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Non-thermal plasma (NTP) shows promise as a potent anti-cancer therapy with both cytotoxic and immunomodulatory effects. In this study, we investigate the chemical and biological effects of NTP-induced oxidation on several key, determinant immune checkpoints of natural killer (NK) cell function. We used molecular dynamics (MD) and umbrella sampling simulations to investigate the effect of NTP-induced oxidative changes on the MHC-I complexes HLA-Cw4 and HLA-E. Our simulations indicate that these chemical alterations do not significantly affect the binding affinity of these markers to their corresponding NK cell receptor, which is supported with experimental read-outs of ligand expression on human head and neck squamous cell carcinoma cells after NTP application. Broadening our scope to other key ligands for NK cell reactivity, we demonstrate rapid reduction in CD155 and CD112, target ligands of the inhibitory TIGIT axis, and in immune checkpoint CD73 immediately after treatment. Besides these transient chemical alterations, the reactive species in NTP cause a cascade of downstream cellular reactions. This is underlined by the upregulation of the stress proteins MICA/B, potent ligands for NK cell activation, 24 h post treatment. Taken together, this work corroborates the immunomodulatory potential of NTP, and sheds light on the interaction mechanisms between NTP and cancer cells.

IntroductionImmune dysregulation plays a major role in cancer progression. The quantification of lymphocytic spatial inflammation may enable spatial system biology, improve understanding of therapeutic resistance, and contribute to prognostic imaging biomarkers.MethodsIn this paper, we propose a knowledge-guided deep learning framework to measure the lymphocytic spatial architecture on human H&E tissue, where the fidelity of training labels is maximized through single-cell resolution image registration of H&E to IHC. We demonstrate that such an approach enables pixel-perfect ground-truth labeling of lymphocytes on H&E as measured by IHC. We then experimentally validate our technique in a genetically engineered, immune-compromised Rag2 mouse model, where Rag2 knockout mice lacking mature lymphocytes are used as a negative experimental control. Such experimental validation moves beyond the classical statistical testing of deep learning models and demonstrates feasibility of more rigorous validation strategies that integrate computational science and basic science.ResultsUsing our developed approach, we automatically annotated more than 111,000 human nuclei (45,611 CD3/CD20 positive lymphocytes) on H&E images to develop our model, which achieved an AUC of 0.78 and 0.71 on internal hold-out testing data and external testing on an independent dataset, respectively. As a measure of the global spatial architecture of the lymphocytic microenvironment, the average structural similarity between predicted lymphocytic density maps and ground truth lymphocytic density maps was 0.86 ± 0.06 on testing data. On experimental mouse model validation, we measured a lymphocytic density of 96.5 ± %1% in a Rag2+/- control mouse, compared to an average of 16.2 ± %5% in Rag2-/- immune knockout mice (p

Rural areas are regaining attention as key resource holders. This includes the attractiveness of intact and traditional cultural elements and heritage which helps to create new opportunities. However, renewal is needed for rural areas to be competitive beyond tourism. Knowledge exchange and transfer is seen as an enabling tool for regeneration and heritage valorization, although it has mostly been applied in an urban context. The aim of this paper is to explore the role of capacity building and knowledge exchange at different levels in promoting rural regeneration through heritage-led initiatives. The article describes a multi-directional knowledge transfer and exchange in 19 rural areas. The applied knowledge exchange methodology was designed to be a dynamic and vibrant exchange of capacity building and mutual learning. This exchange of knowledge enabled the local communities involved to explore new ideas and viable solutions for the regeneration of rural areas through the valorization of cultural and natural heritage. The research findings show that structuring a knowledge transfer and capacity building process that also involves key local stakeholders and the rural communities is an important milestone in the regeneration process. In addition, it can be a unique opportunity to start and build new professional long-term relationships.

Chan before Chan: Meditation, Repentance, and Visionary Experience in Chinese Buddhism. By ERIC M. GREENE. Honolulu: UNIVERSITY OF HAWAI'I PRESS, 2021. Pp. xiv + 313. $68 (cloth); $20 (paper) Chan [...]

There appears to be no “one-size-fits-all” strategy for evolving from a car-dependent urban environment towards a well-balanced modal split. The search for a suitable mobility strategy for a particular setting can be framed as seeking a suitable governance strategy. This article explores the opportunities of design-driven participatory action research (DD-PAR) as a governance strategy for improving mobility within a context of weak governance by investigating a single case study conducted in Paramaribo North, Suriname. Despite available plans, designs, and policy proposals, Surinamese public authorities are struggling to improve mobility. Notwithstanding many efforts, clientelism and patronage are weakening the power of the government, resulting in unimplemented public initiatives. Moreover, there are few civil society organisations to advocate for this weak public power. This creates a context in which neither the government nor civil society is sufficiently equipped to realise the modal shift in Paramaribo. Governance strategies depending on strong government or proactive civil society (e.g., actor-based strategies) are thus not suitable. In contrast, DD-PAR appears to have potential as a governance strategy, as it uses research and academics as forces to create societal enthusiasm, establish actor networks, and generate action. The current case study identifies key actors and preconditions for building a network of actors. It also provides tentative insights into urban tactics for increasing pressure on the government to provide adequate infrastructure and policy to accommodate newly developed action that supports a more diverse modal split.

Introduction: Immune dysregulation plays a major role in cancer progression. The quantification of lymphocytic spatial inflammation may enable spatial system biology, improve understanding of therapeutic resistance, and contribute to prognostic imaging biomarkers. Methods: In this paper, we propose a knowledge-guided deep learning framework to measure the lymphocytic spatial architecture on human H&E tissue, where the fidelity of training labels is maximized through single-cell resolution image registration of H&E to IHC. We demonstrate that such an approach enables pixel-perfect ground-truth labeling of lymphocytes on H&E as measured by IHC. We then experimentally validate our technique in a genetically engineered, immune-compromised Rag2 mouse model, where Rag2 knockout mice lacking mature lymphocytes are used as a negative experimental control. Such experimental validation moves beyond the classical statistical testing of deep learning models and demonstrates feasibility of more rigorous validation strategies that integrate computational science and basic science. Results: Using our developed approach, we automatically annotated more than 111,000 human nuclei (45,611 CD3/CD20 positive lymphocytes) on H&E images to develop our model, which achieved an AUC of 0.78 and 0.71 on internal hold-out testing data and external testing on an independent dataset, respectively. As a measure of the global spatial architecture of the lymphocytic microenvironment, the average structural similarity between predicted lymphocytic density maps and ground truth lymphocytic density maps was 0.86 ± 0.06 on testing data. On experimental mouse model validation, we measured a lymphocytic density of 96.5 ± %1% in a Rag2+/- control mouse, compared to an average of 16.2 ± %5% in Rag2-/- immune knockout mice (p<0.0001, ANOVA-test). Discussion: These results demonstrate that CD3/CD20 positive lymphocytes can be accurately detected and characterized on H&E by deep learning and generalized across species. Collectively, these data suggest that our understanding of complex biological systems may benefit from computationally-derived spatial analysis, as well as integration of computational science and basic science. [ABSTRACT FROM AUTHOR]

Objectives: A phase 1, double-blind, placebo-controlled trial was conducted to evaluate the safety, tolerability, and exploratory efficacy of repeat monthly doses of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) in uninfected adult volunteers. Methods: Participants were randomized (3:1) to SC CAS+IMD 1200 mg or placebo every 4 weeks for up to six doses. Primary and secondary end points evaluated safety, pharmacokinetics, and immunogenicity. Exploratory efficacy was evaluated by the incidence of COVID-19 or SARS-CoV-2 seroconversion. Results: In total, 969 participants received CAS+IMD. Repeat monthly dosing of SC CAS+IMD led to a 92.4% relative risk reduction in clinically defined COVID-19 compared with placebo (3/729 [0.4%] vs 13/240 [5.4%]; odds ratio 0.07 [95% CI 0.01-0.27]), and a 100% reduction in laboratory-confirmed COVID-19 (0/729 vs 10/240 [4.2%]; odds ratio 0.00). Development of anti-drug antibodies occurred in a small proportion of participants (

Anaemia is common in chronic kidney disease (CKD) and has a significant impact on quality of life (QoL), work productivity and outcomes. Current management includes oral or intravenous iron and erythropoiesis-stimulating agents (ESAs), to which hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have been recently added, increasing the available therapeutic options. In randomised controlled trials, only intravenous iron improved cardiovascular outcome, while some ESAs were associated with increased adverse cardiovascular events. Despite therapeutic advances, several challenges and unmet needs remain in the current management of anaemia of CKD. In particular, clinical practice does not include an assessment of QoL, which prompted a group of European nephrologists and representatives of patient advocacy groups to revisit the current approach. In this consensus document, the authors propose a move towards a more holistic, personalised and long-term approach, based on existing evidence. The focus of treatment should be on improving QoL without increasing the risk of adverse cardiovascular events, and tailoring management strategies to the needs of the individual. In addition, the authors discuss the suitability of a currently available anaemia of CKD–specific health-related QoL measure for inclusion in the routine clinical management of anaemia of CKD. The authors also outline the logistics and challenges of incorporating such a measure into electronic health records and how it may be used to improve QoL for people with anaemia of CKD. [ABSTRACT FROM AUTHOR]