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Tertiary lymphoid structure (TLS) can predict the prognosis and sensitivity of tumors to immune checkpoint inhibitors (ICIs) therapy, whether it can be noninvasively predicted by radiomics in hepatocellular carcinoma with liver transplantation (HCC‐LT) has not been explored. In this study, it is found that intra‐tumoral TLS abundance is significantly correlated with recurrence‐free survival (RFS) and overall survival (OS). Tumor tissues with TLS are characterized by inflammatory signatures and high infiltration of antitumor immune cells, while those without TLS exhibit uncontrolled cell cycle progression and activated mTOR signaling by bulk and single‐cell RNA‐seq analyses. The regulators involved in mTOR signaling (RHEB and LAMTOR4) and S‐phase (RFC2, PSMC2, and ORC5) are highly expressed in HCC with low TLS. In addition, the largest cohort of HCC patients is studied with available radiomics data, and a classifier is built to detect the presence of TLS in a non‐invasive manner. The classifier demonstrates remarkable performance in predicting intra‐tumoral TLS abundance in both training and test sets, achieving areas under receiver operating characteristic curve (AUCs) of 92.9% and 90.2% respectively. In summary, the absence of intra‐tumoral TLS abundance is associated with mTOR signaling activation and uncontrolled cell cycle progression in tumor cells, indicating unfavorable prognosis in HCC‐LT. [ABSTRACT FROM AUTHOR]

To identify the mechanism underlying macrosteatosis (MaS)‐related graft failure (GF) in liver transplantation (LT) by multi‐omics network analysis. The transcriptome and metabolome were assayed in graft and recipient plasma in discovery (n = 68) and validation (n = 89) cohorts. Differentially expressed molecules were identified by MaS and GF status. Transcriptional regulatory networks were generated to explore the mechanism for MaS‐related inferior post‐transplant prognosis. The differentially expressed molecules associated with MaS and GF were enriched in ferroptosis and peroxisome‐related pathways. Core features of MaS‐related GF were presented on decreased transferrin and impaired anti‐oxidative capacity dependent upon dysregulation of transcription factors hepatocyte nuclear factor 4A (HNF4A) and hypoxia‐inducible factor 1A (HIF1A). Furthermore, miR‐362‐3p and miR‐299‐5p inhibited transferrin and HIF1A expression, respectively. Lower M2 macrophages but higher memory CD4 T cells were observed in MaS‐related GF cases. These results were validated in clinical specimens and cellular models. Systemic analysis of multi‐omics data depicted a panorama of biological pathways deregulated in MaS‐related GF. Transcriptional regulatory networks centered on transferrin and anti‐oxidant responses were associated with poor MaS graft quality, qualifying as potential targets to improve prognosis of patients after LT. [ABSTRACT FROM AUTHOR]

Recent studies suggest that circular RNA (circRNA)‐mediated post‐translational modification of RNA‐binding proteins (RBP) plays a pivotal role in metastasis of hepatocellular carcinoma (HCC). However, the specific mechanism and potential clinical therapeutic significance remain vague. This study attempts to profile the regulatory networks of circRNA and RBP using a multi‐omics approach. Has_circ_0006646 (circ0006646) is an unreported circRNA in HCC and is associated with a poor prognosis. Silencing of circ0006646 significantly hinders metastasis in vivo. Mechanistically, circ0006646 prevents the interaction between nucleolin (NCL) and the E3 ligase tripartite motif‐containing 21 to reduce the proteasome‐mediated degradation of NCL via K48‐linked polyubiquitylation. Furthermore, the change of NCL expression is proven to affect the phosphorylation levels of multiple proteins and inhibit p53 translation. Moreover, patient‐derived tumor xenograft and lentivirus injection, which is conducted to simulate clinical treatment confirmed the potential therapeutic value. Overall, this study describes the integrated multi‐omics landscape of circRNA‐mediated NCL ubiquitination degradation in HCC metastasis and provides a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Early allograft dysfunction (EAD) is a life‐threatening and fast‐developing complication after liver transplantation. The underlying mechanism needs to be better understood, and there has yet to be an efficient therapeutic target. This study retrospectively reviewed 109 patients undergoing liver transplantation, with dynamic profiling of CD3/4/8/16/19/45/56 on the peripheral immune cells (before transplant and 2–4 days after). Altogether, 35 out of the 109 patients developed EAD after liver transplantation. We observed a significant decrease in the natural killer cell proportion (NK cell shift, p = 0.008). The NK cell shift was linearly correlated with cold ischemic time (p = 0.016) and was potentially related to the recipients' outcomes. In mouse models, ischemic/reperfusion (I/R) treatments induced the recruitment of NK cells from peripheral blood into liver tissues. NK cell depletion blocked a series of immune cascades (including CD8+ CD127+ T cells) and inhibited hepatocyte injury effectively in I/R and liver transplantation models. We further found that I/R treatment increased hepatic expression of the ligands for natural killer group 2 member D (NKG2D), a primary activating cell surface receptor in NK cells. Blockade of NKG2D showed a similar protective effect against I/R injury, indicating its role in NK cell activation and the subsequent immunological injury. Our findings built a bridge for the translation from innate immune response to EAD at the bedside. Peripheral NK cell shift is associated with the incidence of EAD after liver transplantation. NKG2D‐mediated NK cell activation is a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Background: Caudate lobectomy (CLB) remains the most effective treatment for caudate lobe hepatocellular carcinoma (CL‐HCC). However, there is controversy regarding the survival after CLB. This meta‐analysis aims to investigate the survival outcomes following CLB for the treatment of CL‐HCC. Methods: In line with PRISMA and MOOSE guidelines, a search for all eligible studies was performed. The pooled estimates of survival rates and hazard ratios (HRs) with their 95% confidence intervals (CIs) were calculated using fixed‐ or random‐effects models. Results: Sixteen studies comprising 864 patients met the inclusion criteria. The pooled estimates of 3‐ and 5‐year overall survival (OS) rates were 62.3% and 42.9% respectively and the pooled estimate of 3‐ and 5‐year recurrence‐free survival (RFS) rates were 39.3% and 24.4% respectively. CL‐HCC showed inferior OS (HR:1.39, 95% CI: 0.91–1.88, P < 0.001) and RFS (HR:1.33, 95% CI: 1.10–1.56, P < 0.001) than other sites HCC. Isolated CLB showed better OS (HR:0.9, 95% CI:0.39–1.41, p < 0.001) and RFS (HR:0.76, 95% CI: 0.03–1.5, P = 0.04) than combined CLB. Conclusions: The survival outcomes for CL‐HCC after CLB are lower compared to other sites HCC. Isolated CLB offers better survival outcomes compared to combined CLB. However, choosing isolated or combined approaches should be prioritized according to patient and tumour characteristics. [ABSTRACT FROM AUTHOR]

Ubiquitin‐specific protease 22 (USP22) has been identified as a potential marker for cancer stem cells in hepatocellular carcinoma (HCC). It can promote HCC stemness, which is considered a driver of tumorigenesis. Here, we sought to determine the role of USP22 in tumorigenesis, elucidate its underlying mechanism, and explore its therapeutic significance in HCC. As a result, we found that tissue‐specific Usp22 overexpression accelerated tumorigenesis, whereas Usp22 ablation decelerated it in a c‐Myc/NRasGV12‐induced HCC mouse model and that the mammalian target of rapamycin complex 1 (mTORC1) pathway was activated downstream. USP22 overexpression resulted in increased tumorigenic properties that were reversed by rapamycin in vitro and in vivo. In addition, USP22 activated mTORC1 by deubiquitinating FK506‐binding protein 12 (FKBP12) and activated mTORC1, in turn, further stabilizing USP22 by inhibiting autophagic degradation. Clinically, HCC patients with high USP22 expression tend to benefit from mTOR inhibitors after liver transplantation (LT). Our results revealed that USP22 promoted tumorigenesis and progression via an FKBP12/mTORC1/autophagy positive feedback loop in HCC. Clinically, USP22 may be an effective biomarker for selecting eligible recipients with HCC for anti‐mTOR‐based therapy after LT. [ABSTRACT FROM AUTHOR]

Background: Circular RNAs (circRNAs) play a significant role in the initiation and progression of various cancers, including hepatocellular carcinoma (HCC). Circular syntaxin 6 (circSTX6, also known as hsa_circ_0007905) has been identified as a microRNA (miRNA) sponge in pancreatic adenocarcinoma. However, its full range of functions in terms of protein scaffold and translation remain largely unexplored in the context of HCC. Methods: The expression of circSTX6 and its encoded protein was examined in HCC tumour tissues. N6‐methyladenosine (m6A) on circSTX6 was verified and quantified by methylated RNA immunoprecipitation (Me‐RIP), RIP and dual luciferase reporter assays. The biological functions of circSTX6 and its encoded protein in HCC were clarified by in vitro and in vivo experiments. Mechanistically, the interaction between circSTX6 and heterogeneous nuclear ribonucleoprotein D (HNRNPD) was investigated by RNA pull‐down, RIP and fluorescence in situ hybridization (FISH)/IF. The regulatory effects of circSTX6 and HNRNPD on activating transcription factor 3 (ATF3) mRNA were determined by mRNA stability and RIP assays. Furthermore, the presence of circSTX6‐encoded protein was verified by mass spectrometry. Results: CircSTX6 and its encoded 144 amino acid polypeptide, circSTX6‐144aa, were highly expressed in HCC tumour tissues and served as independent risk factors for overall survival in HCC patients. The expression of circSTX6 was regulated by METTL14 in an m6A‐dependent manner. Functionally, circSTX6 accelerated HCC proliferation and tumourigenicity and reinforced tumour metastasis in vitro and in vivo. Mechanistically, circSTX6 acted as a sponge for HNRNPD protein, facilitating its binding to ATF3 mRNA, consequently promoting ATF3 mRNA decay. Meanwhile, circSTX6‐144aa promoted HCC proliferation, migration and invasion independent of circSTX6 itself. Conclusion: Collectively, our study reveals that m6A‐modified circSTX6 drives malignancy in HCC through the HNRNPD/ATF3 axis, while its encoded circSTX6‐144aa contributes to HCC progression independent of circSTX6. CirSTX6 and its encoded protein hold promise as potential biomarkers and therapeutic targets in HCC. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) therapies have had a tremendous impact on cancer therapy. However, most patients harbor a poorly immunogenic tumor microenvironment (TME), presenting overwhelming de novo refractoriness to ICB inhibitors. To address these challenges, combinatorial regimens that employ chemotherapies and immunostimulatory agents are urgently needed. Here, a combination chemoimmunotherapeutic nanosystem consisting of a polymeric monoconjugated gemcitabine (GEM) prodrug nanoparticle decorated with an anti‐programmed cell death‐ligand 1 (PD‐L1) antibody (αPD‐L1) on the surface and a stimulator of interferon genes (STING) agonist encapsulated inside is developed. Treatment with GEM nanoparticles upregulates PD‐L1 expression in ICB‐refractory tumors, resulting in augmented intratumor drug delivery in vivo and synergistic antitumor efficacy via activation of intratumor CD8+ T cell responses. Integration of a STING agonist into the αPD‐L1‐decorated GEM nanoparticles further improves response rates by transforming low‐immunogenic tumors into inflamed tumors. Systemically administered triple‐combination nanovesicles induce robust antitumor immunity, resulting in durable regression of established large tumors and a reduction in the metastatic burden, coincident with immunological memory against tumor rechallenge in multiple murine tumor models. These findings provide a design rationale for synchronizing STING agonists, PD‐L1 antibodies, and chemotherapeutic prodrugs to generate a chemoimmunotherapeutic effect in treating ICB‐nonresponsive tumors. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis, and novel treatment strategies are urgently needed. Mitochondria are key regulators of cellular homeostasis and potential targets for tumor therapy. Here, the role of mitochondrial translocator protein (TSPO) in the regulation of ferroptosis and antitumor immunity is investigated and the potential therapeutic implications for HCC are assessed. TSPO is highly expressed in HCC and associated with poor prognosis. Gain‐ and loss‐of‐function experiments present that TSPO promotes HCC cell growth, migration, and invasion in vitro and in vivo. In addition, TSPO inhibits ferroptosis in HCC cells via enhancing the Nrf2‐dependent antioxidant defense system. Mechanistically, TSPO directly interacts with P62 and interferes with autophagy, leading to the accumulation of P62. The P62 accumulation competes with KEAP1, preventing it from targeting Nrf2 for proteasomal degradation. Furthermore, TSPO promotes HCC immune escape by upregulating PD‐L1 expression through Nrf2‐mediated transcription. Notably, TSPO inhibitor PK11195 combines with anti‐PD‐1 antibody showing a synergistic anti‐tumor effect in a mouse model. Overall, the results demonstrated that mitochondrial TSPO promotes HCC progression by inhibiting ferroptosis and antitumor immunity. Targeting TSPO can be a promising new strategy for HCC treatment. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC), one of the worst prognosis types of tumors, is characterized by dense extracellular matrix, which compresses tumor vessels and forms a physical barrier to inhibit therapeutic drug penetration and efficacy. Herein, losartan, an antihypertension agent, is applied as a tumor stroma modulator and developed into a nanosystem. A series of lipophilic losartan prodrugs are constructed by esterification of the hydroxyl group on losartan to fatty acids. Based on the self‐assembly ability and hydrodynamic diameter, the losartan‐linoleic acid conjugate is selected for further investigation. To improve the stability in vivo, nanoassemblies are refined with PEGylation to form losartan nanoblocker (Los NB), and administered via intravenous injection for experiments. On murine models of pancreatic cancer, Los NB shows a greater ability to remodel the tumor microenvironment than free losartan, including stromal depletion, vessel perfusion increase, and hypoxia relief. Furthermore, Los NB pretreatment remarkably enhances the accumulation and penetration of 7‐ethyl‐10‐hydroxycamptothecin (SN38)‐loaded nanodrugs (SN38 NPs) in tumor tissues. Expectedly, overall therapeutic efficacy of SN38 NPs is significantly enhanced after Los NB pretreatment. Since losartan is one of the most commonly used antihypertension agents, this study may provide a potential for clinical transformation in stroma‐rich PDAC treatment. [ABSTRACT FROM AUTHOR]

Hepatitis B surface antigen (HBsAg) persists after liver transplantation in almost all patients receiving HBsAg‐positive grafts. Chronic hepatitis B virus (HBV) infection is one of the main causes of hepatocellular carcinoma (HCC). We aimed to investigate possible interactions between HBsAg‐positive donors, HCC, HBV‐related transplant indication, and long‐term outcomes. This retrospective study enrolled 1176 patients from two centers between January 2015 and May 2019, of which 135 (11.5%) were HBsAg‐positive and 1041 (88.5%) were HBsAg‐negative donors. Cox regression models were fitted to study the association between variables and patient and graft survival. In univariate and multivariate analyses, the donor HBsAg status was not significantly associated with patient and graft survival in the entire cohort, but there was a significant interaction between HBsAg‐positive donors and HCC, independent of HBV‐related transplant indication. The cumulative incidence of patient and graft survival was significantly lower in the subgroup of HCC recipients receiving HBsAg‐positive grafts, but no significant difference was found in recipients with benign liver disease. In a subgroup analysis of HCC recipients, HBsAg‐positive donors were significantly associated with an increased risk of HCC recurrence (hazard ratio: 1.73; 95% confidence interval: 1.20–2.48; p = 0.003) and similar results were obtained after propensity score matching analysis. We showed excellent outcomes of using HBsAg‐positive grafts in patients with benign liver disease, regardless of HBV‐related transplant indications. However, positive grafts should be used with caution in recipients with HCC, which are associated with an increased risk of HCC recurrence. Highlights: •HBsAg‐positive grafts are safe for use in patients with benign liver disease.•HBsAg‐positive grafts increase mortality in patients with HCC.•HBsAg‐positive grafts are associated with an increased risk of HCC recurrence post‐LT. [ABSTRACT FROM AUTHOR]

Background and Aim: Donor shortage has become worldwide limitation in liver transplantation (LT). Use of hepatitis B virus surface antigen positive (HBsAg+) donors could be an alternative source of donor organs. This study aims to investigate the safety and efficacy of LT using HBsAg+ liver grafts and associated long‐term outcome. Methods: This was a retrospective study of adults LT registered in the database of the China Liver Transplant Registry between January 2015 and September 2018. By propensity score matching (1:1), 503 eligible patients who received HBsAg+ liver grafts were compared with 503 matched patients who received HBsAg− liver grafts. Results: The 1‐, 3‐, and 5‐year patient survival rates were 81.52%, 72.04%, and 66.65% in HBsAg+ donor group, which were comparable with 83.93%, 77.27%, and 65.73% in HBsAg− donor group (P = 0.222). The 1‐, 3‐, and 5‐year graft survival rates were also comparable between the two groups (81.49%, 71.45%, and 67.26% vs 83.62%, 77.11%, and 65.81%, respectively, P = 0.243). Most main complications were not increased in HBsAg+ donor group except for the retaining of HBsAg positivity after LT. Furthermore, transplanting HBsAg+ liver grafts did not result in inferior outcomes either in HBsAg+ or HBsAg− recipients. The risk of tumor recurrence after LT was not increased in hepatocellular carcinoma patients. Conclusions: The outcomes of using HBsAg+ liver grafts were comparable with those of HBsAg− liver grafts. Our study provided strong evidence for the safe use of HBsAg+ grafts in LT to expand the donor liver pool. [ABSTRACT FROM AUTHOR]

Objectives: The discrepancy between supply and demand of organ has led to an increased utilization of steatotic liver for liver transplantation (LT). Hepatic steatosis, however, is a major risk factor for graft failure due to increased susceptibility to ischaemia‐reperfusion (I/R) injury during transplantation. Materials and methods: To assess the plasticity and phenotype of immune cells within the microenvironment of steatotic liver graft at single‐cell level, single‐cell RNA‐sequencing (scRNA‐Seq) was carried out on 23 675 cells from transplanted rat livers. Bioinformatic analyses and multiplex immunohistochemistry were performed to assess the functional properties, transcriptional regulation, phenotypic switching and cell‐cell interactions of different cell subtypes. Results: We have identified 11 different cell types in transplanted livers and found that the highly complex ecosystem was shaped by myeloid‐derived cell subsets that transit between different states and interact mutually. Notably, a pro‐inflammatory phenotype of Kupffer cells (KCs) with high expression of colony‐stimulating factor 3 (CSF3) that was enriched in transplanted steatotic livers was potentially participated in fatty graft injury. We have also detected a subset of dendritic cells (DCs) with highly expressing XCR1 that was correlated with CD8+ T cells, mediating the severer steatotic liver damage by I/R injury. Conclusions: The findings of our study provide new insight into the mechanisms by which steatosis exacerbates liver damage from I/R injury. Interventions based on these observations create opportunities in attenuating fatty liver graft injury and expanding the donor pool. [ABSTRACT FROM AUTHOR]

Background: Sarcomatoid hepatocellular carcinoma (HCC) is a rare and highly lethal histological subtype of HCC, with completely unknown genetic etiology and therapeutic targets. Methods: We included 16 patients with sarcomatoid HCC receiving radical resection among 6731 cases of pathological confirmed HCC in year 2008 to 2018 in our hospital. We compared the clinical features, prognosis and cancer genome between 15 sarcomatoid HCC and propensity score‐matched 75 non‐sarcomatoid HCC patients. The other concurrent case was analyzed using phylogenetic tree to assess the tumor heterogeneity and evolution. Results: Sarcomatoid HCC group showed larger tumor size, more advanced differentiation grade, lower tumor free survival (p = 0.038) and overall survival (p = 0.001), and sarcomatoid type was an independent risk factor for patient death. Integrating sarcomatoid subtype into AJCC staging could increase the diagnostic curve in predicting patient survival. The cancer genome spectrum showed sarcomatoid HCC group had significant higher mutation rates in CDKN2A, EPHA5, FANCM and MAP3K1. Mutations in CDKN2A significantly reduced tumor‐free and overall survival in sarcomatoid HCC patients. Moreover, 46.6% sarcomatoid HCC patients had druggable mutations in cell cycle pathway genes, which were targeted by Abemaciclib, et al. We also found sarcomatoid and non‐sarcomatoid lesions might originate from a common progenitor but progress differently. Conclusion: Our cancer genome analysis showed a specific genomic profile of sarcomatoid HCC, which were characterized by a high mutation rate in cell cycle genes particularly CDKN2A. The results indicate CDK4/6 inhibitors including abemaciclib, ribociclib and palbociclib as potential therapeutic targets and may help for therapeutic decision making. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most aggressive tumours with marked fibrosis. Mycophenolate mofetil (MMF) was well‐established to have antitumour and anti‐fibrotic properties. To overcome the poor bioavailability of MMF, this study constructed two MMF nanosystems, MMF‐LA@DSPE‐PEG and MMF‐LA@PEG‐PLA, by covalently conjugating linoleic acid (LA) to MMF and then loading the conjugate into polymer materials, PEG5k‐PLA8k and DSPE‐ PEG2k, respectively. Hepatocellular carcinoma cell lines and C57BL/6 xenograft model were used to examine the anti‐HCC efficacy of nanoparticles (NPs), whereas NIH‐3T3 fibroblasts and highly‐fibrotic HCC models were used to explore the anti‐fibrotic efficacy. Administration of NPs dramatically inhibited the proliferation of HCC cells and fibroblasts in vitro. Animal experiments revealed that MMF‐LA@DSPE‐PEG achieved significantly higher anti‐HCC efficacy than free MMF and MMF‐LA@PEG‐PLA both in C57BL/6 HCC model and highly‐fibrotic HCC models. Immunohistochemistry further confirmed that MMF‐LA@DSPE‐PEG dramatically reduced cancer‐associated fibroblast (CAF) density in tumours, as the expression levels of alpha‐smooth muscle actin (α‐SMA), fibroblast activation protein (FAP) and collagen IV were significantly downregulated. In addition, we found the presence of CAF strongly correlated with increased HCC recurrence risk after liver transplantation. MMF‐LA@DSPE‐PEG might act as a rational therapeutic strategy in treating HCC and preventing post‐transplant HCC recurrence. [ABSTRACT FROM AUTHOR]

Resistance to sorafenib severely hinders its effectiveness against hepatocellular carcinoma (HCC). Cancer stemness is closely connected with resistance to sorafenib. Methods for reversing the cancer stemness remains one of the largest concerns in research and the lack of such methods obstructs current HCC therapeutics. Ubiquitin‐specific protease 22 (USP22) is reported to play a pivotal role in HCC stemness and multidrug resistance (MDR). Herein, a galactose‐decorated lipopolyplex (Gal‐SLP) is developed as an HCC‐targeting self‐activated cascade‐responsive nanoplatform to co‐delivery sorafenib and USP22 shRNA (shUSP22) for synergetic HCC therapy. Sorafenib, entrapped in the Gal‐SLPs, induced a reactive oxygen species (ROS) cascade and triggered rapid shUSP22 release. Thus, Gal‐SLPs dramatically suppressed the expression of USP22. The downregulation of USP22 suppresses multidrug resistance‐associated protein 1 (MRP1) to induce intracellular sorafenib accumulation and hampers glycolysis of HCC cells. As a result, Gal‐SLPs efficiently inhibit the viability, proliferation, and colony formation of HCC cells. A sorafenib‐insensitive patient‐derived xenograft (PDX) model is established and adopted to evaluate in vivo antitumor effect of Gal‐SLPs. Gal‐SLPs exhibit potent antitumor efficiency and biosafety. Therefore, Gal‐SLPs are expected to have great potential in the clinical treatment of HCC. [ABSTRACT FROM AUTHOR]

The farnesoid X receptor (FXR), as a bile acid (BA) sensor, plays an important role in the regulation of lipid metabolism. However, the effects and underlying molecular mechanisms of FXR on intestinal glucose homeostasis remain elusive. Herein, we demonstrated that FXR and glucose transporter 2 (GLUT2) are essential for BA‐mediated glucose homeostasis in the intestine. BA‐activated FXR enhanced glucose uptake in intestinal epithelial cells by increasing the expression of GLUT2, which depended on ERK1/2 phosphorylation via S1PR2. However, it also reduced the cell energy generation via inhibition of oxidative phosphorylation, which is crucial for intestinal glucose transport. Moreover, BA‐activated FXR signalling potently inhibited specific glucose flux through the intestinal epithelium to the circulation, which reduced the increase in blood glucose levels in mice following oral glucose administration. This trend was supported by the changed ratio of GLUT2 to SGLT1 in the brush border membrane (BBM), including especially decreased GLUT2 abundance in the BBM. Furthermore, impaired intestinal FXR signalling was observed in the patients with intestinal bile acid deficiency (IBAD). These findings uncover a novel function by which FXR sustains the intestinal glucose homeostasis and provide a rationale for FXR agonists in the treatment of IBAD‐related hyperglycaemia. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is still one of the major malignant tumours with poor prognosis. The chromosome 19 microRNA cluster (C19MC) is the largest miRNA cluster, and its functions and regulatory mechanisms remain unclear in HCC. We extracted data from 373 HCC samples and 50 non‐tumour samples from The Cancer Genome Atlas database. The differential expression levels and methylation levels of C19MC as well as the correlation between them were analysed. We evaluated the correlation between the expression levels of C19MC and the clinical features. We further performed prognostic analysis for C19MC and analysed the bioinformatic function. C19MC had upregulated expression levels and promoter hypomethylation in HCC. A significant negative correlation between the high expression and low methylation level of C19MC was obtained. In addition, the positive correlation between the expression levels of C19MC and the tumour grade, tumour stage and T‐stage is shown. Three miRNAs (mir‐512‐1, mir‐516a‐1, mir‐519a‐2) were negatively associated with overall survival on the basis of the Kaplan–Meier analysis and the 3‐miRNA signature was significant for the prognostic assessment of HCC. A bioinformatic enrichment analysis suggested that the target genes of the 3 miRNAs may be associated with mitogen‐activated protein kinase pathways related to cancer invasion. In summary, our novel study demonstrated that the hypomethylation of promoters upregulates the expression levels of C19MC and that C19MC may represent a potential new candidate for the diagnosis and therapy of HCC. [ABSTRACT FROM AUTHOR]

Background: The outcomes of large‐sized graft mismatch in deceased donor liver transplantation (LT) have been rarely studied. The aim of this study was to determine whether a large‐sized graft for recipient influenced the post‐transplant outcomes. Methods: A total of 273 patients undergoing LT were enrolled and divided into a large and a normal‐sized graft group by graft weight to recipient weight (GWRW) >2.5% (n = 76) or GWRW ≤2.5% (n = 197). Post‐operative complications and outcomes were retrospectively analysed. Results: The two groups were comparable in demographic characteristics. The rate of complications was significantly higher in the large‐sized graft group including early allograft dysfunction (36.8% versus 17.8%, P = 0.001), hepatic necrosis (26.3% versus 13.7%, P = 0.01) and massive hydrothorax (25% versus 14.7%, P = 0.04). The large‐sized graft group suffered higher early mortality compared with the normal‐sized graft group (30 days: 14.5% versus 5.6%, P = 0.02, 90 days: 21.1% versus 9.6%, P = 0.01). The primary causes of early death were multiple organ failure (10.5% versus 2%, P = 0.002) and sepsis (2.6% versus 1.5%, P = 0.54). Four parameters including donor alanine transaminase, GWRW, estimated blood loss and model for end‐stage liver disease score were significant on multivariate analysis, and indicated significant risk factors for the early mortality of recipients. Conclusion: In deceased donor LT, GWRW >2.5% is associated with increased liver injury, risk of early mortality and other adverse outcomes. Thus, donor livers should be allocated to recipients with GWRW ≤2.5%. [ABSTRACT FROM AUTHOR]

Superficial surgical site infections (SSIs) are one of the most common postoperative complications of hepatectomy for liver cancer. The objective of this study is to clarify the risk factors and determine a clinical prediction score for SSIs after partial hepatectomy for malignant tumour. A total of 812 consecutive patients were enrolled who underwent partial hepatectomy for liver malignant tumour from January 2017 to December 2017. Univariate and multivariate analyses were conducted to identify the risk factors for SSIs. Clinical prediction score was then constructed using coefficients of identified significant predictors. Risk stratification was then carried out by receiver operating characteristic curve analysis. Of all the 812 patients, SSIs were observed in 31 (3.82%) patients. A multivariate analysis identified four predictors as independent risk factors for SSIs, which were splenomegaly, perioperative blood transfusion, intensive care unit (ICU) admission, and low postoperative serum albumin concentration (<35 g/L). Clinical prediction score ranged from 0 to 4.6 with its discrimination concordance (C) statistic of 0.70 (95% confidence interval [CI] 0.59, 0.81). Risk stratification classified these patients into low, moderate, and high risk in SSIs. This risk score system may credibly stratify the risk of SSIs with relatively high sensitivity and specificity. Splenomegaly, history of blood transfusion, ICU admission, and postoperative serum albumin concentration less than 35 g/L could be used to predict SSIs with acceptable discrimination. This clinical risk score system may be useful in prediction of SSIs after hepatectomy for malignant tumours. [ABSTRACT FROM AUTHOR]

Aim: Glutamine synthetase (GS) levels increase gradually with the development of hepatocellular carcinogenesis. In this study, we aimed to investigate the clinical significance of GS and the underlying mechanism of GS promoting hepatocellular carcinoma (HCC) invasion. Methods: Serum concentration of GS and α‐fetoprotein (AFP) in HCC patients, liver cirrhosis patients, and healthy individuals were detected. The GS‐mRNA level and its prognostic value were explored in an independent HCC cohort from The Cancer Genome Atlas database. GS expression in HCC tissue and matched para‐tumor tissue was determined. The effect of GS on HCC invasion was assessed in vitro and in vivo. Results: The serum GS and AFP level in HCC patients was higher than that in healthy controls and liver cirrhosis patients. The area under the receiver operating characteristic curve for HCC diagnosis was 0.848 and 0.861 for GS and AFP, respectively. The area under the receiver operating characteristic curve of GS for diagnosis of AFP‐negative HCC was 0.913. Combining GS with AFP achieved a diagnostic sensitivity and specificity of 82.5% and 93%, respectively. The GS level was higher in tumor tissues than that in para‐tumor tissues. High GS expression was associated with poor prognosis of moderately differentiated HCC patients. In vitro, GS exerted an influence on HCC cell migration by mediating epithelial–mesenchymal transition. The lung and liver metastatic model of HCC further confirmed that GS expression affected the invasion of HCC cells in vivo. Conclusions: GS is a useful biomarker for HCC diagnosis, especially for AFP‐negative patients. In addition, GS affects HCC metastasis through mediating epithelial–mesenchymal transition. [ABSTRACT FROM AUTHOR]

The intermediate conductance calcium‐activated potassium channel (KCa3.1) plays an important role in maintaining intracellular calcium homeostasis and is involved in the tumorigenesis of many human cancers. However, it is unknown whether KCa3.1 plays a role in the genesis of hepatocellular carcinoma (HCC), one of the most common malignant tumors worldwide with a very poor prognosis. In our study, we found that the expression of KCa3.1 was significantly elevated in poorly differentiated HCC tissues compared to adjacent noncancerous tissues. In vitro and in vivo experiments showed that KCa3.1 could promote cell proliferation, migration, and invasion of HCC. Mechanistically, KCa3.1 promoted cell cycle progression and migration and invasion of HCC cells by activating S‐phase protein kinase 2 (SKP2) to trigger the degradation of p21 and p27 and targeting Reelin (RELN) to induce epithelial‐mesenchymal transition (EMT), respectively. Taken together, our results demonstrate that KCa3.1 plays an important role in the genesis and progression of HCC, implying that it might be a promising therapeutic target in HCC. What's new? The calcium‐activated potassium channel KCa3.1, which regulates cell volume and intracellular calcium homeostasis, is thought to influence the development of various cancers, including hepatocellular carcinoma (HCC). Here, the expression of KCa3.1 was found to be significantly elevated in poorly differentiated HCC tissues compared with adjacent noncancerous tissues. In HCC cell lines, expression of KCa3.1 promoted cell cycle progression via activation of the cell cycle regulator SKP2, with subsequent p21 and p27 degradation. KCa3.1 expression further promoted migration and invasion via RELN targeting to induce epithelial‐mesenchymal transition. KCa3.1 may be a promising target for the development of novel HCC therapies. [ABSTRACT FROM AUTHOR]

Aim Plasma fibrinogen and D-dimer have been reported to predict survival in several types of malignancies. The aim of this study is to investigate their predictive value in patients with hepatocellular carcinoma (HCC). Methods We retrospectively analyzed plasma fibrinogen and D-dimer levels from 252 subjects: control ( n = 20), hepatitis ( n = 20), cirrhosis ( n = 20), and HCC ( n = 192) subjects. The clinical involvement and prognostic value of fibrinogen and D-dimer was analyzed in HCC subjects. To confirm the effects of tumor on hypercoagulability and fibrinolysis, fibrinogen and D-dimer levels were measured in nude mice following HCC inoculation. Results Fibrinogen decreased and D-dimer increased in cirrhosis subjects relative to other groups. In HCC subjects, elevated fibrinogen and D-dimer levels were significantly associated with adverse tumor features (increased size, stage, and grade) and systemic inflammation. Patients with HCC with either elevated fibrinogen or D-dimer levels had significantly higher 3-year tumor recurrence rates (65% vs. 41%, P < 0.001 for fibrinogen; 67% vs. 40%, P = 0.011 for D-dimer) and significantly lower 3-year overall survival rates (57% vs. 79%, P < 0.001 for fibrinogen; 56% vs. 80%, P = 0.001 for D-dimer). After multivariate analysis, elevated fibrinogen levels remained an independent predictor of poor prognosis in HCC patients. Finally, elevated levels of fibrinogen and D-dimer were confirmed in nude mice following tumor inoculation. Conclusion The fibrinogen and D-dimer levels, elevating after carcinogenesis, may serve as simple but effective predictors of adverse tumor profiles and outcomes in HCC. [ABSTRACT FROM AUTHOR]

Background The use of grafts from donors with hypertension ( HTN) in liver transplantation has grown rapidly recently, but whether HTN donors affect post- liver transplantation survival is unclear. Methods We used data from the Scientific Registry of Transplant Recipients database (2004-2008), and evaluated differences in baseline characteristics and outcomes between recipients of grafts from HTN and non- HTN donors. Kaplan-Meier and multivariate Cox regression models were used in assessing patient survival. Results We identified 8,411 recipients of HTN donor grafts (33.2%) and 16,891 (66.8%) recipients of non- HTN donor grafts. Graft and patient survival rates were significantly lower in recipients of HTN donor grafts versus non- HTN donor grafts (1-year, 3-year, and 5-year graft survival rates of 75%, 64%, 50% vs. 80%, 72%, 62% [ P < 0.001], respectively, and patient survival rates of 79%, 69%, 56% vs. 83%, 75%, 65% [ P < 0.001], respectively). A history of HTN >5 years was also associated with lower rates of graft and patient survival ( P < 0.001). A HTN donor was independently associated with a higher risk of graft loss (hazard ratio 1.10, 95% confidence interval 1.01-1.18). Conclusion The present study shows that graft and patient survivals were lower in recipients of hypertensive donor grafts, and highlights the importance of appropriately screening donors for HTN. [ABSTRACT FROM AUTHOR]

Background Whether the introduction of model for end-stage liver disease ( MELD) has an effect on transplant outcome for different age categories remain unclear. Methods We analyzed 49,762 adult hepatitis C virus ( HCV) candidates through 1 January 1995 to 31 December 2012 from the Scientific Registry of Transplant Recipients. Patients were divided into four age categories (18-34, 35-49, 60-64, ≥65 years) in the pre- MELD era and MELD era, respectively. Results Waiting list dropouts have decreased in the MELD era for all categories. A reduced trend in survival was observed for 18-34 years patients in the MELD era compared with the pre- MELD era, with 5-year intention-to-treat, overall and graft survival of 56.5%, 57.9%, 56.3% vs. 56.4%, 69.7%, 64.4% ( P = 0.604, 0.034, and 0.071, respectively). For other age categories, survival rates were all superior in the MELD era. Cox-regression analysis showed values of hazard ratio for age increased with advanced age (all >1) in the pre- MELD era compared with the reference group (18-34 years), while these hazard ratios were <1 for overall and graft survival in MELD era. Conclusions Our study provides useful evidence that the introduction of MELD for liver allocation may adversely affect survival of specific HCV patients. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma ( PDAC) is characterized by remarkable desmoplasia with infiltration of distinct cellular components. Cancer-associated fibroblasts ( CAFs) has been shown to be among the most prominent cells and played a significant role in shaping the tumor microenvironment by interacting with other type of cells. Here, we aimed to investigate the effect of CAFs in modulating phenotype of tumor-associated macrophages ( TAM). Under treatment of CAFs conditioned medium ( CM) or direct co-culture with CAFs, monocytes exhibited enhanced expression of CD206 and CD163 compared with control group ( P < 0.01). The induction of M2 polarization was mediated by increased reactive oxygen species ( ROS) production in monocytes as ROS elimination abolished the effect of CAFs ( P < 0.05). The supernatant analysis showed that pancreatic CAFs produced increased macrophage colony-stimulating factor (M- CSF). Upon treatment of M- CSF neutralizing antibody, the ROS generation and M2 polarization of CAFs CM-stimulated monocytes were significantly inhibited ( P < 0.05). In addition, the CAFs-induced M2 macrophages significantly enhanced pancreatic tumor cell growth, migration, and invasion. Collectively, our data revealed that pancreatic CAFs were able to induce a tumor-promoting TAM phenotype partly through secreted M- CSF and enhanced ROS production in monocytes, indicating possible treatment strategies by targeting stromal cell interaction within PDAC microenvironment. [ABSTRACT FROM AUTHOR]

Aim Neutrophil to lymphocyte ratio (NLR) is an inflammatory biomarker that has a close relationship with tumor progression and metastasis. In this study, we aimed to investigate the role of NLR in the prognosis of male candidates with hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). Methods We analyzed the clinical data of 248 male HCC candidates who underwent LT in our Liver Transplantation Center between 2002 and 2012. All risk factors were analyzed by univariate and multivariate Cox analysis and survival rates were calculated by Kaplan-Meier log-rank test. Results NLR was proved to be an independent risk factor affecting overall survival (OS) ( P < 0.001) and tumor-free survival (TFS) ( P = 0.003) of male candidates with HCC following LT. Additionally, our study showed that elevated NLR (>4) was associated with early tumor recurrence by Kaplan-Meier analysis. Furthermore, we established Model_OS and Model_TFS to predict prognosis based on multivariate Cox analysis. Our study showed that male candidates with HCC who exceeded the Milan criteria but within Model_OS could achieve similar OS as those within the Milan criteria ( P = 0.220). Similarly, male patients who exceeded the Milan criteria but within Model_TFS could achieve similar TFS as those within the Milan criteria ( P = 0.197). Conclusion Proper inflammatory response may effectively reduce tumor recurrence after LT. Elevated NLR (>4) within a certain range is associated with early tumor recurrence. NLR-based models are efficient and safe for prognostic prediction among male candidates with HCC for LT. [ABSTRACT FROM AUTHOR]

Background/Aims New-onset diabetes after transplantation ( NODAT) is a serious complication of liver transplantation ( LT). The present study aimed to investigate the risk factors of NODAT by a national survey using the China Liver Transplant Registry database. Patients A total of 10 204 non-pre-existing diabetic patients undergone primary LT between January 2000 and December 2013 were included. Risk factors were identified by logistic regression analysis. Results NODAT occurred in 24.3% of liver recipients with a median follow-up time of 2.6 years, and was associated with a significantly lower patient survival. NODAT increased not only diabetes related complications (e.g., infection, kidney failure) but also biliary stricture and cholangitis. NODAT patients who received hypoglycaemic treatment had a worse prognosis and a higher hepatocellular carcinoma recurrence compared with those without treatment. New-onset hyperglycaemia (<30 days) was the major predictor of NODAT. Other risk factors included cold ischaemia time >9 h, recipient age >50 years, body mass index >25 kg/m2, other hepatitis (mainly hepatitis C), post-transplant intensive care unit stay >15 days, cytomegalovirus infection and corticosteroid at discharge. Conclusions The incidence of NODAT in China is similar to that in Western countries. However, the NODAT-related complications are more common and severer in China compared with those in Western countries. The major risk factors are different. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma ( HCC) is the sixth most prevalent cancer and the third leading cause of cancer-related deaths worldwide. The fate of a cell is determined by the balance between the processes of fission and fusion that constantly occur in the mitochondria of cells. We previously showed that overexpression of Mitofusin-2 can induce apoptosis in HCC cells by triggering an influx of Ca2+ into the mitochondria from the ER. The function of Mitofusin-2 has been studied extensively, but the mechanism underlying the post-transcriptional regulation of Mitofusin-2 has not been elucidated. In the present study, we aimed to identify the mechanism of Mitofusin-2 regulation in HCC. We demonstrated that Mitofusin-2 is a direct target of miR-761, which was found to be upregulated in HCC tissues. Furthermore, a miR-761 inhibitor impaired mitochondrial function by upregulating Mitofusin-2 and effectively repressed tumor growth and metastasis both in vivo and in vitro. Our findings provide new insight into the mechanism underlying Mitofusin-2 regulation and the potential role of miR-761 in HCC, making it a potential candidate for use in HCC therapy in the future. [ABSTRACT FROM AUTHOR]

Aim The aim of the present study was to evaluate the risk factors and outcomes of gastrointestinal perforation post-liver transplantation. Patients and Methods Eleven patients were found to have complications as a result of gastrointestinal perforation post-liver transplantation at our centre from May 2008 to February 2014. Seven of these patients were selected for statistical analysis. Each patient was randomly matched with six recipients in age (± 10 years), primary disease and sex. Factors, including cold ischaemic time, blood loss volume, previous hepatobiliary surgery history and 1-year survival rate, were compared between the two groups. Results The sites of perforation were the stomach ( n = 2), duodenum ( n = 2), jejunum ( n = 1), ileum ( n = 3) and colon ( n = 3). Univariate analysis showed a significant difference in previous hepatobiliary surgery history ( P < 0.01). No difference was found in portal venous cross-clamp time, cold ischaemic time, model for end-stage liver disease score, body mass index, steroid therapy or blood type incompatibility. Previous hepatobiliary surgery history was found to be an independent risk factor in the multivariate analysis ( P < 0.05). The 1-year survival rate was lower in the perforation group ( P < 0.01). Conclusion Gastrointestinal perforation leads to a high rate of morbidity and mortality, and significantly decreases graft and recipient survival. A history of hepatobiliary surgery is a risk factor of this complication. Careful dissection and avoiding iatrogenic injury during operation are important. [ABSTRACT FROM AUTHOR]

Recurrence of hepatocellular carcinoma (HCC) is one of the leading causes of death after liver transplantation (LT). We aim to evaluate the association of donor and recipient single nucleotide polymorphisms (SNPs) with the risk of HCC recurrence after LT. A total of 155 adult patients who underwent primary LT for HCC were enrolled. Ten SNPs associated with HCC susceptibility were genotyped. Patients who received donor livers with the rs11614913 homozygous CC variant presented significantly higher recurrence rates of HCC (41.7 vs. 15.3%, p50.009) and lower cumulative tumor-free survival (p50.005) than those who received TT wild-type donor livers. The donor rs11614913 genetic variant was an independent risk factor for HCC recurrence (odds ratio52 per each C allele, p < 0.05) and could significantly improve the predictive abilities of clinical models (Milan, UCSF and Hangzhou criteria). Donor livers homozygous for rs11614913 CC were associated with a higher miR-196a expression than TT (p50.002). In a lentiviral infection of mouse liver and orthotopic mouse model of HCC, the liver miR-196a overexpression group showed a significantly larger tumor size than the control group (p50.001). There is a close association between the tumor size and expression of miR-196a in the liver (r50.693, p50.001). In conclusion, the donor miR-196a-2 rs11614913 polymorphism is associated with HCC recurrence after LT and improves the predictive value of clinical models. The overexpression of miR-196a in the liver might provide a tumor-favorable environment for the development of HCC. [ABSTRACT FROM AUTHOR]

The availability of precisely modulated chemical modifications dramatically affects the physicochemical properties of pristine drugs and should facilitate the amphiphilic self-assembly of prodrugs into supramolecular nanoprodrugs (SNPs). However, rationally designing such prodrugs to achieve favorable clinical outcomes still remains a challenge. Here, a library of prodrugs through site-specific attachment of a variety of lipophilic moieties to the antitumor agent SN-38 (7-ethyl-10-hydroxycamptothecin) is constructed. Taking advantage of the role of hydroxyl groups as solvophilic moieties, these prodrugs exhibit self-assembly in aqueous environments, allowing for the identification of five prodrugs capable of self-assembling into SNPs at high drug concentrations. Importantly, in vivo studies demonstrate that the antitumor activity of the SNPs correlates well with their stability and long-term circulation. In addition, the modular feature of this SNP design strategy offers the opportunity to readily incorporate additional valuable functionalities (e.g., tumor-specific targeting ligands) to the particle surface, which is further exploited to improve antitumor efficacy in mouse xenograft models. Thus, this structure-based reconstruction of SN-38 molecules significantly improves the potency of SNPs for clinical use. These results also provide novel mechanistic insights into the rational design of prodrugs. [ABSTRACT FROM AUTHOR]

Background and Aims Absolute lymphocyte count ( ALC) and the recovery of ALC after treatment have been identified as a prognostic biomarker for several malignancies. In this study, we aimed to investigate the prognostic role of peritransplant ALC and ALC recovery after liver transplantation ( LT) in hepatocellular carcinoma ( HCC) patients. Methods A total of 269 HCC patients undergoing LT were enrolled in our study. Clinicopathological data were retrospectively collected and reviewed. Peritransplant ALC and the change of ALC (2 weeks, 1 month, 3 months post- LT) were carefully monitored. All potential risk factors were analyzed by univariate and multivariate cox regression analysis. Results Over a mean follow-up of 35.9 months, 120 recurrences and 89 deaths were recorded. In the multivariate analysis, HCC with ALC no recovery at 1 month after LT ( P < 0.001), high pretransplant alpha fetoprotein ( P = 0.010), total tumor size > 8 cm ( P = 0.003), and beyond Milan criteria ( P < 0.001) were four independent risk factors for HCC recurrence. For overall survival ( OS) after LT, ALC no recovery at 1 month after LT ( P = 0.003), total tumor size > 8 cm ( P = 0.011), pretransplant albumin < 2.8 g/dL ( P = 0.049), model of end-stage liver disease score > 15 ( P = 0.017), and beyond Milan criteria ( P = 0.001) were significantly related to poor OS. When subgroup analyses were performed according to the Milan criteria, the results showed that the recovery of ALC at 1 month after LT still indicated longer recurrence-free survival ( RFS) ( P < 0.001) and OS ( P = 0.005) beyond Milan criteria as well as RFS ( P < 0.001) within Milan criteria, but not OS ( P = 0.157) within Milan criteria. Conclusions ALC recovery at 1 month after LT indicated favorable outcomes of HCC patients. [ABSTRACT FROM AUTHOR]

Hepatic vein reconstruction is one of the crucial issues in living donor liver transplantation ( LDLT). In the present study, we report on a right liver LDLT excluding middle hepatic vein ( MHV) using an MHV-dominant graft. Two large-sized inferior right hepatic veins were anastomosed to the recipient's inferior vena cava, respectively, in an end-to-side fashion. MHV tributaries were reconstructed using Y-shaped cryopreserved iliac artery, but resulted in segment VIII congestion. A Fogarty catheter was then used to take out the thrombus and control the bleeding when anastomosis was being performed. The patient recovered uneventfully. Postoperative computed tomography showed patent interposition grafts and normal perfusion of the liver. The patient was doing well 13 months after transplantation. [ABSTRACT FROM AUTHOR]

Background and Aim Our previous proteomic research found that chloride intracellular channel 1 ( CLIC1) was upregulated in hepatocellular carcinoma ( HCC) tissues with portal vein tumor thrombus. The present study aimed to determine the role of CLIC1 in HCC invasion. Methods Immunohistochemistry was used to explore protein expression of CLIC1 in 15 cirrhotic tissues and 69 pairs of HCC and paracarcinoma tissues. Small interfering RNA ( siRNA) and plasmids were transfected into HepG2 and SMMC7721 cells, and the in vitro function of CLIC1 in these cells were assessed with cell counting kit-8 assays, cell apoptosis assays, scratch assays, and transwell assays. Microarray analysis was also performed to further explore the candidate genes related to CLIC1. Results Our results confirmed that upregulated CLIC1 expression was significantly correlated with vascular invasion ( P = 0.034) in HCC tissues. Knockdown of CLIC1 decreased cell viability and the invasive potency of HepG2 cells, whereas CLIC1 overexpression resulted in an opposite effect in SMMC7721 cells. Microarray analysis identified 618 genes that were differentially expressed (fold change ≥ 2, P < 0.05) between HepG2 cells transfected with CLIC1 siRNA and the negative control. Further studies indicate that knockdown of CLIC1 increased maspin expression and reduced vascular endothelial growth factor ( VEGF), matrixmetalloproteinase-2 ( MMP2), MMP9, MMP11, and MMP12 expression. In contrast, overexpression of CLIC1 decreased maspin expression and increased VEGF, MMP2, MMP12, and MMP13 expression. Conclusions CLIC1 protein expression is significantly correlated with vascular invasion, and the present study suggests a previously unknown mechanism of CLIC1-mediated control of HCC invasiveness by targeting maspin. [ABSTRACT FROM AUTHOR]

Drug-loaded nanoparticles (NPs) are of particular interest for efficient cancer therapy due to their improved drug delivery and therapeutic index in various types of cancer. However, the encapsulation of many chemotherapeutics into delivery NPs is often hampered by their unfavorable physicochemical properties. Here, we employed a drug reform strategy to construct a small library of SN-38 (7-ethyl-10-hydroxycamptothecin)-derived prodrugs, in which the phenolate group was modified with a variety of hydrophobic moieties. This esterification fine-tuned the polarity of the SN-38 molecule and enhanced the lipophilicity of the formed prodrugs, thereby inducing their self-assembly into biodegradable poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEGPLA) nanoparticulate structures. Our strategy combining the rational engineering of prodrugs with the pre-eminent features of conventionally used polymeric materials should open new avenues for designing more potent drug delivery systems as a therapeutic modality. [ABSTRACT FROM AUTHOR]

Aim Myeloid-derived suppressor cells ( MDSC) can be induced or expanded in tumor-bearing mice and cancer patients. The frequency of MDSC denoted here as Lin−/low CD33+ HLA-DR− was investigated in hepatocellular carcinoma ( HCC) patients. The clinical relevance of MDSC and patients' characteristics were examined. Also, MDSC-related immune regulatory pathways in these patients were discussed. Methods The quantity of MDSC was tested in peripheral blood of patients with HCC ( n = 63) and healthy donors ( n = 56). The expressions of interferon ( IFN)-γ, vascular endothelial growth factor ( VEGF), cyclooxygenase ( COX)-2, matrix metalloproteinase ( MMP)-13, nitric oxide synthase ( NOS)-2 and arginase ( ARG)-1 were analyzed. Co-culturing with anti- CD3/ CD28-stimulated T lymphocytes was used to determine the suppressive effect of MDSC on the T lymphocytes. Results Patients with treatment-naive HCC had an increased subpopulation of Lin−/low CD33+ HLA-DR− cells in the peripheral blood mononuclear cells ( PBMC) with characteristics of MDSC and associated to the stage ( P = 0.0004). Patients with splenomegaly had a higher frequency of circulating MDSC. Also, COX-2, MMP-13 and VEGF were expressed differently associated with the alteration of MDSC. Conclusion Our study provides evidence showing an increased population of Lin−/low CD33+ HLA-DR− MDSC in the peripheral blood of HCC patients. Our data also suggest that MMP-13 and COX-2 in PBMC may play a new important role companied with MDSC in HCC patients. [ABSTRACT FROM AUTHOR]

C- X- C motif chemokine ligand 14 ( CXCL14) is a novel gene that is expressed in many normal cells but is absent from or expressed at very low levels in cancerous tissues such as head and neck squamous cell carcinoma ( HNSCC), prostate cancer, and pancreatic cancer. However, the relationship between CXCL14 and hepatocellular carcinoma ( HCC) remains unclear. Therefore, the exact function of CXCL14, which may modulate antitumor immune responses in certain cancers, was evaluated. CXCL14 was downregulated in HCC tissues compared to adjacent normal tissues. Moreover, overexpression of CXCL14 had an inhibitory effect on cell proliferation, induced apoptosis and inhibited the invasion of HCC cells in vitro. Upregulation of CXCL14 by lentivirus also significantly suppressed the growth of subcutaneous tumors in nude mice in vivo. We further demonstrated that the loss of CXCL14 expression was regulated by promoter hypermethylation. CXCL14 induced tumor cell apoptosis through both the mitochondrial and nuclear apoptosis pathways. CXCL14 suppressed tumor cell proliferation through regulation of the cell cycle by downregulation of cyclins and cyclin-dependent kinases. In conclusion, CXCL14 plays a pivotal role as a potential tumor suppressor in HCC. The re-expression or upregulation of this gene may provide a novel strategy in HCC therapy in the future. [ABSTRACT FROM AUTHOR]

Aim To develop a clinical strategy for the interposition of portomesenteric vein (PMV) by means of allograft in pancreatic surgery. Patients and Methods Between January 2004 and September 2011, nine patients had PMV interposition using allograft for massive vascular involvement by pancreatic tumour during pancreaticoduodenectomy. Their clinical outcomes were reviewed. Results After anastomosis of the allografts, three of which were fresh portal venous allografts, and six of which were cryopreserved iliac arterial allografts harvested from cadaveric donors, follow-up Doppler ultrasonography revealed neither thrombosis nor stenosis. Conclusions The allografts might provide a feasible and clinically-attractive option in PMV interposition in the radical resection of pancreatic tumours. [ABSTRACT FROM AUTHOR]

Background and Aim: Portal vein tumor thrombus (PVTT) is one of the factors that can affect prognosis and survival of hepatocellular carcinoma (HCC). In the present study, we aimed to find out some biomarkers associated with vascular invasion features of HCC with the method of comparative proteomic analysis. Methods: The proteins were extracted from a pair of HCC tissues with PVTT and without PVTT, and then separated by two-dimensional polyacrylamide gel electrophoresis. Differentially expressed protein spots were identified by matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Further analysis of two proteins were completed using real-time fluorescence quantitative polymerase chain reaction and western-blot in 40 HCC tissues with PVTT ( n = 20) and without PVTT ( n = 20). Results: Among 465 protein spots displayed on the gels, 33 unique proteins (> twofold change, P < 0.01) were identified, including 24 upregulated in HCC tissue without PVTT and nine upregulated in HCC tissue with PVTT. The real-time fluorescence quantitative PCR showed no statistically significant difference between HCC tissues with PVTT and without PVTT for mRNA expressions of protein disulfide-isomerase, A6 (PDI A6) ( P = 0.137) and apolipoprotein A-I (Apo A-I) ( P = 0.718). However, compared with HCC tissues without PVTT, protein expression of PDI A6 was higher in HCC tissues with PVTT ( P < 0.001), while protein expression of Apo A-I was lower in HCC tissues with PVTT ( P = 0.012). Conclusions: PDI A6 and Apo A-I are closely related to vascular invasion feature of HCC. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B virus (HBV) recurrence is a major risk factor affecting the long-term survival of recipients for liver transplantation (LTx). Therefore, a model that can assess this risk before transplantation is highly desirable. Methods: One hundred and eighty-five consecutive liver transplant recipients because of HBV-related end-stage liver diseases were selected. Their perioperative laboratory examination results, treatment protocol and the status of HBV recurrence were the primary parameters used to assess their risk of post-transplant HBV recurrence. A model that may be generally used to evaluate the risk of post-transplant HBV recurrence was thus established. A cohort for further validation and a cross-validation were designed. Results: After a follow-up time of 26.0 ± 10.8 months, the overall HBV recurrence rate was 8.6%. The 1-, 2- and 3-year cumulative survival rates were 98.5, 89.2 and 83.4% respectively. By correlation with the pretransplant presence of hepatocelluar carcinoma (HCC), serum HBV DNA level and status of antiviral treatment (AVT), the risk assessment model can be summarized using the following equation: RISK=−4.378+1.493 × HCC+1.286 × DNA−2.426 × AVT. The HBV recurrence rate and survival were found to be significantly different between the recipients with risk scores≤−2.8 and>−2.8. The model was well validated in this work. Conclusions: Pretransplant HBV DNA level, presence of HCC, AVT status and post-transplant viral mutation were identified as the major risk factors associated with HBV recurrence after LTx. A novel model incorporating these factors could effectively evaluate the risk of post-transplant HBV recurrence before transplantation. [ABSTRACT FROM AUTHOR]