Chemotherapies are known often to induce severe gastrointestinal tract toxicity but the underlying mechanism remains unclear. This study considers the widely applied cytotoxic agent irinotecan (CPT-11) as a representative agent and demonstrates that treatment induces massive release of double-strand DNA from the intestine that accounts for the dose-limiting intestinal toxicity of the compound. Specifically, "self-DNA" released through exosome secretion enters the cytosol of innate immune cells and activates the AIM2 (absent in melanoma 2) inflammasome. This leads to mature IL-1β and IL-18 secretion and induces intestinal mucositis and late-onset diarrhoea. Interestingly, abrogation of AIM2 signalling, either in AIM2-deficient mice or by a pharmacological inhibitor such as thalidomide, significantly reduces the incidence of drug-induced diarrhoea without affecting the anticancer efficacy of CPT-11. These findings provide mechanistic insights into how chemotherapy triggers innate immune responses causing intestinal toxicity, and reveal new chemotherapy regimens that maintain anti-tumour effects but circumvent the associated adverse inflammatory response.
Free-breathing accurate 3D T2 mapping is feasible and may be applicable in myocardial assessment in lieu of current clinical black blood, T2 -weighted techniques.
Firstly, the MPFL is most easily injured at the FEM, and secondly at the PAT in adults after acute LPD. The complete MPFL tear is more often concomitant with osteochondral lesions of the lateral femoral condyle than the partial MPFL tear. The isolated patellar-sided MPFL tear is more easily concomitant with chondral lesions and osteochondral lesions of the lateral femoral condyle than the isolated femoral-sided MPFL tear.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.