Pleural malignant mesothelioma, genetic susceptibility and asbestos exposure

Pleural malignant mesothelioma (MM) is a rare but extremely aggressive cancer. The limited impact of standard therapeutic treatments on survival rates makes the identification of factors that increase the individual risk a leading priority. The high proportion of cases explained by exposure to asbestos has guided intervention policies to an effective ban of this compound from our environment. However, MM cannot be solely attributed to this agent, and the role of predisposing factors and their interaction with asbestos exposure is increasingly studied. The role of mEH, GSTM1, GSTT1, NAT2, and CYP1A1 genotypes in modulating susceptibility to MM was examined in a case-control study of 80 subjects with a confirmed diagnosis of MM and 255 controls. Subjects with low mEH activity showed a significantly increased risk of MM (OR, 2.51; 95% CI, 1.11-5.68). The association was stronger in the group with low asbestos exposure (OR, 7.83; 95% CI, 0.98-62.60). A significant increased risk of MM was also found in NAT2 fast acetylators (OR, 1.74; 95% CI, 1.02-2.96). The presence of synergisms between genotypes, i.e., mEH and NAT2 (LRT for heterogeneity p<0.023), mEH and GSTM1 (LRT p<0.061), and NAT2 and GSTM1 (LRT p<0.049), combined with the interaction observed with exposure to asbestos, suggests the presence of gene-environment and gene-gene interactions in the development of MM, although the size of the study group does not allow to draw clearcut conclusions. Since genetic polymorphisms can also modify the extent of genetic damage occurring in subjects exposed to carcinogens, we measured the frequency of micronuclei in peripheral blood lymphocytes of a subgroup of MM cases. The limited number of cases (28) did not allow to observe significant effects. In conclusion, these results strengthen the hypothesis that individual susceptibility to MM can be modulated by the interaction between polymorphic genes involved in the metabolism and the intensity of asbestos exposure.     

Trophic niche changes associated with habitat fragmentation in a Neotropical bat species

Habitat fragmentation could alter ecological traits including species trophic habits. Here, we used carbon and nitrogen stable isotope ratios to establish differences in isotopic niche width and food resource use between forest fragments and the continuous forest for the phyllostomid frugivorous bat Artibeus lituratus. Using mist nests, we captured bats from two forest fragments and two sites in continuous forest, and sampled from each individual captured three body tissues with contrasting turnover rates (skin, muscle, and liver). Samples were collected between February and March (austral summer) and between August and September (austral winter). In addition, in each sampling site and season we collected potential food resources (fruits and insects) consumed by our A. lituratus. Our findings indicate that A. lituratus had a predominantly omnivorous diet, with high consumption of insects during summer in forest fragments. The increasing consumption of insects in these fragments seems to have led to a wider isotopic niche, in relation to the continuous forest. Because A. lituratus is typically a seed disperser, changes in trophic habits in the forest fragments from frugivory to insectivory may diminish their role in forest regeneration. Abstract in Portuguese is available with online material.     

Effect of the point mutation H148G on GFPmut2 unfolding kinetics by fluorescence spectroscopy

We have used fluorescence spectroscopy techniques such as fluorescence correlation spectroscopy and fluorescence anisotropy decay on a wide time range, from nanoseconds to seconds, to investigate the unfolding kinetics induced by guanidinium chloride of GFPMut2 and its point mutation H148G, which has proved to be relevant for GFP photochemistry and photophysics. The mutation affects the unfolding kinetics of GFP leading to a much faster process at alkaline pH values, where protonation dynamics is negligible, that can be ascribed to a twofold role of His148, either as a proton shutter towards the chromophore and as a conformation stabiliser. For both mutants a soft region located near beta-strand 3 is found that starts to gain flexibility in the ns range at denaturant concentrations far lower than those required to turn off the chromophore fluorescence, as derived from the anisotropy decay of an extrinsic probe covalently bound to the proteins.     

Docosahexaenoic acid reverts resistance to UV-induced apoptosis in human keratinocytes: involvement of COX-2 and HuR

The dramatic increase in the incidence of nonmelanoma skin cancer over the last decades has been related to the augmented exposure to ultraviolet (UV) radiation (UVR). It is known that apoptosis is induced as a protective mechanism after the acute irradiation of keratinocytes, whereas apoptotic resistance and carcinogenesis may follow the chronic exposure to UVR. We found that not all the human keratinocytes lines studied underwent apoptosis following acute exposure to UVR (10-60 mJ/cm²). Whereas UVR induced apoptosis in the HaCaT cells, NCTC 2544 and nr-HaCaT cells showed apoptosis resistance. The cytokeratin pattern of the apoptosis-resistant cells indicated that they possessed a degree of differentiation lower than that of HaCaT cells. They also showed an enhanced expression of cyclooxygenase-2 (COX-2), an early marker of carcinogenesis in various tissues, including skin. n-3 polyunsaturated fatty acids have drawn increasing interest as nutritional factors with the potential to reduce UVR carcinogenesis, and since they are apoptosis inducers and COX-2 inhibitors in cancer cells, we investigated the ability of n-3 polyunsaturated fatty acids to influence the resistance to UVR-induced apoptosis in keratinocytes. We observed that docosahexaenoic acid (DHA) reverted the resistance of nr-HaCaT cells to UVR-induced apoptosis, increasing the Bax/Bcl-2 ratio and caspase-3 activity, and reduced COX-2 levels by inhibiting the expression of the human antigen R (HuR), a known COX-2 mRNA stabilizer in keratinocytes. The transfection of nr-HaCaT cells with HuR siRNA mimicked the proapoptotic effect of DHA. Overall, our findings further support the role of DHA as a suitable anticarcinogenic factor against nonmelanoma skin cancers.     

The Local Complement Activation on Vascular Bed of Patients with Systemic Sclerosis: A Hypothesis-Generating Study

ObjectiveThe role of complement system in the pathogenesis of systemic sclerosis (SSc) has been debated during the last decade but an evident implication in this disease has never been found. We carried out an explorative study on SSc patients to evaluate the expression of soluble and local C5b-9 complement complex and its relation with a complement regulator, the Membrane Cofactor Protein (MCP, CD46) on skin vascular bed as target distinctive of SSc disease. We also analyzed two polymorphic variants in the complement activation gene cluster involving the MCP region.MethodsC5b-9 plasma levels of SSc patients and healthy subjects were analyzed by ELISA assay. Archival skin biopsies of SSc patients and controls were subjected to immunofluorescence analysis to detect C5b-9 and MCP on vascular endothelial cells. The expression of MCP was validated by immunoblot analysis with specific antibody. Polymorphic variants in the MCP gene promoter were tested by a quantitative PCR technique-based allelic discrimination method.ResultsEven though circulating levels of C5b-9 did not differ between SSc and controls, C5b-9 deposition was detected in skin biopsies of SSc patients but not in healthy subjects. MCP was significantly lower in skin vessels of SSc patients than in healthy controls and was associated with the over-expression of two polymorphic variants in the MCP gene promoter, which has been related to more aggressive phenotypes in other immune-mediated diseases.ConclusionsOur results firsty document the local complement activation with an abnormal expression of MCP in skin vessels of SSc patients, suggesting that a subset of SSc patients might be exposed to more severe organ complications and clinical evolution due to abnormal local complement activation.     

A study of environmental conflict: the economic value of Grey Seals in southwest England

This paper reports an analysis of a typical case of negative bilateral externality – a situation in which two legitimate activities, fishing and wildlife conservation, each give rise to damages to the other party. The Cornish fishing industry believes that its annual profits are reduced by an estimated £100 000 because of the damage by seal populations to caught fish. About 80 individuals belonging to the Cornish Grey Seal population (of about 400 specimens) are killed as a by-catch of trawling. Thus, the status quo is clearly inefficient: seals are perceived to damage fish and fishermen definitely damage seals. The biological dynamics of the seal population is not absolutely clear, so that a precautionary approach requires that care should be taken to avoid the risk of damaging the population in an irreversible way. Moreover, public opinion considers seals to be a high value flagship species. One of the goals of any conflict resolution should be to capture the economic value of seal conservation – i.e. to convert conservation benefits into resource flows – and use at least part of it in order to create incentives for a more efficient allocation of resources. The authorities should invest in seal conservation (i.e. compensating fishermen) if the benefits deriving from conservation exceed the opportunity costs of conservation. Such a solution clearly requires that the conservation benefits be estimated. To investigate the economic value of seal conservation a contingent valuation study is carried out. A contingent valuation study utilises a questionnaire approach and part of the questionnaire seeks to elicit individuals' willingness to pay (WTP) for a change in the state of some good or asset, in this case seal conservation. Due to resource limitations, the sample size of those interviewed in the study reported is small, so that we cannot be extremely confident about the results. However, they are consistent with those derived from similar studies on flagship species. Results show a mean WTP for recreational use of seals of about £8 per person for the option of seeing seals in a specialised sanctuary for seals recovered from accidents, and closer to £9 for seeing seals in the wild. The annual non-use value of seals – i.e. value unassociated with actual viewing – was found to be £526 000 in the most conservative estimation, aggregated over the Seal Sanctuary visitors. This economic potential could be realised in several ways and used to compensate fishermen for changing fishing techniques, targets and fishing areas. Finally, we investigate the role the Seal Sanctuary is playing in this context and some policy suggestions are discussed.