Activation of a helper and not regulatory human CD4+ T cell response by oncolytic H-1 parvovirus

Background

H-1 parvovirus (H-1 PV), a rodent autonomous oncolytic parvovirus, has emerged as a novel class of promising anticancer agents, because of its ability to selectively find and destroy malignant cells. However, to probe H-1 PV multimodal antitumor potential one of the major prerequisites is to decipher H-1 PV direct interplay with human immune system, and so prevent any risk of impairment.

Methodology/Principal findings

Non activated peripheral blood mononuclear cells (PBMCs) are not sensitive to H-1 PV cytotoxic effect. However, the virus impairs both activated PBMC proliferation ability and viability. This effect is related to H-1 PV infection as evidenced by Western blotting detection of H-1 PV main protein NS1. However, TCID50 experiments did not allow newly generated virions to be detected. Moreover, flow cytometry has shown that H-1 PV preferentially targets B lymphocytes. Despite seeming harmful at first sight, H-1 PV seems to affect very few NK cells and CD8+ T lymphocytes and, above all, clearly does not affect human neutrophils and one of the major CD4+ T lymphocyte subpopulation. Very interestingly, flow cytometry analysis and ELISA assays proved that it even activates human CD4+ T cells by increasing activation marker expression (CD69 and CD30) and both effective Th1 and Th2 cytokine secretion (IL-2, IFN-γ and IL-4). In addition, H-1 PV action does not come with any sign of immunosuppressive side effect. Finally, we have shown the efficiency of H-1 PV on xenotransplanted human nasopharyngeal carcinoma, in a SCID mouse model reconstituted with human PBMC.

Conclusions/Significance

Our results show for the first time that a wild-type oncolytic virus impairs some immune cell subpopulations while directly activating a Helper CD4+ T cell response. Thus, our data open numerous gripping perspectives of investigation and strongly argue for the use of H-1 PV as an anticancer treatment.     

Starch crystal solubility and starch granule gelatinisation

The solubility and dissolution behaviour of A- and B-type crystals of short chain amylose were measured both directly and using differential scanning calorimetry in the temperature range 30-110 degrees C. Dissolution in the calorimeter was affected by super-heating to the extent of 24-28 degrees C. Following trends previously found by calorimetry the B-type crystal polymorph was more soluble than the A-type. Analysis of the chain composition of the dissolved material revealed a preferential solubilisation of the short chains at the lower temperatures. The solubility of both crystal polymorphs and the magnitude of the preferential solubilisation effect was reduced in the presence of 30% w/w sucrose. A comparison of calorimetric measurements of crystal dissolution and the gelatinisation of native granular waxy maize and potato starches found some broad similarities, such as transition temperatures and their composition dependence, and some differences, such as the relatively narrow temperature range of granular gelatinisation, which reflects its cooperative nature.     

Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12–q13

Familial cylindromatosis is an autosomal dominant predisposition to multiple neoplasms of the skin appendages. The susceptibility gene has previously been mapped to chromosome 16q12-q13 and has features of a recessive oncogene/tumour suppressor gene. We have now evaluated 19 families with this disease by a combination of genetic linkage analysis and loss of heterozygosity in cylindromas from affected individuals. All 15 informative families show linkage to this locus, providing no evidence for genetic heterogeneity. Recombinant mapping has placed the gene in an interval of approximately 1 Mb. There is no evidence, between families, of haplotype sharing that might be indicative of common founder mutations.     

Both the hippocampus and striatum are involved in consolidation of motor sequence memory

Functional magnetic resonance imaging (fMRI) was used to investigate the cerebral correlates of motor sequence memory consolidation. Participants were scanned while training on an implicit oculomotor sequence learning task and during a single testing session taking place 30 min, 5 hr, or 24 hr later. During training, responses observed in hippocampus and striatum were linearly related to the gain in performance observed overnight, but not over the day. Responses in both structures were significantly larger at 24 hr than at 30 min or 5 hr. Additionally, the competitive interaction observed between these structures during training became cooperative overnight. These results stress the importance of both hippocampus and striatum in procedural memory consolidation. Responses in these areas during training seem to condition the overnight memory processing that is associated with a change in their functional interactions. These results show that both structures interact during motor sequence consolidation to optimize subsequent behavior.     

Cocaine regulates protein kinase B and glycogen synthase kinase-3 activity in selective regions of rat brain

Protein kinase B (also known as Akt) signaling regulates dopamine-mediated locomotor behaviors. Here the ability of cocaine to regulate Akt and glycogen synthase kinase 3 (GSK3) was studied. Rats were injected with cocaine or saline in a binge-pattern, which consisted of three daily injections of 15 mg/kg cocaine or 1 mL/kg saline spaced 1 h apart for 1, 3, or 14 days. Amygdala, nucleus accumbens, caudate putamen, and hippocampus tissues were dissected 30 min following the last injection and analyzed for phosphorylated and total Akt and GSK3(alpha and beta) protein levels using western blot analysis. Phosphorylation of Akt on the threonine-308 (Thr308) residue was significantly reduced in the nucleus accumbens and increased in the amygdala after 1 day of cocaine treatment; however, these effects were not accompanied by a significant decrease in GSK3 phosphorylation. Phosphorylation of Akt and GSK3 was significantly reduced after 14 days of cocaine administration, an effect that was only observed in the amygdala. Cocaine did not alter Akt or GSK3 phosphorylation in the caudate putamen or hippocampus. The findings in nucleus accumbens may reflect dopaminergic motor-stimulant activity caused by acute cocaine, whereas the effects in amygdala may be associated with changes in emotional state that occur after acute and chronic cocaine exposure.     

Alpha Reactivity to Complex Sounds Differs during REM Sleep and Wakefulness

We aimed at better understanding the brain mechanisms involved in the processing of alerting meaningful sounds during sleep, investigating alpha activity. During EEG acquisition, subjects were presented with a passive auditory oddball paradigm including rare complex sounds called Novels (the own first name - OWN, and an unfamiliar first name - OTHER) while they were watching a silent movie in the evening or sleeping at night. During the experimental night, the subjects’ quality of sleep was generally preserved. During wakefulness, the decrease in alpha power (8–12 Hz) induced by Novels was significantly larger for OWN than for OTHER at parietal electrodes, between 600 and 900 ms after stimulus onset. Conversely, during REM sleep, Novels induced an increase in alpha power (from 0 to 1200 ms at all electrodes), significantly larger for OWN than for OTHER at several parietal electrodes between 700 and 1200 ms after stimulus onset. These results show that complex sounds have a different effect on the alpha power during wakefulness (decrease) and during REM sleep (increase) and that OWN induce a specific effect in these two states. The increased alpha power induced by Novels during REM sleep may 1) correspond to a short and transient increase in arousal; in this case, our study provides an objective measure of the greater arousing power of OWN over OTHER, 2) indicate a cortical inhibition associated with sleep protection. These results suggest that alpha modulation could participate in the selection of stimuli to be further processed during sleep.