Targeting the Redox Landscape in Cancer Therapy

Reactive oxygen species (ROS) are produced predominantly by the mitochondrial electron transport chain and by NADPH oxidases in peroxisomes and in the endoplasmic reticulum. The antioxidative defense counters overproduction of ROS with detoxifying enzymes and molecular scavengers, for instance, superoxide dismutase and glutathione, in order to restore redox homeostasis. Mutations in the redox landscape can induce carcinogenesis, whereas increased ROS production can perpetuate cancer development. Moreover, cancer cells can increase production of antioxidants, leading to resistance against chemo- or radiotherapy. Research has been developing pharmaceuticals to target the redox landscape in cancer. For instance, inhibition of key players in the redox landscape aims to modulate ROS production in order to prevent tumor development or to sensitize cancer cells in radiotherapy. Besides the redox landscape of a single cell, alternative strategies take aim at the multi-cellular level. Extracellular vesicles, such as exosomes, are crucial for the development of the hypoxic tumor microenvironment, and hence are explored as target and as drug delivery systems in cancer therapy. This review summarizes the current pharmaceutical and experimental interventions of the cancer redox landscape

Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people

<p>Abstract</p> <p>Background</p> <p>T cell-mediated immunity in elderly people is compromised in ways reflected in the composition of the peripheral T cell pool. The advent of polychromatic flow cytometry has made analysis of cell subsets feasible in unprecedented detail.</p> <p>Results</p> <p>Here we document shifts in subset distribution within naïve (N), central memory (CM) and effector memory (EM) cells defined by CD45RA and CCR7 expression in the elderly, additionally using the costimulatory receptors CD27 and CD28, as well as the coinhibitory receptors CD57 and KLRG-1, to further dissect these. Although differences between young and old were more marked in CD8 than in CD4 cells, a similar overall pattern prevailed in both. Thus, the use of all these markers together, and inclusion of assays of proliferation and cytokine secretion, may enable the construction of a differentiation scheme applicable to CD4 as well as CD8 cells, with the model (based on Romero et al.) suggesting the progression N→CM→EM1→EM2→pE1→pE2→EM4→EM3→E end-stage non-proliferative effector cells.</p> <p>Conclusion</p> <p>Overall, the results suggest that both differences in subset distribution and differences between subsets are responsible for age-related changes in CD8 cells but that differences within rather than between subsets are more prominent for CD4 cells.</p

Computer Interfaces to Organizations: Perspectives on Borg-Human Interaction Design

We use the term borg to refer to the complex organizations composed of people, machines, and processes with which users frequently interact using computer interfaces and websites. Unlike interfaces to pure machines, we contend that borg-human interaction (BHI) happens in a context combining the anthropomorphization of the interface, conflict with users, and dramatization of the interaction process. We believe this context requires designers to construct the human facet of the borg, a structure encompassing the borg's personality, social behavior, and embodied actions; and the strategies to co-create dramatic narratives with the user. To design the human facet of a borg, different concepts and models are explored and discussed, borrowing ideas from psychology, sociology, and arts. Based on those foundations, we propose six design methodologies to complement traditional computer-human interface design techniques, including play-and-freeze enactment of conflicts and the use of giant puppets as interface prototypes.Comment: 10 page

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

Inhibition of postsynaptic density protein-95 (PSD-95) decouples N-methyl-d-aspartate (NMDA) receptor downstream signaling and results in neuroprotection after focal cerebral ischemia. We have previously developed UCCB01-144, a dimeric PSD-95 inhibitor, which binds PSD-95 with high affinity and is neuroprotective in experimental stroke. Here, we investigate the selectivity, efficacy and toxicity of UCCB01-144 and compare with the monomeric drug candidate Tat-NR2B9c. Fluorescence polarization using purified proteins and pull-downs of mouse brain lysates showed that UCCB01-144 potently binds all four PSD-95-like membrane-associated guanylate kinases (MAGUKs). In addition, UCCB01-144 affected NMDA receptor signaling pathways in ischemic brain tissue. UCCB01-144 reduced infarct size in young and aged male mice at various doses when administered 30 min after permanent middle cerebral artery occlusion, but UCCB01-144 was not effective in young male mice when administered 1 h post-ischemia or in female mice. Furthermore, UCCB01-144 was neuroprotective in a transient stroke model in rats, and in contrast to Tat-NR2B9c, high dose of UCCB01-144 did not lead to significant changes in mean arterial blood pressure or heart rate. Overall, UCCB01-144 is a potent MAGUK inhibitor that reduces neurotoxic PSD-95-mediated signaling and improves neuronal survival following focal brain ischemia in rodents under various conditions and without causing cardiovascular side effects, which encourages further studies towards clinical stroke trials

Imaging Biomarkers for Monitoring the Inflammatory Redox Landscape in the Brain

Inflammation is one key process in driving cellular redox homeostasis toward oxidative stress, which perpetuates inflammation. In the brain, this interplay results in a vicious cycle of cell death, the loss of neurons, and leakage of the blood–brain barrier. Hence, the neuroinflammatory response fuels the development of acute and chronic inflammatory diseases. Interrogation of the interplay between inflammation, oxidative stress, and cell death in neurological tissue in vivo is very challenging. The complexity of the underlying biological process and the fragility of the brain limit our understanding of the cause and the adequate diagnostics of neuroinflammatory diseases. In recent years, advancements in the development of molecular imaging agents addressed this limitation and enabled imaging of biomarkers of neuroinflammation in the brain. Notable redox biomarkers for imaging with positron emission tomography (PET) tracers are the 18 kDa translocator protein (TSPO) and monoamine oxygenase B (MAO–B). These findings and achievements offer the opportunity for novel diagnostic applications and therapeutic strategies. This review summarizes experimental as well as established pharmaceutical and biotechnological tools for imaging the inflammatory redox landscape in the brain, and provides a glimpse into future applications

The methodologies to assess the effectiveness of non-pharmaceutical interventions during COVID-19: a systematic review

Non-pharmaceutical interventions, such as school closures and stay-at-home orders, have been implemented around the world to control the spread of SARS-CoV-2. Their effectiveness in improving health-related outcomes has been the subject of numerous empirical studies. However, these studies show fairly large variation among methodologies in use, reflecting the absence of an established methodological framework. On the one hand, variation in methodologies may be desirable to assess the robustness of results; on the other hand, a lack of common standards can impede comparability among studies. To establish a comprehensive overview over the methodologies in use, we conducted a systematic review of studies assessing the effectiveness of non-pharmaceutical interventions between January 1, 2020 and January 12, 2021 (n = 248). We identified substantial variation in methodologies with respect to study setting, outcome, intervention, methodological approach, and effectiveness assessment. On this basis, we point to shortcomings of existing studies and make recommendations for the design of future studies.ISSN:0393-2990ISSN:1573-728

The methodologies to assess the effectiveness of non-pharmaceutical interventions during COVID-19: a systematic review

Non-pharmaceutical interventions, such as school closures and stay-at-home orders, have been implemented around the world to control the spread of SARS-CoV-2. Their effects on health-related outcomes have been the subject of numerous empirical studies. However, these studies show fairly large variation among methodologies in use, reflecting the absence of an established methodological framework. On the one hand, variation in methodologies may be desirable to assess the robustness of results; on the other hand, a lack of common standards can impede comparability among studies. To establish a comprehensive overview over the methodologies in use, we conducted a systematic review of studies assessing the effects of non-pharmaceutical interventions on health-related outcomes between January 1, 2020 and January 12, 2021 (n=248). We identified substantial variation in methodologies with respect to study setting, outcome, intervention, methodological approach, and effect assessment. On this basis, we point to shortcomings of existing studies and make recommendations for the design of future studies

Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people-0

D8+ T cells were subdivided into the main T cell subsets using CD45RA and CCR7. (C) The CD45RA+CCR7+ N, CD45RA-CCR7+ CM, CD45-CCR7- EM and CD45RA+ CCR7- TEMRA CD8+ T cells were plotted against CD27 and CD28. According to the subset model (Figure 1) the different CD27 and CD28 dependent subpopulations (D) CM, (E) N, (F) EM and (G) TEMRA subsets were analyzed for CD57 and KLRG1.<p><b>Copyright information:</b></p><p>Taken from "Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people"</p><p>http://www.immunityageing.com/content/5/1/6</p><p>Immunity & Ageing : I & A 2008;5():6-6.</p><p>Published online 25 Jul 2008</p><p>PMCID:PMC2515281.</p><p></p

Identification of MYOM2 as a candidate gene in hypertrophic cardiomyopathy and tetralogy of fallot, and its functional evaluation in the Drosophila heart

The causal genetic underpinnings of congenital heart diseases, which are often complex and multigenic, are still far from understood. Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the most common cyanotic heart malformation, as well as in patients with hypertrophic cardiomyopathy (HCM), who do not exhibit any mutations in the known disease genes. MYOM2 is a major component of the myofibrillar Moand of the sarcomere, and a hub gene within interactions of sarcomere genes. We show that patient-derived cardiomyocytes exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. Moreover, our comprehensive functional analyses in the Drosophila animal model reveal that the so far uncharacterized fly gene CG14964 [herein referred to as Drosophila myomesin and myosin binding protein (dMnM)] may be an ortholog of MYOM2, as well as other myosin binding proteins . Its partial loss of function or moderate cardiac knockdown results in cardiac dilation, whereas more severely reduced function causes a constricted phenotype and an increase in sarcomere myosin protein. Moreover, compound heterozygous combinations of CG14964 and the sarcomere gene Mhc (MYH6/7) exhibited synergistic genetic interactions. In summary, our results suggest that MYOM2 not only plays a critical role in maintaining robust heart function but may also be a candidate gene for heart diseases such as HCM and TOF, as it is clearly involved in the development of the heart