Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, ...recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly overexpress BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation.
► LSC are prospectively isolated from the bulk tumor on the basis of low ROS levels ► Metabolic dependencies discriminating LSCs, bulk tumor, and normal HSCs are described ► BCL-2 is identified as a regulator of LSC mitochondrial respiration ► BCL-2 pharmacologic inhibitors demonstrate LSC-specific targeting
Human leukemia stem cells upregulate BCL-2 expression as a result of relying on oxidative phosphorylation to produce energy and can therefore be targeted with BCL-2 inhibitors.
Adipose tissue (AT) has previously been identified as an extra-medullary reservoir for normal hematopoietic stem cells (HSCs) and may promote tumor development. Here, we show that a subpopulation of ...leukemic stem cells (LSCs) can utilize gonadal adipose tissue (GAT) as a niche to support their metabolism and evade chemotherapy. In a mouse model of blast crisis chronic myeloid leukemia (CML), adipose-resident LSCs exhibit a pro-inflammatory phenotype and induce lipolysis in GAT. GAT lipolysis fuels fatty acid oxidation in LSCs, especially within a subpopulation expressing the fatty acid transporter CD36. CD36+ LSCs have unique metabolic properties, are strikingly enriched in AT, and are protected from chemotherapy by the GAT microenvironment. CD36 also marks a fraction of human blast crisis CML and acute myeloid leukemia (AML) cells with similar biological properties. These findings suggest striking interplay between leukemic cells and AT to create a unique microenvironment that supports the metabolic demands and survival of a distinct LSC subpopulation.
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•Gonadal adipose tissue (GAT) serves as a reservoir for LSCs•Interplay between leukemia cells and GAT fuels leukemia cell fatty acid metabolism•CD36 segregates LSCs into two metabolically and functionally distinct subsets•GAT provides a niche that confers chemo-resistance for CD36+ LSCs
Ye et al. show that LSCs co-opt the adipose tissue niche to create a microenvironment that supports leukemic growth and resistance to chemotherapy. They also detect metabolically and functionally distinct mouse and human LSC subpopulations delineated by expression of the fatty acid transporter CD36.
Endocannabinoids are released following brain injury and may protect against excitotoxic damage during the acute stage of injury. Brain injury also activates microglia in a secondary inflammatory ...phase of more widespread damage. Most drugs targeting the acute stage are not effective if administered more than 6 hours after injury. Therefore, drugs targeting microglia later in the neurodegenerative cascade are desirable. We have found that cannabinoid CB2 receptors are upregulated during the activation of microglia following brain injury. Specifically, CB2-positive cells appear in the rat brain following both hypoxia-ischemia (HI) and middle cerebral artery occlusion (MCAO). This may regulate post-injury microglial activation and inflammatory functions. In this paper we review in vivo and in vitro studies of CB2 receptors in microglia, including our results on CB2 expression post-injury. Taken together, studies show that CB2 is upregulated during a process in which microglia become primed to proliferate, and then become fully reactive. In addition, CB2 activation appears to prevent or decrease microglial activation. In a rodent model of Alzheimers disease microglial activation was completely prevented by administration of a selective CB2 agonist. The presence of CB2 receptors in microglia in the human Alzheimers diseased brain suggests that CB2 may provide a novel target for a range of neuropathologies. We conclude that the administration of CB2 agonists and antagonists may differentially alter microglia-dependent neuroinflammation. CB2 specific compounds have considerable therapeutic appeal over CB1 compounds, as the exclusive expression of CB2 on immune cells within the brain provides a highly specialised target, without the psychoactivity that plagues CB1 directed therapies.
Food banks are a symptom of a more extensive pressure for emergency food aid, which was summarised for your government in a report to the Department for Environment, Food and Rural Affairs (DEFRA) ...released this year.4 Food bank numbers are an inadequate indicator of need, because many households only ask for emergency food help as a last resort.
Leukemia stem cells (LSCs) are thought to drive the genesis of acute myeloid leukemia (AML) as well as relapse following chemotherapy. Because of their unique biology, developing effective methods to ...eradicate LSCs has been a significant challenge. In the present study, we demonstrate that intrinsic overexpression of the mitochondrial dynamics regulator FIS1 mediates mitophagy activity that is essential for primitive AML cells. Depletion of FIS1 attenuates mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell cycle arrest, and a profound loss of LSC self-renewal potential. Further, we report that the central metabolic stress regulator AMPK is also intrinsically activated in LSC populations and is upstream of FIS1. Inhibition of AMPK signaling recapitulates the biological effect of FIS1 loss. These data suggest a model in which LSCs co-opt AMPK/FIS1-mediated mitophagy as a means to maintain stem cell properties that may be otherwise compromised by the stresses induced by oncogenic transformation.
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•Human AML LSCs display high FIS1 expression and unique mitochondrial morphology•FIS1 loss attenuates mitophagy and impairs AML LSC potential•FIS1 loss induces GSK3 inhibition, differentiation, and cell cycle arrest in AML•AMPK is constitutively active in human AML LSCs and regulates FIS1 expression
Human acute myeloid leukemia stem cells (LSCs) depend on FIS1-mediated mitophagy for self-renewal and survival. AMPK is constitutively active in human LSCs, is upstream of FIS1, and acts to stimulate mitophagy. Disruption of AMPK signaling or FIS1 activity results in eradication of LSCs.
COVID-19 has presented society with a public health threat greater than any in living memory, leaving us to question almost every aspect of our society. An ever increasing concern is how we protect ...the global population from mental illness and whether public mental health policies can achieve this. In this article I reflect on the history of mental health service development, and furthermore on how COVID-19 might impact on the delivery of public mental health strategies into the future.
During cardiac reperfusion after myocardial infarction, the heart is subjected to cascading cycles of ischaemia reperfusion injury (IRI). Patients presenting with this injury succumb to myocardial ...dysfunction resulting in myocardial cell death, which contributes to morbidity and mortality. New targeted therapies are required if the myocardium is to be protected from this injury and improve patient outcomes. Extensive research into the role of mitochondria during ischaemia and reperfusion has unveiled one of the most important sites contributing towards this injury; specifically, the opening of the mitochondrial permeability transition pore. The opening of this pore occurs during reperfusion and results in mitochondria swelling and dysfunction, promoting apoptotic cell death. Activation of mitochondrial ATP-sensitive potassium channels (mitoKATP) channels, uncoupling proteins, and inhibition of glycogen synthase kinase-3β (GSK3β) phosphorylation have been identified to delay mitochondrial permeability transition pore opening and reduce reactive oxygen species formation, thereby decreasing infarct size. Statins have recently been identified to provide a direct cardioprotective effect on these specific mitochondrial components, all of which reduce the severity of myocardial IRI, promoting the ability of statins to be a considerate preconditioning agent. This review will outline what has currently been shown in regard to statins cardioprotective effects on mitochondria during myocardial IRI.
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This paper examines the factors determining household adoption of energy efficiency eco-innovations. We do so by testing hypotheses grounded in diffusion and finance theory and the literature on the ...barriers to energy efficiency. Using two large surveys of UK households, we explore the adoption of nine technologies. Our results indicate ‘investment inefficiency’ amongst household adopters occurs for two reasons. First, contrary to notions of rational choice, we find a negative relationship between the investment return of technologies and their level of diffusion. Second, we show adopters of these technologies display characteristics broadly consistent with diffusion theory, contradicting the prediction of finance theory that investment return, not individual characteristics, should drive adoption. We also find that policy has played a role in inducing the diffusion of these technologies and that tenure and spill-over effects are important in adoption. Finally, adoption is motivated more by a desire to save money than by environmental concern. We conclude by giving examples of how our research can lead to better policy timing and targeting.
•We explore the factors driving household adoption of energy efficiency technologies.•We employ two high quality nationally representative cross sectional surveys.•There is a negative relationship between investment return and level of diffusion.•Adopters display characteristics broadly consistent with diffusion theory.•Policy interventions, tenure effects and spill-over effects also influence adoption.
Most cancers evolve over time as patients initially responsive to therapy acquire resistance to the same drugs at relapse. Cancer stem cells have been postulated to represent a therapy-refractory ...reservoir for relapse, but formal proof of this model is lacking. We prospectively characterized leukemia stem cell populations (LSCs) from a well-defined cohort of patients with acute myelogenous leukemia (AML) at diagnosis and relapse to assess the effect of the disease course on these critical populations. Leukemic samples were collected from patients with newly diagnosed AML before therapy and after relapse, and LSC frequency was assessed by limiting dilution analyses. LSC populations were identified using fluorescent-labeled cell sorting and transplantation into immunodeficient NOD/SCID/interleukin 2 receptor γ chain null mice. The surface antigen expression profiles of pretherapy and postrelapse LSCs were determined for published LSC markers. We demonstrate a 9- to 90-fold increase in LSC frequency between diagnosis and relapse. LSC activity at relapse was identified in populations of leukemic blasts that did not demonstrate this activity before treatment and relapse. In addition, we describe genetic instability and exceptional phenotypic changes that accompany the evolution of these new LSC populations. This study is the first to characterize the evolution of LSCs in vivo after chemotherapy, identifying a dramatic change in the physiology of primitive AML cells when the disease progresses. Taken together, these findings provide a new frame of reference by which to evaluate candidate AML therapies in which both disease control and the induction of more advanced forms of disease should be considered.
•Using AML as a model, we investigated the effect of treatment and disease evolution on functionally defined cancer stem cell populations.•We demonstrate large-scale changes in LSC frequency and phenotype after relapse, best described using high-dimensional space analyses.
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