Transglutaminase 2 (TG2) is a critical cancer cell survival factor that activates several signaling pathways to foster drug resistance, cancer stem cell survival, metastasis, inflammation, epithelial mesenchymal transition, and angiogenesis. All-trans retinoic acid (ATRA) and chemotherapy have been the standard treatments for acute promyelocytic leukemia (APL), but clinical studies have shown that arsenic trioxide (ATO), alone or in combination with ATRA, can improve outcomes. ATO exerts cytotoxic effects in a variety of ways by inducing oxidative stress, genotoxicity, altered signal transduction, and/or epigenetic modification. In the present study, we showed that ATO increased ROS production and apoptosis ratios in ATRA-differentiated NB4 leukemia cells and that these responses were enhanced when TG2 was deleted. The combined ATRA+ATO treatment also increased the amount of nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor, an adaptive regulator of cellular oxidative stress response, and proteolytic activity of calpain, resulting in TG2 degradation and reduced survival of WT leukemia cells. We further showed that upon ATO treatment, the induced TG2 protein expression was degraded in the MCF-7 epithelial cell line, and primary peripheral blood mononuclear cells, thereby sensitizing these cell types to apoptotic signals.

There is increasing interest in automating train operations of mainline services, e.g. to increase network capacity. Automatic train operation (ATO) is already achieved by several pilot projects, but not implemented on a large scale. Before the general introduction of new or adapted technologies can have a transformative effect on the operation of such a complex system as train operation on mainlines, they have to pass functional, interoperability and performance tests. A virtual preliminary analysis is one way to ensure a smooth as well as safe introduction and implementation. This paper aims to present an approach that applies to the performance testing of ATO systems. Therefore, methods and test standards for technologies enabling automatic operation in other transport sectors are reviewed. The main findings have been adapted, transformed and combined to be used as a general strategy for virtual performance testing in the railway sector. Specifically, universal performance indicators, namely punctuality, accuracy, energy consumption, safety and comfort, are presented. A layer model for scenario description is adapted from the automotive sector, as well as the definition of different scenario types. Lastly, factors that can influence the performance of an ATO algorithm are identified. To demonstrate the developed approach, a straightforward investigation of a case study is conducted using a microscopic train simulator in combination with an ATO algorithm.

In this review, we highlight new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in APL. PML-RARa sets the cellular landscape of Acute promyelocytic leukemia (APL) by repressing transcription of RARa target genes and disrupting PML-NBs. RAR receptors control the homeostasis of tissue growth, modeling and regeneration, PML NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. Additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. Treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. Resistance to ATRA and ATO may derive from mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5-10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or induction of apoptosis in APL cells.

This study investigates the use of Au-doped Pd anodic electrocatalysts on ATO support for the conversion of methane to methanol. The study involves cyclic voltammetry, in-situ Raman spectra, polarization curves, and FTIR analysis to determine the optimal composition of gold and palladium for enhancing the conversion process. The results demonstrate the potential for utilizing methane as a feedstock for producing sustainable energy sources. Pd75Au25/ATO electrode exhibited the highest OCP value, and Pd50Au50/ATO had the highest methanol production value at a potential of 0.05 V. Therefore, it can be concluded that an optimal composition of gold and palladium exists to enhance the conversion of methane to methanol. The findings contribute to the development of efficient and sustainable energy sources, highlighting the importance of exploring alternative ways to produce methanol.