The liver has an intrinsic capacity to regenerate in response to injury or surgical resection. Nevertheless, circumstances in which hepatocytes are unresponsive to proliferative signals result in impaired regeneration and hepatic failure. As the Hippo pathway has a canonical role in the maintenance of liver size, we investigated whether it could serve as a therapeutic target to support regeneration. Using a standard two‐thirds partial hepatectomy (PH) model in young and aged mice, we demonstrate that the Hippo pathway is modulated across the phases of liver regeneration. The activity of the core kinases MST1 and LATS1 increased during the early hypertrophic phase and returned to steady state levels in the proliferative phase, coinciding with activation of YAP1 target genes and hepatocyte proliferation. Moreover, following PH in aged mice, we demonstrate that Hippo signaling is anomalous in non‐regenerating livers. We provide pre‐clinical evidence that silencing the Hippo core kinases MST1 and MST2 with siRNA provokes hepatocyte proliferation in quiescent livers and rescues liver regeneration in aged mice following PH. Our data suggest that targeting the Hippo core kinases MST1/2 has therapeutic potential to improve regeneration in non‐regenerative disorders. ![][1] Inhibition of the Hippo core kinases MST1 and MST2 with siRNA has the therapeutic potential to improve liver regeneration in age‐related non‐regenerative disorders. [1]: /embed/graphic-1.gif

Urinary tract infections (UTI) are frequent in outpatients. Fast pathogen identification is mandatory for shortening the time of discomfort and preventing serious complications. Urine culture needs up to 48 hours until pathogen identification. Consequently, the initial antibiotic regimen is empirical. To evaluate the feasibility of qualitative urine pathogen identification by a commercially available real-time PCR blood pathogen test (SeptiFast^®) and to compare the results with dipslide and microbiological culture. Pilot study with prospectively collected urine samples. University hospital. 82 prospectively collected urine samples from 81 patients with suspected UTI were included. Dipslide urine culture was followed by microbiological pathogen identification in dipslide positive samples. In parallel, qualitative DNA based pathogen identification (SeptiFast^®) was performed in all samples. 61 samples were SeptiFast^® positive, whereas 67 samples were dipslide culture positive. The inter-methodological concordance of positive and negative findings in the gram+, gram- and fungi sector was 371/410 (90%), 477/492 (97%) and 238/246 (97%), respectively. Sensitivity and specificity of the SeptiFast^® test for the detection of an infection was 0.82 and 0.60, respectively. SeptiFast^® pathogen identifications were available at least 43 hours prior to culture results. The SeptiFast^® platform identified bacterial DNA in urine specimens considerably faster compared to conventional culture. For UTI diagnosis sensitivity and specificity is limited by its present qualitative setup which does not allow pathogen quantification. Future quantitative assays may hold promise for PCR based UTI pathogen identification as a supplementation of conventional culture methods.

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Paracrine signalling mediated by cytokine secretion is essential for liver regeneration after hepatic resection, yet the mechanisms of cellular crosstalk between immune and parenchymal cells are still elusive. Interleukin‐22 (IL‐22) is released by immune cells and mediates strong hepatoprotective functions. However, it remains unclear whether IL‐22 is critical for the crosstalk between liver lymphocytes and parenchymal cells during liver regeneration after partial hepatectomy (PH). Here, we found that plasma levels of IL‐22 and its upstream cytokine, IL‐23, are highly elevated in patients after major liver resection. In a mouse model of PH, deletion of IL‐22 was associated with significantly delayed hepatocellular proliferation and an increase of hepatocellular injury and endoplasmic reticulum stress. UsingRag1^−/−andRag2−/−γc−/⁻mice, we show that the main producers of IL‐22 post‐PH are conventional natural killer cells and innate lymphoid cells type 1. Extracellular adenosine triphosphate (ATP), a potent danger molecule, is elevated in patients immediately after major liver resection. Antagonism of the P2‐type nucleotide receptors, P2X1 and P2Y6, significantly decreased IL‐22 secretionex vivo.In vivo, specific inhibition of P2X1 was associated with decreased IL‐22 secretion, elevated liver injury, and impaired liver regeneration.Conclusion:This study shows that innate immune cell‐derived IL‐22 is required for efficient liver regeneration and that secretion of IL‐22 in the regenerating liver is modulated by the ATP receptor, P2X1. (Hepatology2016;63:2004‐2017)