Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer

Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8(+) and CD4(+) T cells. A differential compartmentalization was detected between Helioshigh and Helios(low) Treg subsets (thymus-derived versus peripherally induced): while Helios(low) Tregs were enriched in both sites, only Helios(high) Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression

Trehalose-6-phosphate-mediated toxicity determines essentiality of OtsB2 in Mycobacterium tuberculosis in vitro and in mice

Trehalose biosynthesis is considered an attractive target for the development of antimicrobials against fungal, helminthic and bacterial pathogens including Mycobacterium tuberculosis. The most common biosynthetic route involves trehalose-6-phosphate (T6P) synthase OtsA and T6P phosphatase OtsB that generate trehalose from ADP/UDP-glucose and glucose-6-phosphate. In order to assess the drug target potential of T6P phosphatase, we generated a conditional mutant of M. tuberculosis allowing the regulated gene silencing of the T6P phosphatase gene otsB2. We found that otsB2 is essential for growth of M. tuberculosis in vitro as well as for the acute infection phase in mice following aerosol infection. By contrast, otsB2 is not essential for the chronic infection phase in mice, highlighting the substantial remodelling of trehalose metabolism during infection by M. tuberculosis. Blocking OtsB2 resulted in the accumulation of its substrate T6P, which appears to be toxic, leading to the self-poisoning of cells. Accordingly, blocking T6P production in a ΔotsA mutant abrogated otsB2 essentiality. T6P accumulation elicited a global upregulation of more than 800 genes, which might result from an increase in RNA stability implied by the enhanced neutralization of toxins exhibiting ribonuclease activity. Surprisingly, overlap with the stress response caused by the accumulation of another toxic sugar phosphate molecule, maltose-1-phosphate, was minimal. A genome-wide screen for synthetic lethal interactions with otsA identified numerous genes, revealing additional potential drug targets synergistic with OtsB2 suitable for combination therapies that would minimize the emergence of resistance to OtsB2 inhibitors

Patterns of Long Term Care in 29 European countries: evidence from an exploratory study

Background: The challenges posed by the rapidly ageing population, and the increased preponderance of disabled people in this group, coupled with the rising level of public expenditure required to service the complex organization of long term care (LTC) delivery are causing increased pressure on LTC systems in Europe. A pan- European survey was carried out to evaluate whether patterns of LTC can be identified across Europe and what are the trends of the countries along them. Methods: An ecological study was conducted on the 27 EU Member States plus Norway and Iceland, referring to the period 2003-2007. Several variables related to organizational features, elderly needs and expenditure were drawn from OECD Health Data and the Eurostat Statistics database and combined using Multiple Factor Analysis (MFA). Results: Two global Principal Components were taken into consideration given that their expressed total variance was greater than 60%. They were interpreted according to the higher (more than 0.5) positive or negative correlation coefficients between them and the original variables; thus patterns of LTC were identified. High alignment between old age related expenditure and elderly needs characterizes Nordic and Western European countries, the former also having a higher level of formal care than the latter. Mediterranean as well as Central and South Eastern European countries show lower alignment between old age related expenditure and elderly needs, coupled with a level of provision of formal care that is around or slightly above the average European level. In the dynamic comparison, linear, stable or unclear trends were shown for the studied countries. Conclusions: The analysis carried out is an explorative and descriptive study, which is an attempt to reveal patterns and trends of LTC in Europe, allowing comparisons between countries. It also stimulates further researches with lower aggregated data useful to gain meaningful policy-making evidence. Please see related article: http://www.biomedcentral.com/1741-7015/9/12