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ALPPS in mice induces an unprecedented degree of liver regeneration, comparable with humans. Circulating factors in combination with PVL seem to mediate enhanced liver regeneration, associated with ALPPS.

The unique regenerative capacity of liver has its natural limits. Following tissue loss that is too excessive, such as through extended resection in the clinic, liver failure may develop. This is known as small-for-size-syndrome (SFSS) and represents the most frequent cause of death due to liver surgery. Here we show that deficient induction of the protein Car, a central regulator of liver function and growth, is a cause of liver failure following extended resection; reactivation of Car through pharmacological means is sufficient to prevent or rescue the SFSS.

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PTEN down-regulation after hepatectomy promotes the burning of TRAS-derived lipids to fuel hypertrophic liver regeneration. Therefore, the anabolic function of PTEN deficiency in resting liver is transformed into catabolic activities upon tissue loss. These findings portray PTEN as a node coordinating liver growth with its energy demands and emphasize the need of lipids for regeneration. (Hepatology 2017;66:908-921).

Remote ischemic preconditioning (RIPC), the repetitive transient mechanical obstruction of vessels at a limb remote to the operative site, is a novel strategy to mitigate distant organ injury associated with surgery. In the clinic, RIPC has demonstrated efficacy in protecting various organs against ischemia reperfusion (IR), but a common mechanism underlying the systemic protection has not been identified. Here, we reasoned that protection may rely on adaptive physiological reponses toward local stress, as is incurred through RIPC. Standardized mouse models of partial hepatic IR and of RIPC to the femoral vascular bundle were applied. The roles of platelets, peripheral serotonin, and circulating vascular endothelial growth factor (Vegf) were studied in thrombocytopenic mice, Tph1−/− mice, and through neutralizing antibodies, respectively. Models of interleukin‐10 (Il10) and matrix metalloproteinase 8 (Mmp8) deficiency were used to assess downstream effectors of organ protection. The protection against hepatic IR through RIPC was dependent on platelet‐derived serotonin. Downstream of serotonin, systemic protection was spread through up‐regulation of circulating Vegf. Both RIPC and serotonin‐Vegf induced differential gene expression in target organs, with Il10 and Mmp8 displaying consistent up‐regulation across all organs investigated. Concerted inhibition of both molecules abolished the protective effects of RIPC. RIPC was able to mitigate pancreatitis, indicating that it can protect beyond ischemic insults. Conclusions: We have identified a platelet‐serotonin‐Vegf‐Il10/Mmp8 axis that mediates the protective effects of RIPC. The systemic action, the conservation of RIPC effects among mice and humans, and the protection beyond ischemic insults suggest that the platelet‐dependent axis has evolved as a preemptive response to local stress, priming the body against impending harm. (Hepatology 2014;60:1409–1417)

PURPOSE: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standardof-care treatment. EXPERIMENTAL DESIGN: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential. RESULTS: ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. CONCLUSIONS: Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887-97. DOI: https://doi.org/10.1158/1078-0432. Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-125980 Accepted Version Originally published at: Limani, P; Linecker, M; Kachaylo, E; Tschuor, C; Kron, P; Schlegel, A; Ungethuem, U; Jang, J H; Georgiopoulou, S; Claude Nicolau, C; Lehn, J-M; Graf, R; Humar, B; Clavien, P-A (2016). Antihypoxic potentiation of standard therapy for experimental colorectal liver metastasis through myo-inositol trispyrophosphate. Clinical Cancer Research, 22 (23) Results. ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least four weeks after treatment cessation. Compared to FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. Conclusions.Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing antic...