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Induced waves of calcium fluxes initiate multiple signalling pathways that play an important role in the differentiation and maturation of B-cells. Finely tuned transient Ca+2fluxes from the endoplasmic reticulum in response to B-cell receptor (BCR) or chemokine receptor activation are followed by more sustained calcium influxes from the extracellular environment and contribute to the mechanisms responsible for the proliferation of B-cells, their migration within lymphoid organs and their differentiation. Dysregulation of these well-balanced mechanisms in B-cell lymphomas results in uncontrolled cell proliferation and resistance to apoptosis. Consequently, several cytotoxic drugs (and anti-proliferative compounds) used in standard chemotherapy regimens for the treatment of people with lymphoma target calcium-dependent pathways. Furthermore, ~10% of lymphoma associated mutations are found in genes with functions in calcium-dependent signalling, including those affecting B-cell receptor signalling pathways. In this review, we provide an overview of the Ca2+-dependent signalling network and outline the contribution of its key components to B cell lymphomagenesis. We also consider how the oncogenic Epstein-Barr virus, which is causally linked to the pathogenesis of a number of B-cell lymphomas, can modify Ca2+-dependent signalling.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells, with increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken during symptom resolution, identified recovery-associated immune features including increased monocyte CD163 levels, emergence of a new population of immature neutrophils and, in some patients, transiently increased plasma arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL-6 may be preferable to IL-1 or TNF-α. We identified several potential mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C suggesting complement inhibitors could be used to treat the disease., Graphical abstract, Genomics; Immune response; Immune system disorder; Immunology

Simple Summary Epstein–Barr virus (EBV) is associated with a variety of malignancies. In this review, we discuss EBV-encoded microRNAs and ncRNAs and consider how their detection could aid in the diagnosis, prognostication, and monitoring of treatment in patients with EBV-associated malignancies, including classical Hodgkin’s lymphoma (cHL), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), nasopharyngeal carcinoma (NPC), and gastric carcinoma (GC). Abstract EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs.

The Epstein-Barr virus (EBV), a group 1 carcinogen, is a causative factor in nine different cancers that cause ~165,000 deaths globally each year. Almost all adults carry EBV asymptomatically; the virus persisting primarily in rare memory B cells for the lifetime of the host. However, in some infected individuals, for reasons that are unknown, EBV may contribute to the development of cancer. The immune microenvironment in which infected cells reside may influence or trigger cancer development, but we know very little about how this occurs. We have begun to address these critical questions by deploying a spatial biology assay for comprehensive study of the immune microenvironment of EBV-infected tissues. Using AKOYA’s immunofluorescence based Phenocycler assay, we developed an antibody panel that can detect 40 or more different biomarkers in situ at single cell resolution. The panel contains antibodies directed at EBV infected cells at various stages of viral infection, as well as biomarkers for different immune cell lineages, immune cell activation states and tissue structures. This design allows simultaneous identification of infected immune cells within their microenvironment, while, crucially, maintaining spatial relationships between them. We have now set out to produce unbiased and comprehensive spatial phenotypic maps of normal and EBV infected human FFPE tissues. Our data will provide an initial understanding of how the immune microenvironment of virus-infected cells influences tissue pathology and, ultimately, the development of cancer.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Deep immune profiling showed acute MIS-C patients had highly activated neutrophils, classical monocytes and memory CD8+ T-cells; increased frequencies of B-cell plasmablasts and double-negative B-cells. Post treatment samples from the same patients, taken when symptoms were resolving, identified recovery-associated immune features including CD163+ monocytes, emergence of a new population of immature neutrophils and, in some patients, a transient increase in arginase. Plasma profiling identified multiple features shared by MIS-C, Kawasaki Disease and COVID-19 and that therapeutic inhibition of IL6 may be preferable to IL1 or TNF-a. We identified potential new mechanisms of action for IVIG, the most commonly used drug to treat MIS-C. Finally, we showed systemic complement activation with high plasma C5b-9 levels is common in MIS-C, suggesting complement inhibitors could be used to treat the disease. Funding Information: Birmingham Women’s and Children’s Hospital Charity funded the single cell RNA sequencing analysis. No other external funding was received. Declaration of Interests: None declared. Ethics Approval Statement: Reviewed and approved by South of Birmingham Research Ethics Committee (REC: 17/WM/0453, IRAS: 233593).

The Flory&ndash, Rehner theoretical description of the free energy in a hydrogel swelling model can be broken into two swelling components: the mixing energy and the ionic energy. Conventionally for ionized gels, the ionic energy is characterized as the main contributor to swelling and, therefore, the mixing energy is assumed negligible. However, this assumption is made at the equilibrium state and ignores the dynamics of gel swelling. Here, the influence of the mixing energy on swelling ionized gels is quantified through numerical simulations on sodium polyacrylate using a Mixed Hybrid Finite Element Method. For univalent and divalent solutions, at initial porosities greater than 0.90, the contribution of the mixing energy is negligible. However, at initial porosities less than 0.90, the total swelling pressure is significantly influenced by the mixing energy. Therefore, both ionic and mixing energies are required for the modeling of sodium polyacrylate ionized gel swelling. The numerical model results are in good agreement with the analytical solution as well as experimental swelling tests.

Hydrogels have a wide range of applications from medical devices to tissue engineering to industrial health products. The numerical modeling of these porous structures can provide insight into their in-situ performance. However, an accurate constitutive model to replicate the stress-strain behavior of the swelling process is essential in ensuring the efficacy of the simulation. This study presents a strain dependent constitutive model for describing the finite deformation of superabsorbent polymers undergoing solvent induced swelling. Like many elastic materials, stretch-induced softening and hardening of these polymers occurs at large deformations. In order to incorporate the deformation dependent modulus into the new model, the shear modulus of sodium polyacrylate gels were measured using a rheometer as a function of swelling. Through numerical simulations on spherical gels, the effect of both cross-link density and the dependent modulus is investigated against a control model. As experimental quantification of the initial porosity is difficult and often not consistent between samples, Monte-Carlo simulations are implemented to experimentally verify the new model. Furthermore, this model is applied to experimental uniaxial tension data of incompressible rubber to allow comparison to other strain hardening constitutive models.