Moreover, tumors developed from HBx mice exhibited phenotypes of mixed HCC and cholangiocarcinoma (CC) within the same liver. The HCC-like tumors exhibited features of hepatocellular morphologies, whereas CC-like tumors strongly resembled the “cholangiolocellular” subtype described in humans that exhibits poorly differentiated characteristics (Fig. 3B). Staining of tumor 3-MA chemical structure sections with AFP and

CK19 confirmed that the tumors are composed of hepatocytes and cholangiocytes (Fig. 3C). Furthermore, we detected EpCAM+ tumor cells in both HCC and CC tumor tissues (Fig. 3D). The complete penetrance of both tumor types subsequent to HPC expansion suggested that tumors may derive from stem/progenitor cells and supported our hypothesis that HPCs are involved in HBx-induced tumorigenesis. As shown in Fig. 3A, consistent DDC treatment induced bilineage tumors in HBx-expressed livers. The results raised a question if tumors are derived from transformed HPCs. To identify if the bilineage tumor derived from HBx-induced HPCs, we isolated EpCAM+CD45− HPCs from HBx transgenic mice and WT control mice after 1, 2, 3, or 4 months of DCC treatment, respectively. One × 106 cells were then injected subcutaneously into NOD/SCID mice (n = 6). Eight weeks later, EpCAM+CD45− HPCs derived from all WT mice and 1, 2, or 3-month

DDC-treated HBx mice did not produce any tumors, whereas EpCAM+CD45−HPCs Sorafenib BMN 673 concentration from 4-month DDC-treated HBx mice formed tumor in four out of six mice (Fig. 4A,B). H&E staining and immunohistochemical analysis of AFP and CK19 revealed that these tumors contained mixed cell characteristics (Fig. 4C-E). EpCAM+ cells were also detected in these tumors (Fig. 4F). Therefore, these results demonstrate that chronic injury induced by DDC in the long term (at least 4 months) gradually enhanced the effect of HBx on HPCs and increased

their tumorigenicity potential. Our results have shown that HBx induced expansion of HPCs with increased expression of stemness genes and oncogenes (Fig. 2B). Importantly, HPCs isolated from premalignant HBx mice induced a subcutaneous tumor xenograft (Fig. 4A,B). The question is, what is the mechanism underlying HBx-promoted expansion and transformation of HPCs? To answer the question we analyzed the liver injury, inflammatory response, and signaling pathways during the process of HPC’s response to DCC. To determine if it was because of HBx exacerbated DDC-induced liver injury, we detected the serum alanine aminotransferase (ALT) level and found there was no difference between WT and HBx groups at any timepoint (Fig. 5A), concluding that the degree of liver damage is not associated with HPC proliferation.

929; 95% CI: 1.530-5.607; P = 0.001), and SH (OR, 2.316; 95% CI: 1.267-4.241; P = 0.007). Among patients with SH and corresponding Tyrosine Kinase Inhibitor Library controls, gender, preoperative chemotherapy treatment, liver resection approach, extent of liver resection, and underlying SH were associated with any hepatic-related morbidity on univariable analysis (Table 5). On multivariable logistic regression, resection of four or more segments (OR, 9.493; 95% CI: 4.177-21.577; P < 0.001), male gender (OR, 3.252; 95% CI: 1.448-7.303; P = 0.004), and SH (OR, 2.722; 95% CI: 1.201-6.168; P = 0.016) were independently associated with

any hepatic-related morbidity. The relative low numbers of PHI, postoperative hepatic decompensation, and surgical hepatic complication events precluded corresponding multivariable analyses. The aim of this retrospective study was to determine whether simple hepatic steatosis or SH worsens outcomes after liver resection. To achieve this aim, we individually matched patients with either underlying histopathology to control patients based upon extent and approach of liver resection. Controls GSK126 datasheet were then further selected based upon similar diagnoses and potential etiologies of SH or simple steatosis—including alcohol use, MetS, and preoperative chemotherapy

(Table 1). Moreover, the incidence of patients with “two-hits” predisposing to SH (e.g., preoperative chemotherapy treatment and MetS) was similar between SH patients and corresponding controls. Thus, our study accounts for the morbidity derived from factors, such as DM, morbid obesity, and preoperative chemotherapy treatment,

separate from underlying liver injury.41-43 We excluded patients with bridging fibrosis, cirrhosis, cholestasis, or other CLDs in the underlying liver and those who underwent concomitant major extrahepatic procedures (including bile duct resection and bilioenteric Lepirudin anastomosis) to eliminate potential confounding variables that may influence postoperative outcomes. This study design thus avoids the flaws present in other reports that cloud conclusions regarding the association of underlying liver pathology and postoperative outcomes.18, 24-32 Only those with at least moderate underlying steatosis (defined by greater than 33% of liver parenchymal involvement by the NAS)34 were included in the group of patients with simple hepatic steatosis. This relatively high threshold for simple steatosis was selected to maximize the likelihood of detecting differences in postoperative morbidity, when compared to corresponding controls with no underlying liver pathology. Patients with SH in the underlying liver had higher overall (56.9% versus 37.3%; P = 0.008) and any hepatic-related (28.4% versus 15.7%; P = 0.043) morbidity after liver resection, compared to corresponding controls. SH was associated with both outcomes on multivariable logistic regression—indicating that SH leads to higher morbidity after liver resection independent of etiology.