Measles virus causes immunogenic cell death in human melanoma

Oncolytic viruses (OV) are promising treatments for cancer, with several currently undergoing testing in randomised clinical trials. Measles virus (MV) has not yet been tested in models of human melanoma. This study demonstrates the efficacy of MV against human melanoma. It is increasingly recognised that an essential component of therapy with OV is the recruitment of host anti-tumour immune responses, both innate and adaptive. MV-mediated melanoma cell death is an inflammatory process, causing the release of inflammatory cytokines including type-1 interferons and the potent danger signal HMGB1. Here, using human in vitro models, we demonstrate that MV enhances innate antitumour activity, and that MV-mediated melanoma cell death is capable of stimulating a melanoma-specific adaptive immune response

Disease Status and Pubertal Stage Predict Improved Growth in Anti-TNF Therapy for Pediatric Inflammatory Bowel Disease

Background: Growth failure is well-recognised in pediatric Inflammatory Bowel Disease (PIBD; <18 years). We aimed to examine whether anti-Tumor Necrosis Factor (TNF) therapy improves growth in a PIBD population-based cohort. Methods: A retrospective review of all Scottish children receiving anti-TNF (infliximab (IFX) and adalimumab (ADA)) from 2000-2012 was performed; height was collected at: 12 months before anti-TNF (T-12), start (T0) and 12 (T+12) months after anti-TNF. Results: 93/201 treated with IFX and 28/49 for ADA had satisfactory growth data; 66 had full pubertal data. Univariate analysis demonstrated early pubertal stages (Tanner 1-3 n = 44 vs. T4-5 n = 22), disease remission, disease duration >=2 years and duration of IFX >=12 months were associated with improved linear growth for IFX; for ADA only improvement was seen in Tanner 1-3. For IFX, Tanner 1-3 median [DELTA] ht SDS -0.3 (-0.7,0.2) at T0 changed to 0.04 (-0.5, 0.7) at T+12 (p < 0.001) vs -0.01 (-0.5, 0.9) at T0 in T4-5 changed to -0.01 (-0.4, 0.2) at T+12 (p > 0.05). For IFX disease duration >=2 year, median [DELTA] ht SDS was -0.13 (-0.6, 0.3) at T0 then 0.07 (-0.3, 0.6) at T+12 (p < 0.001). Remission improved [DELTA] ht SDS (median [DELTA] ht SDS -0.14 (-0.6, 0.3) at T0 to 0.17 (-0.2, 0.7) at T+12 (p > 0.001)). Multiple regression analysis demonstrated corticosteroid usage at T0 predicted improved [DELTA] ht SDS at T+12 for IFX and ADA. Conclusions: Anti-TNF therapy is more likely to be associated with growth improvement when used at earlier stages of puberty with remission a key growth-promoting strategy in Paediatric Crohn's disease

NO-Donating Aspirin and Aspirin Partially Inhibit Age-Related Atherosclerosis but Not Radiation-Induced Atherosclerosis in ApoE Null Mice

BACKGROUND: We previously showed that irradiation to the carotid arteries of ApoE(-/-) mice accelerated the development of macrophage-rich, inflammatory atherosclerotic lesions, prone to intra-plaque hemorrhage. In this study we investigated the potential of anti-inflammatory and anti-coagulant intervention strategies to inhibit age-related and radiation-induced atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: ApoE(-/-) mice were given 0 or 14 Gy to the neck and the carotid arteries and aortic arches were harvested at 4 or 30 weeks after irradiation. Nitric oxide releasing aspirin (NCX 4016, 60 mg/kg/day) or aspirin (ASA, 30 or 300 mg/kg/day) were given continuously in the chow. High dose ASA effectively blocked platelet aggregation, while the low dose ASA or NCX 4016 had no significant effect on platelet aggregation. High dose ASA, but not NCX 4016, inhibited endothelial cell expression of VCAM-1 and thrombomodulin in the carotid arteries at 4 weeks after irradiation; eNOS and ICAM-1 levels were unchanged. After 30 weeks of follow-up, NCX 4016 significantly reduced the total number of lesions and the number of initial macrophage-rich lesions in the carotid arteries of unirradiated mice, but these effects were not seen in the brachiocephalic artery of the aortic arch (BCA). In contrast, high dose ASA lead to a decrease in the number of initial lesions in the BCA, but not in the carotid artery. Both high dose ASA and NCX 4016 reduced the collagen content of advanced lesions and increased the total plaque burden in the BCA of unirradiated mice. At 30 weeks after irradiation, neither NCX 4016 nor ASA significantly influenced the number or distribution of lesions, but high dose ASA lead to formation of collagen-rich "stable" advanced lesions in carotid arteries. The total plaque area of the irradiated BCA was increased after ASA, but the plaque burden was very low compared with the carotid artery. CONCLUSIONS/SIGNIFICANCE: The development and characteristics of radiation-induced atherosclerosis varied between different arteries but could not be circumvented by anti-inflammatory and anti-coagulant therapies. This implicates other underlying mechanistic pathways compared to age-related atherosclerosis

Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome).

We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome

The malaria parasite sheddase SUB2 governs host red blood cell membrane sealing at invasion.

Red blood cell (RBC) invasion by malaria merozoites involves formation of a parasitophorous vacuole into which the parasite moves. The vacuole membrane seals and pinches off behind the parasite through an unknown mechanism, enclosing the parasite within the RBC. During invasion, several parasite surface proteins are shed by a membrane-bound protease called SUB2. Here we show that genetic depletion of SUB2 abolishes shedding of a range of parasite proteins, identifying previously unrecognized SUB2 substrates. Interaction of SUB2-null merozoites with RBCs leads to either abortive invasion with rapid RBC lysis, or successful entry but developmental arrest. Selective failure to shed the most abundant SUB2 substrate, MSP1, reduces intracellular replication, whilst conditional ablation of the substrate AMA1 produces host RBC lysis. We conclude that SUB2 activity is critical for host RBC membrane sealing following parasite internalisation and for correct functioning of merozoite surface proteins

Transient receptor potential canonical 5 (TRPC5) protects against pain and vascular inflammation in arthritis and joint inflammation

Objective: Transient receptor potential canonical 5 (TRPC5) is functionally expressed on a range of cells including fibroblast-like synoviocytes, which play an important role in arthritis. A role for TRPC5 in inflammation has not been previously shown in vivo. We investigated the contribution of TRPC5 in arthritis. Methods: Male wild-type and TRPC5 knockout (KO) mice were used in a complete Freund’s adjuvant (CFA)-induced unilateral arthritis model, assessed over 14 days. Arthritis was determined by measurement of knee joint diameter, hindlimb weightbearing asymmetry and pain behaviour. Separate studies involved chronic pharmacological antagonism of TRPC5 channels. Synovium from human post-mortem control and inflammatory arthritis samples were investigated for TRPC5 gene expression. Results: At baseline, no differences were observed. CFA-induced arthritis resulted in increased synovitis in TRPC5 KO mice assessed by histology. Additionally, TRPC5 KO mice demonstrated reduced ipsilateral weightbearing and nociceptive thresholds (thermal and mechanical) following CFA-induced arthritis. This was associated with increased mRNA expression of inflammatory mediators in the ipsilateral synovium and increased concentration of cytokines in synovial lavage fluid. Chronic treatment with ML204, a TRPC5 antagonist, augmented weightbearing asymmetry, secondary hyperalgesia and cytokine concentrations in the synovial lavage fluid. Synovia from human inflammatory arthritis demonstrated a reduction in TRPC5 mRNA expression. Conclusions: Genetic deletion or pharmacological blockade of TRPC5 results in an enhancement in joint inflammation and hyperalgesia. Our results suggest that activation of TRPC5 may be associated with an endogenous anti-inflammatory/analgesic pathway in inflammatory joint conditions

A review of the genetic determinants of praziquantel resistance in Schistosoma mansoni: Is praziquantel and intestinal schistosomiasis a perfect match?

Schistosomiasis is a neglected tropical disease (NTD) caused by parasitic trematodes belonging to the Schistosoma genus. The mainstay of schistosomiasis control is the delivery of a single dose of praziquantel (PZQ) through mass drug administration (MDA) programs. These programs have been successful in reducing the prevalence and intensity of infections. Due to the success of MDA programs, the disease has recently been targeted for elimination as a public health problem in some endemic settings. The new World Health Organization (WHO) treatment guidelines aim to provide equitable access to PZQ for individuals above two years old in targeted areas. The scale up of MDA programs may heighten the drug selection pressures on Schistosoma parasites, which could lead to the emergence of PZQ resistant schistosomes. The reliance on a single drug to treat a disease of this magnitude is worrying should drug resistance develop. Therefore, there is a need to detect and track resistant schistosomes to counteract the threat of drug resistance to the WHO 2030 NTD roadmap targets. Until recently, drug resistance studies have been hindered by the lack of molecular markers associated with PZQ resistance. This review discusses recent significant advances in understanding the molecular basis of PZQ action in S. mansoni and proposes additional genetic determinants associated with PZQ resistance. PZQ resistance will also be analyzed in the context of alternative factors that may decrease efficacy within endemic field settings, and the most recent treatment guidelines recommended by the WHO.</jats:p

Acute respiratory infections in hospitalized children in Vientiane, Lao PDR - the importance of Respiratory Syncytial Virus

The Human respiratory syncytial virus (RSV) is one of the most important viral pathogens, causing epidemics of acute respiratory infection (ARI), especially bronchiolitis and pneumonia, in children worldwide. To investigate the RSV burden in Laos, we conducted a one-year study in children <5 years old admitted to Mahosot Hospital, Vientiane Capital, to describe clinical and epidemiological characteristics and predictive factors for severity of RSV-associated ARI. Pooled nasal and throat swabs were tested using multiplex real-time PCR for 33 respiratory pathogens (FTD® kit). A total of 383 patients were included, 277 (72.3%) of whom presented with pneumonia. 377 (98.4%) patients were positive for at least one microorganism, of which RSV was the most common virus (41.0%), with a peak observed between June and September, corresponding to the rainy season. Most RSV inpatients had pneumonia (84.1%), of whom 35% had severe pneumonia. Children <3-months old were a high-risk group for severe pneumonia, independently of RSV infection. Our study suggests that RSV infection is frequent in Laos and commonly associated with pneumonia in hospitalized young children. Further investigations are required to provide a better overall view of the Lao nationwide epidemiology and public health burden of RSV infection over time.This study was funded by the Institute of Research for Development (IRD), Aix-Marseille University, the Wellcome Trust of Great Britain (Grant number 089275/H/09/Z0). Te feldwork was supported by the Bill & Melinda Gates Foundation grant OPP1115490 and the Murdoch Childrens Research Institute, Melbourne, Australia. Te authors declare that no competing interests exist

Prognostic value of the 6-gene OncoMasTR test in hormone receptor–positive HER2-negative early-stage breast cancer: Comparative analysis with standard clinicopathological factors

Aim: The aim of the study was to assess the prognostic performance of a 6-gene molecular score (OncoMasTR Molecular Score [OMm]) and a composite risk score (OncoMasTR Risk Score [OM]) and to conduct a within-patient comparison against four routinely used molecular and clinicopathological risk assessment tools: Oncotype DX Recurrence Score, Ki67, Nottingham Prognostic Index and Clinical Risk Category, based on the modified Adjuvant! Online definition and three risk factors: patient age, tumour size and grade. Methods: Biospecimens and clinicopathological information for 404 Irish women also previously enrolled in the Trial Assigning Individualized Options for Treatment [Rx] were provided by 11 participating hospitals, as the primary objective of an independent translational study. Gene expression measured via RT-qPCR was used to calculate OMm and OM. The prognostic value for distant recurrence-free survival (DRFS) and invasive disease-free survival (IDFS) was assessed using Cox proportional hazards models and Kaplan-Meier analysis. All statistical tests were two-sided ones. Results: OMm and OM (both with likelihood ratio statistic [LRS] P Discussion: Both OncoMasTR scores were significantly prognostic for DRFS and IDFS and provided additional prognostic information to the molecular and clinicopathological risk factors/tools assessed. OM was also the most accurate risk classification tool for identifying DR. A concise 6-gene signature with superior risk stratification was shown to increase prognosis reliability, which may help clinicians optimise treatment decisions. Trial registration: ClinicalTrials.gov NCT02050750 NCT00310180.</p