Mechanisms regulating immune surveillance of cellular stress in cancer

The purpose of this review is to explore immune-mediated mechanisms of stress surveillance in cancer, with particular emphasis on the idea that all cancers have classical hallmarks (Hanahan and Weinberg in Cell 100:57–70, 67; Cell 144:646–674, 68) that could be interrelated. We postulate that hallmarks of cancer associated with cellular stress pathways (Luo et al. in Cell 136:823–837, 101) including oxidative stress, proteotoxic stress, mitotic stress, DNA damage, and metabolic stress could define and modulate the inflammatory component of cancer. As such, the overarching goal of this review is to define the types of cellular stress that cancer cells undergo, and then to explore mechanisms by which immune cells recognize, respond to, and are affected by each stress response.     

Prion protein cleavage fragments regulate adult neural stem cell quiescence through redox modulation of mitochondrial fission and SOD2 expression

Neurogenesis continues in the post-developmental brain throughout life. The ability to stimulate the production of new neurones requires both quiescent and actively proliferating pools of neural stem cells (NSCs). Actively proliferating NSCs ensure that neurogenic demand can be met, whilst the quiescent pool makes certain NSC reserves do not become depleted. The processes preserving the NSC quiescent pool are only just beginning to be defined. Herein, we identify a switch between NSC proliferation and quiescence through changing intracellular redox signalling. We show that N-terminal post-translational cleavage products of the prion protein (PrP) induce a quiescent state, halting NSC cellular growth, migration, and neurite outgrowth. Quiescence is initiated by the PrP cleavage products through reducing intracellular levels of reactive oxygen species. First, inhibition of redox signalling results in increased mitochondrial fission, which rapidly signals quiescence. Thereafter, quiescence is maintained through downstream increases in the expression and activity of superoxide dismutase-2 that reduces mitochondrial superoxide. We further observe that PrP is predominantly cleaved in quiescent NSCs indicating a homeostatic role for this cascade. Our findings provide new insight into the regulation of NSC quiescence, which potentially could influence brain health throughout adult life.     

Blockage of the NLRP3 inflammasome by MCC950 improves anti-tumor immune responses in head and neck squamous cell carcinoma

The NLRP3 inflammasome is a critical innate immune pathway responsible for producing active interleukin (IL)-1β, which is associated with tumor development and immunity. However, the mechanisms regulating the inflammatory microenvironment, tumorigenesis and tumor immunity are unclear. Herein, we show that the NLRP3 inflammasome was over-expressed in human HNSCC tissues and that the IL-1β concentration was increased in the peripheral blood of HNSCC patients. Additionally, elevated NLRP3 inflammasome levels were detected in tumor tissues of Tgfbr1/Pten 2cKO HNSCC mice, and elevated IL-1β levels were detected in the peripheral blood serum, spleen, draining lymph nodes and tumor tissues. Blocking NLRP3 inflammasome activation using MCC950 remarkably reduced IL-1β production in an HNSCC mouse model and reduced the numbers of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). Moreover, inhibiting NLRP3 inflammasome activation increased the numbers of CD4⁺ and CD8⁺ T cells in HNSCC mice. Notably, the numbers of exhausted PD-1⁺ and Tim3⁺ T cells were significantly reduced. A human HNSCC tissue microarray showed that NLRP3 inflammasome expression was correlated with the expression of CD8 and CD4, the Treg marker Foxp3, the MDSC markers CD11b and CD33, and the TAM markers CD68 and CD163, PD-1 and Tim3. Overall, our results demonstrate that the NLRP3 inflammasome/IL-1β pathway promotes tumorigenesis in HNSCC and inactivation of this pathway delays tumor growth, accompanied by decreased immunosuppressive cell accumulation and an increased number of effector T cells. Thus, inhibition of the tumor microenvironment through the NLRP3 inflammasome/IL-1β pathway may provide a novel approach for HNSCC therapy.     

Cost and Service-Level-Based Model for a Seru Production System Formation Problem with Uncertain Demand

With increasing demand diversification and short product lifecycles, industries now encounter challenges of demand uncertainty. The Japanese seru production system has received increased attention owing to its high efficiency and flexibility. In this paper, the problem of seru production system formation under uncertain demand is researched. A multi-objective optimization model for a seru production system formation problem is developed to minimize the cost and maximize the service level of the system. The purpose of this paper is to formulate a robust production system that can respond efficiently to the stochastic demand. Sample average approximation (SAA) is used to approximate the expected objective of the stochastic programming. The non-dominated sorting genetic algorithm II (NSGA-II) is improved to solve the multi-objective optimization model. Numerical experiments are conducted to test the tradeoff between cost and service level, and how the performance of the seru production system varies with the number of product types, mean and deviation of product volume, and skill-level-based cost.     

Human Development in Saudi Education: a Critical Systemic Approach

This paper is drawn from PhD research funded by the Saudi government on the policy and governance of Saudi schools (Algraini 2017. A critical systemic approach to human development in education: a case study of the Ministry of Education in Saudi Arabia). The aim of this article is to address human development challenges using the Critical Systems Heuristics approach. The results show that the central policy framework limits the opportunity for teachers and learners to contribute to shaping the curriculum and the process for human development. The Saudi Ministry of Education needs to: a) develop policy that takes into account the structure and the processes that shape education outcomes and b) to represent the voices of service users and service providers who have different and overlapping views.     

A Simulation Method for Analyzing and Evaluating Rail System Performance Based on Speed Profile

This paper presents and discusses a simulation method for analyzing and evaluating system performance on a rail line from the perspective of speed profile. Dynamic analysis for train motions is introduced, and a discrete time-operation graph is proposed to represent the relation between speed profile and energy consumption. Based on them, an analytical model is formulated to provide a quick insight into the system performance. The discrete-time simulation (DTS) method is then implemented to study the system in detail. Compared to the existing simulations, two innovations are included in the DTS: (1) the analytical lookup tables that can simplify the dynamic computation and, (2) the speed profile adjustment process that forecasts and avoids future conflicts based on practical constraints. The numerical results show that the DTS speed profile has advantages over existing methods. Finally, the DTS method is used to analyze and evaluate the system performance of the current timetable on Beijing Yizhuang Metro Line. The results suggest that the current timetable is not robust enough, and thus possible improvements are discussed at both scheduling and operating stages. The proposed method is verified to be effective and reliable for practical uses.     

Inhibition of protein misfolding and aggregation by natural phenolic compounds

Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer’s and Parkinson’s diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases.