Doxorubicin-induced skeletal muscle atrophy:Elucidating the underlying molecular pathways

AIM: Loss of skeletal muscle mass is a common clinical finding in cancer patients. The purpose of this meta-analysis and systematic review was to quantify the effect of doxorubicin on skeletal muscle and report on the proposed molecular pathways possibly leading to doxorubicin-induced muscle atrophy in both human and animal models. METHODS: A systematic search of the literature was conducted in PubMed, EMBASE, Web of Science and CENTRAL databases. The internal validity of included studies was assessed using SYRCLE's risk of bias tool. RESULTS: Twenty eligible articles were identified. No human studies were identified as being eligible for inclusion. Doxorubicin significantly reduced skeletal muscle weight (ie EDL, TA, gastrocnemius and soleus) by 14% (95% CI: 9.9; 19.3) and muscle fibre cross-sectional area by 17% (95% CI: 9.0; 26.0) when compared to vehicle controls. Parallel to negative changes in muscle mass, muscle strength was even more decreased in response to doxorubicin administration. This review suggests that mitochondrial dysfunction plays a central role in doxorubicin-induced skeletal muscle atrophy. The increased production of ROS plays a key role within this process. Furthermore, doxorubicin activated all major proteolytic systems (ie calpains, the ubiquitin-proteasome pathway and autophagy) in the skeletal muscle. Although each of these proteolytic pathways contributes to doxorubicin-induced muscle atrophy, the activation of the ubiquitin-proteasome pathway is hypothesized to play a key role. Finally, a limited number of studies found that doxorubicin decreases protein synthesis by a disruption in the insulin signalling pathway. CONCLUSION: The results of the meta-analysis show that doxorubicin induces skeletal muscle atrophy in preclinical models. This effect may be explained by various interacting molecular pathways. Results from preclinical studies provide a robust setting to investigate a possible dose-response, separate the effects of doxorubicin from tumour-induced atrophy and to examine underlying molecular pathways. More research is needed to confirm the proposed signalling pathways in humans, paving the way for potential therapeutic approaches

A state-of-the-art review of curve squeal noise: Phenomena, mechanisms, modelling and mitigation

[EN] Curve squeal is an intense tonal noise occurring when a rail vehicle negotiates a sharp curve. The phenomenon can be considered to be chaotic, with a widely differing likelihood of occurrence on different days or even times of day. The term curve squeal may include several different phenomena with a wide range of dominant frequencies and potentially different excitation mechanisms. This review addresses the different squeal phenomena and the approaches used to model squeal noise; both time-domain and frequency-domain approaches are discussed and compared. Supporting measurements using test rigs and field tests are also summarised. A particular aspect that is addressed is the excitation mechanism. Two mechanisms have mainly been considered in previous publications. In many early papers the squeal was supposed to be generated by the so-called falling friction characteristic in which the friction coefficient reduces with increasing sliding velocity. More recently the mode coupling mechanism has been raised as an alternative. These two mechanisms are explained and compared and the evidence for each is discussed. Finally, a short review is given of mitigation measures and some suggestions are offered for why these are not always successful.Squicciarini, G.; Thompson, D.; Ding, B.; Baeza González, LM. (2018). A state-of-the-art review of curve squeal noise: Phenomena, mechanisms, modelling and mitigation. Notes on Numerical Fluid Mechanics and Multidisciplinary Design. 139:3-41. https://doi.org/10.1007/978-3-319-73411-8_1S341139Anderson, D., Wheatley, N., Fogarty, B., Jiang, J., Howie, A., Potter, W.: Mitigation of curve squeal noise in Queensland, New South Wales and South Australia. In: Conference on Railway Engineering. pp. 625–636, Perth, Australia (2008)Hanson, D., Jiang, J., Dowdell, B., Dwight, R.: Curve squeal: causes, treatments and results. 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Veh. Syst. Dyn. 44(sup1), 261–271 (2006)Giménez, J.G., Alonso, A., Gómez, E.: Introduction of a friction coefficient dependent on the slip in the FastSim algorithm. Veh. Syst. Dyn. 43(4), 233–244 (2005)Chiello, O., Ayasse, J.B., Vincent, N., Koch, J.R.: Curve squeal of urban rolling stock—part 3: theoretical model. J. Sound Vib. 293(3), 710–727 (2006)Collette, C.: Importance of the wheel vertical dynamics in the squeal noise mechanism on a scaled test bench. Shock Vibr. 19(2), 145–153 (2012)Brunel, J.F., Dufrénoy, P., Naït, M., Muñoz, J.L., Demilly, F.: Transient models for curve squeal noise. J. Sound Vib. 293(3), 758–765 (2006)Glocker, C., Cataldi-Spinola, E., Leine, R.I.: Curve squealing of trains: measurement, modelling and simulation. J. Sound Vib. 324(1), 365–386 (2009)Pieringer, A.: A numerical investigation of curve squeal in the case of constant wheel/rail friction. J. 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Springer, Heidelberg (2015)Zenzerovic, I., Kropp, W., Pieringer, A.: An engineering time-domain model for curve squeal: tangential point-contact model and Green’s functions approach. J. Sound Vib. 376, 149–165 (2016)Pieringer, A., Torstensson, P.T., Giner, J., Baeza, L.: Investigation of railway curve squeal using a combination of frequency- and time-domain models. In: Anderson, D., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 139, pp 81–93. Springer, Heidelberg (2018)Chen, G.X., Xiao, J.B., Liu, Q.Y., Zhou. Z.R.: Complex eigenvalue analysis of railway curve squeal. In: Schulte-Werning, B., et al. (eds.) Noise and Vibration Mitigation for Rail Transportation Systems. NNFM, vol. 99, pp. 433–439. Springer, Heidelberg (2008)Fourie, D.J., Gräbe, P.J., Heyns, P.S., Fröhling, R.D.: Analysis of wheel squeal due to unsteady longitudinal creepage using the complex eigenvalue method. In: Anderson, D., et al. (eds.) 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Railway-induced ground vibrations – a review of vehicle effects

This paper is a review of the effect of vehicle characteristics on ground- and track borne-vibrations from railways. It combines traditional theory with modern thinking and uses a range of numerical analysis and experimental results to provide a broad analysis of the subject area. First, the effect of different train types on vibration propagation is investigated. Then, despite not being the focus of this work, numerical approaches to vibration propagation modelling within the track and soil are briefly touched upon. Next an in-depth discussion is presented related to the evolution of numerical models, with analysis of the suitability of various modelling approaches for analysing vehicle effects. The differences between quasi-static and dynamic characteristics are also discussed with insights into defects such as wheel/rail irregularities. Additionally, as an appendix, a modest database of train types are presented along with detailed information related to their physical attributes. It is hoped that this information may provide assistance to future researchers attempting to simulate railway vehicle vibrations. It is concluded that train type and the contact conditions at the wheel/rail interface can be influential in the generation of vibration. Therefore, where possible, when using numerical approach, the vehicle should be modelled in detail. Additionally, it was found that there are a wide variety of modelling approaches capable of simulating train types effects. If non-linear behaviour needs to be included in the model, then time domain simulations are preferable, however if the system can be assumed linear then frequency domain simulations are suitable due to their reduced computational demand

UN Peacekeeping at 75: Achievements, Challenges, and Prospects

This year marks the 75th anniversary of what the UN itself understands to be its first peacekeeping operation. It is therefore an appropriate time to reflect on the track record of UN peacekeeping in its efforts to try to maintain and realize peace and security. Moreover, this milestone invites us to ponder what lies ahead in the realm of peacekeeping. For this reason, this forum article brings together both academics and UN officials to assess the achievements and challenges of UN peacekeeping over the past 75 years. Through a dialogue among peacekeeping scholars and practitioners, we hope to identify current trends and developments in UN peacekeeping, as well as explore priorities for the future to improve the effectiveness of peacekeeping operations in terms of achieving their mandate objectives, such as maintaining peace, protecting civilians, promoting human rights, and facilitating reconciliation. This forum article is structured into six thematic sections, each shedding light on various aspects of UN peacekeeping: (1) foundational principles of UN peacekeeping - namely, consent, impartiality, and the (non-)use of force; (2) protection of civilians; (3) the primacy of politics; (4) early warning; (5) cooperation with regional organizations; and (6) the changing geopolitical landscape in which UN peacekeeping operates

Unusual Patterns of Thoracic Metastasis of Urinary Bladder Carcinoma

Urinary bladder carcinoma (UBC) is the ninth most common malignancy and the second most common urological malignancy after prostate cancer in men. Thoracic metastases occur in more than half of those with muscle-invasive disease, and these generally assume the form of multiple solid parenchymal lesions characteristic of hematogenous seeding of the lung. Unusual patterns of thoracic spread of UBC have also been described albeit sporadically in the form of case reports and series. The aim of our case series is to provide illustrations of several atypical patterns of thoracic involvement by UBC such as isolated mediastinal lymphadenopathy, cavitary lung metastases, malignant pleural effusion, endobronchial disease, and pulmonary tumor embolism. This review is meant to highlight the intersection of the fields of urological oncology and thoracic radiology in the care of patients with UBC