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

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

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

INTRODUCTION: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. METHODS: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. RESULTS: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. CONCLUSIONS: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are