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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]

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]

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: 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]

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]

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]

Peliosis hepatis ( PH) is a rare benign liver lesion, characterized by the presence of multiple blood-filled cavities and marked dilation of the hepatic sinusoids throughout the hepatic parenchyma. It is often confirmed after the liver resection or liver biopsy. In the present study, we report a case of a 41-year-old woman who presented with a asymptomatic right hepatic mass. The imaging findings of the mass, including computed tomography and magnetic resonance imaging, showed centrifugal progression of enhancement during the portal and delayed phases. Because of the possibility of hepatic malignancy, partial resection of the liver was performed. The final pathological diagnosis was PH. By referring to the relevant literature, we conclude that, as a result of insignificant clinical manifestation and imaging features, PH should be kept in mind for patients with hepatic mass. [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]

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]

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]

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]

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]

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]

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]

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]

Background: Single-nucleotide polymorphisms (SNP) of two-gene locus cytotoxic T lymphocyte antigen-4 (CTLA-4) +49 and CD86 +1057 were previously reported to influence the outcome of liver transplantation (LT) with respect to allograft acceptance. SNP at CTLA-4 +49 was also suggested to be associated with the individual difference in the clearance of hepatitis B virus (HBV). However, their influence on the incidence of post-LT HBV reinfection was not clear. With the increasing knowledge of costimulatory mechanisms on LT and host immune response, we designed this study to investigate the relationship between different alleles as well as genotypes at these two locations and HBV reinfection after LT. Methods: Genomic DNA from 167 LT recipients with HBV-related diseases was genotyped for CTLA-4 +49 and CD86 +1057 genomic polymorphisms using a sequence-specific primer-polymerase chain reaction (PCR-SSP). HBV recurrence was diagnosed based on the serological and pathological finding of HBV DNA and HBsAg. Results: The present study indicated that the recipients with CTLA-4 +49 GG genotype had a reduced risk (6.67%) of HBV recurrence compared with non-CTLA-4 +49 GG-carrying individuals (20.7%) (relative risk 3.098) ( P=0.032). The allelic frequency of CTLA-4 +49 G was also significantly lower in patients with HBV recurrence, compared with that in patients without HBV recurrence ( P=0.013, odds ratio 2.176, 95% confidence interval 1.170–4.046). However, no significant association was found between CD86 +1057 and HBV recurrence. Conclusion: Our result on CTLA-4 +49 A/G polymorphism indicated that the CTLA-4 +49 GG genotype was related to a reduced risk in the incidence of HBV recurrence. [ABSTRACT FROM AUTHOR]

Hepatocellular Carcinoma: Self-Activated Cascade-Responsive Sorafenib and USP22 shRNA Co-Delivery System for Synergetic Hepatocellular Carcinoma Therapy (Adv. Sci. 5/2021) Resistance to sorafenib remains one of the biggest concerns for hepatocellular carcinoma treatment. In article number 2003042, Xiao Xu, Jiajia Xiang, and co-workers developed a self-activated sorafenib and USP22 shRNA codelivery nanoplatform (Gal-SLP) to reverse cancer stemness and sensitive cancer cells to sorafenib. [Extracted from the article]

Background: Liver transplantation is an effective therapy for end‐stage liver diseases and acute liver failure. After the operation, however, recipients may suffer grafts loss induced by alloimmune reaction, which is termed as acute allograft rejection. The interaction between costimulatory molecules, CD276, and its ligand, TREML2, promotes T cell‐mediated immune response, as well as acute or chronic allograft rejection. Our research aimed at correlating genetic polymorphisms of CD276/TREML2 with acute rejection, and evaluating its prognostic value of acute rejection after liver transplantation. Methods: The study enrolled a total of 388 recipients. Among them, acute allograft rejection was observed in 54 cases. We performed single nucleotide polymorphism genotyping of CD276, including rs11072431, rs11574495, rs12593558, rs12594627, rs2127015, rs3816661 and rs7176654, and TREML2, including rs4714431, rs6915083, rs7754593, and rs9394767 from preoperative peripheral blood genome DNA. Results: We found rs2127015 of CD276, rs6915083 and rs7754593 of TREML2, and HBV infection as well were associated with acute rejection. And, rs2127015 influences CD276 expression. Moreover, we established a risk assessment model, composited by statistically proved risk factors. Conclusion: By integrating both clinical and genetic variables, liver transplant recipients can be categorized into different risk groups, and might benefit from individualized therapies. [ABSTRACT FROM AUTHOR]