer cells and re-distribution of this protein (the effect described for various cellular proteins) into mitochondria