The Role of TLR4 in the Paclitaxel Effects on Neuronal Growth In Vitro

Paclitaxel (Pac) is an antitumor agent that is widely used for treatment of solid cancers. While being effective as a chemotherapeutic agent, Pac in high doses is neurotoxic, specifically targeting sensory innervations. In view of these toxic effects associated with conventional chemotherapy, decreasing the dose of Pac has been recently suggested as an alternative approach, which might limit neurotoxicity and immunosuppression. However, it remains unclear if low doses of Pac retain its neurotoxic properties or might exhibit unusual effects on neuronal cells. The goal of this study was to analyze the concentration-dependent effect of Pac on isolated and cultured DRG neuronal cells from wild-type and TLR4 knockout mice. Three different morphological parameters were analyzed: the number of neurons which developed neurites, the number of neurites per cell and the total length of neurites per cell. Our data demonstrate that low concentrations of Pac (0.1 nM and 0.5 nM) do not influence the neuronal growth in cultures in both wild type and TLR4 knockout mice. Higher concentrations of Pac (1-100 nM) had a significant effect on DRG neurons from wild type mice, affecting the number of neurons which developed neurites, number of neurites per cell, and the length of neurites. In DRG from TLR4 knockout mice high concentrations of Pac showed a similar effect on the number of neurons which developed neurites and the length of neurites. At the same time, the number of neurites per cell, indicating the process of growth cone initiation, was not affected by high concentrations of Pac. Thus, our data showed that Pac in high concentrations has a significant damaging effect on axonal growth and that this effect is partially mediated through TLR4 pathways. Low doses of Pac are devoid of neuronal toxicity and thus can be safely used in a chemomodulation mode. © 2013 Ustinova et al

Interactions among salt marsh plants vary geographically but not latitudinally along the California coast.

The strength of species interactions often varies geographically and locally with environmental conditions. Competitive interactions are predicted to be stronger in benign environments while facilitation is expected to be stronger in harsh ones. We tested these ideas with an aboveground neighbor removal experiment at six salt marshes along the California coast. We determined the effect of removals of either the dominant species, Salicornia pacifica, or the subordinate species on plant cover, aboveground biomass and community composition, as well as soil salinity and moisture. We found that S. pacifica consistently competed with the subordinate species and that the strength of competition varied among sites. In contrast with other studies showing that dominant species facilitate subordinates by moderating physical stress, here the subordinate species facilitated S. pacifica shortly after removal treatments were imposed, but the effect disappeared over time. Contrary to expectations based on patterns observed in east coast salt marshes, we did not see patterns in species interactions in relation to latitude, climate, or soil edaphic characteristics. Our results suggest that variation in interactions among salt marsh plants may be influenced by local-scale site differences such as nutrients more than broad latitudinal gradients

Invasive Allele Spread under Preemptive Competition

We study a discrete spatial model for invasive allele spread in which two alleles compete preemptively, initially only the "residents" (weaker competitors) being present. We find that the spread of the advantageous mutation is well described by homogeneous nucleation; in particular, in large systems the time-dependent global density of the resident allele is well approximated by Avrami's law.Comment: Computer Simulation Studies in Condensed Matter Physics XVIII, edited by D.P. Landau, S.P. Lewis, and H.-B. Schuttler, (Springer, Heidelberg, Berlin, in press

Dispersal-mediated trophic interactions can generate apparent patterns of dispersal limitation in aquatic metacommunities

Dispersal is a major organising force in metacommunities, which may facilitate compositional responses of local communities to environmental change and affect ecosystem function. Organism groups differ widely in their dispersal abilities and their communities are therefore expected to have different adaptive abilities. In mesocosms, we studied the simultaneous compositional response of three plankton communities (zoo-, phyto- and bacterioplankton) to a primary productivity gradient and evaluated how this response was mediated by dispersal intensity. Dispersal enhanced responses in all three planktonic groups, which also affected ecosystem functioning. Yet, variation partitioning analyses indicated that responses in phytoplankton and bacterial communities were not only controlled by dispersal directly but also indirectly through complex trophic interactions. Our results indicate that metacommunity patterns emerging from dispersal can cascade through the food web and generate patterns of apparent dispersal limitation in organisms at other trophic levels.

Habitat Configuration Alters Herbivory across the Tropical Seascape

There exists increasing evidence that top-down ecological processes, such as herbivory are key in controlling marine ecosystems and their community structure. Herbivory has the potential to be altered by numerous environmental and ecological factors that operate at a variety of temporal and spatial scales, one such spatial factor is the influence of the marine landscape. We know little about how ecological processes, such as herbivory change throughout the marine landscape and how the effects of these processes cascade. This is because most landscape scale studies observe species richness and abundance patterns. In terrestrial systems the landscape is well documented to influence ecological processes, but empirical evidence of this is limited in marine systems. In tropical seagrass meadows direct herbivory by parrotfish can be readily observed due to the clear hemispherical bite marks they leave on the seagrass. As with herbivory in other systems, this leaf consumption is thought to assist with leaf turnover, positively influencing leaf growth. Changes in its rate and extent are therefore likely to influence the characteristics of the plant. The faunal communities of seagrass meadows alter with respect to changes in the landscape, particularly with respect to connectivity to adjacent habitats. It might therefore be expected that a key ecological process, such as herbivory will change with respect to habitat configuration and have cascading impacts upon the status of the seagrass. In the present study we examined indirect evidence of parrotfish grazing throughout the marine landscape and assessed this relative to plant condition. Seagrasses in locations of close proximity to mangroves were found to have double the amount of parrotfish grazing than sites away from mangroves. Evidence of herbivory was also found to be strongly and significantly negatively correlated to the abundance of plant attached epicover. The decreased epicover in the presence of elevated herbivory suggests increased leaf turnover. These results indicate that seagrass may have higher levels of ecosystem resilience in the presence of mangroves. Our research highlights how ecological processes can change throughout the marine landscape with cascade impacts on the resilience of the system

Planktotrons: A novel indoor mesocosm facility for aquatic biodiversity and food web research

We established a new indoor mesocosm facility, 12 fully controlled “Planktotrons”, designed to conduct marine and freshwater experiments for biodiversity and food web approaches using natural or artificial, benthic or planktonic communities. The Planktotrons are a unique and custom-tailored facility allowing long-term experiments. Wall growth can be inhibited by a rotating gate paddle with silicone lips. Additionally, temperature and light intensity are individually controllable for each Planktotron and the large volume (600 L) enables high-frequency or volume-intense measurements. In a pilot freshwater experiment various trophic levels of a pelagic food web were maintained for up to 90 d. First, an artificially assembled phytoplankton community of 11 species was inoculated in all Planktotrons. After 22 d, two ciliates were added to all, and three Daphnia species were added to six Planktotrons. After 72 d, dissolved organic matter (DOM, an alkaline soil extract) was added as an external disturbance to six of the 12 Planktotrons, involving three Planktotrons stocked with Daphnia and three without, respectively. We demonstrate the suitability of the Planktotrons for food web and biodiversity research. Variation among replicated Planktotrons (n = 3 minimum) did not differ from other laboratory systems and field experiments. We investigated population dynamics and interactions among the different trophic levels, and found them affected by the sequence of ciliate and Daphnia addition and the disturbance caused by addition of DOM

Tumor-derived interleukin-10 as a prognostic factor in stage III patients undergoing adjuvant treatment with an autologous melanoma cell vaccine.

OBJECTIVES: Interleukin-10 (IL-10) downregulates T-cell-mediated immune responses. We studied the association between IL-10 production by freshly isolated melanoma cell suspensions in vitro and overall survival in patients undergoing adjuvant treatment with a vaccine prepared from the same autologous melanoma cells modified with a hapten, dinitrophenyl (DNP). METHODS: Forty-four patients with cutaneous melanoma (29 stage III and 15 stage IV) were prospectively evaluated. Tumor cells were extracted from metastatic deposits for production of DNP-modified autologous melanoma cell vaccine. Small aliquots of the melanoma cell suspensions were separated prior to vaccine processing and cultured overnight for IL-10 production. Based on a blind assessment of the distribution of IL-10 levels in the culture supernatants, a cutoff of 200 pg/ml was used to define high versus low IL-10 producers. Cox regression model was used for multivariate analysis. Overall survival was calculated using the Kaplan-Meier method, and survival curves were compared with the log-rank test. RESULTS: Out of 44 patients, 29 were low and 15 were high IL-10 producers. The median OS was significantly worse for high compared with low IL-10 producers (10.5 months vs. 42 months; P = 0.022). In stage III patients, the multivariate hazard ratio for high versus low IL-10 producers was 2.92 (95% CI, 1.04-8.20; P = 0.041). The corresponding hazard ratio in stage IV patients was 0.92 (95% CI, 1.04-8.20; P = 0.888). CONCLUSIONS: High IL-10 production in the tumor microenvironment could be a determinant of clinical outcomes in stage III melanoma patients receiving autologous melanoma cell vaccine

Contrasting alpha, beta, and gamma diversity in the littoral zones of mountain lakes: effects of habitat size and within-lake community structuring on bacterial biogeography.

Research on microbial biogeography has revealed key patterns like the diversity-area relationship and distance-decay of similarity. However, how habitat size affects bacterial diversity in freshwater environments remains largely unclear. Here, we characterize bacterial communities in the littoral zones of 10 mountain lakes in the Sierra Nevada, CA, ranging in surface area from 0.92 to 71.72 ha. Despite significant habitat size effects on community composition, dominant bacterial phyla were shared across lakes. We found no evidence for diversity-area relationships, either in single samples (alpha diversity) or cumulative lake-level samples (within-lake gamma diversity), when accounting for environmental variation. Moreover, within-lake beta diversity showed little spatial structuring, with similar bacterial community composition across samples regardless of geographic distance. Gamma diversity did not reach saturation with our sample size, and lake size had no effect on the predicted sample size necessary to reach gamma diversity saturation. Our findings offer new insights into diversity-area dynamics and spatial structuring by investigating alpha, beta, and gamma diversity in freshwater environments. Notably, individual water samples captured much of the bacterial community, with strong correlations between alpha and gamma diversity. These results advance our understanding of microbial biogeography and inform sampling designs for characterizing bacterial diversity in freshwater ecosystems

Neuroimmune Regulation of Surgery-Associated Metastases

Surgery remains an essential therapeutic approach for most solid malignancies. Although for more than a century accumulating clinical and experimental data have indicated that surgical procedures themselves may promote the appearance and progression of recurrent and metastatic lesions, only in recent years has renewed interest been taken in the mechanism by which metastasizing of cancer occurs following operative procedures. It is well proven now that surgery constitutes a risk factor for the promotion of pre-existing, possibly dormant micrometastases and the acceleration of new metastases through several mechanisms, including the release of neuroendocrine and stress hormones and wound healing pathway-associated immunosuppression, neovascularization, and tissue remodeling. These postoperative consequences synergistically facilitate the establishment of new metastases and the development of pre-existing micrometastases. While only in recent years the role of the peripheral nervous system has been recognized as another contributor to cancer development and metastasis, little is known about the contribution of tumor-associated neuronal and neuroglial elements in the metastatic disease related to surgical trauma and wound healing. Specifically, although numerous clinical and experimental data suggest that biopsy- and surgery-induced wound healing can promote survival and metastatic spread of residual and dormant malignant cells, the involvement of the tumor-associated neuroglial cells in the formation of metastases following tissue injury has not been well understood. Understanding the clinical significance and underlying mechanisms of neuroimmune regulation of surgery-associated metastasis will not only advance the field of neuro–immuno–oncology and contribute to basic science and translational oncology research but will also produce a strong foundation for developing novel mechanism-based therapeutic approaches that may protect patients against the oncologically adverse effects of primary tumor biopsy and excision

Cytokine-mediated protection of human dendritic cells from prostate cancer-induced apoptosis is regulated by the Bcl-2 family of proteins

Prostate cancer is the most common cancer in men in the United States, and second in cancer-induced mortality. It is likely that tumour-induced immunosuppression is one of the reasons for low treatment efficacy in patients with advanced prostate cancer. It has been recently demonstrated that prostate cancer tissue is almost devoid of dendritic cells (DC), the major antigen-presenting cells responsible for the induction of specific antitumour immune responses. In this study, we have tested the hypothesis that prostate cancer induces progressive suppression of the DC system. We found that co-incubation of human DC with three prostate cancer cell lines led to the high levels of premature apoptosis of DC, which were significantly higher than in DC cultures co-incubated with normal prostate cells or blood leucocytes. Stimulation of DC for 24 hours with CD40 ligand (CD154), IL-12 or IL-15 prior to their co-incubation with prostate cancer cells resulted in a significant increase in DC survival in the tumour microenvironment. Furthermore, activation of DC with these cytokines was also accompanied by increased expression of the anti-apoptotic protein Bcl-x L in DC, suggesting a possible mechanism involved in DC protection from apoptotic death. In summary, our data demonstrate that prostate cancer induces active elimination of DC in the tumour microenvironment. Stimulation of DC by CD154, IL-12 or IL-15 leads to an increased expression of the anti-apoptotic protein Bcl-x L and increased resistance of DC to prostate cancer-induced apoptosis. These results suggest a new mechanism of tumour escape from immune recognition and demonstrate the cytokine-based approaches which might significantly increase the efficacy of DC-based therapies for cancer. © 2000 Cancer Research Campaig