Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations

The dose-delivery schedule of conventional chemotherapy, which determines its efficacy and toxicity, is based on the maximum tolerated dose. This strategy has lead to cure and disease control in a significant number of patients but is associated with significant short-term and long-term toxicity. Recent data demonstrate that moderately low-dose chemotherapy may be efficiently combined with immunotherapy, particularly with dendritic cell (DC) vaccines, to improve the overall therapeutic efficacy. However, the direct effects of low and ultra-low concentrations on DCs are still unknown. Here we characterized the effects of low noncytotoxic concentrations of different classes of chemotherapeutic agents on human DCs in vitro. DCs treated with antimicrotubule agents vincristine, vinblastine, and paclitaxel or with antimetabolites 5-aza-2-deoxycytidine and methotrexate, showed increased expression of CD83 and CD40 molecules. Expression of CD80 on DCs was also stimulated by vinblastine, paclitaxel, azacytidine, methotrexate, and mitomycin C used in low nontoxic concentrations. Furthermore, 5-aza-2-deoxycytidine, methotrexate, and mitomycin C increased the ability of human DCs to stimulate proliferation of allogeneic T lymphocytes. Thus, our data demonstrate for the first time that in low noncytotoxic concentrations chemotherapeutic agents do not induce apoptosis of DCs, but directly enhance DC maturation and function. This suggests that modulation of human DCs by noncytotoxic concentrations of antineoplastic drugs, i.e. chemomodulation, might represent a novel approach for up-regulation of functional activity of resident DCs in the tumor microenvironment or improving the efficacy of DCs prepared ex vivo for subsequent vaccinations

Biodiversity and species interactions: extending Lotka-Volterra community theory

A new analysis of the nearly century-old Lotka-Volterra theory allows us to link species interactions to biodiversity patterns, including: species abundance distributions, estimates of total community size, patterns of community invasibility, and predicted responses to disturbance. Based on a few restrictive assumptions about species interactions, our calculations require only that the community is sufficiently large to allow a mean-field approximation. We develop this analysis to show how an initial assemblage of species with varying interaction strengths is predicted to sort out into the final community based on the species' predicted target densities. The sorting process yields predictions of covarying patterns of species abundance, community size, and species interaction strengths. These predictions can be tested using enrichment experiments, examination of latitudinal and productivity gradients, and features of community assembly

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

Immunodominant PstS1 antigen of mycobacterium tuberculosis is a potent biological response modifier for the treatment of bladder cancer

BACKGROUND: Bacillus Calmette Guérin (BCG)-immunotherapy has a well-documented and successful clinical history in the treatment of bladder cancer. However, regularly observed side effects, a certain degree of nonresponders and restriction to superficial cancers remain a major obstacle. Therefore, alternative treatment strategies are intensively being explored. We report a novel approach of using a well defined immunostimulatory component of Mycobacterium tuberculosis for the treatment of bladder cancer. The phosphate transport protein PstS1 which represents the phosphate binding component of a mycobacterial phosphate uptake system is known to be a potent immunostimulatory antigen of M. tuberculosis. This preclinical study was designed to test the potential of recombinant PstS1 to serve as a non-viable and defined immunotherapeutic agent for intravesical bladder cancer therapy. METHODS: Mononuclear cells (PBMCs) were isolated from human peripheral blood and stimulated with PstS1 for seven days. The activation of PBMCs was determined by chromium release assay, IFN-γ ELISA and measurement of lymphocyte proliferation. The potential of PstS1 to activate monocyte-derived human dendritic cells (DC) was determined by flow cytometric analysis of the marker molecules CD83 and CD86 as well as the release of the cytokines TNF-α and IL-12. Survival of presensitized and intravesically treated, tumor-bearing mice was analyzed by Kaplan-Meier curve and log rank test. Local and systemic immune response in PstS1-immunotherapy was investigated by anti-PstS1-specific ELISA, splenocyte proliferation assay and immunohistochemistry. RESULTS: Our in vitro experiments showed that PstS1 is able to stimulate cytotoxicity, IFN-γ release and proliferation of PBMCs. Further investigations showed the potential of PstS1 to activate monocyte-derived human dendritic cells (DC). In vivo studies in an orthotopic murine bladder cancer model demonstrated the therapeutic potential of intravesically applied PstS1. Immunohistochemical analysis and splenocyte restimulation assay revealed that local and systemic immune responses were triggered by intravesical PstS1-immunotherapy. CONCLUSION: Our results demonstrate profound in vitro activation of human immune cells by recombinant PstS1. In addition, intravesical PstS1 immunotherapy induced strong local and systemic immune responses together with substantial anti-tumor activity in a preclinical mouse model. Thus, we have identified recombinant PstS1 antigen as a potent immunotherapeutic drug for cancer therapy

Producer Nutritional Quality Controls Ecosystem Trophic Structure

Trophic structure, or the distribution of biomass among producers and consumers, determines key ecosystem values, such as the abundance of infectious, harvestable or conservation target species, and the storage and cycling of carbon and nutrients. There has been much debate on what controls ecosystem trophic structure, yet the answer is still elusive. Here we show that the nutritional quality of primary producers controls the trophic structure of ecosystems. By increasing the efficiency of trophic transfer, higher producer nutritional quality results in steeper ecosystem trophic structure, and those changes are more pronounced in terrestrial than in aquatic ecosystems probably due to the more stringent nutritional limitation of terrestrial herbivores. These results explain why ecosystems composed of highly nutritional primary producers feature high consumer productivity, fast energy recycling, and reduced carbon accumulation. Anthropogenic changes in producer nutritional quality, via changes in trophic structure, may alter the values and functions of ecosystems, and those alterations may be more important in terrestrial ecosystems

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

Rutas tróficas en macrozooplancton del Lago de Tota - Boyacá, Colombia

1 recurso en línea (56 páginas) : ilustraciones, figuras, tablas.In aquatic ecosystems inputs of matter and energy present in greater or lesser extent depending on the basin, given the origin and quality of these resources, you can alter the balance in metabolism or interactions in the food web. Using stable isotopes of carbon and nitrogen, the link between potential sources of funds and use established by macrozooplankton species in Lake Big and Lake Fellow the Lake Tota sectors. Trophic possible ways the role of each species in the proposed network, as well. In general, most of this study, most species have a bond with the autotrophic pathway, being the phytoplankton the food resource base for the food web, commonly found impoverished carbon signals. Particularly, the analysis showed a variation in the source or resource for two species (Daphnia laevis and Bosmina (Bosmina) cf. longirostris), with an enrichment in its signal to 19.92 ‰ -20.34 ‰ δ13C, which can be given by plasticity in their food supply, and even if Boeckella gracilis having a signal indicating a specialization in its appeal with carbon impoverished -30 to -26 ‰ values δ13C while nitrogen values are enriched with an average value 20.21 ‰ in δ15N. To set the trophic fractionation means establishing three groups, the first (herbivores) consisting of (D. laevis, B. (Bosmina) and Ceriodaphnia pulchella cf. longirostris), the second (omnivore) which is (Daphnia pulex, Macrocyclops sp. and Cyclopoida), and a third group (secondary consumer) where is the only calanoido B. gracilis. In comparing the temporal variation is observed that there is a significant change in signals δ13C and δ15N of some species in relation to the influence of sources and allochthonous or autochthonous origin, spatial variation was not significant. It is concluded that the macrozooplanton Lake Tota, has a strong link with the autotrophic pathway and pelagic trophic levels have 3 sections, plus the primary producers and the food web in general tends to have an amplitude of trophic niche.En los ecosistemas acuáticos se presentan aportes de materia y energía, en mayor o menor proporción dependiendo de su cuenca, dado el origen y calidad de estos recursos, se puede alterar el balance en el metabolismo o las interacciones en la red trófica. Utilizando los isotopos estables de Carbono y Nitrógeno, se estableció el vínculo entre fuentes potenciales de recursos y el uso por las especies del macrozooplancton en los sectores Lago grande y Lago chico del lago de Tota (Boyacá). Así, se propusieron las posibles vías tróficas y el rol de cada especie en la red. En general, en la mayor parte de este estudio, las especies tuvieron un vínculo marcado con la vía autotrófica, siendo el fitoplancton el recurso alimenticio base para la red trófica, encontrando comúnmente señales empobrecidas de carbono. Particularmente, el análisis mostró una variación en la fuente o recurso para dos especies (Daphnia laevis y Bosmina (Bosmina) cf. longirostris), con un enriquecimiento en su señal de 19.92‰ δ13C a -20.34‰ δ13C, lo que se puede dar por una plasticidad en su fuente alimenticia, e incluso el caso de Boeckella gracilis que tiene una señal que indica una especialización en su recurso con valores empobrecidos de carbono -30 a -26‰ δ13C mientras que los valores de nitrógeno son enriquecidos con un valor promedio de 20.21‰ en δ15N. Para establecer el fraccionamiento trófico medio se formaron tres grupos, el primero (herbívoros) conformado por (D. laevis, B. (Bosmina) cf. longirostris y Ceriodaphnia pulchella), el segundo (omnívoro) en el que se encuentra (Daphnia pulex, Macrocyclops sp. y Cyclopoida), y un tercer grupo (Consumidor secundario) donde esta B. gracilis el único calanoido. En la comparación de la variación temporal, se observa que hay un cambio significativo en las señales de δ13C y δ15N de algunas especies en relación a la influencia de las fuentes y su origen alóctono o autóctono, la variación espacial no fue significativa. Se concluye que el macrozooplanton del lago de Tota, tiene un fuerte vínculo con la vía autotrófica y que los niveles tróficos pelágicos tienen 3 eslabones, más los productores primarios, y la red trófica en general tiende a tener una amplitud del nicho trófico. En los ecosistemas acuáticos se presentan aportes de materia y energía, en mayor o menor proporción dependiendo de su cuenca, dado el origen y calidad de estos recursos, se puede alterar el balance en el metabolismo o las interacciones en la red trófica. Utilizando los isotopos estables de Carbono y Nitrógeno, se estableció el vínculo entre fuentes potenciales de recursos y el uso por las especies del macrozooplancton en los sectores Lago grande y Lago chico del lago de Tota (Boyacá). Así, se propusieron las posibles vías tróficas y el rol de cada especie en la red. En general, en la mayor parte de este estudio, las especies tuvieron un vínculo marcado con la vía autotrófica, siendo el fitoplancton el recurso alimenticio base para la red trófica, encontrando comúnmente señales empobrecidas de carbono. Particularmente, el análisis mostró una variación en la fuente o recurso para dos especies (Daphnia laevis y Bosmina (Bosmina) cf. longirostris), con un enriquecimiento en su señal de 19.92‰ δ13C a -20.34‰ δ13C, lo que se puede dar por una plasticidad en su fuente alimenticia, e incluso el caso de Boeckella gracilis que tiene una señal que indica una especialización en su recurso con valores empobrecidos de carbono -30 a -26‰ δ13C mientras que los valores de nitrógeno son enriquecidos con un valor promedio de 20.21‰ en δ15N. Para establecer el fraccionamiento trófico medio se formaron tres grupos, el primero (herbívoros) conformado por (D. laevis, B. (Bosmina) cf. longirostris y Ceriodaphnia pulchella), el segundo (omnívoro) en el que se encuentra (Daphnia pulex, Macrocyclops sp. y Cyclopoida), y un tercer grupo (Consumidor secundario) donde esta B. gracilis el único calanoido. En la comparación de la variación temporal, se observa que hay un cambio significativo en las señales de δ13C y δ15N de algunas especies en relación a la influencia de las fuentes y su origen alóctono o autóctono, la variación espacial no fue significativa. Se concluye que el macrozooplanton del lago de Tota, tiene un fuerte vínculo con la vía autotrófica y que los niveles tróficos pelágicos tienen 3 eslabones, más los productores primarios, y la red trófica en general tiende a tener una amplitud del nicho trófico.Bibliografía: páginas 46-56.MaestríaMagíster en Ciencias Biológica

Invasions and Extinctions Reshape Coastal Marine Food Webs

The biodiversity of ecosystems worldwide is changing because of species loss due to human-caused extinctions and species gain through intentional and accidental introductions. Here we show that the combined effect of these two processes is altering the trophic structure of food webs in coastal marine systems. This is because most extinctions (∼70%) occur at high trophic levels (top predators and other carnivores), while most invasions are by species from lower trophic levels (70% macroplanktivores, deposit feeders, and detritivores). These opposing changes thus alter the shape of marine food webs from a trophic pyramid capped by a diverse array of predators and consumers to a shorter, squatter configuration dominated by filter feeders and scavengers. The consequences of the simultaneous loss of diversity at top trophic levels and gain at lower trophic levels is largely unknown. However, current research suggests that a better understanding of how such simultaneous changes in diversity can impact ecosystem function will be required to manage coastal ecosystems and forecast future changes