IntroductionThe lack of clinically sufficient antitumor immune responses has been attributed to soluble inhibitory factors such as TGF␤1 1,2 or PGE 2 3-5 as well as the induction and expansion of regulatory cells. 6,7 CD4 ϩ CD25 high regulatory T cells (T reg cells) were shown to be expanded in murine tumor models. 8 Moreover, their deletion reinstated an efficient antitumor immune response leading to complete tumor regression. [9][10][11] We and others have demonstrated that CD4 ϩ CD25 high FoxP3 ϩ T reg cells are also expanded in patients with solid tumors, [12][13][14][15][16][17][18][19] Hodgkin lymphoma, 20,21 or B-cell chronic lymphocytic leukemia (CLL). 22 Both in humans and in animal models, T reg cells have been described as anergic cells exerting strong suppression after T-cell receptor (TCR) stimulation. [23][24][25] As demonstrated in murine models, natural T reg cells usually originate from the thymus, 26,27 although cells with similar characteristics can also be generated in the periphery under appropriate conditions. 28 More recently, the diversity and developmental stage of thymic emigrants with a T reg -cell phenotype as well as CD4 ϩ CD25 ϩ T reg cells within peripheral blood were examined. 29,30 In healthy individuals, the levels of T-cell receptor excision circles (TRECs) were comparable in both conventional CD4 ϩ CD25 Ϫ and regulatory CD4 ϩ CD25 ϩ thymic populations. However, the number of TRECs was significantly higher in thymic emigrants than in peripheral blood-derived T cells, which strongly suggests thymic development of human CD4 ϩ CD25 high T reg cells. 30 Nevertheless, conventional CD4 ϩ CD25 Ϫ T cells from peripheral blood of healthy donors contained higher TREC numbers than their CD4 ϩ CD25 ϩ counterparts, which is in line with the possibility of extrathymic expansion particularly within the T reg -cell subset. 29 Until recently, CD4 ϩ CD25 high T reg cells have been described to belong to the memory T-cell compartment. 24,[31][32][33] Valmori et al, 34 however, identified a T reg -cell population with a naive phenotype (CCR7 ϩ CD45RA ϩ ), which they termed natural naive T reg cells (NnTregs). As expected, the frequency of these NnTregs was relatively low in healthy individuals. NnTregs were shown to vigorously proliferate in response to contact with autologous antigen-presenting cells, suggesting that particularly this subpopulation is enriched in T cells bearing self-reactive T-cell receptors. 34 Most recently, Seddiki et al 35 described the persistence of a population of naive CD45RA ϩ T reg cells in adult life.Little is known about the differentiation, origin, and mechanisms of expansion of T reg cells in cancer patients. We and others have observed that increase of T reg -cell frequency correlates with disease state, 13,22 which might be explained by an antigendependent mechanism of peripheral expansion in response to tumor progression. However, it is unknown if these T reg cells are also more differentiated toward a central or even effector memory phenotype. M.B. designed res...

With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.

Artificial sweeteners are added to a wide variety of food, drinks, drugs and hygiene products. Since their introduction, the mass media have reported about potential cancer risks, which has contributed to undermine the public's sense of security. It can be assumed that every citizen of Western countries uses artificial sweeteners, knowingly or not. A cancer-inducing activity of one of these substances would mean a health risk to an entire population. We performed several PubMed searches of the National Library of Medicine for articles in English about artificial sweeteners. These articles included 'first generation' sweeteners such as saccharin, cyclamate and aspartame, as well as 'new generation' sweeteners such as acesulfame-K, sucralose, alitame and neotame. Epidemiological studies in humans did not find the bladder cancer-inducing effects of saccharin and cyclamate that had been reported from animal studies in rats. Despite some rather unscientific assumptions, there is no evidence that aspartame is carcinogenic. Case-control studies showed an elevated relative risk of 1.3 for heavy artificial sweetener use (no specific substances specified) of >1.7 g/day. For new generation sweeteners, it is too early to establish any epidemiological evidence about possible carcinogenic risks. As many artificial sweeteners are combined in today's products, the carcinogenic risk of a single substance is difficult to assess. However, according to the current literature, the possible risk of artificial sweeteners to induce cancer seems to be negligible.