Immune activation by combination human lymphokine-activated killer and dendritic cell therapy.

BACKGROUND: Optimal cellular immunotherapy for cancer should ideally harness both the innate and adaptive arms of the immune response. Lymphokine-activated killer cells (LAKs) can trigger early innate killing of tumour targets, whereas long-term adaptive-specific tumour control requires priming of CD8+ cytotoxic lymphocytes (CTLs) following acquisition of tumour-associated antigens (TAAs) by antigen-presenting cells such as dendritic cells (DCs). As DCs stimulate both innate and adaptive effectors, combination cell therapy using LAKs and DCs has the potential to maximise anti-tumour immune priming. METHODS: Reciprocal activation between human clinical grade LAKs and DCs on co-culture, and its immune consequences, was monitored by cell phenotype, cytokine release and priming of both innate and adaptive cytotoxicity against melanoma targets. RESULTS: Co-culture of DCs and LAKs led to phenotypic activation of natural killer (NK) cells within the LAK population, which was associated with increased production of inflammatory cytokines and enhanced innate cytotoxicity against tumour cell targets. The LAKs reciprocally matured DCs, and the combination of LAKs and DCs, on addition of melanoma cells, supported priming of specific anti-tumour CTLs better than DCs alone. CONCLUSION: Clinical-grade LAKs/DCs represents a practical, effective combination cell immunotherapy for stimulation of both innate and adaptive anti-tumour immunity in cancer patients

Environmental differences between sites control the diet and nutrition of the carnivorous plant Drosera rotundifolia

Background and aims: Carnivorous plants are sensitive to small changes in resource availability, but few previous studies have examined how differences in nutrient and prey availability affect investment in and the benefit of carnivory. We studied the impact of site-level differences in resource availability on ecophysiological traits of carnivory for Drosera rotundifolia L. Methods: We measured prey availability, investment in carnivory (leaf stickiness), prey capture and diet of plants growing in two bogs with differences in N deposition and plant available N: Cors Fochno (0.62 g m−2 yr.−1, 353 μg l−1), Whixall Moss (1.37 g m−2 yr.−1, 1505 μg l−1). The total N amount per plant and the contributions of prey/root N to the plants’ N budget were calculated using a single isotope natural abundance method. Results: Plants at Whixall Moss invested less in carnivory, were less likely to capture prey, and were less reliant on prey-derived N (25.5% compared with 49.4%). Actual prey capture did not differ between sites. Diet composition differed – Cors Fochno plants captured 62% greater proportions of Diptera. Conclusions: Our results show site-level differences in plant diet and nutrition consistent with differences in resource availability. Similarity in actual prey capture may be explained by differences in leaf stickiness and prey abundance

Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21

Background: The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible. Methods: This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment. Results: An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response. Conclusion: This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations

Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition

A clinical oncolytic herpes simplex virus (HSV) encoding granulocyte-macrophage colony-stimulating factor (GMCSF), talimogene laherparepvec, causes regression of injected and non-injected melanoma lesions in patients and is now licensed for clinical use in advanced melanoma. To date, limited data are available regarding the mechanisms of human anti-tumor immune priming, an improved understanding of which could inform the development of future combination strategies with improved efficacy. This study addressed direct oncolysis and innate and adaptive human immune-mediated effects of a closely related HSV encoding GM-CSF (HSVGM-CSF) alone and in combination with histone deacetylase inhibition. We found that HSVGM-CSF supported activation of antimelanoma immunity via monocyte-mediated type I interferon production, which activates NK cells, and viral maturation of immature dendritic cells (iDCs) into potent antigen-presenting cells for cytotoxic T lymphocyte (CTL) priming. Addition of the histone deacetylase inhibitor valproic acid (VPA) to HSVGM-CSF treatment of tumor cells increased viral replication, viral GM-CSF production, and oncolysis and augmented the development of anti-tumor immunity. Mechanistically, VPA increased expression of activating ligands for NK cell recognition and induced expression of tumor-associated antigens, supporting innate NK cell killing and CTL priming. These data support the clinical combination of talimogene laherparepvec with histone deacetylase inhibition to enhance oncolysis and anti-tumor immunity

Mortality and causes of death among violent offenders and victims-a Swedish population based longitudinal study

<p>Abstract</p> <p>Background</p> <p>Most previous studies on mortality in violent offenders or victims are based on prison or hospital samples, while this study analyzed overall and cause specific mortality among violent offenders, victims, and individuals who were both offenders and victims in a general sample of 48,834 18-20 year-old men conscripted for military service in 1969/70 in Sweden.</p> <p>Methods</p> <p>Each person completed two non-anonymous questionnaires concerning family, psychological, and behavioral factors. The cohort was followed for 35 years through official registers regarding violent offenses, victimization, and mortality. The impact of violence, victimization, early risk factors and hospitalization for psychiatric diagnosis or alcohol and drug misuse during follow up on mortality was investigated using Cox proportional hazard regression analyses.</p> <p>Results</p> <p>Repeat violent offenses were associated with an eleven fold higher hazard of dying from a substance-related cause and nearly fourfold higher hazard of dying from suicide. These figures remained significantly elevated also in multivariate analyses, with a 3.03 and 2.39 hazard ratio (HR), respectively. Participants with experience of violence and inpatient care for substance abuse or psychiatric disorder had about a two to threefold higher risk of dying compared to participants with no substance use or psychiatric disorder.</p> <p>Conclusions</p> <p>Violent offending and being victimized are associated with excess mortality and a risk of dying from an alcohol or drug-related cause or suicide. Consequently, prevention of violent behavior might have an effect on overall mortality and suicide rates. Prevention of alcohol and drug use is also warranted.</p

The impact of Curtin University's Activity, Food and Attitudes Program on physical activity, sedentary time and fruit, vegetable and junk food consumption among overweight and obese adolescents: A waitlist controlled trial

Background: To determine the effects of participation in Curtin University's Activity, Food and Attitudes Program (CAFAP), a community-based, family-centered behavioural intervention, on the physical activity, sedentary time, and healthy eating behaviours of overweight and obese adolescents. Methods: In this waitlist controlled clinical trial in Western Australia, adolescents (n = 69, 71% female, mean age 14.1 (SD 1.6) years) and parents completed an 8-week intervention followed by 12 months of telephone and text message support. Assessments were completed at baseline, before beginning the intervention, immediately following the intervention, and at 3-, 6-, and 12- months follow-up. The primary outcomes were physical activity and sedentary time assessed by accelerometers and servings of fruit, vegetables and junk food assessed by 3-day food records. Results: During the intensive 8-week intervention sedentary time decreased by −5.1 min/day/month (95% CI: −11.0, 0.8) which was significantly greater than the rate of change during the waitlist period (p = .014). Moderate physical activity increased by 1.8 min/day/month (95% CI: −0.04, 3.6) during the intervention period, which was significantly greater than the rate of change during the waitlist period (p = .041). Fruit consumption increased during the intervention period (monthly incidence rate ratio (IRR) 1.3, 95% CI: 1.10, 1.56) and junk food consumption decreased (monthly IRR 0.8, 95% CI: 0.74, 0.94) and these changes were different to those seen during the waitlist period (p = .004 and p = .020 respectively). Conclusions: Participating in CAFAP appeared to have a positive influence on the physical activity, sedentary and healthy eating behaviours of overweight and obese adolescents and many of these changes were maintained for one year following the intensive intervention. Trial Registration: Australia and New Zealand Clinical Trials Registry ACTRN12611001187932

How DNA Barcodes Complement Taxonomy and Explore Species Diversity: The Case Study of a Poorly Understood Marine Fauna

BACKGROUND: The species boundaries of some venerids are difficult to define based solely on morphological features due to their indistinct intra- and interspecific phenotypic variability. An unprecedented biodiversity crisis caused by human activities has emerged. Thus, to access the biological diversity and further the conservation of this taxonomically muddling bivalve group, a fast and simple approach that can efficiently examine species boundaries and highlight areas of unrecognized diversity is urgently needed. DNA barcoding has proved its effectiveness in high-volume species identification and discovery. In the present study, Chinese fauna was chosen to examine whether this molecular biomarker is sensitive enough for species delimitation, and how it complements taxonomy and explores species diversity. METHODOLOGY/PRINCIPAL FINDINGS: A total of 315 specimens from around 60 venerid species were included, qualifying the present study as the first major analysis of DNA barcoding for marine bivalves. Nearly all individuals identified to species level based on morphological traits possessed distinct barcode clusters, except for the specimens of one species pair. Among the 26 individuals that were not assigned binomial names a priori, twelve respectively nested within a species genealogy. The remaining individuals formed five monophyletic clusters that potentially represent species new to science or at least unreported in China. Five putative hidden species were also uncovered in traditional morphospecies. CONCLUSIONS/SIGNIFICANCE: The present study shows that DNA barcoding is effective in species delimitation and can aid taxonomists by indicating useful diagnostic morphological traits, informing needful revision, and flagging unseen species. Moreover, the BOLD system, which deposits barcodes, morphological, geographical and other data, has the potential as a convenient taxonomic platform

Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy

In our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNβ), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNβ-escape tumors predictably express a point-mutated CSDE1P5S form of the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor of VSV replication by disrupting viral transcription. Given time, VSV-IFNβ evolves a compensatory mutation in the P/M Inter-Genic Region which rescues replication in CSDE1P5S cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1P5S also generates a neo-epitope recognized by non-tolerized T cells. We exploit this predictable neo-antigenesis to drive, and trap, tumors into an escape phenotype, which can be ambushed by vaccination against CSDE1P5S, preventing tumor escape. Combining frontline therapy with escape-targeting immunotherapy will be applicable across multiple therapies which drive tumor mutation/evolution and simultaneously generate novel, targetable immunopeptidomes associated with acquired treatment resistance

Novel concepts in virally induced asthma

Viruses are the predominant infectious cause of asthma exacerbations in the developed world. In addition, recent evidence strongly suggests that viral infections may also have a causal role in the development of childhood asthma. In this article, we will briefly describe the general perception of how the link between infections and asthma has changed over the last century, and then focus on very recent developments that have provided new insights into the contribution of viruses to asthma pathogenesis. Highlighted areas include the contribution of severe early life viral infections to asthma inception, genetic determinants of severe viral infections in infancy, the differences in innate and adaptive immune system cytokine responses to viral infection between asthmatic and nonasthmatic subjects, and a potential vaccine strategy to prevent severe early life virally-induced illness

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny