In our published work, we reported that HMGB1 is actively released from autophagy-deficient hepatocytes via a pathway from NRF2 to inflammasomes to promote ductular reaction, hepatic progenitor cell expansion, and tumorigenesis. We based our conclusions on multiple lines of evidence. Release of HMGB1 from autophagy-deficient hepatocytes was documented by immunoblotting, immunostaining, and ELISA analysis in different age groups of autophagy-deficient mice. The release of HMGB1 through an active mechanism is supported by kinetics analysis that shows tissue injury can be separated from the release process and by pharmacological and genetic analyses showing that the molecular elements of NRF2 and CASPASE 1 are required. The impact of HMGB1 on ductular reaction and tumor progression was also documented by both in vivo and in vitro evidence using knockout mice, cell fractionation, and transcriptional analysis. Figure 1G showed the results of an analysis of HMGB1 isoforms by mass spectrometry that was undertaken in a separate laboratory by Daniel J. Antoine. In February 2019, we learned that these data were likely compromised. We contacted the journal, and the Editorial Board gave us permission to correct the study. In the corrected version, all conclusions based on Figure 1G have been removed, and the journal has published an online version of the original article with the unreliable statements crossed out and the modified text highlighted in red (Supplemental File, Redaction). Figure 1G only suggested the formation of the released HMGB1, but carried no significance as to the releasing mechanisms and the functional significance of HMGB1 release in autophagy-deficient conditions. We thus believe that the major conclusions of the study on the releasing mechanism and functional significance of HMGB1 in autophagy-deficient conditions are independent of Figure 1G and are accurate and that the corrected paper is reliable.

No abstract

Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression.

No abstract

The impact of discontinuation of anti-VEGF cancer therapy in promoting cancer metastasis is unknown. Here we show discontinuation of anti-VEGF treatment creates a time-window of profound structural changes of liver sinusoidal vasculatures, exhibiting hyper-permeability and enlarged open-pore sizes of the fenestrated endothelium and loss of VE-cadherin. The drug cessation caused highly leaky hepatic vasculatures permit tumour cell intravasation and extravasation. Discontinuation of an anti-VEGF antibody-based drug and sunitinib markedly promotes liver metastasis. Mechanistically, host hepatocyte, but not tumour cell-derived vascular endothelial growth factor (VEGF), is responsible for cancer metastasis. Deletion of hepatocyte VEGF markedly ablates the ‘off-drug'-induced metastasis. These findings provide mechanistic insights on anti-VEGF cessation-induced metastasis and raise a new challenge for uninterrupted and sustained antiangiogenic therapy for treatment of human cancers.

Drawing on the relational and knowledge-based views of competitive advantage, this study links leaders' social ties and knowledge acquisition capability to competitive advantage of a firm. Specifically, it posits that leaders' business ties and government ties have differential effects on firm competitive advantage. It further posits that the effect of leaders' business ties on firm competitive advantage will be positively moderated by knowledge acquisition capability, and the effect of leaders' government ties on firm competitive advantage will be negatively moderated by knowledge acquisition capability. The hypotheses are tested based on a survey of 386 firms in China. The results provide support for the hypotheses.

Autophagy is important for hepatic homeostasis, nutrient regeneration, and organelle quality control. We investigated the mechanisms by which liver injury occurred in the absence of autophagy function. We found that mice deficient in autophagy because of the lack of autophagy-related gene 7 or autophagy-related gene 5, key autophagyrelated genes, manifested intracellular cholestasis with increased levels of serum bile acids, a higher ratio of tauromuricholic acid/taurocholic acid in the bile, increased hepatic bile acid load, abnormal bile canaliculi, and altered expression of hepatic transporters. In determining the underlying mechanism, we found that autophagy sustained and promoted the basal and up-regulated expression of farnesoid X receptor (Fxr ) in the fed and starved conditions, respectively. Consequently, expression of Fxr and its downstream genes, particularly bile salt export pump, and the binding of FXR to the promoter regions of these genes, were suppressed in autophagy-deficient livers. In addition, codeletion of nuclear factor erythroid 2-related factor 2 (Nrf2 ) in autophagy deficiency status reversed the FXR suppression. Furthermore, the cholestatic injury of autophagy-deficient livers was reversed by enhancement of FXR activity or expression, or by Nrf2 deletion. Conclusion: Together with earlier reports that FXR can suppress autophagy, our findings indicate that autophagy and FXR form a regulatory loop and deficiency of autophagy causes abnormal FXR functionality, leading to the development of intracellular cholestasis and liver injury. (Hepatology 2019;69:2196-2213).

New venture, Resource-based view, Growth strategy, Performance, China,