Th-1 lymphocytes induce dendritic cell tumor killing activity by an IFN-γ-dependent mechanism

Dendritic cells (DCs) encompass a heterogeneous population of cells capable of orchestrating innate and adaptive immune responses. The ability of DCs to act as professional APCs has been the foundation for the development and use of these cells as vaccines in cancer immunotherapy. DCs are also endowed with the nonconventional property of directly killing tumor cells. The current study investigates the regulation of murine DC cytotoxic function by T lymphocytes. We provide evidence that CD4(+) Th-1, but not Th-2, Th-17 cells, or regulatory T cells, are capable of inducing DC cytotoxic function. IFN-γ was identified as the major factor responsible for Th-1-induced DC tumoricidal activity. Tumor cell killing mediated by Th-1-activated killer DCs was dependent on inducible NO synthase expression and NO production. Importantly, Th-1-activated killer DCs were capable of presenting the acquired Ags from the killed tumor cells to T lymphocytes in vitro or in vivo. These observations offer new possibilities for the application of killer DCs in cancer immunotherapy.     

Application of solid waste from anaerobic digestion of poultry litter in Agrocybe aegerita cultivation: mushroom production, lignocellulolytic enzymes activity and substrate utilization

The degradation and utilization of solid waste (SW) from anaerobic digestion of poultry litter by Agrocybe aegerita was evaluated through mushroom production, loss of organic matter (LOM), lignocellulolytic enzymes activity, lignocellulose degradation and mushroom nutrients content. Among the substrate combinations (SCs) tested, substrates composed of 10–20% SW, 70–80% wheat straw and 10% millet was found to produce the highest mushroom yield (770.5 and 642.9 g per 1.5 kg of substrate). LOM in all SCs tested varied between 8.8 and 48.2%. A. aegerita appears to degrade macromolecule components (0.6–21.8% lignin, 33.1–55.2% cellulose and 14–53.9% hemicellulose) during cultivation on the different SCs. Among the seven extracellular enzymes monitored, laccase, peroxidase and CMCase activities were higher before fruiting; while xylanase showed higher activities after fruiting. A source of carbohydrates (e.g., millet) in the substrate is needed in order to obtain yield and biological efficiency comparable to other commercially cultivated exotic mushrooms.     

Native harvester ants threatened with widespread displacement exert localized effects on serpentine grassland plant community composition

Seed-harvesting ants can influence the abundance and distribution of plant species through both the selective harvesting of seeds and the construction of nutrient-rich nest mounds, but the relative contributions of these two mechanisms have not been addressed by previous studies. Furthermore, the impact of ant seed harvesting in California serpentine grasslands remains unresolved because of divergent results from several previous experiments. This study investigates the influence of harvester ants on serpentine grassland plant species composition by examining two potential signatures of seed harvesting ants on plant community composition: species composition on versus off ant nest mounds, and species abundance as a function of distance from nest mounds. Of the 28 plant species identified in this study, 22 exhibited spatial patterns consistent with effects of seed harvesting, nest construction, or both. Although most species showed significant gradients in abundance with distance from a nest, there were no clear relationships between plant species distributions and previously reported harvester ant seed foraging patterns. Harvester ant nest mounds supported plant communities that were distinct from the surrounding serpentine grassland, with notably higher densities of legumes and invasive annual grasses. Comparison of our results with those of previous studies indicates that the patterns we observed are generally consistent over time, but affect more species and a larger fraction of the grassland than previously reported. Unaffected areas of the grassland seem likely to serve as important refuges for some plant species.     

Whole Exome Sequencing in Atrial Fibrillation

Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13–1.43, P = 6.6x10^-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.     

Definitive,intensity modulated tomotherapy with a simultaneous integrated boost for prostate cancer patients – Long term data on toxicity and biochemical control

AimTo report long-term data regarding biochemical control and late toxicity of simultaneous integrated boost intensity modulated radiotherapy (SIB-IMRT) with tomotherapy in patients with localized prostate cancer.BackgroundDose escalation improves cancer control after curative intended radiation therapy (RT) to patients with localized prostate cancer, without increasing toxicity, if IMRT is used.Materials and methodsIn this retrospective analysis, we evaluated long-term toxicity and biochemical control of the first 40 patients with intermediate risk prostate cancer receiving SIB-IMRT. Primary target volume (PTV) 1 including the prostate and proximal third of the seminal vesicles with safety margins was treated with 70 Gy in 35 fractions. PTV 2 containing the prostate with smaller safety margins was treated as SIB to a total dose of 76 Gy with 2.17 Gy per fraction. Toxicity was evaluated using an adapted CTCAE-Score (Version 3).ResultsMedian follow-up of living patients was 66 (20–78) months. No late genitourinary toxicity higher than grade 2 has been reported. Grade 2 genitourinary toxicity rates decreased from 58% at the end of the treatment to 10% at 60 months. Late gastrointestinal (GI) toxicity was also moderate, though the prescribed PTV Dose of 76 Gy was accepted at the anterior rectal wall. 74% of patients reported any GI toxicity during follow up and no toxicity rates higher than grade 2 were observed. Grade 2 side effects were reported by 13% of the patients at 60 months. 5-year freedom from biochemical failure was 95% at our last follow up.ConclusionSIB-IMRT using daily MV-CT guidance showed excellent long-term biochemical control and low toxicity rates.     

Responses of temporal distribution of gastropods to individual and combined effects of elevated CO2 and N deposition in annual grassland

Terrestrial gastropods have been shown to exert major impacts on the plant structure and species composition of temperate grasslands and other terrestrial plant communities. In order to develop predictions of plant community responses to changing environments, it is critical to understand how factors structuring plant communities will be influenced by global changes. Nevertheless, little is known about the potential for the size and abundance of gastropods to be altered by the individual and combined effects of elevated atmospheric CO₂ and increased deposition of N. Previous work suggests that responses of herbivore abundance to these global changes seem likely to depend, in part, upon the changes in the quantity of plant biomass available for consumption, and changes in the nutritional quality of this plant material for gastropod survival, development, and reproduction. Therefore, in this study we investigated the effect of elevated CO₂ and increased N deposition on gastropod size and abundance, as well as the effects on plant community production and N status. Elevated CO₂ depressed the size of gastropods early in the growing season by 29% to 42%, increased mid-season gastropod abundance by 38% to 43%, and depressed abundance late in the growing season by 21% to 29%. These changes in gastropod size and abundance were due largely to the modification of plant tissue quality and quantity. Increased N deposition, in contrast, influenced neither gastropod abundance nor per capita biomass during any part of the growing season. Neither elevated CO₂ nor increased N deposition disrupted the temporal synchrony between plant production and slug abundance.     

Cytotoxic dendritic cells generated from cancer patients

Known for years as professional APCs, dendritic cells (DCs) are also endowed with tumoricidal activity. This dual role of DC as killers and messengers may have important implications for tumor immunotherapy. However, the tumoricidal activity of DCs has mainly been investigated in animal models. Cancer cells inhibit antitumor immune responses using numerous mechanisms, including the induction of immunosuppressive/ tolerogenic DCs that have lost their ability to present Ags in an immunogenic manner. In this study, we evaluated the possibility of generating tumor killer DCs from patients with advanced-stage cancers. We demonstrate that human monocyte-derived DCs are endowed with significant cytotoxic activity against tumor cells following activation with LPS. The mechanism of DC-mediated tumor cell killing primarily involves peroxynitrites. This observed cytotoxic activity is restricted to immature DCs. Additionally, after killing, these cytotoxic DCs are able to activate tumor Ag-specific T cells. These observations may open important new perspectives for the use of autologous cytotoxic DCs in cancer immunotherapy strategies.