Local host competition in the evolution of virulence

The evolution of parasite life histories should usually have correlated effects on host survivorship and/or reproductive success. For example, parasites that reproduce more rapidly might be expected to cause greater reductions in host fitness. Important theoretical advances have recently been made on virulence evolution, but the results are not always consistent. Here I compare two models [ Q. Rev. Biol. 71 (1996) 37 ; Q. Rev. Biol. 75 (2000) 261 ] on the evolution of virulence that get qualitatively different results with respect to the effects of coinfection. I also construct a third model that attempts to connect these two formulations. The results suggest that parasite growth rates should increase as local host competition increases, unless relatedness is at equilibrium. In addition, the qualitative effect of adding coinfections on parasite growth rates depends critically on how the number of coinfections affects transmission success.     

The Mitogen-activated Protein (MAP) Kinases p38 and Extracellular Signal-regulated Kinase (ERK) Are Involved in Hepatocyte-mediated Phenotypic Switching in Prostate Cancer Cells

The greatest challenge for the seeding of cancer in metastatic sites is integration into the ectopic microenvironment despite the lack of an orthotopic supportive environment and presence of pro-death signals concomitant with a localized “foreign-body” inflammatory response. In this metastatic location, many carcinoma cells display a reversion of the epithelial-to-mesenchymal transition that marks dissemination in the primary tumor mass. This mesenchymal to epithelial reverting transition (MErT) is thought to help seeding and colonization by protecting against cell death. We have previously shown that hepatocyte coculture induces the re-expression of E-cadherin via abrogation of autocrine EGFR signaling pathway in prostate cancer (PCa) cells and that this confers a survival advantage. Herein, we show that hepatocytes educate PCa to undergo MErT by modulating the activity of p38 and ERK1/2. Hepatocytes inhibited p38 and ERK1/2 activity in prostate cancer cells, which allowed E-cadherin re-expression. Introduction of constitutively active MEK6 and MEK1 to DU145 cells cocultured with hepatocytes abrogated E-cadherin re-expression. At least a partial phenotypic reversion can be achieved by suppression of p38 and ERK1/2 activation in DU145 cells even in the absence of hepatocytes. Interestingly, these mitogen-activated protein kinase activities were also triggered by re-expressed E-cadherin leading to p38 and ERK1/2 activity in PCa cells; these signals provide protection to PCa cells upon challenge with chemotherapy and cell death-inducing cytokines. We propose that distinct p38/ERK pathways are related to E-cadherin levels and function downstream of E-cadherin allowing, respectively, for hepatocyte-mediated MErT and tumor cell survival in the face of death signals.     

Differential susceptibility to hydrogen sulfide-induced apoptosis between PHLDA1-overexpressing oral cancer cell lines and oral keratinocytes: Role of PHLDA1 as an apoptosis suppressor

Hydrogen sulfide (H₂S) is a novel gasotransmitter that plays multiple biological roles in various body systems. In addition to its endogenous production, H₂S is produced by bacteria colonizing digestive organs, including the oral cavity. H₂S was previously shown to enhance pro-apoptotic effects in cancer cell lines, although the mechanisms involved remain unclear. To properly assess the anti-cancer effects of H₂S, however, investigations of apoptotic effects in normal cells are also necessary. The aims of this study were (1) to compare the susceptibility to H₂S-induced apoptosis between the oral cancer cell line Ca9-22 and oral keratinocytes that were derived from healthy gingiva, and (2) to identify candidate genes involved in the induction of apoptosis by H₂S. The susceptibility to H₂S-induced apoptosis in Ca9-22 cells was significantly higher than that in keratinocytes. H₂S exposure in Ca9-22 cells, but not keratinocytes, enhanced the expression of pleckstrin homology-like domain, family A, member 1 (PHLDA1), which was identified through a differential display method. In addition, PHLDA1 expression increased during actinomycin D-induced apoptosis in Ca9-22 cells. Knockdown of PHLDA1 expression by small interfering RNA in Ca9-22 cells led to expression of active caspase 3, thus indicating apoptosis induction. The tongue cancer cell line SCC-25, which expresses PHLDA1 at a high level, showed similar effects. Our data indicate that H₂S is an anti-cancer compound that may contribute to the low incidence of oral cancer. Furthermore, we demonstrated the role of PHLDA1 as an apoptosis suppressor.     

Contingent valuation and biodiversity: measuring the user surplus of Kenyan protected areas

The financial returns to Kenyan tourism demonstrate the importance of the country's tourist potential to its economic development. Protected areas and their inhabitants are the principal focus of the tourist industry, the nations's main foreign exchange earner, and a source of wonder and value for a global population of non-users. It might be expected that such assets would be accorded some degree of security with sufficient funding to safeguard current and potential economic benefits. Yet park use is haphazard, and there is frequently little coincidence between those that benefit and those that pay for the continued existence of such areas. Growing economic and demographic pressures which threaten to swamp protected areas only emphasize the implicit subsidy currently paid by Kenyans to support conservation for the benefit of the world at large. In this climate the case for conservation depends on the measurement and capture of economic benefits. Using a contingent valuation survey of expressed preference this study estimates the consumer surplus attached to current non-consumptive use of protected areas by foreign visitors at some $450 million per annum. This sum alone is more than double the best available estimate of opportunity cost and appears to justify current resource use. The estimate is additional to current financial returns from tourism and makes no allowance for other direct and indirect benefits and potential returns from consumptive uses. Measured consumer surplus contains some margin of willingness to pay that could be captured through the current fee structure. Moreover, park fees represent the most accessible market mechanism to finance revenue sharing and additional park investment before potential recourse to emerging global market institutions.     

Potential pitfalls of the PTV concept in dose-to-medium planning optimization

In typical treatment planning of 3D IMRT, the incident energy fluence is optimized to achieve a homogeneous dose distribution to the PTV. The PTV includes the tumour but also healthy tissues that may have a different dose response for the same incident energy fluence, like bony structures included in the PTV (mandibles in head and neck tumours or femoral bones in sarcomas). Dose to medium optimization compensates for this heterogeneous response, leading to a non-homogeneous energy fluence in the PTV and a non-homogeneous dose in the CTV in the presence of geometric errors. We illustrate qualitatively this statement in a cylindrical geometry where the PTV includes a CTV (7 cm diameter) made of water surrounded by ICRU compact bone (1.2 cm thickness); such configuration was chosen to exaggerate the aforementioned effect. Optimization was performed assuming dose equals photon energy fluence times mass energy absorption coefficient. Bone has a 4% lower dose response in a 6 MV flattening filter free spectrum. After optimization either in medium or assuming everything as water composition, the geometry was shifted by 1.2 cm and dose recomputed. As expected, compensating for the under-response of the bone material during optimization in medium leads to an overdosage of the CTV when patient geometric errors are taken into account. Optimization in dose assuming everything as water composition leads to a uniform coverage. Robust optimization or forcing a uniform atomic composition in the PTV margin may resolve this incompatibility between the PTV concept and dose to medium optimization.     

An improved approach to evaluate car sharing options

We develop an improved approach to evaluate car sharing options under uncertain environments with the combination of Fuzzy Analytic Hierarchy Process (F-AHP) and Fuzzy Technique for Order Preference by Similarity to Ideal Solution (F-TOPSIS), which consists of three steps. In the first step, we propose a SCUMN (Specific, Comprehensive, Understandable, Measurable, and Neutral) methodology to identify appropriate indicators and obtain a final list of 24 indicators according to their relevance to car sharing options. In the second step, we determine the weight of each indicator with F-AHP and conduct consistency check of the comparison matrix of selected indicators. In the third step, comparison of different options is performed with selected indicators and F-TOPSIS. A case study is provided to validate the proposed approach. Twenty-four indicators are identified to evaluate five different car sharing options and rank them according to their closeness coefficients in decreasing order. And thirty-one sensitivity analysis experiments are conducted to figure out the influence of indicators on decision making. The experimental results show that the proposed approach is capable of evaluating car sharing options with uncertainty and vagueness. F-AHP is able to determine the weight for each selected indicator and F-TOPSIS demonstrates its advantage in comparing potential options.