Tumor Progression Locus 2 (Tpl2) Deficiency Does Not Protect against Obesity-Induced Metabolic Disease

Obesity is associated with a state of chronic low grade inflammation that plays an important role in the development of insulin resistance. Tumor progression locus 2 (Tpl2) is a serine/threonine mitogen activated protein kinase kinase kinase (MAP3K) involved in regulating responses to specific inflammatory stimuli. Here we have used mice lacking Tpl2 to examine its role in obesity-associated insulin resistance. Wild type (wt) and tpl2−/− mice accumulated comparable amounts of fat and lean mass when fed either a standard chow diet or two different high fat (HF) diets containing either 42% or 59% of energy content derived from fat. No differences in glucose tolerance were observed between wt and tpl2−/− mice on any of these diets. Insulin tolerance was similar on both standard chow and 42% HF diets, but was slightly impaired in tpl2−/− mice fed the 59% HFD. While gene expression markers of macrophage recruitment and inflammation were increased in the white adipose tissue of HF fed mice compared with standard chow fed mice, no differences were observed between wt and tpl2−/− mice. Finally, a HF diet did not increase Tpl2 expression nor did it activate Extracellular Signal-Regulated Kinase 1/2 (ERK1/2), the MAPK downstream of Tpl2. These findings argue that Tpl2 does not play a non-redundant role in obesity-associated metabolic dysfunction

Innovative education and training in high power laser plasmas (PowerLaPs) for plasma physics, high power laser matter interactions and high energy density physics: experimental diagnostics and simulations

The second and final year of the Erasmus Plus programme "Innovative Education and Training in high power laser plasmas", otherwise known as PowerLaPs, is described. The PowerLaPs programme employs an innovative paradigm in that it is a multi-centre programme where teaching takes place in five separate institutes with a range of different aims and styles of delivery. The "in class" time is limited to four weeks a year, and the programme spans two years. PowerLaPs aims to train students from across Europe in theoretical, applied, and laboratory skills relevant to the pursuit of research in laser plasma interaction physics and inertial confinement fusion (ICF). Lectures are intermingled with laboratory sessions, and continuous assessment activities. The programme, which is led by workers from the Hellenic Mediterranean University, and supported by co-workers from Queens University Belfast, the University of Bordeaux, the Czech Technical University in Prague, Ecole Polytechnique, the University of Ioannina, the University of Salamanca, and the University of York, has just finished its second and final year. Six Learning Teaching Training (LTT) activities have been held, at the Queens University Belfast, the University of Bordeaux, the Czech Technical University, the University of Salamanca, and the Institute of Plasma Physics and Lasers (CPPL) of the Hellenic Mediterranean University. The last of these institute hosted two two-week long Intensive Programmes (IPs), whilst the activities at the other four universities were each five days in length. In addition to this a "Multiplier Event" was held at the University of Ioannina, which will be briefly described. In this second year the work has concentrated upon training in both experimental diagnostics and simulation techniques appropriate to the study of Plasma Physics, High Power Laser-Matter Interactions and High Energy Density Physics. The nature of the programme will be described in detail and some metrics relating to the activities carried out will be presented. In particular this paper will focus upon the overall assessment of the programme

c-Rel Controls Multiple Discrete Steps in the Thymic Development of Foxp3+ CD4 Regulatory T Cells

The development of natural Foxp3+ CD4 regulatory T cells (nTregs) proceeds via two steps that involve the initial antigen dependent generation of CD25+GITRhiFoxp3−CD4+ nTreg precursors followed by the cytokine induction of Foxp3. Using mutant mouse models that lack c-Rel, the critical NF-κB transcription factor required for nTreg differentiation, we establish that c-Rel regulates both of these developmental steps. c-Rel controls the generation of nTreg precursors via a haplo-insufficient mechanism, indicating that this step is highly sensitive to c-Rel levels. However, maintenance of c-Rel in an inactive state in nTreg precursors demonstrates that it is not required for a constitutive function in these cells. While the subsequent IL-2 induction of Foxp3 in nTreg precursors requires c-Rel, this developmental transition does not coincide with the nuclear expression of c-Rel. Collectively, our results support a model of nTreg differentiation in which c-Rel generates a permissive state for foxp3 transcription during the development of nTreg precursors that influences the subsequent IL-2 dependent induction of Foxp3 without a need for c-Rel reactivation

Deactylase inhibition in myeloproliferative neoplasms

Myeloproliferative neoplasms (MPN) are clonal haemopoietic progenitor cell disorders characterized by the proliferation of one or more of the haemopoietic lineages (myeloid, erythroid and/or megakaryocytic). The MPNs include eight haematological disorders: chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), systemic mastocytosis (SM), chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), chronic neutrophilic leukemia (CNL), and unclassifiable MPN (MPN, U). Therapeutic interventions for MPNs include the use of tyrosine kinase inhibitors (TKIs) for BCR-ABL1+ CML and JAK2 inhibitors for PV, ET and PMF. Histone deacetylase inhibitors (HDACi) are a novel class of drugs capable of altering the acetylation status of both histone and non-histone proteins, thereby affecting a repertoire of cellular functions in neoplastic cells including proliferation, differentiation, immune responses, angiogenesis and survival. Preliminary studies indicate that HDACi when used in combination with tyrosine kinase or JAK2 inhibitors may overcome resistance to the latter agents and enhance the pro-apoptotic effects on MPN cells. This review provides a review of pre-clinical and clinical studies that have explored the use of HDACi as potential therapeutics for MPNs

Innovative Education and Training in high power laser plasmas (PowerLaPs) for plasma physics, high power laser-matter interactions and high energy density physics - Theory and experiments

The Erasmus Plus programme 'Innovative Education and Training in high power laser plasmas', otherwise known as PowerLaPs, is described. The PowerLaPs programme employs an innovative paradigm in that it is a multi-centre programme where teaching takes place in five separate institutes with a range of different aims and styles of delivery. The 'in class' time is limited to four weeks a year, and the programme spans two years. PowerLaPs aims to train students from across Europe in theoretical, applied and laboratory skills relevant to the pursuit of research in laser-plasma interaction physics and inertial confinement fusion (ICF). Lectures are intermingled with laboratory sessions and continuous assessment activities. The programme, which is led by workers from the Technological Educational Institute (TEI) of Crete, and supported by co-workers from the Queen's University Belfast, the University of Bordeaux, the Czech Technical University in Prague, Ecole Polytechnique, the University of Ioannina, the University of Salamanca and the University of York, has just completed its first year. Thus far three Learning Teaching Training (LTT) activities have been held, at the Queen's University Belfast, the University of Bordeaux and the Centre for Plasma Physics and Lasers (CPPL) of TEI Crete. The last of these was a two-week long Intensive Programme (IP), while the activities at the other two universities were each five days in length. Thus far work has concentrated upon training in both theoretical and experimental work in plasma physics, high power laser-matter interactions and high energy density physics. The nature of the programme will be described in detail and some metrics relating to the activities carried out to date will be presented

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response