Automatically Proving and Disproving Feasibility Conditions

[EN] In the realm of term rewriting, given terms s and t, a reachability condition s>>t is called feasible if there is a substitution O such that O(s) rewrites into O(t) in zero or more steps; otherwise, it is called infeasible. Checking infeasibility of (sequences of) reachability conditions is important in the analysis of computational properties of rewrite systems like confluence or (operational) termination. In this paper, we generalize this notion of feasibility to arbitrary n-ary relations on terms defined by first-order theories. In this way, properties of computational systems whose operational semantics can be given as a first-order theory can be investigated. We introduce a framework for proving feasibility/infeasibility, and a new tool, infChecker, which implements it.Supported by EU (FEDER), and projects RTI2018-094403-B-C32, PROMETEO/2019/098, and SP20180225. 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Metabolic implication of tigecycline as an efficacious second-line treatment for sorafenib-resistant hepatocellular carcinoma

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Metabolic implication of tigecycline as an efficacious second-line treatment for sorafenib-resistant hepatocellular carcinoma.

Sorafenib represents the current standard of care for patients with advanced-stage hepatocellular carcinoma (HCC). However, acquired drug resistance occurs frequently during therapy and is accompanied by rapid tumor regrowth after sorafenib therapy termination. To identify the mechanism of this therapy-limiting growth resumption, we established robust sorafenib resistance HCC cell models that exhibited mitochondrial dysfunction and chemotherapeutic crossresistance. We found a rapid relapse of tumor cell proliferation after sorafenib withdrawal, which was caused by renewal of mitochondrial structures alongside a metabolic switch toward high electron transport system (ETS) activity. The translation-inhibiting antibiotic tigecycline impaired the biogenesis of mitochondrial DNA-encoded ETS subunits and limited the electron acceptor turnover required for glutamine oxidation. Thereby, tigecycline prevented the tumor relapse in vitro and in murine xenografts in vivo. These results offer a promising second-line therapeutic approach for advanced-stage HCC patients with progressive disease undergoing sorafenib therapy or treatment interruption due to severe adverse events