Dying cell-derived SAM switches off inflammation

The clearance of dying cells by macrophages releases mediators that switch off inflammation. Ampomah et al. reveal how an amino acid derived from apoptotic cargo changes the methylation epigenome of macrophages to take the brakes off an ERK-dependent pathway that terminates inflammatory responses

Aging and frailty immune landscape

Frailty is an important age-related prognostic for mortality, and little is known about its immune landscape. Luo et al.1 use single-cell profiling to gather a comprehensive understanding of immune changes that happen from birth to old age, and provide new insights into the often-overlooked state of frailty

A GIS for flood risk management in Flanders

In the past decades, Flanders, a region of north Belgium that extends from the coastline inland (in northwest Europe), has suffered several serious riverine floods that caused substantial property damage. As Flanders is one of the most densely populated regions in the world, a solid water management policy is needed in order to mitigate the effects of this type of calamity. In the past, Flemish water managers chose to drain off river water as quickly as possible by heightening the dikes along the rivers. However, this method leads to a higher flood probability further downstream. Moreover, water defence infrastructure can always suffer from technical failures (e.g., breaching) creating even more damage than would have occurred if no defences were in place. In a search for a better solution to this recurring problem, the Flemish administration proposed a new approach in the 1990 s. This approach focuses on minimizing the consequences of flooding instead of attempting to prevent floods. To implement this approach, large amounts of data were gathered for the Flemish Region. Using a Geographic Information System (GIS), a risk-based methodology was created to quantitatively assess flood risk based on hydrologic models, land use information and socio-economic data. Recently, this methodology was implemented in a specifically designed GIS-based flood risk assessment tool called LATIS. By estimating the potential damage and number of casualties during a flood event, LATIS offers the possibility to perform risk analysis quickly and effectively. This chapter presents a concise overview of LATIS’ methodology and its implementation for flood risk management in Flanders

A new model measuring bacterial phagocytosis and phagolysosomal oxidisation in humans using the intradermal injection of methylene blue-labelled Escherichia coli

Phagocytosis is an important leucocyte function, however using existing models it cannot be measured in human tissues in vivo. To address this, we characterized a new phagocytosis model using intradermal methylene blue-labelled Escherichia coli injection (MBEC). Methylene blue (MB) is a licensed human medicine and bacterial stain potentially useful for labelling E. coli that are safe for human injection. Ex vivo co-culture of leucocytes with MBEC caused MB to transfer into neutrophils and macrophages by phagocytosis. During this, a ‘red shift’ in MB fluorescence was shown to be caused by phagolysosomal oxidisation. Hence, MBEC co-culture could be used to measure phagocytosis and phagolysosomal oxidisation in humans, ex vivo. In healthy volunteers, inflammatory exudate sampling using suction blisters 2-24h after intradermal MBEC injection showed that tissue-acquired neutrophils and monocytes contained more MB than their circulating counterparts, whereas blood and inflamed tissue T, B and NK cells were MBlo. This was validated with spectral flow cytometry by visualizing the MB emission spectrum in tissue-acquired neutrophils. Neutrophil MB emission spectra demonstrated more ‘red shift’ at 24h compared to earlier time-points, in-keeping with progressive phagolysosomal MB oxidisation in neutrophils over time in vivo. This new MBEC model can therefore measure bacterial phagocytosis and phagolysosomal oxidisation in human skin, in vivo. This has a number of important research applications, for example in studying human phagocyte biology, testing novel antimicrobials, and understanding why certain groups such as males, the elderly or those with diabetes, recent surgery or malnutrition are at increased risk of bacterial infection

Phenotyping of lymphoproliferative tumours generated in xenografts of non-small cell lung cancer

Background: Patient-derived xenograft (PDX) models involve the engraftment of tumour tissue in immunocompromised mice and represent an important pre-clinical oncology research method. A limitation of non-small cell lung cancer (NSCLC) PDX model derivation in NOD-scid IL2Rgammanull (NSG) mice is that a subset of initial engraftments are of lymphocytic, rather than tumour origin. / Methods: The immunophenotype of lymphoproliferations arising in the lung TRACERx PDX pipeline were characterised. To present the histology data herein, we developed a Python-based tool for generating patient-level pathology overview figures from whole-slide image files; PATHOverview is available on GitHub (https://github.com/EpiCENTR-Lab/PATHOverview). / Results: Lymphoproliferations occurred in 17.8% of lung adenocarcinoma and 10% of lung squamous cell carcinoma transplantations, despite none of these patients having a prior or subsequent clinical history of lymphoproliferative disease. Lymphoproliferations were predominantly human CD20+ B cells and had the immunophenotype expected for post-transplantation diffuse large B cell lymphoma with plasma cell features. All lymphoproliferations expressed Epstein-Barr-encoded RNAs (EBER). Analysis of immunoglobulin light chain gene rearrangements in three tumours where multiple tumour regions had resulted in lymphoproliferations suggested that each had independent clonal origins. / Discussion: Overall, these data suggest that B cell clones with lymphoproliferative potential are present within primary NSCLC tumours, and that these are under continuous immune surveillance. Since these cells can be expanded following transplantation into NSG mice, our data highlight the value of quality control measures to identify lymphoproliferations within xenograft pipelines and support the incorporation of strategies to minimise lymphoproliferations during the early stages of xenograft establishment pipelines

Immunomodulation of murine collagen-induced arthritis by N, N-dimethylglycine and a preparation of Perna canaliculus

<p>Abstract</p> <p>Background</p> <p>Rheumatoid arthritis (RA) and its accepted animal model, murine collagen-induced arthritis (CIA), are classic autoimmune inflammatory diseases which require proinflammatory cytokine production for pathogenesis. We and others have previously used N, N-dimethylglycine (DMG) and extracts from the New Zealand green-lipped mussel <it>Perna canaliculus </it>(Perna) as potent immunomodulators to modify ongoing immune and/or inflammatory responses.</p> <p>Methods</p> <p>In our initial studies, we treated lipopolysaccahride (LPS) stimulated THP-1 monocytes <it>in vitro </it>with increasing concentrations of Perna extract or DMG. Additionally, we treated rat peripheral blood neutrophils with increasing concentrations of Perna extract and measured superoxide burst. In subsequent <it>in vivo </it>experiments, CIA was induced by administration of type II collagen; rats were prophylactically treated with either Perna or DMG, and then followed for disease severity. Finally, to test whether Perna and/or DMG could block or inhibit an ongoing pathologic disease process, we induced CIA in mice and treated them therapeutically with either of the two immunomodulators.</p> <p>Results</p> <p>Following LPS stimulation of THP-1 monocytes, we observed dose-dependent reductions in TNF-α and IL-12p40 production in Perna treated cultures. DMG treatment, however, showed significant increases in both of these cytokines in the range of 0.001–1 μM. We also demonstrate that <it>in vitro </it>neutrophil superoxide burst activity is dose-dependently reduced in the presence of Perna. Significant reductions in disease incidence, onset, and severity of CIA in rats were noted following prophylactic treatment with either of the two immunomodulators. More importantly, amelioration of mouse CIA was observed following therapeutic administration of Perna. In contrast, DMG appeared to have little effect in mice and may act in a species-specific manner.</p> <p>Conclusion</p> <p>These data suggest that Perna, and perhaps DMG, may be useful supplements to the treatment of RA in humans.</p