Molecular predictive for progession of high grade preinvasive bronchial lesions

International audienc

Drastic Effect of Germline TP53 Missense Mutations in Li-Fraumeni Patients

International audienceIn contrast to other tumor suppressor genes, the majority of TP53 alterations are missense mutations. We have previously reported that in the Li–Fraumeni syndrome (LFS), germline TP53 missense mutations are associated with an earlier age of tumor onset. In a larger series, we observed that mean age of tumor onset in patients harboring dominant negative missense mutations and clearly null mutations was 22.6 and 37.5 years, respectively. To assess the impact of heterozygous germline TP53 mutations in the genetic context of the patients, we developed a new functional assay of the p53 pathway on the basis of induction of DNA damage in Epstein–Barr‐virus‐immortalized lymphocytes, followed by comparative gene‐expression profiling. In wild‐type lymphocytes, we identified a core of 173 genes whose expression was induced more than twofold, of which 46 were known p53 target genes. In LFS lymphocytes with canonical missense mutations, the number of induced genes and the level of known p53 target genes induction were strongly reduced as compared with controls and LFS lymphocytes with null mutations. These results show that certain germline missense TP53 mutations, such as those with dominant negative effect, dramatically alter the response to DNA damage. This probably explains why TP53 alterations are predominantly missense mutations

Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy

International audienceColorectal cancers with microsatellite instability (MSI) represent 15% of all colorectal cancers, including Lynch syndrome as the most frequent hereditary form of this disease. Notably, MSI colorectal cancers have a higher density of tumor-infiltrating lymphocytes (TIL) than other colorectal cancers. This feature is thought to reflect the accumulation of frameshift mutations in sequences that are repeated within gene coding regions, thereby leading to the synthesis of neoantigens recognized by CD8(+) T cells. However, there has yet to be a clear link established between CD8(+) TIL density and frameshift mutations in colorectal cancer. In this study, we examined this link in 103 MSI colorectal cancers from two independent cohorts where frameshift mutations in 19 genes were analyzed and CD3(+), CD8(+), and FOXP3(+) TIL densities were quantitated. We found that CD8(+) TIL density correlated positively with the total number of frameshift mutations. TIL densities increased when frameshift mutations were present within the ASTE1, HNF1A, or TCF7L2 genes, increasing even further when at least one of these frameshift mutations was present in all tumor cells. Through in vitro assays using engineered antigen-presenting cells, we were able to stimulate peripheral cytotoxic T cells obtained from colorectal cancer patients with peptides derived from frameshift mutations found in their tumors. Taken together, our results highlight the importance of a CD8(+) T cell immune response against MSI colorectal cancer-specific neoantigens, establishing a preclinical rationale to target them as a personalized cellular immunotherapy strategy, an especially appealing goal for patients with Lynch syndrome

Orexigenic Neuropeptide 26RFa: New Evidence for an Adaptive Profile of Appetite Regulation in Anorexia Nervosa

International audienceRestrictive anorexia nervosa (AN) presents an adaptive appetite regulating profile including mainly high levels of ghrelin. Because this adaptive mechanism is not effective on food intake, other appetite-regulating peptides need to be explored. 26RFa is a hypothalamic neuropeptide that stimulates appetite, gonadotropin release, and bone metabolism

First image revisited: human nature, original sin and international relations

In Waltz’s famous classification, human nature’s propensity to evil is catalogued as a first-image causal explanation of war. Ever since, human nature explanations of conflict have been attacked for resting on metaphysical assumptions and a priori pessimism. This paper argues that modern conceptions about the inherent wickedness of human nature or, equally, reductionist sociobiological explanations about its hard-wired conflict-proneness are impoverished secularised versions of Christian anthropological assumptions grounded in the doctrine of original sin. Itself a widely contested dogma, in its Augustinian formulation it was closely connected with a soteriological perspective, that is, a defence of its status as a corollary of the doctrine that all human beings are equally in need of salvation in Jesus Christ. However, its use was never entirely disconnected from the purposes of theodicy and Christian apologetics striving to reconcile the existence of a benevolent and omnipotent God with the reality of evil and suffering in the world. It is this latter legacy – associated with the explanation of suffering and evil in the world but stripped of its salvific eschatological content – that is picked up by secularist theorisations of human nature which tend to reduce the paradox of original sin to the parody of man’s evil nature