Imatinib mesylate inhibits antigen-specific memory CD8 T cell responses in vivo

Imatinib mesylate (IM) is effective at inducing complete cytogenetic remission in patients with chronic myelogenous leukemia. Because its influence on CD8 T cell responsiveness in vivo is unknown, we investigated the effects of IM by analyzing the response of OT-1 CD8 T cells to Listeria monocytogenes (LM) that express the cognate epitope OVA(257-264) (LM-OVA). In vitro, IM had no effect on Ag-specific expansion, cell division, cell cycle progression, or IFN-gamma expression in naive or memory OT-1 T cells. However, IM induced apoptosis of naive and memory OT-1 T cells at doses of >5 microM. At 15 microM IM, OT-1 T cells did not survive in in vitro cultures. The primary response of OT-1 T cells in vivo to LM-OVA infection was unaltered. In contrast, continuous IM treatment resulted in a diminished memory OT-1 response. The expression of IL-7Ralpha, a receptor required for memory cell survival, was lower (on OT-1 cells) in animals receiving IM. These results indicate that IM treatment affects the ability of the CD8 memory pool to respond to Ag and has the potential to increase susceptibility to infection.     

Estimating Dengue Transmission Intensity from Sero-Prevalence Surveys in Multiple Countries

Background

Estimates of dengue transmission intensity remain ambiguous. Since the majority of infections are asymptomatic, surveillance systems substantially underestimate true rates of infection. With advances in the development of novel control measures, obtaining robust estimates of average dengue transmission intensity is key for assessing both the burden of disease from dengue and the likely impact of interventions.

Methodology/Principal Findings

The force of infection (λ) and corresponding basic reproduction numbers (R₀) for dengue were estimated from non-serotype (IgG) and serotype-specific (PRNT) age-stratified seroprevalence surveys identified from the literature. The majority of R₀ estimates ranged from 1–4. Assuming that two heterologous infections result in complete immunity produced up to two-fold higher estimates of R₀ than when tertiary and quaternary infections were included. λ estimated from IgG data were comparable to the sum of serotype-specific forces of infection derived from PRNT data, particularly when inter-serotype interactions were allowed for.

Conclusions/Significance

Our analysis highlights the highly heterogeneous nature of dengue transmission. How underlying assumptions about serotype interactions and immunity affect the relationship between the force of infection and R₀ will have implications for control planning. While PRNT data provides the maximum information, our study shows that even the much cheaper ELISA-based assays would provide comparable baseline estimates of overall transmission intensity which will be an important consideration in resource-constrained settings.     

Assessment of the Economic Impact of Belimumab for the Treatment of Systemic Lupus Erythematosus in the Italian Setting: A Cost-Effectiveness Analysis

ObjectiveThe purpose of this analysis is to evaluate the cost-effectiveness of belimumab, a new biological treatment specifically developed for the treatment of Systemic Lupus Erythematosus (SLE), in the Italian setting. SLE is a chronic non-organ specific autoimmune disease characterized by a disregulation of the immune system that involves many organs and systems.MethodsA cost-effectiveness micro-simulation model with a lifetime horizon originally developed for the UK was adapted to the Italian setting. The analysis compared Standard of Care (SoC) alone vs belimumab plus SoC from a National Healthcare Service (NHS) and societal perspective. Health-economic consequences of treatments and organ damage progression were calculated. When available, Italian data were used, otherwise UK costs were converted using Purchasing Power Parities (PPPs). Utility values were based on the EQ-5D™ assessments in the belimumab clinical trials (BLISS 52 and 76). Results were discounted with 3% for costs and effects. A maximum belimumab treatment duration of 6 years was assumed and wastage costs were considered.ResultsCost per life year gained (Incremental Cost-Effectiveness Ratio, ICER) and cost per Quality Adjusted Life Year (QALY) (Incremental Cost-Utility Ratio, ICUR) were €22,990 and €32,859, respectively. These values reduced to €20,119 and €28,754, respectively, when indirect costs were included.ConclusionsIt may be concluded that in the Italian setting and according to the guidelines of the Italian Association of Health Economics (IAHE), belimumab was shown to be cost-effective, in terms of both ICER and ICUR, (€25–40,000/QALY).     

Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5

The Eph receptor tyrosine kinase/ephrin ligand system regulates a wide spectrum of physiological processes, while its dysregulation has been implicated in cancer progression. The human EphA3 receptor is widely upregulated in the tumor microenvironment and is highly expressed in some types of cancer cells. Furthermore, EphA3 is among the most highly mutated genes in lung cancer and it is also frequently mutated in other cancers. We report the structure of the ligand-binding domain of the EphA3 receptor in complex with its preferred ligand, ephrin-A5. The structure of the complex reveals a pronounced tilt of the ephrin-A5 ligand compared to its orientation when bound to the EphA2 and EphB2 receptors and similar to its orientation when bound to EphA4. This tilt brings an additional area of ephrin-A5 into contact with regions of EphA3 outside the ephrin-binding pocket thereby enlarging the size of the interface, which is consistent with the high binding affinity of ephrin-A5 for EphA3. This large variation in the tilt of ephrin-A5 bound to different Eph receptors has not been previously observed for other ephrins.     

An Innovative Pseudotypes-Based Enzyme-Linked Lectin Assay for the Measurement of Functional Anti-Neuraminidase Antibodies

Antibodies (Ab) to neuraminidase (NA) play a role in limiting influenza infection and might help reduce the disease impact. The most widely used serological assay to measure functional anti-NA immune responses is the Enzyme-Linked Lectin Assay (ELLA) which relies on hemagglutinin (HA) mismatched virus reassortants, or detergent treated viruses as the NA source to overcome interference associated with steric hindrance of anti-HA Ab present in sera. The difficulty in producing and handling these reagents, which are not easily adapted for screening large numbers of samples, limits the routine analysis of functional anti-NA Ab in clinical trials. In this study, we produced influenza lentiviral pseudoparticles (PPs) containing only the NA antigen (NA-PPs) with a simple two-plasmid co-transfection system. NA-PPs were characterized and tested as an innovative source of NA in the NA inhibition (NI) assay. Both swine A/California/07/2009 (H1N1) and avian A/turkey/Turkey/01/2005 (H5N1) N1s within NA-PPs retained their sialidase activity and were specifically inhibited by homologous and N1 subtype-specific, heterologous sheep sera. Moreover, A/California/07/2009 N1-PPs were a better source of NA compared to whole live and detergent treated H1N1 viruses in ELLA, likely due to lack of interference by anti-HA Ab, and absence of possible structural modifications caused by treatment with detergent. This innovative assay is safer and applicable to all NAs. Taken together, these results highlight the potential of NA-PPs-based NI assays to be developed as sensitive, flexible, easy to handle and scalable serological tests for routine NA immune response analysis.     

Neutrophils fan cancer’s flames

A new study published in this issue of The EMBO Journal looks into the crosstalk between inflammation and cancer (Antonio et al, 2015 ). By using a zebrafish melanoma model, the authors reveal that neutrophils recruited at the wound site directly interact with cells undergoing oncogenic transformation and provide them with a paracrine proliferative support. Importantly, the authors demonstrate the clinical relevance of this association, showing that neutrophil infiltration has an independent prognostic value for human melanoma. This study reinforces the notion that inflammation flames carcinogenesis, which might have important implications for the improvement of antitumour therapies.     

Biological investigation of N-methyl thiosemicarbazones as antimicrobial agents and bacterial carbonic anhydrases inhibitors

The enormous burden of the COVID-19 pandemic in economic and healthcare terms has cast a shadow on the serious threat of antimicrobial resistance, increasing the inappropriate use of antibiotics and shifting the focus of drug discovery programmes from antibacterial and antifungal fields. Thus, there is a pressing need for new antimicrobials involving innovative modes of action (MoAs) to avoid cross-resistance rise. Thiosemicarbazones (TSCs) stand out due to their easy preparation and polypharmacological application, also in infectious diseases. Recently, we reported a small library of TSCs (1–9) that emerged for their non-cytotoxic behaviour. Inspired by their multifaceted activity, we investigated the antibacterial, antifungal, and antidermatophytal profiles of derivatives 1–9, highlighting a new promising research line. Furthermore, the ability of these compounds to inhibit selected microbial and human carbonic anhydrases (CAs) was assessed, revealing their possible involvement in the MoA and a good selectivity index for some derivatives.     

miR‐24 and its target gene Prdx6 regulate viability and senescence of myogenic progenitors during aging

Satellite cell‐dependent skeletal muscle regeneration declines during aging. Disruptions within the satellite cells and their niche, together with alterations in the myofibrillar environment, contribute to age‐related dysfunction and defective muscle regeneration. In this study, we demonstrated an age‐related decline in satellite cell viability and myogenic potential and an increase in ROS and cellular senescence. We detected a transient upregulation of miR‐24 in regenerating muscle from adult mice and downregulation of miR‐24 during muscle regeneration in old mice. FACS‐sorted satellite cells were characterized by decreased levels of miR‐24 and a concomitant increase in expression of its target: Prdx6. Using GFP reporter constructs, we demonstrated that miR‐24 directly binds to its predicted site within Prdx6 mRNA. Subtle changes in Prdx6 levels following changes in miR‐24 expression indicate miR‐24 plays a role in fine‐tuning Prdx6 expression. Changes in miR‐24 and Prdx6 levels were associated with altered mitochondrial ROS generation, increase in the DNA damage marker: phosphorylated‐H2Ax and changes in viability, senescence, and myogenic potential of myogenic progenitors from mice and humans. The effects of miR‐24 were more pronounced in myogenic progenitors from old mice, suggesting a context‐dependent role of miR‐24 in these cells, with miR‐24 downregulation likely a part of a compensatory response to declining satellite cell function during aging. We propose that downregulation of miR‐24 and subsequent upregulation of Prdx6 in muscle of old mice following injury are an adaptive response to aging, to maintain satellite cell viability and myogenic potential through regulation of mitochondrial ROS and DNA damage pathways.