The Bcl-2 repertoire of mesothelioma spheroids underlies acquired apoptotic multicellular resistance

Three-dimensional (3D) cultures are a valuable platform to study acquired multicellular apoptotic resistance of cancer. We used spheroids of cell lines and actual tumor to study resistance to the proteasome inhibitor bortezomib in mesothelioma, a highly chemoresistant tumor. Spheroids from mesothelioma cell lines acquired resistance to bortezomib by failing to upregulate Noxa, a pro-apoptotic sensitizer BH3-only protein that acts by displacing Bim, a pro-apoptotic Bax/Bak-activator protein. Surprisingly, despite their resistance, spheroids also upregulated Bim and thereby acquired sensitivity to ABT-737, an inhibitor of anti-apoptotic Bcl-2 molecules. Analysis using BH3 profiling confirmed that spheroids acquired a dependence on anti-apoptotic Bcl-2 proteins and were ‘primed for death'. We then studied spheroids grown from actual mesothelioma. ABT-737 was active in spheroids grown from those tumors (5/7, ∼70%) with elevated levels of Bim. Using immunocytochemistry of tissue microarrays of 48 mesotheliomas, we found that most (33, 69%) expressed elevated Bim. In conclusion, mesothelioma cells in 3D alter the expression of Bcl-2 molecules, thereby acquiring both apoptotic resistance and sensitivity to Bcl-2 blockade. Mesothelioma tumors ex vivo also show sensitivity to Bcl-2 blockade that may depend on Bim, which is frequently elevated in mesothelioma. Therefore, mesothelioma, a highly resistant tumor, may have an intrinsic sensitivity to Bcl-2 blockade that can be exploited therapeutically

Another look at the comparisons of the health systems expenditure indicators

For policy purposes expenditure in health systems of extremely different natures are often compared without having a clear question to be addressed in such a comparison. For instance, comparisons made among OECD countries which have differing levels of development, and/or where the fusion of public and private finance differ; along with their sources of revenue, their finance levels and their degree of taxes and co-payments. Our objective in this paper is to analyze the factors that complicate international comparisons of health care expenditure across countries. We comment on some of these issues and shows how results and the interpretation of the gaps differ according to the refinements we make to the sampling and sub-sampling, as well as the definition of the variables we adopt. We considered as dependent variables total and health care expenditure per capita and as a percentage of GDP with and without out-of-pocket payments. We analyse the (complete) OECD sample for the period 2000–2010, as well as three sub-samples (European Union, countries with the Bismark model and countries with the Beveridge model). After calculating the means of the dependent variables, both without weights and weighting by GDP and population, we specified two different panel data models to explain the variation in the dependent variables, including as explanatory variables those that are most likely to affect health expenditure. Although other countries are mentioned in this paper, we take Spain as our example. We show how the results and the consequent interpretations of the gaps can differ according to the refinements we introduce into the sample and sub-samples; akin to the adjustments we are willing to make to the definition of the variables we choose to adopt. We show how Spanish ratios, as example, are generally well above those expected. In conclusion, there is a need for a better understanding of the settings of any comparison, along with a more appropriate sub sampling of the systems being analyzed in order to align any demand to the financial capabilities of the health care sector

Ageing and health care expenditure in EU-15

Health care expenditure, Ageing, EU-15 countries, H2, H51, I1, J14,

Growth history and intrinsic factors influence risk assessment at a critical life transition for a fish

Making the appropriate decision in the face of predation risk dictates the fate of prey, and predation risk is highest at life history boundaries such as settlement. At the end of the larval phase, most coral reef fishes enter patches of reef containing novel predators. Since vision is often obscured in the complex surroundings, chemical information released from damaged conspecific is used to forewarn prey of an active predator. However, larvae enter the reef environment with their own feeding and growth histories, which will influence their motivation to feed and take risks. The present study explored the link between recent growth, feeding history, current performance and behavioural risk taking in newly settling stages of a coral reef damselfish (Pomacentrus amboinensis). Older and larger juveniles in good body condition had a stronger response to chemical alarm cues of injured conspecifics; these fish spent a longer time in shelter and displayed a more dramatic decrease in foraging behaviour than fish in lower body condition. Feeding experiments supported these findings and emphasized the importance of body condition in affecting risk assessment. Evidently, larval growth history and body condition influences the likelihood of taking risks under the threat of predation immediately after settlement, thereby affecting the probability of survival in P. amboinensis