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

Cognition and the brain of brood parasitic cowbirds.

Cowbirds are brood parasites. Females lay their eggs in the nests of other species, which then incubate the cowbird eggs and raise the young cowbirds. Finding and returning to heterospecific nests presents cowbirds with several cognitive challenges. In some species, such as brown-headed cowbirds (Molothrus ater), females but not males search for and remember the locations of potential host nests. We describe recent research on sex differences in cognition and the hippocampus associated with this sex difference in search for host nests. Female brown-headed cowbirds perform better than males on some, but not all, tests of spatial memory and females show a pattern of adult hippocampal neurogenesis not found in males or in closely related non-parasitic birds. Because of the apparent specialization of the hippocampus, brown-headed cowbirds may be a good model in which to examine spatial information processing in the avian hippocampus and we also describe recent research on the spatial response properties of brown-headed cowbird hippocampal neurons

Polymorphisms of the Steroid Sulfatase [STS] Gene are Associated With Attention Deficit Hyperactivity Disorder and Influence Brain Tissue mRNA Expression

Previous studies in animals and humans have implicated the X-chromosome STS gene in the etiology of attentional difficulties and attention deficit hyperactivity disorder (ADHD). This family based association study has fine mapped a region of the STS gene across intron 1 and 2 previously associated with ADHD, in an extended sample of 450 ADHD probands and their parents. Significant association across this region is demonstrated individually with 7 of the 12 genotyped SNPs, as well as an allele specific haplotype of the 12 SNPs. The over transmitted risk allele of rs12861247 was also associated with reduced STS mRNA expression in normal human post-mortem frontal cortex brain tissue compared to the non-risk allele (P = 0.01). These results are consistent with the hypothesis arising from previous literature demonstrating that boys with deletions of the STS gene, and hence no STS protein are at a significantly increased risk of developing ADHD. Furthermore, this study has established the brain tissue transcript of STS, which except from adipose tissue, differs from that seen in all other tissues investigated. © 2010 Wiley-Liss, Inc

Parathyroid hormone secretion is controlled by both ionised calcium and phosphate during exercise and recovery in men

The mechanism by which PTH is controlled during and after exercise is poorly understood due to insufficient temporal frequency of measurements. Objective: To examine the temporal pattern of PTH, PO4, ACa and Ca2+ during and after exercise. Design and setting: A laboratory-based study with a cross-over design, comparing 30 min of running at 55%, 65% and 75%VO2max, followed by 2.5-h of recovery. Blood was obtained at baseline, after 2.5, 5, 7.5, 10, 15, 20, 25 and 30 min of exercise and after 2.5, 5, 7.5, 10, 15, 20, 25, 30, 60, 90 and 150 min of recovery. Participants: Ten men (age 23±1 y, height 1.82±0.07 m, body mass 77.0±7.5 kg) participated. Main Outcome Measures: PTH, PO4, ACa and Ca2+ Results: Independent of intensity, PTH concentrations decreased with the onset of exercise (-21 to -33%; P≤0.001), increased thereafter and were higher than baseline by the end of exercise at 75%VO2max (+52%; P≤0.001). PTH peaked transiently after 5–7.5 min of recovery (+73 to +110%; P≤0.001). PO4 followed a similar temporal pattern to PTH and Ca2+ followed a similar but inverse pattern to PTH. PTH was negatively correlated with Ca2+ across all intensities (r=-0.739 to -0.790; P≤0.001). When PTH was increasing, the strongest cross-correlation was with Ca2+ at 0 lags (3.5 min) (r=-0.902 to -0.950); during recovery, the strongest cross-correlation was with PO4 at 0 lags (8 min) (r=0.987 to 0.995). Conclusions: PTH secretion during exercise and recovery is controlled by a combination of changes in Ca2+ and PO4 in men

The South Asian genome

Genetics of disease Microarrays Variant genotypes Population genetics Sequence alignment AllelesThe genetic sequence variation of people from the Indian subcontinent who comprise one-quarter of the world's population, is not well described. We carried out whole genome sequencing of 168 South Asians, along with whole-exome sequencing of 147 South Asians to provide deeper characterisation of coding regions. We identify 12,962,155 autosomal sequence variants, including 2,946,861 new SNPs and 312,738 novel indels. This catalogue of SNPs and indels amongst South Asians provides the first comprehensive map of genetic variation in this major human population, and reveals evidence for selective pressures on genes involved in skin biology, metabolism, infection and immunity. Our results will accelerate the search for the genetic variants underlying susceptibility to disorders such as type-2 diabetes and cardiovascular disease which are highly prevalent amongst South Asians.Whole genome sequencing to discover genetic variants underlying type-2 diabetes, coronary heart disease and related phenotypes amongst Indian Asians. Imperial College Healthcare NHS Trust cBRC 2011-13 (JS Kooner [PI], JC Chambers)

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

Drinking behaviour and alcohol-related harm amongst older adults: analysis of existing UK datasets.

Older adults experience age-related physiological changes that increase sensitivity and decrease tolerance to alcohol and there are a number of age-related harms such as falls, social isolation and elder abuse, which are compounded by alcohol misuse. Despite this unique vulnerability and the fact that the number of older adults is increasing, the literature on drinking behaviour and alcohol-related harm in older adults is sparse. This article describes a secondary analysis of UK data to address this knowledge gap